Conditions: FAP Familial Amyloid Polyneuropathy TTR Transthyretin Amyloidosis
Keywords: FAP Familial Amyloid Polyneuropathy TTR Transthyretin Amyloidosis
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 135
Healthy volunteers: no

Brief summary:
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.

Detailed description:
Familial Amyloid Polyneuropathy (FAP) is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP.

IONIS-TTR Rx is an antisense drug that is designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein will result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.

This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.

Arms:
arm 1: Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group. arm 2: Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.

Interventions: intervention 1: Inotersen
Intervention descriptions: intervention 1: Inotersen SC

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy 
of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (FAP) 
NCT02175004 
27 January 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Official Title: An Open-Label Extension Study to Assess the Long-Term Safety and 
Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
NCT Number: NCT02175004 
Document Dates: 
Protocol Amendment Version 5: 13-May-2020 


1 
 
Clinical Study Report 
CONFIDENTIAL 
Ionis Pharmaceuticals, Inc 
Study Number: ISIS 420915-CS3 
16.1 Study Information 
Version 1 
 
16.1.1 PROTOCOL AND PROTOCOL AMENDMENTS 
 
ROW 
UK 
Brazil 
France 
Original – 19Dec2013 
- 
- 
- 
Amend 1 – 08May2015 
Suppl 1 – 08May2015 
Suppl 1 – 22Mar2016 
- 
Amend 2 – 10Aug2015 
Suppl 2 – 04Nov2015 
- 
Suppl 1 – 07Jul2015 
Amend 3 – 07Mar2016 
Suppl 3 – 07Mar2016 
- 
Suppl 2 – 07Mar2016 
Amend 4 – 13May2016 
Suppl 4 – 13May2016 
- 
- 
Amend 5 – 22Feb2017 
Suppl 5 – 23Mar2017 
- 
- 
Addendum 1 to Amend 5 – 
13May2020 


2 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
 
ISIS 420915-CS3 
 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
 
Addendum 1 to Protocol Amendment 5 – 13 May 2020 
 
EudraCT No: 2013-004561-13 
 
 
Trial Sponsor 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: +01 760 931 9200 
Fax: 
+01 760 603 2700 
Key Sponsor Contact 
Ph.D 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 


3 
 
ISIS420915-CS3 
Protocol 
CONFIDENTIAL 
Addendim I to Protocol Amelldment 5 
13 May2020 
 
ISIS 42091S-CS3 
 
Addeadum 1 to Protoml Amendment S 
E11draCT No: 2013-004561-13 
Clinical Phase: 3 
 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyoeuropathy (FAP) 
 
 
 
 
 
 
 
 
Sponsor 
lonis Phannaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
Coaf"ldeatialityStatement 
Thisdocument coma.ins confidential information of lonis Pharmaceuticals, Inc that most not be disclosed to anyone 
other than therecipient Sllldy staffand membersof the indq,cndeot ethics committee, institutional review board, Of" 
authori2£d regulatory agencies. This infonnation cannot be used forany purpose other than the evalualion or 
conduct oflhe clinical investigation without the priorwriuen consent oflonis Pharmaceuticals,loc. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Addendum 1 to Protocol Amendment 5 
13 May 2020 
3 
4 
 
 
 
ADDENDUM SIGNATURE PAGE 
 
 
Protocol Number: 
ISIS 420915-CS3 
Protocol Title: 
An Open-Label Extension Study to Assess the Long-Term Safety and 
Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
Addendum: 
Addendum 1 to Protocol Amendment 5 
Date: 
13 May 2020 
 
 
I hereby acknowledge that I have read and understand the attached addendum to the clinical 
protocol, entitled “An Open-Label Extension Study to Assess the Long-Term Safety and 
Efficacy of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy (FAP)” dated 
13 May 2020, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc. 
 
 
 
 
 
Investigator’s Signature 
Investigator’s Name (please print) 
Date (DD Month YYYY) 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Addendum 1 to Protocol Amendment 5 
13 May 2020 
4 
5 
 
 
 
 
SUMMARY OF ADDENDUM 
 
Protocol Number: 
ISIS 420915-CS3 
Protocol Title: 
An Open-Label Extension Study to Assess the Long-Term Safety and 
Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
Protocol Amendment: 
5 
Addendum Number: 
1 
Addendum Date: 
13 May 2020 
 
 
Due to the COVID-19 pandemic, patients participating in ISIS 420915-CS3 may be prevented 
from attending study visits at study centers because of the policies of the centers (or the 
institution in which they are located), governmental restrictions on movement, or a patient’s 
desire to minimize risk of infection. 
In ISIS 420915-CS3, visits to study centers are required only for the study visits in Week 24 and 
Week 52 of Treatment Years 2, 3, 4, and 5 (all current study participants have progressed past 
Year 1). Therefore, the Sponsor issued guidance, on 17 March 2020, to the study centers with 
patients actively participating in ISIS 420915-CS3 that the Week 24 and Week 52 visits may be 
conducted remotely. The memorandum is attached as Appendix A. 
Briefly, when patients do not attend on-site Week 26 or Week 52 visits, telephone contact 
between site staff and patients is required to collect adverse event and concomitant medication 
usage information and to assess the patients’ general well-being. Collection of specimens for 
serum chemistry, hematology, and urinalysis is also required. Where possible, collection of 
specimens for the other laboratory tests specified for the visit are also to be collected. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Addendum 1 to Protocol Amendment 5 
13 May 2020 
5 
5 
 
 
 
APPENDIX A. MEMORANDUM TO STUDY INVESTIGATORS AND 
SITE PERSONNEL 


 
 
 
 
 
MEMORANDUM 
 
 
To: 
Tegsedi ISIS 420915-CS3 ARG and BRA Study Investigators and Site Personnel 
From: 
Ionis Clinical Management Team 
RE: 
Study Modifications due to Coronavirus or COVID-19 
Date: 
17 MAR 2020 
 
 
Given the rapid spread of the Coronavirus, or COVID-19, it is critical that we do our best to 
mitigate the impact of this outbreak, prevent illness, and ensure patient safety while patients are 
participating in ISIS 420915-CS3. 
Ionis understands the need for flexibility and modifications during this time of heightened 
COVID-19 risk. For the next month, and continuing on a month by month basis: 
• 
All study visits including the semi-annual visits required to be on-site (Wk 26 and 52) by 
the protocol may be conducted remotely. 
• 
In place of the semi-annual required on-site visits (Wk 26 and 52), 
o We require a telephone contact with the patient(s) to collect AE(s) and conmed 
usage information and to assess the patient’s general well-being. 
o We require collection of specimens for serum chemistry, hematology, and 
urinalysis. 
o Where possible, we ask for collection of specimens for the other laboratory tests 
[thyroid panel, the coagulation panel (PT, aPTT, INR), retinol, hs-CRP, PD panel, 
NT-proBNP, immunogenicity, and trough PK] if specified by protocol. 
• 
For the Wk 13 and 39 visits and all of the Additional Visits, the protocol specified 
collections should be performed. 
• 
Should a patient report any symptoms that are concerning, the PI can triage the patient 
accordingly. 
• 
Protocol Deviations will need to be entered for any efficacy measure not performed due 
to the COVID-19 outbreak. 
Ionis will continue to assess these modifications and will update this guidance on a monthly 
basis as we monitor the COVID-19 outbreak. Please escalate any concerns to the Clinical 
Study Management Team, as we continue to stay in operation. 
7 


From: 
Sent: 
8 
 
 
To: 
Cc: 
Subject: 
Attachments: 
 
Importance: 
 
 
 
 
 
lorns CS3 COVID-19 memo 
TTR-CS3-COVID-19 Memo_17_Mar_2020.pdf 
 
High 
Centro de Pesquisa Clfnica (Lar 
' · 
Lar Escola) 
ntractor);1111 
 
 
Dear Dr.• 
, Dr,_ 
and Dr.• 
, 
 
Please see the attached memo from Ionis regarding the recent corona virus outbreak and instructions regarding the CS3 
study and future patient visits. 
 
Thank you and please revert with any questions or concerns. 
Kind Regards, 
 


From: 
Sent: 
9 
 
 
To: 
Cc: 
Subject: 
 
 
FW: lonis CS3 COVID-19 memo 
 
(Contractor) 
Attachments: 
Importance: 
TTR-CS3-COVID-19 Memo_17_Mar_2020.pdf 
 
High 
 
 
 
So sorry I forgot to add you to the email I just sent to LATAM sites, see attached please. 
 
 
Importance: High 
 
Dear Dr.• 
, Dr,_ 
and Dr.• 
, 
 
Please see the attached memo from Ionis regarding the recent corona virus outbreak and instructions regarding the CS3 
study and future patient visits. 
 
Thank you and please revert with any questions or concerns. 
Kind Regards, 
 


10 
 
 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
 
ISIS 420915-CS3 
 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
 
 
Protocol Supplement 5 - UK – 23 March 2017 
 
 
EudraCT No: 2013-004561-13 
 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 


2 
11 
 
 
1S1S 420915-CS3 
CONFIDENTIAL 
Protocol Supplement 5 - UK 
23March 2017 
 
 
 
 
ISIS 420915-CS3 
 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FA.P) 
 
Protocol Supplement S - UK- 23 March 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
Jonis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 


ISIS 420915-CS3 
CONFIDENTIAL 
Protocol Supplement 5 - UK 
23 March 2017 
3 
12 
 
 
 
Protocol Supplement Signature Page 
 
 
 
Protocol Number: 
ISIS 420915-CS3 
Protocol Title: 
An Open-Label Extension Study to Assess the Long-Term Safety and 
Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
Supplement: 
5 - UK 
Date: 
23 March 2017 
 
 
 
I hereby acknowledge that I have read and understand the attached clinical protocol supplement 
(Supplement 5 – UK), dated 23 March 2017, for the protocol entitled “An Open-Label Extension 
Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients with Familial 
Amyloid Polyneuropathy (FAP)”, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
Investigator’s Signature 
Investigator’s Name (please print) 
Date (DD Month YYYY) 


ISIS 420915-CS3 
CONFIDENTIAL 
Protocol Supplement 5 - UK 
23 March 2017 
4 
12 
 
 
 
Protocol Supplement - UK 
 
 
 
Protocol Number: 
ISIS 420915-CS3 
Protocol Title: 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
Supplement Number: 
5 - UK 
Date: 
23 March 2017 
 
 
The purpose of this supplement (to the global study protocol) is to fulfill MHRA requirements. 
The following changes will be made to the protocol: 
1. The term “abstinence” will be further defined as “true abstinence” i.e., when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial, and withdrawal are not acceptable methods of contraception.” 
The following table provides a summary list of the modifications to the protocol. 
 
List of Protocol Modifications 
 
Section 
Modification 
Rationale 
Protocol Synopsis; 
Section 5.1 
Inclusion Criteria #3 
a and b 
Was: 
3. Satisfy one of the following: 
a 
Females: Non-pregnant and non-lactating; surgically 
sterile, postmenopausal, abstinent, or if engaged in 
sexual relations of childbearing potential, patient is using 
an acceptable contraceptive method (refer to 
Section 6.3.1) from the time of signing the informed 
consent form until at least 3 months after the last dose of 
ISIS 420915. 
b. Males: Surgically sterile, abstinent, or if engaged in 
sexual relations with a female of childbearing potential, 
patient is utilizing an acceptable contraceptive method 
(refer to Section 6.3.1) during and for 3 months after the 
last dose of ISIS 420915. 
The definition of 
abstinence as “true 
abstinence” is needed 
per the long duration of 
the clinical trial. 


ISIS 420915-CS3 
CONFIDENTIAL 
Protocol Supplement 5 - UK 
23 March 2017 
5 
12 
 
 
 
List of Protocol Modifications Continued 
 
Section 
Modification 
Rationale 
Is: 
3. 
Satisfy 1 of the following: 
a. 
Females: Non-pregnant and non-lactating; surgically 
sterile, postmenopausal, abstinent*, or if engaged in 
sexual relations of childbearing potential, patient is using 
an acceptable contraceptive method (refer to 
Section 6.3.1) from the time of signing the informed 
consent form until at least 3 months after the last dose of 
ISIS 420915. 
b. 
Males: Surgically sterile, abstinent*, or if engaged in 
sexual relations with a female of childbearing potential, 
patient is utilizing an acceptable contraceptive method 
(refer to Section 6.3.1) during and for 3 months after the 
last dose of ISIS 420915. 
*Abstinence is only acceptable as true abstinence, i.e., when this 
is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration 
of a trial, and withdrawal are not acceptable methods of 
contraception.” 


15 
 
 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
 
ISIS 420915-CS3 
 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
 
 
Protocol Amendment 5 – 22 Feburary 2017 
 
 
EudraCT No: 2013-004561-13 
 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 


16 
 
 
ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
 
 
 
 
 
ISIS 420915-CSJ 
 
 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
 
Protocol Amendment 5 - 22 Feburary 2017 
 
 
 
 
 
 
Protocol History: 
Original Protocol: 
Protocol Amendment I: 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
 
 
19 December 2013 
8 May 2015 
10 August 2015 
7 March 2016 
13 May 2016 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad CA 920I0 
 
 
 
 
 
 
 
 
 
 
 
2 


3 
17 
 
 
ISIS 4209l 5-CS3 
Protocol 
CONFIDENTIAL 
Amendment5 
22 Februa1y 2017 
 
 
 
ISIS 420915 
Ionis Protocol Number ISIS 420915-CS3 
Protocol Amendment 5 
EudraCT No: 2013-004561-13 
 
 
Clinical Phase: 3 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
 
 
Trial Sponsor: 
Ionis Phaimaceuticals, Inc. 
2855 Gazelle Court 
Cai·lsbad, CA 92010 
Phone: +01 760 931 9200 
Fax: 
+01 760 603 2700 
 
 
Key Sponsor Contact: 
 
Ionis Phaimaceuticals, Inc. 
2855 Gazelle Comt 
Cai·lsbad, CA 92010 
Phone: +01 760 603 2700 
 
 
Date: 
22 Feburaiy 2017 
 
 
Confidentiality Statement 
This document contains confidential infonnation of Ionis Pha1maceuticals, 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 regulato1y agencies. This info1mation 
cannot be used for any pmpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Phannaceuticals, Inc. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
4 
4 
 
 
 
Protocol Signature Page 
 
 
 
Protocol Number: 
ISIS 420915-CS3 
Protocol Title: 
An Open-Label Extension Study to Assess the Long-Term Safety and 
Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
Amendment: 
Amendment 5 
Date: 
22 Feburary 2017 
 
 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in 
Patients with Familial Amyloid Polyneuropathy (FAP)”, dated 22 Feburary 2017, and agree to 
conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
Investigator’s Signature 
Investigator’s Name (please print) 
Date (DD Month YYYY) 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
5 
5 
 
 
 
TABLE OF CONTENTS  
 
Page 
 
PROTOCOL AMENDMENT ....................................................................................................... 9 
PROTOCOL SYNOPSIS ........................................................................................................... 14 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 18 
STUDY GLOSSARY ................................................................................................................... 19 
1. 
OBJECTIVES.................................................................................................................. 21 
1.1 
Primary Objective ........................................................................................................... 21 
1.2 
Secondary Objectives ..................................................................................................... 21 
1.3 
Exploratory Objectives ................................................................................................... 21 
2. 
BACKGROUND AND RATIONALE ........................................................................... 22 
2.1 
Overview of Disease ...................................................................................................... 22 
2.2 
Therapeutic Rationale .................................................................................................... 22 
2.3 
ISIS 420915 .................................................................................................................... 22 
2.3.1 
Mechanism of Action ............................................................................................. 22 
2.3.2 
Chemistry ................................................................................................................ 23 
2.3.3 
Preclinical Experience ............................................................................................ 24 
2.3.4 
Clinical Experience ................................................................................................. 24 
2.4 
Rationale for Dose and Schedule of Administration ...................................................... 25 
3. 
EXPERIMENTAL PLAN .............................................................................................. 25 
3.1 
Study Design .................................................................................................................. 25 
3.2 
Number of Study Centers ............................................................................................... 26 
3.3 
Number of Patients ......................................................................................................... 26 
3.4 
Overall Study Duration and Follow-up .......................................................................... 26 
3.4.1 
Screening Assessment.............................................................................................. 26 
3.4.2 
Treatment ................................................................................................................ 26 
3.4.3 
Post-Treatment ........................................................................................................ 26 
3.5 
End of Study................................................................................................................... 26 
3.6 
Data and Safety Monitoring Board ................................................................................ 26 
4. 
PATIENT ENROLLMENT ........................................................................................... 27 
4.1 
Screening ........................................................................................................................ 27 
4.2 
Randomization ............................................................................................................... 27 
4.3 
Replacement of Patients ................................................................................................. 27 
5. 
PATIENT ELIGIBILITY ............................................................................................... 27 
5.1 
Inclusion Criteria ............................................................................................................ 27 
5.2 
Exclusion Criteria .......................................................................................................... 28 
6. 
STUDY PROCEDURES ................................................................................................. 28 
6.1 
Study Schedule ............................................................................................................... 28 
6.1.1 
Screening Assessment Period ................................................................................. 28 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
6 
6 
 
 
6.1.2 
Treatment Period .................................................................................................... 28 
6.1.3 
Post-Treatment Period ............................................................................................ 30 
6.2 
Additional Study Assessments ........................................................................................ 30 
6.2.1 
Laboratory Assessments ......................................................................................... 30 
6.2.2 
Congestive Heart Failure ........................................................................................ 30 
6.2.3 
Arrhythmias ............................................................................................................ 31 
6.2.4 
Myocardial Ischemia .............................................................................................. 31 
6.2.5 
Event-Specific Supplemental eCRF Pages ............................................................. 31 
6.3 
Restriction on the Lifestyle of Patients .......................................................................... 32 
6.3.1 
Contraception Requirements ................................................................................... 32 
6.3.2 
Other Requirements ................................................................................................ 33 
7. 
STUDY DRUG ................................................................................................................ 33 
7.1 
Study Drug Description .................................................................................................. 33 
7.2 
Packaging and Labeling ................................................................................................. 33 
7.3 
Study Drug Accountability ............................................................................................. 33 
8. 
TREATMENT OF PATIENTS ....................................................................................... 33 
8.1 
Study Drug Administration ............................................................................................ 33 
8.2 
Other Protocol-Required Drugs ..................................................................................... 34 
8.3 
Other Protocol-Required Treatment Procedures ............................................................ 34 
8.4 
Treatment Precautions .................................................................................................... 34 
8.5 
Safety Monitoring Rules ................................................................................................ 34 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ............................................... 35 
8.5.2 
Safety Monitoring Rules for Renal Function .......................................................... 36 
8.5.3 
Safety Monitoring Rules for Ocular Effects ........................................................... 36 
8.5.4 
Safety Monitoring Rules for Platelet Count Results ............................................... 37 
8.6 
Stopping Rules ............................................................................................................... 38 
8.6.1 
Stopping Rules for Liver Chemistry Elevations ..................................................... 38 
8.6.2 
Stopping Rules for Renal Function Test Results .................................................... 38 
8.6.3 
Stopping Rule for Platelet Count Results ............................................................... 38 
8.6.4 
Stopping Rule for Ocular Effects ........................................................................... 39 
8.6.5 
Stopping Rule for QTc Prolongation ...................................................................... 40 
8.7 
Adjustment of Dose and/or Treatment Schedule ........................................................... 40 
8.8 
Discontinuation of Study Treatment .............................................................................. 40 
8.9 
Withdrawal of Patients from the Study .......................................................................... 41 
8.10 
Concomitant Therapy and Procedures ............................................................................ 42 
8.10.1 
Concomitant Therapy ............................................................................................. 42 
8.10.2 
Concomitant Procedures ......................................................................................... 42 
8.11 
Treatment Compliance ................................................................................................... 42 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ....................... 43 
9.1 
Sponsor Review of Safety Information .......................................................................... 43 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
7 
7 
 
 
9.2 
Regulatory Requirements ............................................................................................... 43 
9.3 
Definitions ...................................................................................................................... 43 
9.3.1 
Adverse Event ......................................................................................................... 43 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction .............................................. 43 
9.3.3 
Serious Adverse Event (SAE)................................................................................. 43 
9.4 
Monitoring and Recording Adverse Events ................................................................... 44 
9.4.1 
Serious Adverse Events .......................................................................................... 44 
9.4.2 
Non-Serious Adverse Events .................................................................................. 45 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ..................................... 45 
9.4.3.1 
Relationship to ISIS 420915 ............................................................................. 45 
9.4.3.2 
Severity ............................................................................................................ 45 
9.4.3.3 
Action Taken with ISIS 420915 ....................................................................... 46 
9.4.3.4 
Treatment Given for Adverse Event ................................................................ 46 
9.4.3.5 
Outcome of the Adverse Event ........................................................................ 46 
9.5 
Procedures for Handling Special Situations ................................................................... 46 
9.5.1 
Abnormalities of Laboratory Tests ......................................................................... 46 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............ 47 
9.5.3 
Dosing Errors .......................................................................................................... 47 
9.5.4 
Contraception and Pregnancy ................................................................................. 47 
10. 
STATISTICAL CONSIDERATIONS ........................................................................... 48 
10.1 
Study Endpoints, Subsets, and Covariates ..................................................................... 48 
10.1.1 
Safety Endpoints ..................................................................................................... 48 
10.1.2 
Efficacy Endpoints .................................................................................................. 48 
10.1.3 
Pharmacodynamic Endpoints ................................................................................. 49 
10.1.4 
Pharmacokinetic Endpoints .................................................................................... 49 
10.1.5 
Exploratory Efficacy Endpoints .............................................................................. 49 
10.2 
Sample Size Considerations ........................................................................................... 49 
10.3 
Populations ..................................................................................................................... 49 
10.4 
Definition of Baseline .................................................................................................... 50 
10.5 
Interim Analysis ............................................................................................................. 50 
10.6 
Planned Methods of Analysis ......................................................................................... 50 
10.6.1 
Demographic and Baseline Characteristics............................................................. 51 
10.6.2 
Safety Analysis ....................................................................................................... 51 
10.6.3 
Efficacy Analysis .................................................................................................... 51 
10.6.4 
Pharmacokinetic Analysis ...................................................................................... 52 
10.6.5 
Pharmacodynamic Analysis .................................................................................... 52 
10.6.6 
Additional Analyses................................................................................................ 52 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 52 
11.1 
Informed Consent ........................................................................................................... 52 
11.2 
Ethical Conduct of the Study ......................................................................................... 52 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
8 
8 
 
 
11.3 
Independent Ethics Committee/Institutional Review Board ........................................... 52 
11.4 
Patient Confidentiality .................................................................................................... 53 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 53 
12.1 
Protocol Amendments .................................................................................................... 53 
12.2 
Study Termination .......................................................................................................... 53 
12.3 
Study Documentation and Storage ................................................................................. 54 
12.4 
Study Monitoring ........................................................................................................... 54 
12.5 
Language ........................................................................................................................ 55 
12.6 
Compensation for Injury ................................................................................................ 55 
13. 
REFERENCES ................................................................................................................ 56 
14. 
APPENDICES ................................................................................................................. 58 
Appendix A 
Schedule of Procedures .................................................................................... 59 
Appendix B 
List of Laboratory Analytes ............................................................................. 67 
Appendix C 
Additional Visits for Platelet and Serum Creatinine ........................................ 69 
TABLE OF TABLES 
 
 
 
 
Page 
 
Table 1 
Study Drug Characteristics ..................................................................................... 33 
 
 
 
TABLE OF FIGURES 
 
 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides 
 
 
 
 
 
Page 
(MOE-Gapmer). The sequence of ISIS 420915 is shown ..................................... 23 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
9 
9 
 
 
 
PROTOCOL AMENDMENT 
 
 
Protocol Number: 
ISIS 420915-CS3 
Protocol Title: 
An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
Amendment Number: 
5 
Amendment Date: 
22 Feburary 2017 
 
 
The main purpose of this amendment is to provide the opportunity for patients to receive a fourth 
and fifth year of treatment with a modified assessment schedule if at the end of 3 years of 
treatment ISIS 420915 is not commercially available in the country of the patient. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design. 
The following table provides a summary list of major changes to the protocol; added text in 
underlined bold, deleted text in strikethrough: 
 
Protocol Section 
Description of Change 
Rationale 
Synopsis 
3.1 Study Design 
3.4.3 Post-Treatment 
If at the end of 3 years of treatment, 
ISIS 420915 is not commercially available 
in the country of the patient, the patient 
may continue to receive treatment in this 
study for up to 2 years more or until 
ISIS 420915 becomes commercially 
available in the patient’s country, 
whichever occurs earlier. At the end of 
the 5 years of treatment with ISIS 420915 
in this study, if ISIS 420915 is not 
commercially available, patients may be 
allowed to continue receiving treatment 
with ISIS 420915 via an early access route 
to be defined by the Sponsor and 
depending on local regulations. After 
completing the treatment period, patients will 
enter the 3-month post-treatment evaluation 
period. If a patient discontinues treatment 
in this study, but is continuing to receive 
treatment with ISIS 420915 via another 
mechanism, the entry of the patient into 
the 3-month post-treatment evaluation 
period may be omitted. Alternatively, after 
completing the 3 year treatment period (Week 
156 visit), a patient may be offered the 
opportunity to continue to receive ISIS 
To provide the opportunity for patients to 
receive a fourth and fifth year of 
treatment if at the end of 3 years of 
treatment, ISIS 420915 is not 
commercially available in the country of 
the patient. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
10 
10 
 
 
 
Protocol Section 
Description of Change 
Rationale 
Synopsis 
3.1 Study Design 
3.4.3 Post-Treatment 
Continued 
420915. Continuation of ISIS 420915 may 
occur via early access, a separate open label 
extension protocol, or other programs 
depending on local regulations. Patients may 
continue to receive treatment via 1 of these 
mechanisms until ONE (1) of the following is 
met: 
• 
ISIS 420915 is commercially 
available in the local country; or 
• 
ISIS 420915 is rejected by the 
regulatory authority in the local 
country, or 
Sponsor terminates access to ISIS 420915 for 
reasons including, but not limited to safety 
issues or emergent data 
Synopsis 
Study Design and 
Treatment Schema 
3.4.3 Post-Treatment 
6.1.3 Post-Treatment 
Period 
If a patient discontinues treatment in this 
study, but will continue to receive 
treatment with ISIS 420915 via another 
mechanism, the entry of the patient into 
the 3-month post-treatment evaluation 
period may be omitted. 
To avoid interruptions in therapy. 
Synopsis 
Study Design and 
Treatment Schema 
2.4 Rationale for 
Dose and Schedule 
of Administration 
3.4 Overall Study 
Duration and 
Follow-up 
3.4.2 Treatment 
8.1 Study Drug 
Administration 
Appendix A 
Appendix C 
Treatment period up to 5 years (Week 1 up 
to Y5-W52) 
To provide the opportunity for patients to 
receive a fourth and fifth year of 
treatment if at the end of 3 years of 
treatment, ISIS 420915 is not available in 
the country of the patient. 
Study Design and 
Treatment Schema 
Appendix A 
Appendix C 
Post-treatment evaluation period is 
3 months from last dose 
To provide flexibility, applicable to early 
terminations as well as completing 
Year 3 or Year 5 of treatment. 
Synopsis 
3.4.2 Treatment 
6.1.2 Treatment 
Period 
During the treatment period patients will 
report to the Study Center for evaluation and 
tests 95 times in year 1 (Weeks 1, 7, 13, 26, 
52), and 2 times in each subsequent year 
(26th and 52nd week of each year). 
Language modified to provide generic 
description for Years 2-5. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
11 
11 
 
 
 
Protocol Section 
Description of Change 
Rationale 
Synopsis 
6.1.2 Treatment 
Period 
There are 128 non-clinic visits (Weeks 4, 
10, 15, 18, 21, 23, 29, 39) in Year 1 and 2 in 
each subsequent year (13th and 39th week 
of each year), where labs will be collected by 
the Sponsor-appointed home healthcare 
service or the Study Center as arranged by 
the Study Center personnel or by local 
laboratory with prior Sponsor approval. 
Language modified to provide generic 
description for Years 2-5. 
6.1.2 Treatment 
Period 
Appendix A 
The mNIS+7 assessment and Norfolk QOL 
DN questionnaire are will be conducted at 
Weeks 26, 52, 78, 104, 130, and 156. The 
NIS assessment is conducted at Y4-W52 
and Y5-W52. The Norfolk QOL-DN 
questionnaire is conducted at Weeks 26, 
52, 78, 104, 130, and 156 as well as Y4-W52 
and Y5-W52. 
Language modified to provide generic 
description for Years 2-5. 
6.1.2 Treatment 
Period 
8.5.3 Safety 
Monitoring Rules for 
Ocular Effects 
During the treatment period, an 
ophthalmology examination will be performed 
at Weeks 26, 52, 78, 104, 130, 156 and 
2 times in each subsequent year (26th and 
52nd week of each year). 
Language modified to provide generic 
description for Years 2-5. 
8.9 Withdrawal of 
Patients from the 
Study 
Other reasons for withdrawal of patients from 
the study might include: 
• At the discretion of the Investigator or 
Sponsor for medical reasons 
• At the discretion of the Investigator or 
Sponsor for noncompliance 
• Significant protocol deviation 
• Administrative decision by the Investigator 
or Sponsor 
• ISIS 420915 becomes commercially 
available in the local country (patients in 
Year 4 or Year 5) 
• ISIS 420915 is rejected by the regulatory 
authority in the local country 
Language modified to include alternative 
reasons for withdrawal. 
10.1.2 Efficacy 
Endpoints 
• Change in the NIS score and 
components from baseline to Y5-W52 
and Y4-W52 
• Change in the Norfolk QOL-DN 
questionnaire scores from baseline to 
Week 78 and Week 156 and at the end of 
each subsequent treatment year 
(52nd week of each year) 
 
• Change in PND score from baseline to 
Week 78 and Week 156 and at the end of 
each subsequent treatment year 
(52nd week of each year) 
 
• Change in GLS by ECHO from baseline to 
Week 78 and Week 156 and at the end of 
each subsequent treatment year 
(52nd week of each year) in the 
 
ISIS 420915-CS2 ECHO subgroup and in 
the Cardiomyopathy-ECHO (CM-ECHO) 
Set 
Language modified to provide generic 
description for Years 2-5 and to reflect 
the change of NIS score as an efficacy 
measure in the study 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
12 
12 
 
 
 
Protocol Section 
Description of Change 
Rationale 
10.1.3 
Pharmacodynamic 
Endpoints 
10.6.5 
Pharmacodynamic 
Analysis 
• Change from baseline in TTR level to 
Week 78 and Week 156 and at the end 
of each subsequent treatment year 
(52nd week of each year) 
 
• Change from baseline in RBP4 level to 
Week 78 and Week 156 and at the end 
of each subsequent treatment year 
(52nd week of each year) 
Language modified to provide generic 
description for Years 2-5. 
10.1.5 Exploratory 
Efficacy Endpoints 
• Change in the ECHO parameters (except 
GLS) in the ISIS 420915-CS2 ECHO 
subgroup and in the Cardiomyopathy- 
ECHO (CM-ECHO) Set from baseline to 
Week 78 and Week 156 and at the end 
of each subsequent treatment year 
(52nd week of each year) 
 
• Change in NT-proBNP from baseline to 
Week 78 and Week 156 and at the end 
of each subsequent treatment year 
and at the end of each subsequent 
treatment year (52nd week of each 
year) 
• Change in the SF-36 questionnaire 
scores from baseline to Week 78 and 
Week 156 and at the end of each 
subsequent treatment year (52nd week 
of each year) 
Language modified to provide generic 
description for Years 2-5. 
10.3 Populations 
The CM-ECHO set will include the subset of 
the safety set that has 420915-CS2 
Randomized Set that had a diagnosis of 
TTR cardiomyopathy at least 1 evaluable 
post baseline study entry of the parent 
study, but are not in the ECHO Subgroup 
in the parent study, plus patients who 
qualified to participate in the ECHO 
Subgroup (whether consented or not). 
Patients who did not meet the criteria for 
the ECHO assessment and Subgroup or the 
CM-ECHO Set in ISIS 420915-CS2, but who 
are found to meet those criteria upon entry 
into ISIS 420915-CS3, may also be 
included in additional analysis will include 
patients that participated in the 
ISIS 420915 CS2 ECHO subgroup plus those 
patients that did not participate in the ECHO 
subgroup but who had a diagnosis of TTR 
cardiomyopathy at ISIS 420915 CS2 study 
entry. Patients who did not meet criteria for 
the ECHO Subgroup or the CM ECHO Set in 
ISIS 420915 CS2, but who are found to meet 
those criteria upon entry into ISIS 420915- 
CS3, may also be included in additional 
analyses (details will be found in the SAP). 
Updated language to be consistent with 
SAP. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
13 
13 
 
 
 
Protocol Section 
Description of Change 
Rationale 
10.4 Definition of 
Baseline 
For safety, baseline for patients on active 
treatment in the parent study will be the 
parent study baseline. For patients on 
placebo in the parent study, baseline for 
safety will be the last non-missing 
assessment prior to the first dose of 
ISIS 420915 in this study (Study Day 1) 
(details will be found in the SAP). The Day 
1 pre dose value in this study 
For efficacy, 2 baselines are defined for each 
patient: the parent study baseline and the 
baseline assessment in this study (details 
will be found in the SAP). The baseline for 
this study is defined as the End of Treatment 
assessment in the parent study (EOT Week 
66 assessment). Further details of which 
assessments will be considered baseline for 
Echo analyses for this study will be included 
in the SAP. 
The baselines for additional analyses can 
be found in the SAP. 
Updated language to be consistent with 
SAP. 
Synopsis 
10.6.3 Efficacy 
Analysis 
Change from baseline to Week 78 and 
Week 156 and at Week 52 of each 
subsequent treatment year will be 
summarized by treatment group of the parent 
study for the following efficacy measures: 
mNIS+7 score; NIS score; Norfolk QOL DN 
(total score, symptoms domain score for 
Stage 1 patients, and physical 
functioning/large fiber neuropathy domain 
score for Stage 2 patients); mBMI and BMI; 
components of the mNIS+7 (NIS, heat-pain 
sensory, touch-pressure sensory, nerve 
conduction and heart rate to deep breathing 
tests); and PND score; and the following 
exploratory measures: ECHO parameters, 
NT-proBNP, and SF-36 questionnaire. 
To reflect the change of NIS score as an 
efficacy measure in the study. 
Appendix A 
Appendix C 
Added schedule for Year 4 and Year 5 
• 
Visit Window was increased to +/- 14 
days aside from early termination visit 
• 
ERG exam is not performed 
• 
Body Weight (fasting) is not performed 
• 
Immunogenicity is only performed once a 
year 
• 
PK trough is performed 3 times a year 
• 
Transthoracic ECHO is not performed 
and is not performed at the early 
termination visit if early termination is 
from Year 4-5 treatment 
• 
NIS is substituted for mNIS+7 and 
performed once per year 
• 
NIS is performed if early termination is 
from Year 4-5 treatment instead of 
mNIS+7 
• 
Norfolk QOL-DN, SF-36 Questionnaire, 
and PND Score are performed once per 
year 
Maintain safety schedule, simplify 
efficacy schedule. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
14 
14 
 
 
 
PROTOCOL SYNOPSIS 
 
Protocol Title 
An Open-Label Extension Study to Assess the Long-Term Safety and 
Efficacy of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy 
(FAP) 
Study Phase 
3 
Indication 
Familial Amyloid Polyneuropathy 
Primary Objective 
To evaluate the safety and tolerability of extended dosing with ISIS 420915 in 
patients with Familial Amyloid Polyneuropathy 
Secondary Objectives 
To evaluate the efficacy of extended dosing with ISIS 420915, based on 
change from baseline and progression rates, if applicable, in the following 
measures: 
• 
Modified Neuropathy Impairment Score +7 (mNIS+7) 
• 
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) 
questionnaire: 
o 
total score (all patients) 
o 
symptoms domain score (Stage 1 patients) 
o 
physical functioning/large fiber neuropathy domain score (Stage 2 
patients) 
• 
Modified body mass index (mBMI) and body mass index (BMI) 
• 
NIS, heat-pain sensory, touch-pressure sensory, nerve conduction 
and heart rate to deep breathing tests (components of mNIS+7) 
• 
Polyneuropathy disability score (PND) 
• 
Global longitudinal strain (GLS) by echocardiogram (ECHO) in the 
ISIS 420915-CS2 ECHO subgroup and in the Cardiomyopathy-ECHO 
(CM-ECHO) Set 
To evaluate the pharmacodynamic (PD) effect of extended dosing with 
ISIS 420915 based on change from baseline in transthyretin (TTR) and 
retinol binding protein 4 (RBP4) 
To evaluate the plasma trough levels of ISIS 420915 
Exploratory Objective(s) 
To evaluate the change from baseline in the following measures: 
• 
ECHO parameters (except GLS) in the ISIS 420915-CS2 ECHO 
subgroup and in the Cardiomyopathy-ECHO (CM-ECHO) Set 
• 
Plasma N-terminal prohormone of brain natriuretic peptide 
(NT-proBNP) 
• 
SF-36 questionnaire 
Study Design 
This is a multicenter open-label study. Eligible patients who have 
satisfactorily completed ISIS 420915-CS2 will receive 300 mg ISIS 420915 
once weekly for 156 weeks (3 years). Patients will also receive supplemental 
doses of the recommended daily allowance of vitamin A. If at the end of 
3 years of treatment, ISIS 420915 is not commercially available in the country 
of the patient, the patient may continue to receive treatment in this study for 
up to 2 years more or until ISIS 420915 becomes commercially available in 
the patient’s country, whichever occurs earlier. At the end of the 5 years of 
treatment with ISIS 420915 in this study, if ISIS 420915 is not commercially 
available, patients may be allowed to continue receiving treatment with 
ISIS 420915 via an early access route to be defined by the Sponsor and 
depending on local regulations. After completing the treatment period, 
patients will enter the 3-month post-treatment evaluation period. If a patient 
discontinues treatment in this study, but is continuing to receive treatment 
with ISIS 420915 via another mechanism, the entry of the patient into the 
3-month post-treatment evaluation period may be omitted. 
Number of Patients 
Approximately 135 patients may be eligible to enroll in this study 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
PROTOCOL SYNOPSIS Continued 
15 
15 
 
 
 
 
 
Study Population 
Inclusion Criteria: 
1. 
Completion of ISIS 420915-CS2 treatment with the following as 
judged by the Investigator and Sponsor: 
a. 
Satisfactory completion of dosing and EOT efficacy assessments 
b. 
No significant tolerability issues 
c. 
Satisfactory compliance to the ISIS 420915-CS2 protocol 
requirements 
Under special circumstances, patients that participated in 
ISIS 420915-CS2 but did not complete the full treatment period may 
be allowed to participate in this study with approval from the Sponsor. 
2. 
Willingness to take vitamin A supplement 
3. 
Satisfy 1 of the following: 
a. 
Females: non-pregnant and non-lactating; surgically sterile, 
postmenopausal, abstinent, or if engaged in sexual relations of 
childbearing potential, patient is using an acceptable 
contraceptive method from the time of signing the informed 
consent form until at least 3 months after the last dose of 
ISIS 420915 
b. 
Males: Surgically sterile, abstinent, or if engaged in sexual 
relations with a female of childbearing potential, patient is utilizing 
an acceptable contraceptive method during and for 3 months 
after the last dose of ISIS 420915 
4. 
Must have given written informed consent (signed and dated) and any 
authorization required by local law and be able to comply with all 
study requirements 
Exclusion Criteria: 
1. 
Have any new condition or worsening of existing condition that in the 
opinion of the Investigator or Sponsor would make the patient 
unsuitable for enrollment, or could interfere with the patient 
participating in or completing the study 
Treatment Groups 
All patients will receive 300 mg ISIS 420915 given once weekly. However, 
patients that had a dose reduction or schedule change in ISIS 420915-CS2 
may continue with the same dose or schedule in this study. 
Study Drug Dosage and 
Administration 
ISIS 420915 will be administered as a weekly subcutaneous (SC) injection. 
Rationale for Dose and Schedule 
Selection 
This is the same dose and schedule used during Weeks 2 to 65 in the 
ISIS 420915-CS2 study. 
Study Visit Schedule and 
Procedures 
For an individual patient, a maximum period of 4 weeks is allowed between a 
patient’s last dose in ISIS 420915-CS2 (CS2 Week 65 Visit) and initiation of 
dosing in this study (CS3 Day 1 visit). Periods longer than 4 weeks may be 
considered after discussion and approval by the Study Medical Monitor. 
However, the intention is to minimize the treatment pause between the two 
studies. Ideally, the first dose in this study should be administered 1-week 
after the last dose in ISIS 420915-CS2. 
The study for an individual patient will generally consist of the following 
periods: 
• 
A ≤ 4-week screening period 
• 
A 3 to 5-year treatment period during which ISIS 420915 will be 
administered as a once weekly SC injection 
• 
A 3-month post-treatment evaluation period 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
PROTOCOL SYNOPSIS Continued 
16 
16 
 
 
 
 
 
Study Visit Schedule and 
Procedures Continued 
Screening Period: 
A period of ≤ 4 weeks is allowed to complete the screening procedures 
outlined in the schedule of procedures in Appendix A. Safety clinical 
laboratory parameters and assessments from the ISIS 420915-CS2 study 
may be used for screening evaluation provided that they were taken within 
4 weeks of Day 1. Periods longer than 4 weeks may be considered after 
discussion and approval by the Study Medical Monitor. 
Treatment Period: 
During the treatment period patients will report to the Study Center for 
evaluation and tests 5 times in Year 1 (Weeks 1, 7, 13, 26, 52) and 2 times in 
each subsequent year (26th and 52nd week of each year). Physical 
examination, collection of blood for measurement of safety clinical laboratory 
parameters and specialty labs, measurement of vital signs, and collection of 
adverse events and concomitant medication/procedure information 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, NIS, Norfolk QOL-DN questionnaire, SF-36 questionnaire, 
PND score, body weight, ophthalmology examination, electroretinogram 
(ERG), electrocardiogram (ECG), and transthoracic ECHO examination. 
There are 8 non-clinic visits in Year 1 (Weeks 4, 10, 15, 18, 21, 23, 29, 39) 
and 2 in each subsequent year (13th and 39th week of each year) where labs 
will be collected by the Sponsor appointed home healthcare service or the 
Study Center as arranged by the Study Center personnel or by local 
laboratory with prior Sponsor approval. In addition, platelets will be collected 
weekly and serum creatinine every 2-3 weeks (Appendices A and C). 
Patients may also be contacted by phone to collect adverse events, 
concomitant medication and concomitant procedure information 
(Appendix A). 
Patients may be provided with prefilled syringes, when available in each 
country. Once available a patient preference questionnaire may be 
conducted. 
ISIS 420915 will be administered by either the Study Center personnel or at 
home by the patient/caregiver. 
In order to ensure maintenance of the study blind in ISIS 420915-CS2, TTR, 
RBP4, retinol, and NT-proBNP from the first 13 weeks of treatment in this 
study will not be available to the Sponsor, Investigators, Study Center 
Personnel, or the patients until the ISIS 420915-CS2 study is unblinded. 
Post-Treatment Evaluation Period: 
After discontinuation of treatment with ISIS 420915 patients will enter a 
3-month post-treatment evaluation period as outlined in the Schedule of 
Procedures in Appendix A and C. If a patient discontinues treatment in this 
study, but is continuing to receive treatment with ISIS 420915 via another 
mechanism, the entry of the patient into the 3-month post-treatment 
evaluation period may be omitted. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
PROTOCOL SYNOPSIS Continued 
17 
17 
 
 
 
 
 
Safety and Tolerability 
Evaluations 
The safety and tolerability of ISIS 420915 will be assessed on an ongoing 
basis by the Study Medical Monitor and by the Independent Data and Safety 
Monitoring Board (DSMB), as outlined in the Safety Management Plan and 
DSMB Charter. 
Safety and tolerability assessments include: adverse events, vital signs, 
physical examination, clinical laboratory tests, 12 lead ECG, use of 
concomitant medications, ophthalmology examination, and ERG examination. 
Efficacy Evaluations 
Efficacy evaluations include change from baseline and progression rates, if 
applicable, in mNIS+7, NIS, Norfolk QOL-DN questionnaire scores, 
mBMI/BMI, PND, ECHO parameters, and NT-proBNP. 
Pharmacokinetic Evaluations 
Plasma samples will be taken for measurement of ISIS 420915 trough and 
post-distribution levels at the time points detailed in Appendix A. 
Pharmacodynamic Evaluations 
Circulating levels of TTR and RBP4 will be determined throughout the study 
as detailed in Appendix A. 
Statistical Considerations 
No sample size calculations were performed as this is an extension study to 
the double-blind placebo controlled ISIS 420915-CS2 study. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
18 
18 
 
 
SCREEN 
1-month 
(Days -28 to -1) 
Patient 
terminates 
treatment 
early 
TREATMENT PERIOD 
• Year 1-3 
• Year 4 and 5; if ISIS 420915 is not 
commercially available 
• Once-Weekly SC dose of 
ISIS 420915 
 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* The post-treatment evaluation period may be omitted if the patient discontinues treatment in this study, but 
continues to receive treatment with ISIS 420915 via another mechanism 
EARLY 
TREATMENT 
TERMINATION 
VISIT 
POST-TREATMENT 
EVALUATION PERIOD* 
3 months from Last Dose 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
19 
19 
 
 
 
 
STUDY GLOSSARY 
 
Abbreviation/Acronym 
Definition 
ACE 
angiotensin-converting enzyme 
Alb/C ratio 
Albumin/Creatinine ratio (performed on urine sample) 
aPTT 
activated partial thromboplastin time 
ARB 
angiotensin II receptor blockers 
ASO 
antisense oligonucleotide 
BMI 
body mass index 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
DSMB 
Data and safety monitoring board 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
EOT 
End-of-Treatment 
ERG 
electroretinogram 
ET 
Early termination 
FAC 
Familial amyloid cardiomyopathy 
FAP 
Familial amyloid polyneuropathy 
GLS 
Global longitudinal strain 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LLN 
lower limit of normal 
mBMI 
Modified body mass index (requires determination of plasma 
albumin levels; mBMI = BMI x serum albumin g/L) 
MMRM 
Mixed Effects Model with Repeated Measures 
mNIS+7 
Modified neuropathy impairment score +7. Standard NIS but 
with modifications made to the +7 component 
MOE 
2′-O-(2-methoxyethyl) 
NIS 
Neuropathy impairment score 
Non-clinic visit 
Patients can choose to have these visits via the Sponsor 
appointed home healthcare service or at the Study Center. In 
addition, local laboratory can be used with Sponsor approval. 
Norfolk QOL-DN 
Norfolk quality of life-diabetic neuropathy questionnaire 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
20 
20 
 
 
 
Abbreviation/Acronym 
Definition 
NSAID 
nonsteroidal anti-inflammatory drugs 
NT-proBNP 
N-terminal prohormone of brain natriuretic peptide 
OLE 
Open label extension 
P/C ratio 
Protein/Creatinine ratio (performed on urine sample) 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PND Score 
Polyneuropathy disability score 
RDA 
Recommended daily allowance 
RBP4 
Retinol binding protein 4 
SAE 
serious adverse event 
SC 
subcutaneous 
Study Day 1 
Defined as the first day ISIS 420915 is administered to the 
patient 
Study Drug 
ISIS 420915 
SUSARs 
suspected unexpected serious adverse reactions 
TTR 
Transthyretin 
TUCA 
Tauroursodeoxycholic acid 
ULN 
Upper limit of normal 
UTR 
Untranslated region 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
21 
21 
 
 
 
1. 
OBJECTIVES 
 
1.1 
Primary Objective 
To evaluate the safety and tolerability of extended dosing with ISIS 420915 in patients with 
Familial Amyloid Polyneuropathy. 
 
1.2 
Secondary Objectives 
To evaluate the efficacy of extended dosing with ISIS 420915 based on change from baseline 
and progression rate, if applicable, in the following measures: 
• Modified Neuropathy Impairment Score +7 (mNIS+7) 
• Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire: 
o total score (all patients) 
o symptoms domain score (Stage 1 patients) 
o physical functioning/large fiber neuropathy domain score (Stage 2 patients) 
• Modified body mass index (mBMI) and body mass index (BMI) 
• NIS, heat-pain sensory, touch-pressure sensory, nerve conduction, and heart rate to deep 
breathing tests (components of mNIS+7) 
• Polyneuropathy disability score (PND score) 
• To evaluate the pharmacodynamic (PD) effect of extended dosing with ISIS 420915 
based on change from baseline in transthyretin (TTR) and retinol binding protein 4 
(RBP4) 
• Global longitudinal strain (GLS) by echocardiogram (ECHO) in the ISIS 420915-CS2 
ECHO subgroup and in the Cardiomyopathy-ECHO (CM-ECHO) Set 
To evaluate the plasma trough levels of ISIS 420915. 
 
1.3 
Exploratory Objectives 
To evaluate the change from baseline in the following measures: 
• ECHO parameters (except GLS) in the ISIS 420915-CS2 ECHO subgroup and in the 
Cardiomyopathy-ECHO (CM-ECHO) Set 
• Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) 
• SF-36 questionnaire 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
22 
22 
 
 
 
2. 
BACKGROUND AND RATIONALE 
 
2.1 
Overview of Disease 
Transthyretin is synthesized primarily in the liver and is secreted into the plasma as a 55 KD 
protein composed of 4 identical subunits of 14 KD each. A major function of TTR in the plasma 
is to transport retinol (vitamin A) to tissues through an association with RBP4. Transthyretin 
amyloidosis is a rare hereditary disease caused by mutations in the TTR protein. The disease 
causing mutations destabilize the normal tetrameric structure of TTR causing its dissociation into 
free monomers and subsequent aggregation into insoluble fibril deposits. These deposits are 
found in multiple organs including the peripheral nervous system, gastrointestinal tract and heart. 
They result in local damage to cells leading to a peripheral polyneuropathy (called Familial 
Amyloid Polyneuropathy or FAP) and a cardiomyopathy (called Familial Amyloid 
Cardiomyopathy or FAC). FAP can be classified into 3 stages of disease based on ambulatory 
status: Stage 1 – do not require assistance with ambulation; Stage 2 – require assistance with 
ambulation; Stage 3 – wheelchair bound (Coutinho et al. 1980). The total worldwide prevalence 
of FAP has been estimated at approximately 10,000 patients (Coelho et al. 2008). 
 
2.2 
Therapeutic Rationale 
ISIS 420915 is an antisense drug targeted to human TTR mRNA and its hybridization to the 
cognate TTR mRNA results in the RNase H-mediated degradation of the TTR mRNA, thus 
preventing production of the TTR protein (see Section 2.3). The strategy of treating FAP 
patients with ISIS 420915 is to reduce the levels of mutated and wild-type TTR protein secreted 
by the liver. It should be noted that antisense oligonucleotides (ASOs) are highly charged 
hydrophilic molecules that do not cross the blood brain barrier (Levin et al. 2008) and thus 
systemic treatment with ISIS 420915 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 ISIS 420915 will result in a decrease in the formation of TTR amyloid fibril 
deposits, and thus slow or halt disease progression. This strategy is a similar strategy to 
orthotopic liver transplantation, with the exception that ISIS 420915 reduces wild-type protein in 
addition to the mutated protein. Given that wild-type TTR can continue to deposit as amyloid 
after liver transplant, this distinction may represent a therapeutic advantage. 
There is a high unmet medical need for both Stage 1 and Stage 2 FAP patients worldwide. For 
Stage 2 patients, there is currently no approved therapy and these patients are often not 
candidates for liver transplant due to advanced age, health reasons, or cardiac involvement. For 
Stage 1 patients, Vyndaqel® is currently the only approved therapy. However, it is only 
approved in some countries and is not yet widely reimbursed or established as the standard of 
care. 
 
2.3 
ISIS 420915 
 
2.3.1 
Mechanism of Action 
ISIS 420915 is a second-generation ASO drug targeted to transthyretin. It is complementary to a 
region within the 3′ untranslated region (3′ UTR) of the transthyretin mRNA and binds to the 
mRNA by Watson and Crick base pairing. The hybridization (binding) of ISIS 420915 to the 
cognate mRNA results in the RNase H-mediated degradation of the transthyretin mRNA, thus 


23 
23 
 
 
ISIS 4209 l 5-CS3 
Protocol 
CONFIDENTIAL 
Amendment5 
22 Februa1y 2017 
 
 
preventing production of the transthyretin protein. Maximal antisense-mediated reduction of 
target mRNA levels is typically greater than 90% of contrnl levels in sensitive tissues 
(Crooke and Bennett 1996; Zhang et al. 2010). Furthe1more, reduction in target mRNA levels 
using this approach correlates directly with a subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, ISIS 420915 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages. The nucleotide sequence of ISIS 420915 
(Figure 1) is complementaiy to a 20-nucleotide stretch within the 3' UTR region of the 
transthyretin protein mRNA. Strncturally, the oligonucleotide has 3 regions. Two (2) of them, 
the 5 nucleotides at the 5' end and the 5 nucleotides at the 3' end, ai·e composed of 
2'-0-(2-methoxyethyl) (MOE)-modified ribonucleotides. These MOE-modified nucleotides 
confer (1) increased affinity to the target mRNA (Altmann et al. 1996; McKay et al. 1999), 
(2) increased resistance to exonucleases and endonucleases (thereby increasing stability in tissue) 
(Geary et al. 2003), and (3) ainelioration of some of the high dose toxicities thereby resulting in 
an improved safety profile compai·ed to first generation antisense diugs containing 
phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000). The third region, 
the central po1tion of the oligonucleotide, is composed of 10 oligodeoxynucleotides. This 
chimeric design is called a MOE-Gapmer, and ISIS 420915 employs this chimeric strncture to 
enable use of the RNase H-mechanism for antisense activity. This is because while the 2'-MOE 
modification confers increased stability and affinity, it does not suppo1t RNase H catalysis of 
RNA hybridized to 2'-MOE-modified nucleotides (McKay et al. 1999). This is caused by 
confonnational changes induced in the heteroduplex by 2'-alkoxy:RNA hybrids that are not 
recognized by RNase H enzymes (Inoue et al. 1987; Monia et al. 1993). By limiting the 2'-MOE 
modification to nucleotides flanking the phosphorothioate oligodeoxynucleotide core, the 
beneficial attributes of the 2'-MOE chemistry ai·e preserved while also retaining RNase H 
recognition. 
 
 
2'-MOE 
2'-Deoxy 
2'-MOE 
Ir c 1 1 a I 
(RNase H  -Sensitive) 
a T T A c A T a A A 
IA 1 cc  c I 
 
 
 
Phosphorothioate 
Backbone 
 
 
Figure 1 
 Design of Chimeric 2'-MOE Phosphorothioate Oligonucleotides 
(MOE-Gapmer). The sequence of ISIS 420915 is shown 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
24 
24 
 
 
 
2.3.3 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ISIS 420915 can be 
found in the Investigator’s Brochure. A summary is included below. 
The nonclinical pharmacokinetics and toxicology evaluation of ISIS 420915 includes repeat dose 
studies up to 6 and 9 months in the CD-1 mouse and cynomolgus monkey, respectively. 
Nonclinical findings following ISIS 420915 treatment were, in general, non-specific class effects 
that are typical for 2′-MOE ASOs (Henry et al. 2008) and no findings were considered related to 
pharmacologic inhibition of TTR. Class effects occurred in a dose- and duration-dependent 
manner. In the monkey they included transient effects on acute complement activation (at doses 
≥ 10 mg/kg/wk) and acute elevations in activated partial thromboplastin time (aPTT) (at doses 
≥ 12 mg/kg/wk). The changes in aPTT were not cumulative over the course of the 9-month 
monkey study. In the mice, there was evidence of inflammation that included the presence of 
minimal to moderate mononuclear cell infiltrates in the sinusoids of liver, lymph nodes and the 
subcutaneous injection site at doses ≥ 40 mg/kg/wk after 3 and 6 months of treatment. 
Nonclinical pharmacokinetics (PK) of ISIS 420915 was similar to other second-generation 
ASOs. The exposure of ISIS 420915 in plasma and tissue was dose-dependent. The majority of 
ISIS 420915 was cleared from plasma within hours due mainly to distribution to tissues, with 
kidneys and liver having the highest concentrations. The half-life in kidney and liver was 
approximately 13.5 days and 18.8 days, respectively, consistent with the plasma terminal 
elimination half-life of 17.0 days (at 8 mg/kg) after 4 doses. 
 
2.3.4 
Clinical Experience 
Two (2) clinical studies have been conducted with ISIS 420915; ISIS 420915-CS1 which is 
complete and ISIS 420915-CS2 which is ongoing. Detailed information concerning the 
ISIS 420915-CS1 and ISIS 420915-CS2 studies can be found in the Investigator’s Brochure. 
A summary of each study is included below. 
ISIS 420915-CS1 was a Phase 1 double-blind, placebo-controlled, dose escalation study 
designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single 
and multiple doses of ISIS 420915 administered by subcutaneous injection to healthy subjects. 
The study enrolled 65 healthy volunteers (16 in the single dose cohorts and 49 in the multiple 
dose cohorts). Four (4) single dose levels (50, 100, 200, and 400 mg) and 5 multiple dose levels 
(50, 100, 200, 400 and 300 mg) were evaluated sequentially in the order listed. Subjects enrolled 
in the multiple-dose cohorts received a total of 6 doses of Study Drug administered by 
subcutaneous (SC) injection: 3 doses on alternate days during the first week (Days 1, 3, and 5) 
and then once a week for the next 3 weeks (Days 8, 15, and 22). 
ISIS 420915 was well-tolerated at the dose levels and dose regimens tested in ISIS 420915-CS1. 
There were no serious adverse advents (SAEs). Two (2) discontinuations were considered 
possibly related to ISIS 420915 by the Sponsor, 1 due to constitutional symptoms (400 mg 
subject) and 1 due to injection site reactions (300 mg subject). The main safety findings 
included; 1) mild injection site reactions characterized most often by pain and erythema, 
2) transient C-reactive protein elevations, primarily associated with the first injection and not 
associated with symptoms, and 3) retinol reductions below the lower limit of normal (LLN) 
which were asymptomatic and an expected consequence of transthyretin reduction. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
25 
25 
 
 
 
Plasma transthyretin levels were evaluated in all cohorts and dose-dependent reductions were 
observed after both single and multiple-dose administration. In the multiple-dose cohorts, the 
mean percent reductions in transthyretin were -8%, -22%, -53%, -75% and -76% in the 50, 100, 
200, 300, and 400 mg cohorts, respectively. The therapeutic goal for ISIS 420915 is to reduce 
transthyretin levels as much as possible at a dose level that will not cause unacceptable toxicity. 
Therefore, the 300 mg dose level which gave similar transthyretin reductions as the 400 mg dose 
level, was selected for the ISIS 420915-CS2 Phase 2/3 study. 
ISIS 420915-CS2 is a Phase 2/3 multicenter, double-blind, placebo-controlled study to assess the 
efficacy and safety of ISIS 420915 in patients with FAP. The study plans to enroll 
approximately 135 patients randomized 2:1 (ISIS 420915 to placebo) to receive 300 mg 
ISIS 420915 or placebo. The Study Drug is administered 3 times during the Week 1 and once 
weekly during Weeks 2 to 65. 
 
2.4 
Rationale for Dose and Schedule of Administration 
The dose level and schedule in the present open label extension (OLE) study (300 mg 
ISIS 420915 administered once weekly) is the same dose and schedule used during Weeks 2 to 
65 in the preceding ISIS 420915-CS2 study. Antisense oligonucleotides of this class have been 
safely administered intravenously and subcutaneously in multiple clinical studies at doses up to 
1000 mg (Kwoh 2008) and treatment duration’s ≥ 6 months (Chi et al 2008; Raal et al. 2010) and 
> 24 months (Santos et al. 2012). The patients randomized to ISIS 420915 in ISIS 420915-CS2 
receive 65 weeks (15 months) of treatment in that study followed by up to an additional 
260 weeks (5 years) in the present OLE study. The safety and tolerability of the proposed 
325-week dosing period is also supported by nonclinical chronic toxicology studies with 
ISIS 420915. 
 
3. 
EXPERIMENTAL PLAN 
 
3.1 
Study Design 
This is a multicenter open-label study. Eligible patients who have satisfactorily completed 
ISIS 420915-CS2 will receive 300 mg ISIS 420915 once weekly for 156 weeks (3 years). 
Exceptions will be given to patients that had a dose reduction or schedule change in 
ISIS 420915-CS2 who may continue with the same dose level or schedule in this study. 
All patients will receive supplemental doses of the recommended daily allowance (RDA) of 
vitamin A. 
If at the end of 3 years of treatment, ISIS 420915 is not commercially available in the country of 
the patient, the patient may continue to receive treatment in this study for up to 2 years more or 
until ISIS 420915 becomes commercially available in the patient’s country, whichever occurs 
earlier. At the end of the 5 years of treatment with ISIS 420915 in this study, if ISIS 420915 is 
not commercially available, patients may be allowed to continue receiving treatment with 
ISIS 420915 via an early access route to be defined by the sponsor and depending on local 
regulations. After completing the treatment period, patients will enter the 3-month 
post-treatment evaluation period. If a patient discontinues treatment in this study, but is 
continuing to receive treatment with ISIS 420915 via another mechanism, the entry of the 
patient into the 3-month post-treatment evaluation period may be omitted. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
26 
26 
 
 
 
3.2 
Number of Study Centers 
This is a multicenter, worldwide study to be conducted at study centers that enroll patients in 
ISIS 420915-CS2. 
 
3.3 
Number of Patients 
Approximately 135 patients may be eligible to enroll in this study. 
 
3.4 
Overall Study Duration and Follow-up 
The study will consist of the following periods: 
• A ≤ 4-week screening assessment period 
• A treatment period of up to 260 weeks (Y5-W52) 
• A 3-month post-treatment evaluation period 
3.4.1 
Screening Assessment 
A maximum period of 4 weeks is allowed between a patient’s last dose in ISIS 420915-CS2 
(CS2 Week 65 visit) and initiation of dosing in this study (CS3 Day 1 visit). Periods longer than 
4 weeks may be considered after discussion and approval by the Study Medical Monitor. 
However, the intention is to minimize the treatment pause between the 2 studies. Ideally the first 
dose in this study should be administered 1-week after the last dose in ISIS 420915-CS2. 
 
3.4.2 
Treatment 
The treatment period is up to 260 weeks (5 years) in duration. ISIS 420915 will be administered 
as a once-weekly SC injection at the Study Center or at home by the patient or caregiver. 
Patients are to report to the Study Center for evaluations 5 times in Year 1 (Weeks 1, 7, 13, 26, 
52) and 2 times in each subsequent year (26th and 52nd week of each year). There are also 
non-clinic visits including weekly platelet monitoring where patients will have blood collected 
by local laboratory, Sponsor appointed home healthcare service, or the Study Center. 
 
3.4.3 
Post-Treatment 
After completion of treatment, patients will enter a 3-month post-treatment evaluation period that 
consists of clinic and non-clinic visits for safety monitoring. 
If a patient discontinues treatment in this study, but is continuing to receive treatment with 
ISIS-420915 via another mechanism, the entry of the patient into the 3-month post-treatment 
evaluation period may be omitted. 
 
3.5 
End of Study 
The End-of-Study is last patient, last visit. 
 
3.6 
Data and Safety Monitoring Board 
The independent Data and Safety Monitoring Board (DSMB) for ISIS 420915-CS2 will review 
the safety and tolerability of ISIS 420915 during this OLE study at a frequency and duration as 
outlined in the Safety Management Plan and DSMB Charter. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
27 
27 
 
 
 
4. 
PATIENT ENROLLMENT 
 
4.1 
Screening 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information and/or recruitment material. 
Patients 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. Patients will maintain 
the same patient identification number that was assigned in ISIS 420915-CS2 throughout this 
OLE study. 
 
4.2 
Randomization 
There is no randomization in this OLE study. All patients will receive ISIS 420915, including 
patients randomized to either ISIS 420915 or placebo in ISIS 420915-CS2. 
 
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 4 weeks of Study Day 1. 
 
5.1 
Inclusion Criteria 
1. Completion of ISIS 420915-CS2 with the following as judged by the Investigator and 
Sponsor: 
a. Satisfactory completion of dosing and End-of-Treatment (EOT) efficacy assessments 
b. No significant tolerability issues 
c. Satisfactory compliance to the ISIS 420915-CS2 protocol requirements 
Under special circumstances, patients that participated in ISIS 420915-CS2 but did not 
complete the full treatment period may be allowed to participate in this study with 
approval from the Sponsor. 
2. Willingness to take vitamin A supplements 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
28 
28 
 
 
 
3. Satisfy 1 of the following: 
a. Females: Non-pregnant and non-lactating; surgically sterile, postmenopausal, 
abstinent, or if engaged in sexual relations of childbearing potential, patient is using 
an acceptable contraceptive method (refer to Section 6.3.1) from the time of signing 
the informed consent form until at least 3 months after the last dose of ISIS 420915. 
b. Males: Surgically sterile, abstinent, or if engaged in sexual relations with a female of 
childbearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) during and for 3 months after the last dose of ISIS 420915. 
4. Must have given written informed consent (signed and dated) and any authorization 
required by local law and be able to comply with all study requirements 
 
5.2 
Exclusion Criteria 
1. Have any new condition or worsening of existing condition that in the opinion of the 
Investigator or Sponsor would make the patient unsuitable for enrollment, or could 
interfere with the patient participating in or completing the study 
 
6. 
STUDY PROCEDURES 
 
6.1 
Study Schedule 
All required study procedures are outlined in Appendix A. 
 
6.1.1 
Screening Assessment Period 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form. A maximum period of 4 weeks is allowed between a patient’s last dose 
in ISIS 420915-CS2 (CS2 Week 65 visit) and initiation of dosing in this study (CS3 Day 1 visit). 
Periods longer than 4 weeks may be considered after discussion and approval by the Study 
Medical Monitor. All screening assessments must be completed during this period. An 
exception is the 24-hour urine collection (which includes a serum creatinine blood draw) that 
may be done at any time during the screening period or during Week 1 on treatment. Safety 
clinical laboratory parameters and assessments from ISIS 420915-CS2 may be used for screening 
evaluation if they were obtained within 4 weeks of Study Day 1. A longer period may be 
considered after discussion and approval from the Study Medical Monitor. 
 
6.1.2 
Treatment Period 
Patients will report to the Study Center for evaluations and tests 5 times during Year 1 
(Study Weeks 1, 7, 13, 26, 52) and 2 times in each subsequent year (26th and 52nd week of each 
year). Physical examination, collection of blood for measurement of safety clinical laboratory 
parameters and specialty labs, measurement of vital signs, and collection of adverse events and 
concomitant medication/procedure information 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, NIS, Norfolk QOL-DN questionnaire, SF-36 questionnaire, PND 
score, body weight, ophthalmology examination, electroretinogram (ERG), electrocardiogram 
(ECG), and transthoracic ECHO examination. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
29 
29 
 
 
 
Non-clinic visits will occur 8 times during Year 1 (Weeks 4, 10, 15, 18, 21, 23, 29, 39) and 
2 times in each subsequent year (13th and 39th week of each year), where patients’ labs will be 
collected by the Sponsor appointed home healthcare service, or the Study Center as arranged by 
the Study Center personnel or by local laboratory with prior Sponsor approval. In addition, 
platelets will be collected weekly and serum creatinine will be collected every 2-3 weeks 
(see Appendices A and C). Patients may also be contacted by phone to collect adverse events, 
concomitant medication, and concomitant procedure information. 
ISIS 420915 can be administered once weekly by Study Center personnel or at home by the 
patient/caregiver. If ISIS 420915 is administered during a clinic or non-clinic visit, all blood 
samples should be drawn prior to administration. Ideally, blood draws should occur 7 days after 
the previous dose. Dosing instructions and training will be provided to the patient/caregiver 
where applicable. It is anticipated that the Study Drug configuration may change during the 
course of the study, from the configuration of stoppered glass vials to prefilled syringes (PFS). 
During this transition, patients may be requested to complete a short patient preference 
questionnaire. 
Patients will also take daily oral supplemental doses of the RDA of vitamin A (approximately 
3000 IU or closest approximate dose as available in the region where the patient resides). 
Vitamin A may be provided 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 periods. 
To ensure maintenance of the study blind in the ongoing ISIS 420915-CS2 study, TTR, RBP4, 
retinol, and NT-proBNP from the first 13 weeks of treatment in this study will not be available to 
the Sponsor, Investigators, Study Center Personnel, or the patients until the ISIS 420915-CS2 
study is unblinded. 
The mNIS+7 assessment will be conducted at Weeks 26, 52, 78, 104, 130, and 156. The 
NIS assessment will be conducted at Y4-W52 and Y5-W52. The Norfolk QOL-DN 
questionnaire is conducted at Weeks 26, 52, 78, 104, 130, 156, and Y4-W52 and Y5-W52. 
The Norfolk QOL-DN questionnaire should be the first assessment performed at these visits. 
If ISIS 420915 administration, ERG, or ophthalmology examinations are to be performed on the 
same day as an mNIS+7 or NIS assessment, they should be performed after the mNIS+7 or 
NIS assessment is complete. For Week 78 and Week 156 visits, 2 mNIS+7 assessments will be 
performed on separate days. A maximum of 2 weeks from the visit (Week 78 or Week 156) will 
be allowed to complete both assessments. 
For Weeks 4-52 there is a ± 7-day visit window. After Week 52 the visit window is ± 10-day. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in the schedule of procedures (Appendix A). However, if 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. 
The Study Day 1 ECHO can be done any time in the screening period or up to 2 weeks after 
Day 1. The Day 1 ECHO is not done if the Week 65 ECHO was conducted in ISIS 420915-CS2. 
A ± 2-week window is given for all other ECHOs. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
30 
30 
 
 
 
During the treatment period, an ophthalmology examination will be performed at Weeks 26, 52, 
78, 104, 130, 156, and 2 times in each subsequent year (26th and 52nd week of each year). An 
ERG examination will be performed at Weeks 78 and 156. A window of ± 2 weeks is allowed 
for these eye examinations. Early termination ERG and ophthalmology examinations are only 
done if the patient discontinues treatment after ≥ 9 months of dosing or unless deemed necessary 
by Investigator or Study Medical Monitor. 
 
6.1.3 
Post-Treatment Period 
After discontinuation of treatment with ISIS 420915, patients will enter the 3-month 
post-treatment evaluation period. This period consists of clinic and non-clinic visits for safety 
monitoring as outlined in the Schedule of Procedures (Appendix A and C). Weekly platelet and 
every 2-3 week serum creatinine testing is required for a minimum of 6 weeks after the last dose 
of Study Drug (this includes early termination patients as well as patients that complete the full 
treatment period). Patients that terminate treatment early and do not withdraw consent should 
have the post-treatment visit Week 169 conducted 3 months after the last dose of Study Drug. 
The 3-month post-treatment evaluation period may be omitted if the patient discontinues 
treatment in this study, but is continuing to receive treatment with ISIS 420915 via another 
mechanism. 
 
6.2 
Additional Study Assessments 
 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study. A list of these analytes is 
contained in Appendix B. 
 
6.2.2 
Congestive Heart Failure 
Any patient who develops signs, symptoms, or test results suggestive of new onset or worsening 
(if pre-existing) congestive heart failure should have the following evaluations performed (in 
addition to any tests deemed to be necessary by the attending physician) as soon as possible and 
the Investigator should consider referral to a cardiologist: 
• Chest x-ray 
• 12 lead ECG 
• Echocardiogram 
In addition the Congestive Heart Failure supplemental eCRF pages should be completed in the 
eCRF. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
31 
31 
 
 
 
6.2.3 
Arrhythmias 
Any patient who develops signs, symptoms, or test results suggestive of new cardiac arrhythmia 
should have the following evaluations performed (in addition to any tests deemed to be necessary 
by the attending physician) as soon as possible and the Investigator should consider referral to a 
cardiologist: 
• 12 lead ECG 
• Echocardiogram 
In addition, the Arrhythmias supplemental eCRF pages should be completed in the eCRF. 
 
6.2.4 
Myocardial Ischemia 
Any patient who develops signs, symptoms, or test results suggestive of myocardial ischemia 
should have the following evaluations performed (in addition to any tests deemed to be necessary 
by the attending physician) and the Investigator should consider referral to a cardiologist: 
• Serial 12 lead ECGs 
• Serial cardiac enzyme evaluation (CKMB, cardiac troponin I or cardiac troponin T) 
In addition, the Myocardial Infarction supplemental eCRF pages should be completed in the 
eCRF. 
 
6.2.5 
Event-Specific Supplemental eCRF Pages 
In the event of any of the following, the corresponding supplemental eCRF pages should be 
completed in the eCRF: 
• Death 
• Valvulopathy (i.e., signs, symptoms or test results suggestive of impairment of function 
of 1 or more cardiac valves) 
• Deep vein thrombosis or pulmonary embolism 
• Peripheral arterial thromboembolism 
• Cerebrovascular event or transient ischemic attack 
• Revascularization 
• Pulmonary hypertension 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
32 
32 
 
 
 
6.3 
Restriction on the Lifestyle of Patients 
 
6.3.1 
Contraception Requirements 
All patients of childbearing potential must refrain from sperm/egg donation and practice 
effective contraception from the time of signing the informed consent form until at least 
3 months after their last dose of ISIS 420915. 
For the purposes of this study, a woman of childbearing potential is 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, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/cream/ 
suppository. Male patients must also encourage their female partner to use effective 
contraception from the time of signing the informed consent until 3 months after the 
patient’s last dose of ISIS 420915. Effective contraceptive for the female partner 
includes surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository. Male 
patients with partners who are pregnant must use condoms to ensure that the fetus is not 
exposed to ISIS 420915. 
For female patients: 
• Using 2 or more of the following acceptable methods of contraception: 
o Surgical sterilization (e.g., bilateral tubal ligation) 
o Hormonal contraception 
▪ Oral contraceptive (either combined or progestogen alone) 
▪ Injectable progestogen 
▪ Implants of etonogestrel or levonorgestrel 
▪ Percutaneous contraception/device 
• Intrauterine contraception/device 
• Combination of male condom* with female diaphragm together with spermicidal 
foam/gel/ film/cream/suppository 
*Note: A female condom and a male condom should not be used together as friction 
between the two can result in either product failing. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
33 
33 
 
 
 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 8 hours before a blood sample is taken for the 
chemistry panel, PD and retinol assessments. 
 
7. 
STUDY DRUG 
 
7.1 
Study Drug Description 
ISIS 420915 characteristics are listed in Table 1. 
ISIS 420915 is contained in stoppered glass vials or glass prefilled syringes (PFS) and will be 
provided to the Study Center by the Sponsor. The ISIS 420915 storage and preparation 
instructions will be provided by the Sponsor. For long-term storage at clinical sites, ISIS 420915 
must be stored securely at 2° to 8° Celsius and be protected from light. 
Table 1 
Study Drug Characteristics 
 
Study Drug 
ISIS 420915 
Strength 
200 mg/mL 
Volume/Formulation 
1.5 mL solution per 3 mL vial 
Or 
1.5 mL solution per prefilled syringe 
Route of Administration 
SC 1.5 mL 
 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged ISIS 420915 labeled in accordance with 
specific country regulatory requirements. 
 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
ISIS 420915 supplies provided by the Sponsor. The Study Center must return all used and 
unused ISIS 420915 vials to the Sponsor or designee. All used syringes must be disposed of as 
per the site’s hazardous waste destruction policy. 
 
8. 
TREATMENT OF PATIENTS 
 
8.1 
Study Drug Administration 
For each individual patient, ISIS 420915 will be administered SC as a single 1.5 mL injection 
once-weekly for Weeks 1 to Y5-W52. ISIS 420915 may be administered by the Study Center 
personnel or at home by the patient/caregiver. If ISIS 420915 is administered during a clinic or 
non-clinic visit, all blood samples should be drawn prior to administration. It is not necessary for 
ISIS 420915 to be administered during clinic visits. Ideally blood draws should occur 7 days 
after the previous dose. If needed, dosing instructions and training will be provided to the 
patient/caregiver by the Study Center personnel. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
34 
34 
 
 
 
If needed for tolerability reasons, the single 1.5 mL injection may be administered as 2 injections 
of smaller volume, but prior discussion with the Study Medical Monitor is encouraged. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
ISIS 420915 preparation and administration. 
 
8.2 
Other Protocol-Required Drugs 
All patients will take daily oral supplemental doses of the RDA of vitamin A (approximately 
3000 IU or the closest approximate dose as available in the region where the patient resides). 
Commercially available vitamin A as a single supplement or as part of a multivitamin will be 
provided by the Study Center or designee, in accordance with local regulatory requirements and 
availability. The vitamin A supplement should be taken throughout the treatment and post- 
treatment evaluation periods. 
 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures. 
 
8.4 
Treatment Precautions 
No specific treatment precautions are required for this study. 
 
8.5 
Safety Monitoring Rules 
Please refer also to the “Guidance for the Investigator” section of the Investigator’s Brochure. 
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. 
Confirmation Guidance: At any time during the study (treatment or post-treatment periods), the 
initial clinical laboratory results meeting the safety monitoring or stopping 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). 
Stopping Rule Guidance: In the event of an initial clinical laboratory result that meets a stopping 
criterion, patients must not be re-dosed until a confirmatory test result has been reviewed by the 
Study Medical Monitor. If any of the stopping criteria described in Section 8.6 are met and are 
confirmed, the patient will be permanently discontinued from further treatment with 
ISIS 420915, evaluated fully as outlined below and in consultation with the Study Medical 
Monitor or appropriately qualified designee, and will be entered into the post-treatment 
evaluation period of the study (after completing the early termination [ET] assessments). In 
general, patients who do not meet the stopping rules based upon retest may continue dosing. 
However, the Investigator and the Study Medical Monitor (or appropriately qualified designee) 
should confer as to whether additional close monitoring of the patient is appropriate. 
Additional Guidance: If possible, a pharmacokinetic sample should be collected as soon as 
possible after an SAE has occurred (preferably within 2 weeks). In addition, if a patient is asked 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
35 
35 
 
 
 
to return to the clinic for additional evaluations due to an AE, then a pharmacokinetic sample 
should be taken at the time of the unscheduled visit. 
For all safety monitoring rules below “baseline” will be defined as the ISIS 420915-CS3 
Day 1 value. 
 
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. 
In the event of an ALT or AST measurement that is > 3 x the upper limit of normal (ULN) (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN), at any time during 
the study (treatment or post-treatment period), the initial measurement(s) should be confirmed as 
described above. Similarly, confirmatory measurements should also be performed if ALT or 
AST levels increase to 5 x ULN. 
Frequency of Repeat Measurements: Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN), that are 
continuing to rise should have their liver chemistry tests (ALT, AST, ALP, INR, and total 
bilirubin) retested at least once-weekly until levels stabilize and begin to recover (ALT and AST 
levels become ≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN). 
Further Investigation into Liver Chemistry Elevations: For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Total, direct, and indirect bilirubin 
5. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, HCV mRNA, CMV IgM, 
and EBV antibody panel) 
6. Serology for autoimmune hepatitis (e.g., antinuclear antibody (ANA), antismooth muscle 
antibody, type 1 anti-liver kidney microsomal antibody) 
7. Serum acetaminophen-protein adducts by high pressure liquid chromatography if recent 
acetaminophen usage by patient 
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 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
36 
36 
 
 
 
Study Medical Monitor. Repetition of the above evaluations should be considered if a patient’s 
ALT and/or AST levels reach 5 x ULN. 
 
8.5.2 
Safety Monitoring Rules for Renal Function 
In the event of a confirmed (as described in Section 8.5) laboratory result meeting 1 or more of 
the following criteria, urinalysis (see Appendix B) will be required approximately every 
2-3 weeks.* 
a. Creatinine clearance by CKD-EPI < 60 mL/min/1.73 m2 
b. Creatinine clearance by CKD-EPI decrease from baseline** > 25% 
c. Urine Alb/Cr ratio > 5 x ULN 
d. Serum creatinine increase from baseline** > 0.5 mg/dL 
* Urine collection should be performed at the same time as the protocol specified collection of 
serum creatinine (see Appendices A and C) 
** Baseline is the study CS3 Day 1 value 
In addition, the first confirmed result meeting a criterion (at any time on study) will trigger an 
immediate evaluation by a local nephrologist, ideally within 1-week. The following labs should 
be obtained immediately: fasting serum creatinine, urine culture, 24-hour urine sample for 
creatinine clearance and urine protein, and urine microscopy sample with nephrologist’s 
inspection of sediment. Consideration of a dose pause (for example with a confirmed CKD-EPI 
decrease > 25%) should be discussed with the Study Medical Monitor. A mandatory dose pause 
will occur with a 24-hour urine protein result of > 2.0 g. 
If a patient remains stable over time they may be moved to less frequent monitoring of urinalysis 
at the discretion of the Study Medical Monitor in consultation with a nephrologist and the 
Investigator. 
If a patient meets a renal monitoring rule that is confirmed on repeat testing, the Investigator 
should review the patient’s concomitant medications for potentially nephrotoxic agents, and 
carefully consider discontinuing non-essential medications. Consultation with the Study Medical 
Monitor is encouraged. 
 
8.5.3 
Safety Monitoring Rules for Ocular Effects 
All patients should receive an ophthalmology examination by an eye specialist at Weeks 26, 52, 
78, 104, 130, and 156 and twice each subsequent treatment year (26th and 52nd week of each 
year). An ERG will also be performed at Weeks 78 and 156. In addition, any patient who 
complains of persistent ocular symptoms compatible with vitamin A deficiency (e.g., night 
blindness or 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 an ERG examination 
should be conducted and analyzed by the central reader. In addition, it is suggested that a review 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
37 
37 
 
 
 
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. 
If an ERG is changed from baseline and shows clear signs of vitamin A deficiency as assessed 
by the central reader and described below, then the patient should be monitored more frequently. 
Frequency will be determined by the Study Medical Monitor in consultation with the 
Investigator and ophthalmologist. 
Clear signs of vitamin A deficiency as assessed by ERG include: 
a. Change from baseline > 50%, and 
b. Values below normal range (if baseline values were within normal range), and 
c. Changes that are approximately symmetrical between eyes (unless there is an alternative 
explanation for asymmetry) 
Dosing with Study Drug may continue while these evaluations are being performed. 
 
8.5.4 
Safety Monitoring Rules for Platelet Count Results 
Platelets will be monitored weekly throughout the treatment period and for a minimum of 
6 weeks after the last dose of Study Drug (this includes early termination patients as well as 
patients that complete the full treatment period). For patients participating in the Post-Treatment 
Evaluation Period, frequency of testing after 6 weeks from the last dose of Study Drug will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
All platelet count results must be promptly reviewed by the Investigator to ensure that the count 
has not met the stopping rule 
If for any reason there is more than 14 days between platelet values (e.g. lab report of an 
unreadable sample due to clumping, hemolysis, or quantity not sufficient, or a missed lab 
assessment), the Investigator will contact the patient to hold dosing until a new platelet value is 
obtained and reviewed. 
If a patient’s platelet counts fall below 100,000/mm3, additional lab tests may be requested as 
determined by the Investigator in consultation with the Study Medical Monitor. 
Due to the 3 to 5-year study duration it is anticipated that patients may undertake travel including 
vacations, which may impede weekly platelet monitoring. In some situations it may be possible 
to arrange for local laboratory testing or use of the home healthcare service at their temporary 
location. The intent is to maintain weekly platelet monitoring and dosing where possible, as well 
as Investigator site contact with the study patients. However, if the above options are not 
possible, a temporary interruption of study treatment will be planned with a prompt blood draw 
upon the patient’s return which must be reported and reviewed by the Investigator prior to the 
patient resuming dosing. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
38 
38 
 
 
 
8.6 
Stopping Rules 
 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of confirmed laboratory results meeting the following criteria, and the event is 
without an alternative explanation as discussed with the Study Medical Monitor, dosing of 
a patient with ISIS 420915 will be stopped permanently: 
1. ALT or AST > 8 x ULN 
2. ALT or AST > 5 x ULN at 2 consecutive weekly measurements (not less than 7 days nor 
more than 10 days apart) both of which are confirmed. Treatment with ISIS 420915 may 
continue until the second consecutive weekly ALT or AST measurement is confirmed to 
be > 5 x ULN 
3. ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
4. ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or concomitant eosinophilia (> 5%) 
 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of an estimated creatinine clearance by CKD-EPI meeting any of the following 
criteria, a serum creatinine and 24-hour urine sample for creatinine clearance and protein should 
be obtained: 
• CKD-EPI decrease of > 50% from baseline* 
• Value < 45 mL/min/1.73 m2 (if baseline CKD-EPI > 60 mL/min/1.73 m2) 
• Value < 30 mL/min/1.73 m2 (if baseline CKD-EPI ≤ 60 mL/min/1.73 m2) 
* baseline is study CS3 Day 1 value 
Dosing of a patient with ISIS 420915 will be stopped permanently if the 24-hour urine testing 
confirms any of the following values in the absence of an alternative explanation agree by a 
consulting nephrologist: 
• urine protein is > 3.5 g 
• 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 
In the event of a confirmed platelet count less than 75,000/mm3, and in the presence of major 
bleeding or clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing 
of a patient with ISIS 420915 will be stopped permanently. The follow-up schedule for any 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
39 
39 
 
 
 
events meeting this stopping criterion will be determined by the Investigator in consultation with 
the Study Medical Monitor. 
In the event of a confirmed platelet count less than 75,000/mm3, and in the absence of major 
bleeding or clinically-relevant non-major bleeding, further dosing of a patient with ISIS 420915 
must be held until the platelet count returns to at least 100,000/mm3. Weekly platelet monitoring 
should continue during this period. In addition, the Investigator should give consideration to 
collecting duplicate platelet samples for study in a local lab in parallel to the central lab if it 
would provide quicker access to the patients platelet count. If the platelet count was confirmed 
to be < 50,000/mm3, then monitoring should be increased to daily until two successive values 
show improvement. The Investigator must notify the Study Medical Monitor within 24 hours of 
any local lab platelet results that show a level < 50,000/mm3. 
The suitability of the patient for continued dosing and the need for any modification to treatment 
schedule or dose (refer to Section 8.7) 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 by the patient, and the 
speed of recovery of platelet count upon holding of dosing. 
Definition of major bleeding events: 
International Society on Thrombosis and Haemostasis (ISTH) Major Bleeding: 
1. Fatal bleeding, and/or 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome, and/or 
3. Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole blood or red cells 
Definition of clinically-relevant, non-major bleeding events: 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
8.6.4 
Stopping Rule for Ocular Effects 
A patient should be permanently discontinued from Study Drug if an ERG is changed from 
baseline and shows clear signs of vitamin A deficiency (as described in Section 8.5.3) and an 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
40 
54 
 
 
 
ophthalmology examination reveals significant changes from baseline in any 1 of certain 
physical signs (Bitot’s spots, xerophthalmic ulcers, keratomalacia, or other signs and symptoms 
of corneal necrosis) and a consultation with the central reader has occurred. 
 
8.6.5 
Stopping Rule for QTc Prolongation 
In the event of an ECG QTc (average of triplicates) above the thresholds described below, repeat 
triplicate ECGs should be performed approximately 1-hour later and further dosing should be 
discussed with the Study Medical Monitor: 
• QTc > 500 msec (if baseline QTc ≤ 470 msec) or 
• Increase in QTc value > 60 msec from baseline (all patients) 
The suitability of the patient for continued dosing, the need for any modification to treatment 
schedule or dose (refer to Section 8.7), and the most appropriate follow-up schedule, will be 
determined by the Investigator in consultation with the Study Medical Monitor. Suitability of 
continued dosing will be based on factors such as clinical symptoms, width of QRS complex, 
presence or absence of paced rhythm, and the firing of a defibrillator (in the case that the patient 
has an implantable defibrillator). In addition, consideration should be given to an expert 
cardiology read of the patients’ ECGs and a cardiology consult. If a patient is deemed suitable 
for continued dosing, more frequent ECGs will be performed, with the frequency to be 
determined by the Investigator and Sponsor Medical Monitor. Any additional 
monitoring/investigation will also be determined by the Investigator and Sponsor Medical 
Monitor. 
 
8.7 
Adjustment of Dose and/or Treatment Schedule 
Adjustments of dose and/or treatment schedule should occur only on rare occasions. Any 
proposed adjustment to treatment schedule or dose level must be discussed with and approved by 
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 adverse events after consultation with the 
Study Medical Monitor. 
 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant. Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
41 
55 
 
 
 
The reason for discontinuation of study treatment must be recorded in the eCRF and source 
documentation. 
Patients who discontinue from treatment are encouraged to remain in the study. Every effort 
should be made to complete the ET visit and the post-treatment evaluation visits which include 
weekly platelet and every 2-3 week serum creatinine testing for 6 weeks after the last dose of 
Study Drug. If the patient declines to participate in the post-treatment evaluation visit, at a 
minimum the ET visit procedures should be performed at the time of withdrawal 
(See Appendix A) and ideally within 14 days from the last dose of ISIS 420915. 
 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
• The patient receives a liver transplant 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator or Sponsor for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
• Administrative decision by the Investigator or Sponsor 
• ISIS 420915 becomes commercially available in the local country (patients in Year 4 or 
Year 5) 
• ISIS 420915 is rejected by the regulatory authority in the local country 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal. All information, including the reason for withdrawal from Study, must 
be recorded in the eCRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request. Patients withdrawn for 
any reason should be encouraged to complete the ET visit at the time of withdrawal 
(Appendix A). 
Patients who receive a liver transplant should be encouraged to return to the clinic to complete 
the ET visit as soon as feasible after the transplant procedures. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
42 
55 
 
 
 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded in the patient’s 
eCRF. AEs related to administration of these therapies or procedures must also be documented 
in 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 final post-treatment visit. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
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 or designee. A patient may choose to substitute the Study Center-provided vitamin 
A supplement with his/her own only after consultation with the Study Medical Monitor. 
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). 
Doxycycline and tauroursodeoxycholic acid (TUCA) are not allowed during the treatment period 
unless approved by the Study Medical Monitor. 
Diflunisal is not allowed at any time during the treatment period. Vyndaqel® may be allowed 
after 18 months at the discretion of the Study Medical Monitor. 
Due to known potential adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs), 
angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) 
on renal function, it is recommended that they should be used with caution. Discussion with the 
Study Medical Monitor prior to initiation of drugs that may affect renal function is 
recommended. 
 
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 final post-treatment visit. 
 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff. 
The Study Center staff is required to document the receipt, dispensing, and return of ISIS 420915 
supplies. Patients who self-administer ISIS 420915 at home must record treatment in a provided 
dosing diary that will be reviewed by the Study Center staff and monitor. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
43 
57 
 
 
 
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 Safety Management Plan throughout the conduct of the clinical trial. 
 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and 
ICH E6. Country-specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines. 
IECs/IRBs will be notified of any SAE according to applicable regulations. The DSMB will be 
notified of any SAE as specified in the DSMB charter. 
The Sponsor will evaluate the available information and decide if there is a reasonable possibility 
that ISIS 420915 caused the AE and, therefore, meets the definition of a SUSAR. 
For ISIS 420915 “expected” events, refer to the Investigator Brochure. 
 
9.3 
Definitions 
 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by ISIS 420915. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
ISIS 420915 caused the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than an adverse reaction. 
 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening: that is, poses an immediate risk of death at the time of the event 
• An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the 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 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
44 
58 
 
 
 
• 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 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 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
9.4 
Monitoring and Recording 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 exception is AEs from the parent study 
(ISIS 420915-CS2) that are ongoing at the time the patient enters this study. These should be 
recorded as ongoing AEs from ISIS 420915-CS2. The Investigator should always group signs 
and symptoms into a single term that constitutes a single unifying diagnosis if possible. 
 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to ISIS 420915) should be reported to the Sponsor or designee within 24 hours 
of the Study Center’s first knowledge of the event. The collection of SAEs will begin after the 
patient signs the informed consent form and stop at the end of the patient’s follow-up period, 
which is defined as the final post-treatment visit. When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message. An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
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. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
45 
58 
 
 
 
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 
post-treatment visit. The Investigator will monitor each patient closely and record all observed 
or volunteered AEs on the Adverse Event CRF. 
 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented in the Adverse Event eCRF: 
 
9.4.3.1 
Relationship to ISIS 420915 
The event’s relationship to ISIS 420915 is characterized by 1 of the following: 
• Related: There is clear evidence that the event is related to the use of ISIS 420915, 
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 ISIS 420915 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 ISIS 420915 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 ISIS 420915. 
 
9.4.3.2 
Severity 
The event’s severity is characterized by 1 of the following: 
• 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 9.3.3). 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
46 
58 
 
 
 
9.4.3.3 
Action Taken with ISIS 420915 
Action taken with ISIS 420915 due to the event is characterized by 1 of the following: 
• None: No changes were made to ISIS 420915 administration and dose 
• Permanently Discontinued: ISIS 420915 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 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded in the 
Adverse Event eCRF (treatment should also be recorded in the concomitant treatment or 
ancillary procedures eCRF as appropriate). 
 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists: Patient terminates from the trial and the AE continues 
• Recovered: Patient recovered completely from the AE 
• Became Serious: The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable): AE severity changed 
If the event is an SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing: SAE continuing 
• Persists (as non-serious AE): Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE in the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered: Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal: Patient died (the date of death should be entered as the SAE resolution date) 
9.5 
Procedures for Handling Special Situations 
 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE. Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia. Whenever possible, the 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
47 
58 
 
 
 
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 the Study 
Medical Monitor. Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs. Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports. The signed 
clinical laboratory reports will serve as source documents. 
 
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 
ISIS 420915 errors should be documented as Protocol Deviations. A brief description should be 
provided in the deviation, including whether the patient was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. 
Dosing details should be captured in the Dosing eCRF. If the patient administers a dose of 
ISIS 420915 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. 
Should an overdose occur, the Investigator or designee should refer to the Guidance for the 
Investigator section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately. An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy. Follow-up 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
48 
58 
 
 
 
information including delivery or termination is reported on Follow-up 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 ISIS 420915. However, the patient will be encouraged to 
complete the post-treatment follow-up period 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’s and infant’s medical records for an additional 
8 weeks after birth. 
Male patients: The progress of the pregnancy in 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, additional follow-up information may 
be requested for the mother and infant. Follow-up will be performed to the extent permitted by 
applicable regulations and privacy considerations. 
 
10. 
STATISTICAL CONSIDERATIONS 
 
10.1 
Study Endpoints, Subsets, and Covariates 
 
10.1.1 
Safety Endpoints 
• Adverse events 
• Vital signs and weight 
• Physical examination 
• Clinical laboratory tests 
• ECG 
• Use of concomitant medication 
• Ophthalmology and ERG examinations 
10.1.2 
Efficacy Endpoints 
• Change in the mNIS+7 score and components from baseline to Week 78 and Week 156 
• Change in the NIS score and components from baseline to Y5-W52 and Y4-W52 
• Change in the Norfolk QOL-DN questionnaire scores from baseline to Week 78 and 
Week 156 and at the end of each subsequent treatment year (52nd week of each year) 
• Change in the mBMI and BMI from baseline to Week 78 and Week 156 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
49 
58 
 
 
 
• Change in PND score from baseline to Week 78 and Week 156 and at the end of each 
subsequent treatment year (52nd week of each year) 
• Change in GLS by ECHO from baseline to Week 78 and Week 156 and at the end of 
each subsequent treatment year (52nd week of each year) in the ISIS 420915-CS2 ECHO 
subgroup and in the Cardiomyopathy-ECHO (CM-ECHO) Set 
For the mNIS+7 score, NIS score, and Norfolk QOL-DN score, the degree of progression will 
be estimated for the parent study period and the extension study period by treatment group of the 
parent study. Further details will be outlined in the Statistical Analysis Plan (SAP). 
 
10.1.3 
Pharmacodynamic Endpoints 
• Change from baseline in TTR level to Week 78 and Week 156 and at the end of each 
subsequent treatment year (52nd week of each year) 
• Change from baseline in RBP4 level to Week 78 and Week 156 and at the end of each 
subsequent treatment year (52nd week of each year) 
10.1.4 
Pharmacokinetic Endpoints 
Trough ISIS 420915 plasma concentrations will be measured throughout the study. Further 
details of the various planned plasma PK assessments are outlined in Section 10.6.4. 
 
10.1.5 
Exploratory Efficacy Endpoints 
• Change in the ECHO parameters (except GLS) in the ISIS 420915-CS2 ECHO subgroup 
and in the Cardiomyopathy-ECHO (CM-ECHO) Set from baseline to Week 78 and 
Week 156 and at the end of each subsequent treatment year ( 52nd week of each year) 
• Change in NT-proBNP from baseline to Week 78 and Week 156 and at the end of each 
subsequent treatment year ( 52nd week of each year) 
• Change in the SF-36 questionnaire scores from baseline to Week 78 and Week 156 and 
at the end of each subsequent treatment year ( 52nd week of each year) 
10.2 
Sample Size Considerations 
No sample size calculations were performed as this is an extension study to the double-blind, 
placebo-controlled ISIS 420915-CS2 study. Approximately 135 patients are planned in the 
ISIS 420915-CS2 study and may be eligible to enroll into this study. 
 
10.3 
Populations 
The Full Analysis Set will include all enrolled patients who received at least 1 injection of 
ISIS 420915 and who have at least 1 post-baseline efficacy assessment for the mNIS+7 score or 
Norfolk QOL-DN questionnaire total score. 
The Safety Set will include all enrolled patients who received at least 1 injection of ISIS 420915. 
The CM-ECHO set will include the subset of the 420915-CS2 Randomized Set that had a 
diagnosis of TTR cardiomyopathy at study entry of the parent study, but are not in the ECHO 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
50 
58 
 
 
 
Subgroup in the parent study, plus patients who qualified to participate in the ECHO Subgroup 
(whether consented or not). Patients who did not meet the criteria for the ECHO Subgroup or the 
CM-ECHO Set in ISIS 420915-CS2, but who are found to meet those criteria upon entry into 
ISIS 420915-CS3, may also be included in additional analysis (details will be found in the SAP). 
The Per-Protocol Set will include the subset of the Full Analysis Set that have received at least 
70% of the prescribed doses of ISIS 420915 and that have no significant protocol deviations that 
would be expected to affect efficacy assessments. 
 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For safety, baseline for patients on active treatment in the parent study will be the parent study 
baseline. For patients on placebo in the parent study, baseline for safety will be the last 
non-missing assessment prior to the first dose of ISIS 420915 in this study (Study Day 1) 
(details will be found in the SAP). 
For efficacy, 2 baselines are defined for each patient: the parent study baseline and the baseline 
assessment in this study (details will be found in the SAP). Further details of which assessments 
will be considered baseline for Echo analyses for this study will be included in the SAP. 
The baselines for additional analyses can be found in the SAP. 
 
10.5 
Interim Analysis 
An interim analysis may be conducted when the database of the parent study is locked and 
unblinded. Both safety and efficacy information from this study may be summarized during this 
interim analysis. Additional interim analyses may be performed, with the timing of the analyses 
coinciding with regulatory requirements or study milestones. At Week 13 and beyond, TTR, 
RBP4, retinol, and NT-proBNP will be analyzed periodically using descriptive statistics. 
 
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. 
All (except GLS) secondary and exploratory efficacy and pharmacodynamic 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. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
51 
58 
 
 
 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group. All patients enrolled will be included in a summary of patient disposition. 
 
10.6.2 
Safety Analysis 
Treatment duration and amount of ISIS 420915 received (including duration and amount in the 
parent study) will be summarized by treatment group, as well as reasons for withdrawal from 
ISIS 420915. 
All treatment-emergent adverse events (AEs with onset after the first dose of ISIS 420915) in 
this study and SAEs will be summarized by the treatment group of the parent study using the 
MedDRA™ coding system, by system organ class, preferred term, relationship to ISIS 420915, 
and severity. Narratives of deaths, serious adverse events, including early withdrawals from 
ISIS 420915 and from study due to adverse events, will also be provided. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count with 
differential, and coagulation panel will be summarized by study visit and by the treatment of the 
parent study. These safety variables will also be presented as change and percent change from 
baseline over time after ISIS 420915 administration, as appropriate. 
Vital signs, weight, and ECG measures will be summarized by treatment group of the parent 
study. In addition, the number of patients who experience abnormalities in clinical laboratory 
evaluations will be summarized by treatment group of the parent study. 
 
10.6.3 
Efficacy Analysis 
Change from baseline to Week 78 and Week 156 and at Week 52 of each subsequent 
treatment year will be summarized by treatment group of the parent study for the following 
efficacy measures: mNIS+7 score; NIS score; Norfolk QOL DN (total score, symptoms domain 
score for Stage 1 patients, and physical functioning/large fiber neuropathy domain score for 
Stage 2 patients); mBMI and BMI; components of the mNIS+7 (NIS, heat-pain sensory, 
touch-pressure sensory, nerve conduction and heart rate to deep breathing tests); and PND score; 
and the following exploratory measures: ECHO parameters, NT-proBNP, and 
SF-36 questionnaire. Changes from both the parent study baseline and the extension study 
baseline will be summarized. 
The change from parent study baseline and extension study baseline for the endpoints listed in 
the paragraph above will also be analyzed using a Mixed Effects Model with Repeated Measures 
(MMRM). Details of the MMRM will be described in the statistical analysis plan. The MMRM 
will be used to estimate adjusted means at each visit but no formal hypothesis tests will be 
performed. 
For the mNIS+7 score, the degree of progression will be estimated for the parent study period 
and the extension study period by treatment group of the parent study. Similar summaries of 
progression will be performed for the components of the mNIS+7 scores, NIS scores, Norfolk 
QOL-DN and its domain scores. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
52 
58 
 
 
 
10.6.4 
Pharmacokinetic Analysis 
Trough ISIS 420915 plasma concentrations will be summarized. Further details of the 
pharmacokinetic analysis and evaluation of immunogenicity (anti-ISIS 420915 antibodies) will 
be outlined in the SAP. 
 
10.6.5 
Pharmacodynamic Analysis 
Change from baseline to Week 78 and Week 156 and at the end of each subsequent treatment 
year (52nd week of each year) will be summarized by treatment group for TTR and RBP4. 
10.6.6 
Additional Analyses 
Not applicable. 
 
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 ISIS 420915 is administered. The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient 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. 
 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent forms, 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 ISIS 420915. 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 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
53 
58 
 
 
 
shipment of ISIS 420915. The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB for all 
subsequent protocol amendments and changes to the informed consent document. The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with 
ICH GCP Section 4.5.2. The Investigator should also notify the IEC/IRB of SAEs occurring at 
the Study Center and other adverse event 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. In the eCRFs or 
other documents submitted to the Sponsor, patients should be identified by patient study 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. 
 
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 IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial. The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study, according to the terms of the study 
contract. The Sponsor should notify the IEC/IRB in writing of the trial’s completion or early 
termination. Reasons for terminating the study include, but are not limited to safety issues or 
emergent data from ISIS 420915 clinical studies or ISIS 420915 is rejected by the regulatory 
authority in the local country. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
54 
58 
 
 
 
12.3 
Study Documentation and Storage 
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 eCRF data 
are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence. In this study, eCRFs 
may not be used as source documents. 
The Investigator and Study Center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities. Elements should include: 
• Patient files containing completed eCRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If drug supplies are maintained at the Study Center, proof of receipt, Study Drug Product 
Accountability Record, Return of Study Drug Product for Destruction, final Study Drug 
product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
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., eCRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The monitor is responsible for inspecting the eCRFs 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 eCRFs. 
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 eCRFs, are resolved. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
55 
58 
 
 
 
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 the Sponsor. 
The Principal Investigator will sign and date the indicated places on eCRF. These signatures will 
indicate that the principal Investigator inspected or reviewed the data on the eCRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
 
12.5 
Language 
The eCRFs must be completed in English. Generic names for concomitant medications should 
be recorded in English if possible, unless it is a combination drug, then record the trade name in 
English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws. Patients will be treated and/or compensated for any study- 
related illness/injury in accordance with the information provided in the Compensation for Injury 
section of the Informed Consent document. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
56 
58 
 
 
 
13. 
REFERENCES 
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Chi KN, Zoubeidi A, Gleave ME. Custirsen (OGX-011): A second-generation antisense inhibitor of clusterin for the 
treatment of cancer. Expert Opin Investig Drugs 2008; 12: 1955-1962. 
Coelho T, Ericzon B, Falk R, et al. A physician's guide to transthyretin amyloidosis. Amyloidosis Foundation 2008: 
1-16. 
Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. NEJM 
2013a; 369(9): 819-829. 
Coelho T, Maurer MS, Suhr OB. THAOS – The transthyretin amyloidosis outcomes survey: initial report on clinical 
manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin 2013b; 
29(1): 63-76. 
Coutinho P, Martins da Silva A, Lopas Lima J, Resende Barbosa A. Forty years of experience with type 1 amyloid 
neuropathy. Review of 483 cases. In: Glenner GG, Pinho e Costa P, Falcao de Freitas A, editors. Amyloid and 
Amyloidosis. Amsterdam, the Netherlands 1980. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2'-O-(2- 
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Henry SP, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation 
in mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Henry SP, Kim TW, Kramer-Stickland K, et al. Toxicologic properties of 2′-O-methoxyethyl chimeric antisense 
inhibitors in animals and man. In Crooke ST, editor, Antisense Drug Technology, Principles, Strategies and 
Applications. Boca Raton, FL, Taylor & Francis Group, 2nd Edition. 2008; 2: 327-364. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. FEBS Letters 1987; 215: 327-330. 
Kwoh TJ. An overview of the clinical safety experience of first and second generation antisense oligonucleotides. 
In: Crooke ST, editor. Antisense Drug Technology: Principles, Strategies and Applications, 2nd Edition. 
Boca Raton. FL. Taylor & Francis Group 2008; 365-400. 
Levin AA, Yu RZ, Geary RS. Basic principles of the pharmacokinetics of antisense oligonucleotide drugs. In: 
Crooke ST, editor. Antisense Drug Technology: Principles, Strategies and Applications. 2nd Edition. Boca Raton, 
FL. Taylor and Francis Group 2008; 183-215. 
Maurer MS, Kristen A, Rapezzi C, et al; Columbia University College of Physicians and Surgeons. Poster: Cardiac 
biomarkers in patients with transthyretin amyloidosis as documented in THAOS: The transthyretin amyloidosis 
survey. Pericardial/Myocardial Disease/Pulmonary Hypertension. JACC 62nd Annual Scientific Session & Expo 
March 12, 2013; 61(10): 1. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Quarta CC. The prevalence of cardiac amyloidosis in familial amyloidotic polyneuropathy with predominant 
neuropathy: The diflunisal trial. XIV International Symposium on Amyloidosis, Amyloid: insoluble, but solvable. 
2014; Indianapolis, Indiana. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
57 
58 
 
 
 
Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL 
cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomized, double-blind, 
placebo-controlled trial. Lancet 2010 Mar 20; 375(9719): 998-1006. 
Rapezzi C, Quarta CC, Obici L, et al. Disease profile and differential diagnosis of hereditary transthyretin-related 
amyloidosis with exclusively cardiac phenotype: an Italian perspective. Euro Heart J 2012; 1-9. 
Santos R, Duell PB, East C, et al. Long-term safety and efficacy of mipomersen in patients with familial 
hypercholesterolemia not controlled by maximally tolerated lipid lowering therapy. XVI International Symposium 
on Atherosclerosis – ISA, March 25-29 2012; Sydney, Australia. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Zhang H, Löwenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692. 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
58 
58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14. 
APPENDICES 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
59 
58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 


ISIS 4209 l 5-CS3 
Protocol 
CONFIDENTIAL 
Amendment5 
22 February 2017 
60 
74 
 
 
 
Appendix A  Schedule of Procedures 
 
Screen 
Year 1 
Year 2 
Year3 
Study Week 
s 4 weeks 1 
w w w w w w w w w w w w w w w w w w w w 
w 
1 
4 
7 10 13 15 
18 
21 
23 
26 
29 
39 
52 
65 
78 
91 
104 117 130 143 
156 
Study Day 
S-28 to S-1 
D D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
1 22 43 64 85 99 120 141 155 176 197 267 358 449 540 631 722 813 904 995 1086 
Visit Window (+/- Days) 
0 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
10 
10 
10 
10 
10 
10 
10 
10 
Informed Consent 
X 
Inclusion/Exclusion 
X 
ISIS 420915 Admin. 
(weekly)2 
X
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments 
Full Physical Exam 
x3 
X 
X 
X 
X 
X 
X 
X 
Vital SignsA(BP4, HR, RR, 
temp) 
x3 
X
X 
X 
X 
X 
X 
X 
X 
X 
ECGA(12-Lead, triplicate) 
x3 
X 
X 
X 
X 
X 
X 
ERG Exams 
X 
X 
Ophthalmology Exams 
X 
X 
X 
X 
X 
X 
AE & Con Meds & 
Concomitant procedures 
X 
X
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contact6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


ISIS 4209l 5-CS3 
Protocol 
CONFIDENTIAL 
Amendment5 
22 February 2017 
Appendix A  Schedule of Procedures Continued 
61 
61 
 
 
 
 
 
Screen 
Year 1 
Year 2 
Year3 
Study Week 
:S 4 weeks1 
w w w w w w w w w w w w w w w w w w w w 
w 
1 
4 
7 10 13 15 18 
21 
23 
26 
29 
39 
52 
65 
78 
91 
104 117 130 143
156 
Study Day 
S-28 to S-1 
D D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
1 22 43 64 85 99 120 141 155 176 197 267 358 449 540 631 722 813 904 995 1086 
Visit Window(+/- Days) 
0 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
10 
10 
10 
10 
10 
10 
10 
10 
Labs 
Pregnancy Test7·A 
x3 
X 
X 
X 
X 
X 
X xs X xs X xs X 
Chemistry PanelA(fasting) 
x3 
X xs X xs X xs xs xs xs X xs xs X xs X xs X xs X xs X 
Additional Platele1t a3nd 
Serum Creatinine 
See visit schedule Appendix C 
Hematologl 
x3 
X XS X XS X x8 XS 
XS XS 
X 
XS 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
UrinalysisA 
x3 
X XS X XS X x8 XS 
XS XS 
X 
XS 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
24 hour Urine (serum 
creatinine required)9 
X 
Thyroid PanelA 
x3 
X 
X 
X 
X 
X 
X 
X 
PT, aPTT, INRA 
x3 
X 
X 
X 
X 
X 
X 
X 
RetinolA(fasting) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hs-cRpA 
X 
X 
X 
X 
X 
X xs X xs X xs X 
PD PanelA(fasting) 
X 
X 
X 
XS 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
NT-proBNPA 
X 
X 
X 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
XS 
X 
lmmunogeniciif 
X 
X 
xs 
X 
xs X xs X xs X xs X xs X 
PK TroughA 
X 
X 
X 
xs 
X 
xs X xs X xs X xs X xs X 


ISIS 4209l 5-CS3 
Protocol 
CONFIDENTIAL 
Amendment5 
22 February 2017 
Appendix A  Schedule of Procedures Continued 
62 
62 
 
 
 
 
 
Screen 
Year 1 
Year 2 
Year3 
Study Week 
:S 4 weeks1 
w w w w w w w w w w w w w w 
w 
w 
w 
w 
w 
w 
w 
1 
4 
7 
10 13 15 18 21 23 26 29 39 52 
65 
78 91 
104 
117 
130 
143 
156 
Study Day 
S-28 to S-1 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
1 
22 43 64 85 
99 120 141 155 176 197 267 358 449 540 631 722 
813 
904 
995 
1086 
Visit Window(+/- Days) 
0 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
10 
10 
10 
10 
10 
10 
10 
10 
Efficacy Assessments 
mNIS+7 Assessment10 
X 
X 
2X 
X 
X 
2X 
Norfolk QOL-DN11 
X 
X 
X 
X 
X 
X 
SF-36 Questionnaire 
X 
X 
X 
X 
X 
X 
PND Score 
X 
X 
X 
X 
X 
X 
X 
Body Weight (fasting) 
X 
X 
X 
X 
X 
X 
X 
X 
Transthoracic ECH012 
X 
X 
X 
X 
X 


ISIS 4209l 5-CS3 
Protocol 
CONFIDENTIAL 
Amendment5 
22 February 2017 
Appendix A  Schedule of Procedures Continued 
63 
63 
 
 
 
 
 
Vear4 
Years 
Early Term14 
Post- 
Treatment 
Evaluation 
Study Week 
Y4-W13 
Y4-W26 
Y4-W39 
Y4-W52 Y5-W13
Y5-W26 Y5-W39
Y5-W52 
Last Dose+ 
13 weeks 
Study Day 
Visit Window(+/- Days) 
14 
14 
14 
14 
14 
14 
14 
14 
7 
14 
Informed Consent 
Inclusion/Exclusion 
ISIS 420915 Admin. 
(weekly)2 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments 
Full Physical Exam 
X 
X 
X 
X 
X 
X 
Vital SignsA(BP4, HR, RR, 
temp) 
X 
X 
X 
X 
X 
X 
ECGA(12-Lead, triplicate) 
X 
X 
X 
X 
X 
X 
ERG Exams 
Ophthalmology Exams 
X 
X 
X 
X 
X 
AE & Con Meds & 
Concomitant procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contact6 
X 
X 
X 
X 


ISIS 4209l 5-CS3 
Protocol 
CONFIDENTIAL 
Amendment5 
22 February 2017 
Appendix A  Schedule of Procedures Continued 
64 
64 
 
 
 
 
 
Year4 
Years 
Early Term14 
Post- 
Treatment 
Evaluation 
Study Week 
Y4-W13 
Y4-W26 
Y4-W39 
Y4-W52 Y5-W13 Y5-W26 Y5-W39 Y5-W52 
Last Dose+ 
13weeks 
Study Day 
Visit Window 
(+/- Days) 
14 
14 
14 
14 
14 
14 
14 
14 
7 
14 
Labs 
Pregnancy Test7A· 
X 
XB 
X 
XB 
X 
XB 
X 
X 
X 
Chemistry PanelA 
(fasting) 
xa 
X 
x8 
X 
xa 
X 
xa 
X 
X 
X 
Additional Platelet and 
Serum Creatinine13 
See visit schedule Appendix C 
Hematolog/ 
XB 
X 
XB 
X 
XB 
X 
XB 
X 
X 
X 
UrinalysisA 
XB 
X 
XB 
X 
XB 
X 
XB 
X 
X 
X 
24 hour Urine (serum 
creatinine required)9 
Thyroid PanelA 
X 
X 
X 
X 
X 
PT, aPTT, INRA 
X 
X 
X 
X 
X 
RetinolA(fasting) 
X 
X 
X 
X 
X 
X 
hs-CRPA 
X 
XB 
X 
XB 
X 
XB 
X 
X 
X 
PD PanelA(fasting) 
XB 
X 
XB 
X 
XB 
X 
XB 
X 
X 
X 
NT-proBNPA 
XB 
X 
XB 
X 
XB 
X 
XB 
X 
X 
X 
lmmunogenicit/ 
X 
X 
X 
X 
PK TroughA 
X 
XB 
X 
X 
XB 
X 
X 
X 


ISIS 4209l 5-CS3 
Protocol 
CONFIDENTIAL 
Amendment5 
22 February 2017 
Appendix A  Schedule of Procedures Continued 
65 
65 
 
 
 
 
 
Year 4 
Years 
Early Term14 
Post- 
Treatment 
Evaluation 
Study Week 
Y4-W13 
Y4-W26 
Y4-W39 
Y4-W52 
Y5-W13 Y5-W26 Y5-W39 Y5-W52 
Last Dose 
+ 13 weeks 
Study Day 
Visit Window 
(+/- Days) 
14 
14 
14 
14 
14 
14 
14 
14 
7 
14 
Efficacy Assessments 
mNIS+7 Assessment10 
2X16 
NIS 
X 
X 
x11 
Norfolk QOL-DN11 
X 
X 
X 
SF-36 Questionnaire 
X 
X 
X 
PND Score 
X 
X 
X 
Body Weight (fasting) 
X 
x1s 
Transthoracic ECH 12 
O 
x1s 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
Appendix A Schedule of Procedures Continued 
66 
66 
 
 
 
 
Shaded columns represent non-clinic visits. Labs as indicated may be collected by the Sponsor’s home healthcare service or by a local laboratory (with prior 
Sponsor approval). Patients also have the option to go to clinic for these visits. 
Note: If not specifically labeled, “X” means anytime 
1 
For an individual patient, a maximum period of 4 weeks is allowed between a patient’s last dose in ISIS 420915-CS2 (CS2 Week 65 visit) and initiation of 
dosing in this study (CS3 Day 1 visit). All screening assessments must be completed during this period. Longer periods may be considered after discussion 
and approval from the Study Medical Monitor 
2 
ISIS 420915 can be administered in the clinic or at home by the patient/caregiver. It is not necessary for ISIS 420915 to be administered on site during clinic 
visits. Clinic visits should occur on a dosing day, 7 days after the previous dose 
3 
Assessments from ISIS 420915-CS2 may be used for screening evaluation if they were obtained within 4 weeks of Study Day 1. A longer period may be 
considered after discussion and approval from the Study Medical Monitor 
4 
Blood pressure should be taken after the patient has been sitting for ≥ 5 min 
5 
A +/- 2-week window is given for ERG and ophthalmology examinations. The early termination ERG and ophthalmology examinations are only done if the 
patient discontinues treatment after ≥ 9 mo of dosing or unless deemed necessary by Investigator or Study Medical Monitor 
6 
To collect AEs, conmeds, and the general wellbeing of the patient 
7 
For females of childbearing potential only, by serum βhCG except on Day 1 by urine hCG (pre-dose) 
8 
To be collected by either a local laboratory (if approved by Sponsor), Sponsor appointed home healthcare service, or Study Center as arranged by the Study 
Center personnel 
9 
The 24-hour urine collection can be done any time during the screening period or during Week 1 on treatment. Serum creatinine blood draw required 
10 If ISIS 420915 administration, ERG, or ophthalmology examinations are to be performed on the same day as a mNIS+7 assessment, they should be 
performed after the mNIS+7 assessment is complete. For the Week 78 and Week 156 visits, 2 mNIS+7 assessments will be performed on separate days. A 
maximum of 2 weeks from the visit (Week 78 or Week 156) will be allowed to complete both assessments 
11 Norfolk QOL-DN should be the first assessment performed at the visit 
12 Study Day 1 ECHO can be done any time in the screening period or up to 2 weeks after Day 1. The Day 1 ECHO is not done if the Week 65 ECHO was 
conducted in ISIS 420915-CS2. A +/- 2-week window is given for all other ECHOs 
13 Weekly platelet and every 2-3 week serum creatinine monitoring is required throughout the treatment period and for a minimum of 6 weeks after the last dose 
of Study Drug (this includes early termination patients as well as patients that complete the full treatment period). The frequency of monitoring after 6 weeks 
from the last dose of Study Drug will be determined by the Study Medical Monitor. The visits required to collect platelets and serum creatinine not included in 
this table are shown in Appendix C. These visits may be completed in clinic, by home healthcare service, or by a local laboratory 
14 Early termination should be performed at the time of withdrawal, ideally within 14 days from the last dose of Study Drug 
15 Omit if following Year 4 or Year 5 treatment 
16 Perform mNIS+7 only if early termination is from Year 1-3 treatment 
17 
Perform NIS only if early termination is from Year 4-5 treatment 
Time (time is in reference to ISIS 420915 administration): 
A 
Pre-dose 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
67 
81 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
68 
82 
 
 
Appendix B List of Laboratory Analytes 
 
Clinical Chemistry 
Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Uric Acid 
• Total bilirubin 
• Direct (conjugated) 
bilirubin 
• Indirect 
(unconjugated) 
bilirubin 
• ALT 
• AST 
• Alkaline phosphatase 
• Creatine kinase 
• Estimated creatinine 
clearance (CKD-EPI) 
• Total IgG 
• Total IgM 
Screening Tests 
• FSH (women only) 
• Serum βhCG 
• Urine hCG 
Coagulation 
• aPTT (sec) 
• PT (sec) 
• INR 
PD Panel1 
 
• Transthyretin 
• Retinol binding 
protein 4 (RBP4) 
24-hour Urine4 
 
• Creatinine 
• Protein 
• Albumin 
Other 
• Retinol1 
• Retinyl Palmitate 
• NT-proBNP1 
• Immunogenicity 
(anti-ISIS 420915 
antibodies) 
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• Platelets 
• White blood cells 
• WBC Differential (% 
and absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
Thyroid Panel 
• TSH 
• Free T4 (FT4) 
Pharmacokinetics2 
 
• ISIS 420915 levels in 
plasma 
Inflammatory 
• Hs-CRP 
Urinalysis1 
 
• Color 
• Appearance 
• Specific gravity 
• pH 
• P/C and Alb/C Ratios 
• Protein 
• Blood 
• Ketones 
• Urobilinogen 
• Glucose 
• Leukocyte esterase 
• Nitrate 
• Microscopic 
examination3 
1 
Other biomarkers may be measured at the discretion of the Sponsor. Back-up samples will be collected and 
stored. For transthyretin and retinol, back-up samples may be analyzed in more sensitive transthyretin or retinol 
assays at the discretion of the Sponsor. Back-up urine samples may be analyzed for additional renal biomarkers 
2 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, or to assess other actions of ISIS 420915 with plasma 
constituents 
3 
Will be performed on abnormal findings (if the initial analysis is positive for protein, blood, nitrite, &/or leukocyte 
esterase) unless otherwise specified (to include: casts, crystals, bacteria, epithelial cells, RBC, WBC, yeast) 
4 
Serum creatinine blood draw required 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
69 
82 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C 
Additional Visits for Platelet and Serum Creatinine 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
70 
84 
 
 
 
Appendix C Additional Visits for Platelet and Serum Creatinine 
Note: These visits do not have specified windows to allow flexibility of scheduling but with the intent that platelets are assessed each 
calendar week and serum creatinine every 2-3 weeks. 
Year 1 
Additional Visits Between Weeks 1-29 
Study Week 
2 
3 
5 
6 
8 
9 
11 
12 
14 
16 
17 
19 
20 
22 
24 
25 
27 
28 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Creatinine 
 
 
Year 1 
Additional Visits Between Weeks 29-52 
Study Week 
30 
31 
32 
33 
34 
35 
36 
37 
38 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Year 2 
Additional Visits Between Weeks 52-78 
Study Week 
53 
54 
55 
56 
57 
58 
59 
60 
61 
62 
63 
64 
66 
67 
68 
69 
70 
71 
72 
73 
74 
75 
76 
77 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Year 2 
Additional Visits Between Weeks 78-104 
Study Week 
79 
80 
81 
82 
83 
84 
85 
86 
87 
88 
89 
90 
92 
93 
94 
95 
96 
97 
98 
99 
100 
101 
102 
103 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
Appendix C Additional Visits for Platelet and Serum Creatinine Continued 
71 
85 
 
 
 
 
 
Year 3 
Additional Visits Between Weeks 104-130 
Study Week 
105 
106 
107 
108 
109 
110 
111 
112 
113 
114 
115 
116 
118 
119 
120 
121 
122 
123 
124 
125 
126 
127 
128 
129 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Year 3 
Additional Visits Between Weeks 130-156 
Study Week 
131 
132 
133 
134 
135 
136 
137 
138 
139 
140 
141 
142 
144 
145 
146 
147 
148 
149 
150 
151 
152 
153 
154 
155 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
Appendix C Additional Visits for Platelet and Serum Creatinine Continued 
72 
85 
 
 
 
 
 
Year 4 
Additional Visits Between Weeks 156 to Y4-W26 
Study 
Week 
Y4- 
W1 
Y4- 
W2 
Y4- 
W3 
Y4- 
W4 
Y4- 
W5 
Y4- 
W6 
Y4- 
W7 
Y4- 
W8 
Y4- 
W9 
Y4- 
W10 
Y4- 
W11 
Y4- 
W12 
Y4- 
W14 
Y4- 
W15 
Y4- 
W16 
Y4- 
W17 
Y4- 
W18 
Y4- 
W19 
Y4- 
W20 
Y4- 
W21 
Y4- 
W22 
Y4- 
W23 
Y4- 
W24 
Y4- 
W25 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Year 4 
Additional Visits Between Weeks Y4-W26 to Y4-W52 
Study 
Week 
Y4- 
W27 
Y4- 
W28 
Y4- 
W29 
Y4- 
W30 
Y4- 
W31 
Y4- 
W32 
Y4- 
W33 
Y4- 
W34 
Y4- 
W35 
Y4- 
W36 
Y4- 
W37 
Y4- 
W38 
Y4- 
W40 
Y4- 
W41 
Y4- 
W42 
Y4- 
W43 
Y4- 
W44 
Y4- 
W45 
Y4- 
W46 
Y4- 
W47 
Y4- 
W48 
Y4- 
W49 
Y4- 
W50 
Y4- 
W51 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


ISIS 420915-CS3 
Protocol 
CONFIDENTIAL 
Amendment 5 
22 February 2017 
Appendix C Additional Visits for Platelet and Serum Creatinine Continued 
73 
85 
 
 
 
 
 
Year 5 
Additional Visits Between Weeks Y4-W52 to Y5-W26 
Study Week 
Y5- 
W1 
Y5- 
W2 
Y5- 
W3 
Y5- 
W4 
Y5- 
W5 
Y5- 
W6 
Y5- 
W7 
Y5- 
W8 
Y5- 
W9 
Y5- 
W10 
Y5- 
W11 
Y5- 
W12 
Y5- 
W14 
Y5- 
W15 
Y5- 
W16 
Y5- 
W17 
Y5- 
W18 
Y5- 
W19 
Y5- 
W20 
Y5- 
W21 
Y5- 
W22 
Y5- 
W23 
Y5- 
W24 
Y5- 
W25 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Year 5 
Additional Visits Between Weeks Y5-W26 to Y5-W52 
Study Week 
Y5- 
W27 
Y5- 
W28 
Y5- 
W29 
Y5- 
W30 
Y5- 
W31 
Y5- 
W32 
Y5- 
W33 
Y5- 
W34 
Y5- 
W35 
Y5- 
W36 
Y5- 
W37 
Y5- 
W38 
Y5- 
W40 
Y5- 
W41 
Y5- 
W42 
Y5- 
W43 
Y5- 
W44 
Y5- 
W45 
Y5- 
W46 
Y5- 
W47 
Y5- 
W48 
Y5- 
W49 
Y5- 
W50 
Y5- 
W51 
Platelets 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Post Treatment Evaluation 
Additional Visits Between Last Dose to LD + 13 weeks 
Last Dose (LD) + Week 
LD + W1 
LD + W2 
LD + W3 
LD + W4 
LD + W5 
LD + W6 
Platelets 
x 
x 
x 
x 
x 
x 
Serum Creatinine 
x 
x 
x 


 
 
Official Title: 
 An Open-Label Extension Study to Assess the Long-Term Safety 
and Efficacy of ISIS 420915 in Patients with Familial 
Amyloid Polyneuropathy (FAP) 
 
 
NCT Number: 
NCT02175004 
 
 
Document Date: 
SAP Version 4: 27-January-2022 


194 
 
 
Ionis Pharmaceuticals, Inc. 
 
CONFIDENTIAL 
Jan 27, 2022 
Statistical Analysis Plan 
ISIS 420915-CS3 
 
 
 
 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
 
 
Statistical Analysis Plan 
 
 
 
ISIS 420915-CS3 
An Open-Label Extension Study to Assess the Long-Term Safety and 
Efficacy of ISIS 420915 in Patients with Familial Amyloid 
Polyneuropathy (FAP) 
 
 
 
Date: January 27, 2022 
Final Version: 4.0 
 
 
 
 
 
CONFIDENTIAL 
 
 
Confidential/Trade Secret information subject to 18-USC-1905 and to which all claims of privilege and 
confidentiality are asserted in both statutory and common law. Further dissemination may be made 
only with the express written permission of Ionis Pharmaceuticals, Inc. 


195 
 
 
Statistical Analysis Plan Signature Page 
lonis Pharmaceuticals, Inc. 
2855 Gazelle Court 
 
Carlsbad, CA 92010 
 
 
Compound Name: 
Protocol: 
Study Title: 
 
 
Issue Date: 
ISIS 420915 
ISIS 420915-CS3 
An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy 
of ISIS420915 in Patients with Familial Amyloid Polyneuropathy (FAP) 
22Feb2017 (Amendment 5) 
 
 
 
Signature: 
 
Date: Jan 27, 2022 
 
 
-Ph.D. 
 
lonis Pharmaceuticals, Inc. 
 
 
 
 
S1.gnat ure: 
 
 
lonis Pharmaceuticals, Inc. 
Date: Jan 27, 2022_ 
 
 
 
 
 
 
 
Signature: 
 
Date: Jan 27, 2022_ 
 
 
 
 
lonis Pharmaceuticals, Inc. 
 
 
 
 
2 
_12_,4_6P_sn 


196 
 
 
Table of Contents 
Abbreviations ......................................................................................................................................... 7 
Amendment History ............................................................................................................................. 10 
1. 
Introduction ................................................................................................................................. 16 
1.1 
Study Overview ................................................................................................................... 16 
1.2 
Objectives............................................................................................................................ 17 
1.2.1 
Primary Objective ......................................................................................................................... 17 
1.2.2 
Secondary Objectives ................................................................................................................... 17 
1.2.3 
Exploratory Objectives ................................................................................................................. 17 
1.3 
Hypotheses ......................................................................................................................... 17 
1.4 
Endpoints ............................................................................................................................ 17 
2. 
Procedures ................................................................................................................................... 18 
2.1 
General Overview of Procedures ....................................................................................... 18 
2.2 
Randomization & Treatment Allocation ............................................................................ 19 
2.3 
Conduct ............................................................................................................................... 19 
2.4 
Data Monitoring.................................................................................................................. 19 
2.4.1 
Safety Data Monitoring ................................................................................................................ 19 
2.4.2 
Data and Safety Monitoring Board ............................................................................................... 20 
2.5 
Data Management .............................................................................................................. 20 
2.5.1 
Case Report Form Data ................................................................................................................ 20 
2.5.2 
Laboratory Data ........................................................................................................................... 21 
2.5.3 
Pharmacokinetics (PK) Data and Immunogenicity (IM) Data ........................................................ 21 
2.5.4 
Echocardiogram (ECHO) Data ....................................................................................................... 21 
2.5.5 
Electrocardiogram (ECG) Data ...................................................................................................... 21 
2.5.6 
Modified Neuropathy Impairment Score +7 (mNIS+7) and Neuropathy Symptoms and Change 
Score (NSC) ................................................................................................................................................. 22 
2.6 
Blinding ............................................................................................................................... 22 
3. 
Analytical Plan ............................................................................................................................. 22 
3.1 
Statistical Design Summary ................................................................................................ 22 
3 


197 
 
 
3.2 
General Overview of Analyses............................................................................................ 23 
3.2.1 
Analysis Conventions .................................................................................................................... 23 
3.2.1.1 
Definitions and Computational Formulas ........................................................................... 25 
3.2.1.2 
Scoring of Assessment Instruments ......................................................................................29 
3.2.1.3 
Handling of Missing or Replicated Data, Unscheduled Visits, and Early Termination Visits 
33 
3.2.1.4 
Data Summary Plan ............................................................................................................ 40 
3.2.1.5 
Multicenter Studies .............................................................................................................42 
3.2.2 
Patient Populations Analyzed ....................................................................................................... 42 
3.2.3 
Patient Characteristics ................................................................................................................... 43 
3.3 
Safety Analyses .................................................................................................................... 46 
3.3.1 
Imputation of Missing/Partial Dates ............................................................................................. 46 
3.3.2 
Adverse Events (AEs) .................................................................................................................... 46 
3.3.2.1 
Adverse Events of Special Interest (AESI) ............................................................................48 
3.3.2.2 
Other Adverse Events of Interest ........................................................................................ 48 
3.3.2.3 
Local Cutaneous Reactions at Injection Site (LCRIS) .............................................................49 
3.3.2.4 
Flu-Like Reactions ................................................................................................................ 50 
3.3.2.5 
Mortality ............................................................................................................................. 50 
3.3.2.6 
OLE Study Analysis of TEAEs ............................................................................................... 50 
3.3.2.7 
Longitudinal Safety Analysis of TEAEs ................................................................................. 52 
3.3.3 
Vital Signs, Weight, and Physical Examination Findings ................................................................53 
3.3.4 
Laboratory Measurements ............................................................................................................ 53 
3.3.4.1 
Hepatobiliary Laboratory Abnormalities ............................................................................. 53 
3.3.4.2 
Platelets .............................................................................................................................. 55 
3.3.4.3 
Renal Parameters ............................................................................................................... 56 
3.3.4.4 
Longitudinal Safety Analysis of Laboratory Measurements .................................................57 
3.3.5 
Electrocardiograms ...................................................................................................................... 57 
3.3.6 
Electroretinograms (ERG) and Ophthalmology Exam ................................................................... 58 
3.4 
Efficacy Analyses ................................................................................................................. 58 
3.4.1 
Descriptive Statistics .................................................................................................................... 58 
4 


198 
 
 
3.4.2 
Efficacy Endpoints: mNIS+7 Score and Components, Norfolk QOL-DN Total Score and Domain 
Scores 59 
3.4.2.1 
Additional Efficacy Analysis on the Change from the Parent Study Baseline ...................... 59 
3.4.2.2 
Additional Efficacy Analysis on the Change from the OLE Study baseline .......................... 60 
3.4.3 
Other Efficacy Endpoints .............................................................................................................. 61 
3.5 
Pharmacodynamic (PD) Analyses ....................................................................................... 61 
3.6 
Pharmacokinetic (PK) and Immunogenicity (IM) Analyses ................................................ 62 
3.6.1 
Plasma Pharmacokinetics ............................................................................................................. 62 
3.6.2 
Immunogenicity (IM) Analyses ..................................................................................................... 63 
4. 
Sample Size .................................................................................................................................. 65 
5. 
Interim Analyses .......................................................................................................................... 65 
5.1 
Interim Analysis at EOT of the Parent Study ...................................................................... 65 
5.2 
Interim Analysis for Day-90 Updates ................................................................................. 67 
5.3 
Interim Analysis II ............................................................................................................... 69 
6. 
Study Conduct to Minimize Bias .................................................................................................. 72 
7. 
References.................................................................................................................................... 75 
8. 
Appendices ................................................................................................................................... 76 
8.1 
Appendix 1 Components and Subcomponents of the mNIS+7, and NIS+7 ....................... 76 
8.2 
Appendix 2 Scoring of Assessment Instruments ................................................................ 85 
8.3 
Appendix 3 Analysis Visit Windows and Follow-Up Visit Window ................................... 88 
8.3.1 
Table 1. Efficacy Endpoints and PD Endpoints (On-Treatment Analysis Visit Wondow) .............. 88 
8.3.2 
Table 2. Efficacy Endpoints and PD Endpoints (Post-Treatment Analysis Follow-Up Visit 
Wondow): ................................................................................................................................................... 91 
8.3.3 
Table 3. Safety Endpoints (On-Treatment Analysis Visit Wondow): ............................................. 92 
8.3.4 
Table 4. Safety Endpoints (Post-Treatment Analysis Follow-Up Visit Wondow) ........................ 106 
9. 
Updates and Additional Analysis in Final Analyses .................................................................. 106 
9.1 
Analyses Removed from Final Analyses ........................................................................... 106 
9.2 
Additional Analyses added for Final Analyses ................................................................. 107 
9.2.1 
Based on OLE data only .............................................................................................................. 107 
5 


199 
 
 
9.2.2 
Based on both CS2 and CS3 data .................................................................................................108 
9.2.2.1 Add More Population Definition .............................................................................................. 108 
9.2.2.2 Study Period Definition (On-Treatment, Post-Treatment and On-Study) ................................. 108 
9.2.2.3 Itegrated Summary of Efficacy based on CS2 and CS3 data ...................................................... 109 
9.2.2.4 PK and IM Analyses .................................................................................................................. 110 
9.2.2.5 Patient Characteristics and Population .....................................................................................110 
9.2.2.6 ECG QRS Analyses .................................................................................................................... 110 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 


200 
 
 
Abbreviations 
 
Abbreviation/Acronym 
Definition 
+7 
Sum 7 test. Includes measurements of nerve conduction, vibration 
threshold, and heart rate to deep breathing 
%CV 
Coefficient of variation, expressed as a percent 
ACI 
Applied Clinical Intelligence, LLC 
ADA 
Anti-ISIS 420915 antibodies 
ADaM 
Analysis Data Model 
AE 
Adverse event 
AESI 
Adverse event of special interest 
BMI 
Body mass index 
CM-ECHO 
Cardiomyopathy-ECHO 
CI 
Confidence interval 
CICL 
Cardiac Imaging Core Laboratory 
CRO 
Contract research organization 
CS2 Study Day 1 
The first day ISIS 420915 is administered to the patient in the parent 
study 
CS3 Study Day 1 
The first day ISIS 420915 is administered to the patient in this present 
OLE study 
DSMB 
Data and safety monitoring board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
ERG 
Electroretinogram 
FAC 
Familial amyloid cardiomyopathy 
FAP 
Familial amyloid polyneuropathy 
FAS 
Full Analysis Set 
GLS 
Global Longitudinal Strain 
HLT 
Higher level term 
HP 
Heat Pain 
HRDB 
Heart Rate to Deep Breathing 
IM 
Immunogenicity 
Parent study 
ISIS 420915-CS2 
LCRIS 
Local cutaneous reaction at the injection site 
7 


201 
 
 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LLT 
Lower level term 
LSS 
Longitudinal Safety Set 
mBMI 
Modified body mass parent (requires determination of serum albumin 
levels; mBMI = BMI x serum albumin g/L) 
MC Core 
Mayo Clinic Polyneuropathy Quality Assurance Core Facility 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS+7 
Modified neuropathy impairment Score +7. Standard NIS but with 
modifications made to the +7 component 
Modified +7 
+7 test with modifications made to the sensory and nerve conduction 
testing 
MRT 
Mean residence time 
NCT 
Nerve Conduction Test 
NIS 
Neuropathy impairment score 
NIS+7 
Neuropathy impairment score +7 
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 Score 
Neuropathy symptoms and change score 
NT-proBNP 
N-terminal prohormone of brain natriuretic peptide 
OLE 
Open label extension 
P25 
25th percentile 
P75 
75th percentile 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic set 
PND Score 
Polyneuropathy disability score 
PPS 
Per Protocol Set 
QTcB 
formula 
QTcF 
QT interval corrected for heart rate 
formula 
RBP4 
Retinol binding protein 4 
 
8 


202 
 
 
SAE 
SAP 
Serious adverse event 
Statistical analysis plan 
SF-36 
Short Form (36) Health Survey 
SMQ 
Standardized MedDRA query 
SOC 
System Organ Class 
SS 
Safety set 
SUSARs 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment emergent adverse event 
TP 
Touch Pressure 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
VDT 
Vibration Detection Threshold 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 


203 
 
 
 
Amendment History 
 
Section 
Section Title 
Change 
Version 1.0, dated April 07, 2017 
Version 2.0, dated February 09, 2018 
1.3 
Hypotheses 
Hypothesis tests for efficacy endpoints have been 
removed. 
3.2.1 
Analysis Conventions 
Three statements have been removed since 
hypothesis tests for efficacy endpoints have been 
removed: 
• Should the randomization stratum recorded from 
Interactive voice-response system (IVRS) be different 
from the actual data recorded in eDC of the parent 
study, the randomization stratum recorded from 
IVRS will be used in the analysis. 
• All endpoints will beevaluated in an exploratory 
manner, including the endpoints where p-values or 
Cl are presented. 
• All tables and figures containing models for efficacy 
and pharmacodynamic endpoints will present raw 
data from the statistical model, with footnotes 
indicating the model used and covariates included in 
the model." 
3.2.1.4 
Data Summary Plan 
For concomitant medication, the following statement 
has been removed: 
"All medications collected in the OLEstudy are treated as 
Concomitant medication." 
 
 
 
 
 
 
 
 
 
 
10 


204 
 
 
Section 
Section Title 
Change 
3.2.3 
Patient Characteristics 
Missing/partial datesimputation for FAP/FAC has been 
modified as below: 
"since CRFonly collects year and month for FAP and 
FACDiagnosis and onset of symptoms, for calculating 
the duration, a day of 15th will be used if only day is 
missing. JULOl will be used if both day and month are 
missing. If the imputed date is after the date of 
informed consented at CS2, use the informed 
consented at CS2 as the imputed date. Calculate as 
following 
(a) Duration (month)= number of month (date of 
informed consented at CS3- date of FAPor FAC 
diagnosis+ 1) 
(b) Duration (month)= number of month (date of 
informed consented at CS3- date of onset of FAP or 
FACsymptoms+ 1)" 
3.2.3 
Patient Characteristics 
Summaries for medications have been clarified. 
3.3.2.2 
Other Adverse Events of 
Interest 
The term of "Complement activation" has been 
modified as "Potential complement activation". 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 


205 
 
 
Section 
Section Title 
Change 
3.3.2.6 
OLE Study Analysis of 
TEAEs 
The following changes have been done: 
• Removing "TEAE during the safety treatment period 
of the OLEstudy'' from summary plan since the 
summary will be based on on-study data but not on- 
treatment data. 
• Adding "Australasia" in Region. 
• Adding following: 
"A plot of incidence rates and relative risks for 
common TEAEs, with anincidence of 5% or more, by 
treatment group assigned in the parent study will be 
provided. 
Summary of non-serious common TEAEs, with an 
incidence of 5% or more, will be presented by 
Preferred Term. 
Summary tables of the number and percentage of 
patients with drug related bleeding TEAEs will be 
presented by bleeding location and Preferred Term." 
3.3.3 
Vital Signs, Weight, and 
Physical Examination 
Findings 
The summary for weight based on the parent study 
baseline and the OLE study baseline have been added. 
3.3.4 
Laboratory 
Measurements 
The following underlined summary has been added: 
''The mean value (and associated standard error) will 
be plotted by treatment group in the parent study .2!. 
by V30M TTR mutation at randomization during the 
parent study over visits for the following laboratory 
parameters: platelets, creatinine clearance by CKD-EPI, 
Albumin. urine AC ratio, and urine PC ratio. 
Summar:vfor Albumin will also be presented based on 
the parent studl£baseline and the OLE studl£ 
baseline." 
3.3.4.1 
Hepatobiliary 
Laboratory 
Abnormalities 
The following categories have been modified by 
replacing "or" by "and": 
ti 
• ALT<!:3x ULN and ALT<!:2 x ISIS 420915 baseline 
• Confirmed ALT<!:3x ULN and confirmed ALT<!:2 x 
ISIS 420915 baseline " 
12 


206 
 
 
Section 
Section Title 
Change 
3.3.4.2 
Platelets 
The following categorieshave been added: 
II 
• Confirmed Platelet count decrease - Grade la [ 
10010"9/L to< 140x 10"9/L] 
• 
Confirmed Platelet count decrease - Grade lb [ 
7510"9/Lto< 100x 10"9/L] 
• 
Confirmed Platelet count decrease - Grade 2 [[ 
50 10"9/L to < 75 x 10"9/L) 
• 
Confirmed Platelet count decrease - Grade 3 [ 
25 10"9/Lto < 50 x 10"9/L] 
• 
Confirmed Platelet count decrease - Grade 4 [< 
25 x 10"9/L]" 
The underlined editions have been done: 
"Time from Qa'l' I ei llilli 4 QQI§ CS3 Stud)£Da)l 1 to 
the onset of each of these events collected in the OLE 
study will be summarized for the patients in SS that 
met the criterion. Summaries including the following 
descriptive statistics: mean, standard deviation, 
median, P25, P75, and minimum and maximum. 
Kaplan-Meier plots for time to first event will also be 
provided for value< 140 x10"9/L, value< 100 x10"9/L 
and value < 75 x10"9/L ." 
The following plots have been added: 
"Scatter plots for nadir platlets versus the ISIS 420915 
baseline of BMI, mBMI, and weight will be provided." 
The following listing has been added: 
"A listing of patients with dose pause due to Platelet< 
75 x10"9/L will also be provided." 
3.3.4.3 
Renal Parameters 
The following summaries has been added: 
"Shift tables from baseline for hemoglobin will be 
provided using the nadir value. Categories for the shift 
table will be Grade O ( LLN, Absent), Grade 1 (< LLN - 
100.0 g/L, Mild), Grade 2 (< 100.0 - 80.0 g/L, 
Moderate) and Grade 3 (< 80.0 g/L, Severe)." 
 
 
13 


207 
 
 
Section 
Section Title 
Change 
3.4 
Efficacy Analyses 
The following two paragaraphs have also been 
removed: 
"P-values reported for testing of efficacy endpoints 
will be evaluated in an exploratory manner. No 
adjustment for multiple hypothesistesting will be 
done."; 
"As not all subjects will getto year 4 and 5 of the 
study, the efficacy analyses in section Error! Reference 
source not found. -3.4.2.2 will only be performed on 
the first 3 years of data. However, data from year 4 
and 5 will be summarized." 
3.4.2.1 
Efficacy Analysis on the 
Change from the Parent 
Study Baseline 
This session have been removed. 
3.4.2.2 
Additional Efficacy 
Analysis on the Change 
from the Parent Study 
Baseline 
• This session number has been moved up as 3.4.2.1. 
• Non-parametic analysis and MMRM models have 
been removed. 
• Inferential comparison for response rate has been 
removed. 
3.4.2.3 
Efficacy Analysis on the 
change from the OLE 
Study baseline 
This session have been removed. 
3.4.2.4 
Additional Efficacy 
Analysis on the Change 
from the OLE Study 
baseline 
• This session number has been moved up as 3.4.2.2. 
• Non-parametic analysis and MMRM models have 
been removed. 
• Inferential comparison for response rate has been 
removed. 
5.2 
Interim Analysis for Day- 
90 Updates 
A new session for describing 90-day safety udpates 
has been added. 
Version 3.0, dated Oct 28, 2021 
5.3 
Interim Analysis II 
A new session for describing Interim Analysis II (data 
cutoff 31MAR2018) 
9 
Additioal Analysis and 
updates in Final Analysis 
Add new section 
 
 
14 


208 
 
 
Section 
Section Title 
Change 
Appendix 1 
Add NIS-LL 
Two new tables for NIS-LLcalculation. 
Version 4.0, dated January 27, 2021 
9 
Additioal Analysis and 
updates in Final Analysis 
Update section 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 


209 
 
 
1. Introduction 
This statistical analysis plan describes the final reporting for study ISIS 420915-CS3 as per protocol 
amendment #5 (22 Feb 2017). It also describes the interim analyses to support the interim 
reporting. Any changes from these planned analyses will be stated in the clinical study report. 
 
1.1 Study Overview 
Transthyretin (TTR) is synthesized primarily in the liver and is secreted into the plasma as a 55 KD 
protein composed of four identical subunits of 14 KD each. A major function of TTR in the plasma is 
to transport retinol (vitamin A) to tissues through an association with Retinol binding protein 4 
(RBP4). Transthyretin amyloidosis is a rare hereditary disease caused by mutations in the TTR 
protein. The disease-causing mutations destabilize the normal tetrameric structure of TTR causing 
its dissociation into free monomers and subsequent aggregation into insoluble fibril deposits. 
These deposits are found in multiple organs including the peripheral nervous system, 
gastrointestinal tract and heart. They result in local damage to cells leading to a peripheral 
polyneuropathy (called Familial Amyloid Polyneuropathy or FAP) and a cardiomyopathy (called 
Familial Amyloid Cardiomyopathy or FAC). FAP can be classified into 3 stages of disease based on 
ambulatory status: Stage 1  do not require assistance with ambulation; Stage 2 require assistance 
with ambulation; Stage 3 wheelchair bound (Coutinho et al. 1980). The total worldwide prevalence 
of FAP has been estimated at approximately 10,000 patients (Coelho et al. 2008). 
ISIS 420915 is an antisense drug targeted to human TTR mRNA and its hybridization to the cognate 
TTR mRNA results in the RNase H-mediated degradation of the TTR mRNA, thus preventing 
production of the TTR protein. 
ISIS 420915-CS2 (the parent study) is a Phase 2/3 multicenter, double-blind, placebo-controlled 
study to assess the efficacy and safety of ISIS 420915 in patients with FAP. The study plans to enroll 
approximately 135 patients randomized 2:1 (90 ISIS 420915 to 45 placebo) to receive 300 mg ISIS 
420915 or placebo. The study drug is administered 3 times during Week 1 and once weekly during 
Weeks 2 to 65. 
The dose level and schedule in the present open label extension (OLE) study (300 mg ISIS 420915 
administered once weekly) is the same dose and schedule used during Weeks 2 to 65 in the 
preceding parent study. Therefore, in Week 1, ISIS 420915 was administered once instead of the 
three times used in the parent study. Antisense oligonucleotides of this class have been safely 
administered intravenously and subcutaneously in multiple clinical studies at doses up to 1000 mg 
(Kwoh 2008) and treatment duration 
(Santos et al. 2012). The patients randomized to ISIS 420915 in the parent study receive 65 weeks 
(15 months) of treatment in that study followed by up to an additional 156 weeks (3 years) in the 
present OLE study. The safety and tolerability of the proposed 221-week dosing period is also 
supported by nonclinical chronic toxicology studies with ISIS 420915. 
 
 
 
16 


210 
 
 
1.2 Objectives 
 
1.2.1 
Primary Objective 
To evaluate the safety and tolerability of extended dosing with ISIS 420915 in patients with FAP. 
 
1.2.2 
Secondary Objectives 
To evaluate the efficacy of extended dosing with ISIS 420915 based on change from baseline and 
progression rate, if applicable, in the following measures: 
 
Modified Neuropathy Impairment Score +7 (mNIS+7) 
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire: 
o total score (all patients) 
o symptoms domain score (Stage 1 patients) 
o physical functioning/large fiber neuropathy domain score (Stage 2 patients) 
Modified body mass index (mBMI) and body mass index (BMI) 
Neuropathy impairment score (NIS), heat-pain sensory, touch-pressure sensory, nerve 
conduction, and heart rate to deep breathing tests (components of mNIS+7) 
Polyneuropathy disability score (PND score) 
To evaluate the pharmacodynamic (PD) effect of extended dosing with ISIS 420915 based on 
change from baseline in TTR and RBP4 
Global longitudinal strain (GLS) 
To evaluate the plasma trough levels of ISIS 420915. 
 
1.2.3 
Exploratory Objectives 
To evaluate the change from baseline in the following measures: 
Echocardiogram (ECHO) parameters (except GLS) 
Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) 
Short Form (36) Health Survey (SF-36) questionnaire 
1.3 Hypotheses 
There are no formal study hypotheses as this is an extension study to the double-blind placebo 
controlled parent study. 
 
1.4 Endpoints 
Details of safety, efficacy, pharmacokinetic (PK), and PD endpoints are described in Sections 3.3 
through 3.6. 
 
17 


211 
 
 
2. Procedures 
2.1 General Overview of Procedures 
The OLE study will consist of the following periods: 
 
-week screening assessment period 
A treatment period of up to 260 weeks 
A 3-month post-treatment evaluation period 
Screening assessments include safety and specialty labs, physical exam, vital signs, 
electrocardiogram (ECG), adverse event (AE), concomitant medication and concomitant procedures. 
A maximum period of 4 weeks is allowed be
      the parent study (the 
parent study Week 65 visit) and initiation of dosing in this present OLE study (the OLE study Day 1 
visit). Periods longer than 4 weeks may be considered after discussion and approval by the Study 
Medical Monitor. However, the intention is to minimize the treatment pause between the two 
studies. Ideally the first dose in this present OLE study should be administered one week after the 
last dose in the parent study. 
Patients will report to the Study Center for evaluations and tests 5 times in Year 1 (Study Weeks 1, 7, 
13, 26, 52) and 2 times in each subsequent year (26th and 52nd week of each year). Physical 
examination, collection of blood for measurement of safety clinical laboratory parameters and 
specialty labs, measurement of vital signs, and collection of AEs and concomitant 
medication/procedure information will be performed according to the schedule of procedures in the 
protocol Appendix A. The following assessments will also be performed at specified visits during the 
OLE study: mNIS+7, Norfolk QOL-DN questionnaire, SF-36 questionnaire, PND score, body weight, 
ophthalmology examination, electroretinogram (ERG), ECG, and transthoracic ECHO examination. 
During Weeks 4, 10, 15, 18, 21, 23, 29, 39, 65, 91, 117, 143, Y4-W13, Y4-W36, Y5-W13 and Y5-W39 
patients labs will be collected by the Sponsor appointed home healthcare service, or the Study 
Center as arranged by the Study Center personnel or by local laboratory with prior Sponsor 
approval. In addition, platelets will be collected weekly and serum creatinine will be collected every 
2-3 weeks (see the protocol Appendices A and C). Patients may also be contacted by phone to 
collect AEs, concomitant medication, and concomitant procedure information. 
The mNIS+7 assessment is conducted at Weeks 26, 52, 78, 104, 130, and 156. Norfolk QOL-DN 
questionnaire is conducted at Weeks 26, 52, 78, 104, 130, 156, Y4-W52, and Y5-W52. The Norfolk 
QOL-DN questionnaire should be the first assessment performed at these visits. If ISIS 420915 
administration, ERG, or ophthalmology examinations are to be performed on the same day as an 
mNIS+7 assessment, they should be performed after the mNIS+7 assessment is complete. For the 
Week 78 and 156 visits, two mNIS+7 assessments will be performed on separate days. A maximum 
of 2 weeks from the visit (Week 78 or Week 156) will be allowed to complete both assessments. 
For Weeks 4-52 there is a ± 7-day visit window. For Years 2-3 the visit window is ± 10-day. After Year 
3 the visit window is ± 14-day. All reasonable attempts should be made to ensure compliance with 
the visit schedule as outlined in the schedule of procedures (the protocol Appendix A). However, if a 
18 


212 
 
 
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. 
After completion of the treatment period, patients will enter the 3-month post-treatment 
evaluation period. This period consists of clinic and non-clinic visits for safety monitoring as outlined 
in the schedule of procedures (the protocol Appendix A and C). Weekly platelet and every 2-3 week 
serum creatinine testing are required for a minimum of 6 weeks after the last dose of Study Drug 
(this includes early termination patients as well as patients that complete the full treatment period). 
Patients that terminate treatment early and do not withdraw consent should have the post- 
treatment visit conducted 13 weeks after the last dose of Study Drug. 
Patients may be allowed to take Vyndaqel® after 18 months at the discretion of the Study Medical 
Monitor. 
 
2.2 Randomization & Treatment Allocation 
There is no randomization in this present OLE study. All patients will receive ISIS 420915, including 
patients randomized to either ISIS 420915 or placebo in the parent study. 
All patients will receive 300 mg ISIS 420915 given once weekly. However, patients that had a dose 
reduction or schedule change in the parent study may continue with the same dose or schedule in 
this present OLE study. 
Adjustments of dose and/or treatment schedule in the OLE study should occur only on rare 
occasions. Any proposed adjustment to treatment schedule or dose level must be discussed with 
and approved by 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 adverse events after 
consultation with the Study Medical Monitor. 
 
2.3 Conduct 
The Guidelines of the World Medical Association Declaration of Helsinki dated October 2002, the 
applicable regulations and guidelines of the current Good Clinical Practice, as well as demands of 
national drug and data protection laws and other applicable regulatory requirements will be strictly 
followed. 
 
2.4 Data Monitoring 
 
2.4.1 
Safety Data Monitoring 
Ionis Pharmaceuticals, Inc. (or designee) is responsible for processing all reported AEs. All serious 
adverse events (SAEs), reported to Ionis Pharmaceuticals, Inc. (or designee), are reviewed according 
to standard operating procedures. The medical monitor reviews all AEs and SAEs on an ongoing 
basis throughout the OLE study. Ionis Pharmaceuticals, Inc. (or designee) prepares and submits 
safety reports to the health authorities worldwide in accordance with local requirements. If it 
 
 
19 


213 
 
 
becomes necessary to communicate new safety information, Ionis Pharmaceuticals, Inc. (or 
designee) will also prepare a safety notification letter and transmit it to all applicable study sites. 
 
2.4.2 
Data and Safety Monitoring Board 
The independent Data and Safety Monitoring Board (DSMB) for the parent study currently also 
reviews the safety and tolerability of ISIS 420915 during this present OLE study as outlined in the 
Safety Management Plan and DSMB Charter. 
Data summaries and listings are presented by treatment group of the parent study in an unblinded 
fashion and for all patients from both CS2 treatment groups together. These summaries are 
prepared by an independent statistician. No statistical comparisons across treatment groups are 
provided, and no hypothesis testing is done. 
Further detail on the period of DSMB oversight for this study, meeting schedule, assessments to be 
reviewed and controlled access to data are outlined in the DSMB Charter. 
 
2.5 Data Management 
 
2.5.1 
Case Report Form Data 
BioClinica was responsible for creating the Electronic Data Capture (EDC) data entry screens, 
database and edit checks using definitions developed by Ionis Pharmaceuticals, Inc. A contract 
research organization (CRO), named TRENNIC Data Services, is responsible 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 and 
automatic queries are generated. Ionis Pharmaceuticals, Inc. reviews all data for accuracy and 
validity and generates additional queries in the EDC system when necessary. Exceptions are the 
mNIS+7, Norfolk QOL-DN, SF-36, PND, NSC, and body weight information that is entered into the 
EDC but firewalled from review by Ionis Pharmaceuticals, Inc until the parent study is unblinded. The 
data are corrected or an explanation concerning the query is provided in the EDC system. For the 
purpose of pre-programming and data cleaning, PAREXEL (the contract research organization (CRO) 
performing the statistical analysis) and a firewalled data manager working at the CRO contracted to 
perform data management (TRENNIC Data Services) will have access to the post-baseline mNIS+7, 
NSC, Norfolk-QOL-DN, SF-36, PND and body weight. After all data are entered, reviewed, and 
queried, the database is closed and sent to the statistics group for review and for identification of 
protocol deviations. After any further queries that arose from this review are resolved, the database 
is locked. Database closing and locking will be done at the following milestones: 
1. When the last patient in the parent study has completed their last assessments in the 
Treatment Period in the parent study. The parent study will be unblinded at this milestone. 
Therefore, all treatment information are available for this OLE study; 
2. After all patients complete the OLE study, referred to as end of study (EOS). 
 
 
 
20 


214 
 
 
Details can be found in the Data Management Plan. Additional closing and locking may be done to 
support additional interim analyses, with the timing of the database closing and locking coinciding 
with regulatory requirements or study milestones. 
 
2.5.2 
Laboratory Data 
Ionis Pharmaceuticals, Inc. is responsible for the format of the laboratory electronic data transfers 
and the transfer schedule. Ionis Pharmaceuticals, Inc. is responsible for the review of the clinical 
laboratory data. Central laboratory data is not stored in the EDC system. Investigator sites have 
portal (in which case Investigators only have access to data from their site). To ensure maintenance 
of the study blind in the ongoing parent study, TTR (also called pre-albumin), RBP4, retinol (also 
called vitamin A), and NT-proBNP from the first 13 weeks of treatment in this present OLE study is 
not available to the Sponsor, Investigators, Study Center Personnel, or the patients until the parent 
study is unblinded. 
 
2.5.3 
Pharmacokinetics (PK) Data and Immunogenicity (IM) Data 
Ionis Pharmaceuticals, Inc. is responsible for the management and review of the PK and IM data. 
This process involves reviewing the patient and visit identifiers (i.e., patient demographics) with the 
clinical data collected in the EDC system. The PK and IM data are not stored in the EDC system. Prior 
to the parent study unblinding, any ISIS 420915 concentration data sets and IM data sets provided 
to Ionis Pharmaceuticals, Inc. by the respective bioanalytical labs do not include results for samples 
collected prior to Week 13, nor do they include results for Unscheduled or early term (ET) samples. 
 
2.5.4 
Echocardiogram (ECHO) Data 
The ECHO data is collected, analyzed and stored in a secure database by an independent CRO 
 
Hospital (CICL)). The sites upload the ECHO data on a secure web-portal for analysis by CICL. ECHO 
data is firewalled from review by Ionis Pharmaceuticals, Inc until the parent study is unblinded. For 
the purpose of pre-programming and data cleaning, PAREXEL and a firewalled data manager 
working at the CRO contracted to perform data management (TRENNIC Data Services) have access 
to the post-baseline ECHO data. 
 
2.5.5 
Electrocardiogram (ECG) Data 
All ECG data (machine read) are entered into the Bioclinica EDC by the sites. The Bioclinica data will 
be used for ECG summary and analysis. 
All triplicate ECG waveforms are collected and stored in a secure database by an independent CRO 
(Applied Clinical Intelligence, LLC (ACI)). Selected ECGs are analyzed by ACI and the resulting data 
captured in the ACI database as an ECG over-read database. The ECG over-read data are used to 
support medical monitoring and will not be used for the ECG summary and analysis. 
 
 
 
21 


215 
 
 
2.5.6 
Modified Neuropathy Impairment Score +7 (mNIS+7) and Neuropathy Symptoms and 
Change Score (NSC) 
The 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) that is under 
the direction of Dr. 
. The Neuropathy Symptoms and Change (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 faxed to MC Core for processing and quality assurance. Faxed copies 
will be maintained in secure rooms within locked cabinets. The NIS and NSC data are stored in the 
RedCap (a database). The other components of the mNIS+7 (nerve conduction, sensory testing and 
heart rate to deep breathing) are entered by the MC Core into a firewalled portion of the study EDC 
system. MC Core only has access to this portion of the EDC system and 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. Up until the parent study EOT database lock and unblinding, the Sponsor will 
only have access to patient parent study baseline values of the mNIS+7. 
 
2.6 Blinding 
The Statistical Analysis Plan (SAP) for this OLE study will be finalized prior to the parent study 
unblinding. An interim analysis specified in section 5 will be performed at the parent study 
unblinding. At that time, all unblinded information and firewalled datasets in the parent study for 
this OLE study will be available. 
To ensure maintenance of the study blind in the ongoing parent study, TTR, RBP4, retinol, NT- 
proBNP, PK and Immunogenicity data from the first 13 weeks of treatment in this present OLE study 
are not made available to the Sponsor, Investigators, Study Center Personnel, or the patients until 
the parent study is unblinded. 
Derived mNIS+7 and the components including NIS, +7 and modified +7, as well as NSC, Norfolk 
QOL-DN, SF-36, PND, body weight and ECHO information are not made available for sponsor review 
until the parent study is unblinded. For the purpose of pre-programming and data cleaning, 
PAREXEL and a firewalled data manager working at the CRO contracted to perform data 
management (TRENNIC Data Services) have access to the post-baseline mNIS+7, NSC, Norfolk QOL- 
DN, SF-36, PND, ECHO and body weight. Details are discussed in section 5.2. 
 
3. Analytical Plan 
3.1 Statistical Design Summary 
This SAP specifies the study endpoints to be analyzed, the study populations, and the methods of 
analysis. Section 3.2 provides general guidelines to be followed for all analyses, and covers the 
analysis populations, handling of missing data, and other general topics. Analyses of baseline 
characteristics are also covered in this section. Section 3.3 discusses the safety analyses. 
Section 3.4 and 3.5 specifies the efficacy and PD endpoints and methods of analysis for these 
endpoints. Section 3.6 covers PK analyses. 
22 


216 
 
 
Section 4 is for the sample size justification. Section 5 presents details on the interim analyses to be 
conducted for this present OLE study. 
The SAP concludes with a references section and appendices. 
 
3.2 General Overview of Analyses 
This SAP describes the reporting of data at the EOS for this OLE study (unless specified otherwise). 
Additionally, some of these data will also be reported for the purposes of the interim analyses. 
 
3.2.1 
Analysis Conventions 
All reporting will be performed in SAS version 9.3 or higher. 
Efficacy results will be summarized under the treatment to which patients were randomized in the 
parent study. Safety and PK results by treatment group of parent study will be summarized under 
the treatment to which patients received in the parent study. Should there be any cases after the 
parent study unblinding in which a patient received treatment other than what was randomized, 
such cases will be discussed in the OLE study report and noted in footnotes where applicable. 
All electronic case report form data, lab data transfers, ECHO, ECG, and 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 OLE study, will include all data collected 
during the OLE phase, and will be sorted by treatment group of parent study, patient ID, visit, and 
time point (where appropriate). 
Central laboratory assessments will be included in the summary tables; local laboratory assessments 
will only be included in listings. Exceptions to the use of local laboratory assessment in summary 
tables are made for platelets, where summary tables will use both local and central laboratory 
results. 
All tables will present the population frequencies in each treatment group in the parent study 
and/or subgroup (where appropriate) and will indicate the number of patients with non-missing 
data and the denominators for percentages. 
Descriptive summary statistics including n, mean, percentiles (e.g., median, 25th percentile [P25], 
and 75th percentile [P75]), standard deviation, and range (minimum, maximum) for continuous 
variables, and counts and percentages for categorical variables, will be used to summarize data by 
treatment group of the parent study. Summaries of PK parameters, if applicable, will also present 
geometric mean, standard deviation of log-transformed data, and coefficient of variation, expressed 
as a percent (%CV). Where appropriate, p-values will be reported. All statistical tests will be 
conducted using 2-sided tests with a 5% Type I error rate, unless otherwise specified. 
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 (SI 
units). Precision for displays will use the following conventions. Means, percentiles (e.g., median, 
P25, and P75), least squares means, difference in least squares means will be displayed to one more 
decimal place than measured values. Standard deviations and standard errors will be displayed to 
 
23 


217 
 
 
two more decimal places than measured values. The minimum, maximum and confidence intervals 
(CI) will be displayed using the same number of decimal places as the recorded values. All raw 
values presented in listings will be displayed to the measured precision. Percentages will be 
displayed to one decimal place. P-values will be displayed to 3 decimal places. CI will be presented 
using a comma separator rather than a dash. 
As shown in the schematic below, boxplots will display values from minimum to maximum within 
the upper and lower fences, the likely range of variation from P25 to P75 and the median. A symbol 
inside the box will indicate the mean. A segment inside the box will show the median and "whiskers" 
above and below the box will show the locations of the minimum and maximum observations within 
the upper and lower fences (see definition below). Individual observations outside the upper or 
lower fences will also be marked. 
 
All efficacy and PD endpoints, except GLS will be assessed on the Full Analysis Set (FAS) and Per- 
Protocol Set (PPS). Refer to Section 3.2.2 for a description of the patient populations. Safety analysis 
will be performed on the Safety Set (SS) or Longitudinal Safety Set (LSS). PK endpoints will be 
assessed in the Pharmacokinetic Set (PKS) as applicable. ECHO endpoints including GLS will be 
assessed for all enrolled subjects, the ECHO subgroups and in the Cardiomyopathy-ECHO (CM-ECHO) 
Set. 
An interim analysis of this OLE study will take place at the same time when the parent study 
database is locked and unblinded at EOT. Other interim analyses may be performed with the timing 
of the analyses coinciding with regulatory requirements or study milestones. See section 5 for 
details on the interim analyses. The final EOS analyses will take place after all patients have 
completed the study and the database has been locked. 
 
 
24 


218 
 
 
3.2.1.1 Definitions and Computational Formulas 
3.2.1.1.1 
Day 1 of ISIS 420915 and CS3 Study Day 1: 
Day 1 of ISIS 420915 will refer to the first day ISIS 420915 is administered to the patient. For 
patients on active treatment in the parent study, Day 1 of ISIS 420915 will be the first day ISIS 
420915 is administered in the parent study. For patients on placebo in the parent study, Day 1 of 
ISIS 420915 will be the first day ISIS 420915 is administered in this OLE study. 
CS3 Study Day 1 will refer to the first day ISIS 420915 is administered to the patient in this OLE 
study. 
CS2 Study Day 1 will refer to the first day study drug (ISIS 420915 or Placebo) is administered to 
the patient in the parent study. 
3.2.1.1.2 
Three baselines are defined as following: 
Parent study baseline will be the baseline of the parent study, which is defined for most 
endpoints, unless specified, as the last non-missing value prior to the Day 1 of treatment, ISIS 
420915 or Placebo, in the parent study. Considerations for mNIS+7, ECG, NSC, ERG and laboratory 
assessment are detailed below. 
o For mNIS+7 and its individual components, the parent study baseline will be defined as the 
average of two assessments taken within 60 days prior to the first dose of Study Drug. If only 
one assessment has been done, the single assessment will be used in place of the average. 
Rarely, for patient convenience, the parent study baseline mNIS+7 assessment(s) (or a subset of 
this assessment) will have been completed early in the parent study treatment period rather 
than pre-treatment. These assessments will be included in the analysis as valid baseline 
assessments provided they are taken within one 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 
ent level data 
imputation are described in Section 3.2.1.3 of this document. Note that the NIS screening 
assessment can be used as one of the two assessments provided it was done within 60 days of 
first dose of Study Drug. Further details on how to handle missing baseline results are described 
in section 3.2.1.3. 
o For NSC and individual components, the parent study baseline will be defined as the average of 
two assessments taken within 60 days prior to the first dose of Study Drug in the parent study. If 
only one 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 in the parent study, it is 
possible it could be completed early in the treatment period rather than pre-treatment. These 
assessments will be included in the analysis as valid parent study baseline assessments provided 
they are taken within one week after the first dose of the parent study. 
o For ECG, the parent study baseline will be defined as the average of the triplicate taken on Day 
1 Pre-dose in the parent study. If only one or two assessments are available, the single 
 
 
25 


219 
 
 
assessment or average of the two assessments will be used. In the case that Day 1 Pre-dose is 
missing, screening visit results of the parent study will be used as baseline. 
o The protocol permitted baseline ERG and ophthalmology examinations can be done up to one 
week after CS2 Study Day 1. Assessments done within one week of first dose will be included in 
the analysis as valid parent study baseline assessments. 
o The parent study baseline laboratory assessment including PD will be defined as the average of 
all non-missing pre-dose assessments in the parent study. 
OLE study baseline will be defined as the last non-missing assessment prior to the first dose of ISIS 
420915 in the OLE study (CS3 Study Day 1). However the last assessment must be collected 
within 3 months (90 days) before CS3 Study Day 1 of OLE study in order to be used to derive the 
baseline, i.e. if there is no assessment within 3 months, the OLE study baseline will be missing. 
Depending on when the assessments are scheduled to be collected this may be derived from the 
CS3 Study Day 1 or the screening visit in the OLE study or the last non-missing assessment from 
the parent study. Considerations for mNIS+7, NSC, and ECG are detailed below: 
o For mNIS+7 (and its individual components) and NSC (and its individual components), if the last 
assessment is the Week 66 assessment in CS2, the average of the two Week 66 assessments 
will be taken (as defined in the CS2 Statistical analysis plan). If only one assessment has been 
done, the single assessment will be used. 
o For ECG, the OLE study baseline will be defined as the average of the triplicate taken at the 
screening visit of the OLE study. If only one or two assessments are available, the single 
assessment or average of the two assessments will be used. 
screening visit of the OLE study, the last visit in the parent study collected within 3 months (90 
days) before CS3 Study Day 1 of OLE study will be used as baseline. 
ISIS 420915 baseline will be the parent study baseline for patients randomized to ISIS 420915 in 
the parent study, and will be the OLE study baseline for patients randomized to placebo in the 
parent study. 
3.2.1.1.3 
Three baselines for analyses: 
Efficacy analyses and PD analyses are based on the parent study baseline and the OLE study 
baseline. Details of separate analyses based on each baseline will be specified in the section 3.4 
and 3.5. 
Safety analyses are based on ISIS 420915 baseline. Details of separate analyses based on each 
baseline will be specified in the section 3.3. 
Further details of which assessments will be considered baseline for ECHO analyses for this 
present OLE study are included in a separate SAP for the ECHO data. 
 
 
3.2.1.1.4 
On-treatment, post-treatment and on-study in either the parent study or the OLE 
study (Details on the planned summary/analysis at each period are discussed in 
the section 3.2.1.4): 
26 


220 
 
 
For efficacy endpoints except for BMI and mBMI: 
o  The efficacy on-treatment period for the parent study spans the time during which the 
study treatment is administered from the CS2 Study Day 1 until 52 days after the last dose 
of medication in the parent study. The efficacy on-treatment period for the OLE study is 
from the CS3 Study Day 1 until 52 days after the last dose of medication in the OLE study 
o For both studies the efficacy post-treatment period starts on the day after the efficacy 
          within the study. 
For BMI, mBMI and PD endpoints: 
o The on-treatment period for the parent study spans the time during which the study 
treatment is administered from the CS2 Study Day 1 until 28 days after the last dose of 
medication in the parent study. The on-treatment period for the OLE study is from the CS3 
Study Day 1 until 28 days after the last dose of medication in the OLE study. 
o For both studies the post-treatment period starts on the day after the treatment period and 
ends on the day of the patie 
For safety endpoints except for ERG: 
o The on-treatment period for the parent study spans the time during which the study 
treatment is administered from the CS2 Study Day 1 until 7 days after the last dose of 
medication in the parent study. The on-treatment period for the OLE study is from the CS3 
Study Day 1 until 7 days after the last dose of medication in the OLE study. 
o For both studies the safety post-treatment period starts on the day after the safety 
treatment 
o For both studies the Safety on-study period spans the time drug is first administered until 
o The period for the longitudinal safety analysis spans the time from the first dose of ISIS 
study. The subject s last contact date is defined as follows: 
(1) for subjects who signed an informed consent form in the OLE study, it is the last contact 
date within the OLE study; 
(2) for subjects who did not sign an informed consent form in the OLE study but had been 
administered ISIS 420915 in the parent study, it is the last contact date within the parent 
study. The details of longitudinal safety analysis for AEs and safety lab results will be 
addressed in section 3.3. 
For ERG: 
o The on-treatment period for the parent study spans the time during which the study 
treatment is administered from the CS2 Study Day 1 until 28 days after the last dose of 
medication in the parent study. The on-treatment period for the OLE study is from the CS3 
Study Day 1 until 28 days after the last dose of medication in the OLE study. 
27 


221 
 
 
o For both studies the safety post-treatment period starts on the day after the safety 
 
. 
The PK on-study period for the OLE study spans the time ISIS420915 is administered in the OLE 
study (CS3 Study Day 1) 
OLE study. 
The Immunogenicity (IM) on-study period for the OLE study spans the time the first dose of 
 
OLE study. This period is for defining patient IM status (Details in section 3.2.1.1.6). 
3.2.1.1.5 
Durations of study drug exposure and total dose of ISIS 420915: 
Durations of overall drug exposure (days) across both studies will be derived as the difference in 
days between the date of the last dose of ISIS 420915 and Day 1 of ISIS 420915 plus one. For 
patients who are not enrolled in the OLE study, the last dose of ISIS 420915 is administered in the 
parent study; for patients who are enrolled in the OLE study, the last dose of ISIS 420915 is 
administered in the OLE study. 
The total dose of study drug during the treatment period for either the parent study or the OLE 
study will be computed for patients receiving ISIS 420915 by summing the dose administered 
between Day 1 of ISIS 420915 and the last dose date in the parent study for patients who are not 
enrolled in the OLE study or the last dose date in the OLE study for patients who are enrolled in 
the OLE study. Total dose will be summarized in milligrams as part of longitudinal safety analysis. 
Duration of drug exposure in OLE study (days) will be derived as the difference in days between 
the date of the last dose of ISIS 420915 in OLE study and CS3 Study Day 1 plus one. 
The total dose of study drug during the treatment period for the OLE study will be computed for 
patients receiving ISIS 420915 in the OLE study by summing the dose assigned between CS3 Study 
Day 1 and the EOT date or date of early termination in OLE study. Total dose will be summarized 
in milligrams. 
3.2.1.1.6 
Immunogenicity (IM): 
For subjects with negative IM status in the parent study, the onset (Tfirst) of anti-ISIS 420915 
antibodies in OLE study will be derived as difference in days between the date when first 
immunogenicity sample becomes confirmed positive (i.e., positive sample IM status) in OLE study 
and Day 1 of ISIS 420915 plus one. 
For subjects with positive IM status in the parent study, the onset (Tfirst) of anti-ISIS 420915 
antibodies in the parent study will be used as the onset of the OLE study. 
3.2.1.1.7 
BMI and mBMI: 
Body mass index (BMI) will be computed using the formula: 
BMI = (weight in kilograms) / [height in cm / 100]2 
Modified BMI (mBMI) will be computed from BMI and serum albumin levels by: 
mBMI = BMI * serum albumin (g/L). 
28 


222 
 
 
3.2.1.2 Scoring of Assessment Instruments 
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 
Muscle Weakness (NIS-W), maximum 152 points 
Reflexes (NIS-R), maximum 20 points 
Sensation (NIS-S), maximum 32 points. 
Questions that make up each composite are listed in the table below. 
 
NIS composite 
Question number 
Cranial Nerves 
1-5 
Muscle Weakness 
6-24 
Reflexes 
25-29 
Sensation 
30-37 
Note that each question is separately assessed for the right and left side of the body, meaning that 
questionnaire is comprised of 74 subcomponents (37 for the left side, and 37 for the right side). 
Modified +7 
The modified +7 composite score consists of 4 components: 
1 component for autonomic nerve assessment: 
o Heart Rate to Deep Breathing (HRDB), minimum -3.72 points, maximum 3.72 points, 
1 component for the nerve conduction assessment of the lower and upper limbs: 
o Nerve Conduction Tests ( 5 NC), maximum 18.6 points from 5 subcomponents (PMAK, 
TMAK, UMAE, USAW, SSAB) with minimum -3.72 points and maximum +3.72 points each, 
2 components for the sensory nerve assessment: 
o Touch-Pressure (TP), maximum 40 points 
o Heat-Pain (HP), maximum 40 points. 
NOTE: Testing for both TP and HP is done at up to 10 sites on one side of the body. To 
obtain the full body score for TP and HP, the summation scores from all 10 anatomical sites 
 
29 


223 
 
 
is multiplied by 2 (only one side of the body is tested as FAP is symmetrical neuropathy, 
identical results are assumed for the other side). 
 
Component 
Data entry convention /Comment 
Pre-processingstep 
Heart Rate 
Deep 
Breathing 
If HRDB could not be measured due to 
pacemaker or arrhythmia, MC Core checked 
either the box "no reliable data to due 
pacemaker" or "no reliable measure points 
due to arrhythmia," and left the HRDB score 
as blank in the BioClinica database 
None 
If HRDB was not measured in error or missing 
for other reasons, MC Core entered a "-9" 
into the BioClinica database 
Set "-9" to missing 
Transform normaldeviate score so that 
larger values coincide with worse outcomes 
Multiply subcomponent score by "-1" 
Nerve 
conduction 
test 
If the nerve attribute was not tested in error, 
MCCore entered a "-9" into the BioClinica 
database 
Set "-9" to missing 
For all 5 subcomponent (SSAB, USAW, UMAE, 
PMAK, TMAK) transform subcomponent 
normal deviate score so that larger values 
coincide with worse outcomes 
Multiply each subcomponent score by 
"-1" 
Touch 
Pressure 
If an anatomicalsite was assessed, , MC Core 
entered a "O", "1" or "2" into the BioClinica 
database 
None 
If an anatomicalsite was skipped because it 
was assumed to be< 95%, MC Core left the 
field blank in the BioClinica database (the last 
assessed more distalanatomical site has a 
"O" entered) 
Set blank field to "O" 
If an anatomicalsite was not tested in error, 
MC Core entered a "-9" into the BioClinica 
database 
Set "-9" to missing 
Heat Pain 
If an anatomicalsite was assessed, MC Core 
entered a "O", "1" or "2" into the BioClinica 
database 
None 
If an anatomicalsite was skipped because it 
was assumed to be< 95%, MC Core left the 
field blank in the BioClinica database (the last 
assessed more distalanatomical site has a 
"O" entered) 
Set blank field to "O" 
30 


224 
 
 
If an anatomical site was not tested in error, 
MC Core entered a "-9" into the BioClinica 
database 
Set "-9" to missing 
Additionally, for Heat Pain and Touch Pressure, the composite scores are calculated by multiplying 
the sum of the 10 averaged subcomponent scores (defined below) by 2. 
NIS+7 
 
The NIS+7 consists of two composite scores: the NIS composite score (above) and the +7 composite 
score (maximum of 26.04 points). 
+7 
 
The +7 composite score consists of 3 components: 
 
• 1 component for autonomic nerve assessment: 
 
o 
Heart Rate to Deep Breathing (same as modified +7), minimum -3.72 points, maximum 3.72 
points, 
• 1 component for the peripheral nerve assessment of the lower limb: 
 
o 
Nerve Conduction Tests (LS NC nds), maximum 18.6 points from 5 subcomponents (PMAK, 
PMCVK, PMLA, TMLA, SSAB) with minimum -3.72 points and maximum +3.72 points each. 
Please note that 3 of the subcomponents used in +7 (PMCVK, PMLA, TMLA) are different 
from 3 of the subcomponents used in modified +7 (TMAK, UMAE, USAW). 
• 1 component for the sensory nerve assessment 
 
o 
Vibration Detection Threshold (VDT), minimum -3.72 points, maximum 3.72 points. 
 
Due to the testing algorithm and the MC Core data entry conventions, raw+ 7 data need to undergo 
a pre-processing step before the scores can be derived. The different pre-processing steps are 
summarized in the table below. 
 
Component 
Data entry convention /Comment 
Pre-processing step 
Heart Rate 
Deep 
Breathing 
If HRDB could not be measured due to 
pacemaker or arrhythmia, MC Corechecked 
either the box "no reliable data to due 
pacemaker" or "no reliable measure points 
due to arrhythmia," and left the HRDB score 
as blank in the BioClinica database 
None 
If HRDB was not measured in error or missing 
for other reasons, MC Core entered a "-9" 
into the BioClinica database 
Set "-9" to missing 
Transform normal deviate score so that 
larger valuescoincide with worse outcomes 
Multiply subcomponent score by "-1" 
 
31 


225 
 
 
Nerve 
conduction 
test 
If the nerve attribute was not tested in error, 
MC Core entered a "-9" into the BioClinica 
database 
Set "-9" to missing 
For PMCVK, PMLA, TMLA, if the attribute 
could not be estimated/ measured due to 
an amplitude (CMAPS) of O in the fibular or 
tibial nerve, MC Core left the field blank in 
the BioClinica database 
See imputation method for group B 
below 
For PMAK, PMCVK, SSAB, transform normal 
deviate subcomponent score so that larger 
valuescoincide with worse outcomes 
Multiply subcomponent score by "-1" 
Vibration 
Detection 
If the vibration test was not tested in error, 
MC Core entered a "-9" into the BioClinica 
database 
Set "-9" to missing 
 
 
Norfolk QOL-DN 
 
The Norfolk QOL-DN (version: 2003) consists of one composite score (Total QOL) and five sub- 
domain scores (physical functioning/large fiber neuropathy, activities of daily living, symptoms, 
small fiber neuropathy, and autonomic neuropathy). The scoring of the Norfolk QOL-DN will be 
conducted according to the scoring manual developed at the Eastern Virginia Medical School, and is 
summarized below. 
Questions that make up each domain are listed in the table below 
 
Norfolk QOL-DN Domain 
Question number 
physical functioning/large fiber neuropathy 
8, 11, 13-15, 24, 27-35 
activities of daily living 
12,22,23,25,26 
symptoms 
1-7, 9 
small fiber neuropathy 
10, 16, 17, 18 
autonomic neuropathy 
19,20,21 
All symptoms (Questions 1 to 7) are a simple inventory of symptoms of neuropathy. Each of these 
questions are assessed for the feet, legs, hands and arms, with presence of a symptom scored as a 1 
and absence as a 0. The Question Score is calculated by summing the scores for the individual sites 
for the Question, with the Question Score ranging from O (no symptoms) to 4 (symptoms in the feet, 
legs, hands, and arms). The other Questions, except Questions 31 and 32, are scaled on a 5 point 
Likert scale, ranging from O ("Not a problem") to 4 ("Severe Problem"). In Question 31, "Good" is 
scored as 0, "Very Good" is scored as -1, "Excellent'' is scored as -2, "Fair" is scored as 1, and "Poor" 
 
32 


226 
 
 
-1, 
- 
SF-36 
 
The SF-36 (version: 2) consists of two composite scores, the Physical Component Summary score 
and the Mental Component Summary score, as well as eight domain scores (physical function, role- 
physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health). 
The scoring of the SF-36 will be conducted using Quality Metrics Certified Scoring Software v 4.5. 
NSC 
The NSC questionnaire (version: 04Jan2009) consists of one total score and five domains (muscle 
weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic 
(gastro intestinal (GI) 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 the Appendix 2 Scoring of 
Assessment Instruments. 
3.2.1.3 Handling of Missing or Replicated Data, Unscheduled Visits, and Early Termination 
Visits 
 
Composite score: NIS score, +7 score, NIS+7 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/NIS+7 assessment is not conducted at a visit, then the mNIS+7/NIS+7 and the composite, 
components and subcomponents will be considered to be missing at that visit. 
Missing data imputation strategies for missing assessment level data 
In the parent study, two independent assessments of mNIS+7 are planned at the baseline visit and 
Week 66 visit, and the early termination visit (for patients that terminate treatment early). A single 
mNIS+7 assessment is also planned at the Week 35 visit. In this present OLE study, two independent 
assessments of mNIS+7 are planned at the Week 78 and 156 visit, and the early termination visit for 
patients that terminate treatment early during years 1 to 3. A single mNIS+7 assessment is also 
planned at the Week 26, 52, 104 and 130 visit. The mean of the two replicate assessments within 
visit will be used for analysis of the parent study baseline, the parent study Week 66 visits (provided 
both visits fall in the visit window and are within 52 days of the last dose of medication), the OLE 
study Week 78 and 156 visit (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. These will be referred to 
as the averaged subcomponent scores. 
At the parent study baseline and Week 66 visit, and the OLE study Weeks 78 and 156 visit, in the 
event that only one subcomponent has been performed, the single subcomponent will be used in 
place of the mean value for that visit for the averaged subcomponent score. If both of the 
subcomponent values are missing, the averaged subcomponent score is missing. At the parent study 
 
33 


227 
 
 
and OLE study visits where one assessment is performed, the single subcomponent will be used as 
the averaged subcomponent score for that visit. These values will be used in the summary of 
averaged subcomponent scores. The component scores will be computed by summing the averaged 
subcomponent scores and the composite scores will be computed by summing the component 
scores. 
For both CS2 and CS3, two independent assessments of mNIS+7 are planned at early termination 
visits. If both assessments are within the same visit window, the mean of the two will be used. At 
early terminations, in the event that only one subcomponent has been performed, the single 
subcomponent will be used in place of the mean value for that visit for the averaged subcomponent 
score. 
Imputation of missing averaged subcomponents 
If a patient has completed at least part of the mNIS+7/NIS+7 at a visit then the following imputation 
method will be used to impute this missing assessment level data for the purposes of determining 
component scores for summary and analysis. 
The following missing data imputation steps will be considered and will be used as described below 
for Groups A, B, and C: 
Step 1: If at least 50% of averaged subcomponent scores within a component are available, the 
 
non-missing averaged subcomponent scores in that component. The component score is then 
calculated. 
Step 2 (Parent study baseline): In the unlikely event that there are more than 50% of the 
averaged subcomponents scores within a component that are missing at baseline, the missing 
averaged subcomponent scores will be set to equal to mean baseline averaged subcomponent 
score from the parent study Randomized Set (across treatment groups). The component score is 
then calculated. This is the same definition as used in the parent study. 
Step 3 (OLE study baseline and CS2 and CS3 post-baseline visits): For certain components, and 
only under certain conditions which will be listed below, the missing averaged subcomponent 
scores at that visit within that component only will be set equal to the mean averaged 
subcomponent score among the subjects randomized to placebo in the parent study in the 
Randomized and Enrolled set for CS2 and CS3 respectively. The component score is then 
calculated. This is the same definition as used in the parent study for post-baseline visits. 
If a post-baseline assessment does not fall into the scheduled analysis windows, there is no 
obvious visit on which the mean subcomponent scores in the placebo group can be derived. In 
order to apply step 3, the following visits will be used to derive the mean scores in the placebo 
group: 
 
Timing of Assessment 
Visit used for deriving the mean subcomponent scores in 
the placebo group* 
 
34 


228 
 
 
 
Before Week 26 
OLE baseline 
Between Week 26 and Week 52 
Week 26 
Between Week 52 and Week 78 
Week 52 
Between Week 78 and Week 104 
Week 78 
Between Week 104 and Week 130 
Week 104 
Between Week 130 and Week 156 
Week 130 
After Week 156 
Week 156 
*Note: the Placebo group refers to the group of patients randomized to placebo in the parent study in the 
Enrolled set for CS3. 
The components of the mNIS+7 and NIS+7 are grouped into A, B and C based on the imputation step 
used, as follows. A detailed list of components by group can be found in Table 1 Table 3 in 
Appendix 1 Components and Subcomponents of the mNIS+7, and NIS+7: 
Group A: For components with multiple subcomponents except the NCT component of +7, 
imputation step 1 and 2 will be applied. 
If, after applying step 1 for post-baseline visits, 6 out of the 7 components of the mNIS+7 
composite score (NIS-C, NIS-R, NIS-S, NIS-W, HP, TP or NCT) are available and only one is missing 
at that visit, then step 3 will be applied for the missing component. 
If, after applying step 1 for post-baseline visits, 4 out of the 5 components of the NIS+7 
composite score (NIS-C, NIS-R, NIS-S, NIS-W, or NCT ) are available and only one is missing at 
that visit, then step 3 will be applied for that the missing component. 
Mean averaged subcomponent score used in the imputation described in step 3 are derived 
from the averaged subcomponent scores before step 1 imputation among the group of patients 
who were randomized to placebo in the parent study. 
If, after applying steps 1-3 as appropriate, there are still missing subcomponent scores, the 
component score will be set to missing. 
Group B: For the NCT component of +7, it should be noted that the following 3 of the 5 
subcomponents of this 
 as an additional category to missing: 
1) fibular nerve motor conduction velocity (PMCVK), 2) fibular nerve distal latency (PMLA), 3) 
tibial nerve distal latency (TMLA) (see Table 3 in Appendix 1 Components and Subcomponents of 
the mNIS+7, and NIS+7). These nerve conduction attributes are not evaluable when the tibial or 
fibular nerve amplitude is 0, therefore, these 
considered informative 
missing results and a slightly different imputation method is applied here. The following 
imputation rule will be used for Nerve Conduction Tests component score of +7: The normal 
deviate score for PMCVK, PMLA and TMLA will be respectively set to 3.72 (the worse response) 
 
35 


229 
 
 
 and 2 will 
be applied. 
If, after applying step 1 for post-baseline visits, 4 out of the 5 components of the NIS+7 
composite score (NIS-C, NIS-R, NIS-S, NIS-W, or NCT ) are available and only one is missing at 
that visit, then step 3 will be applied for that the missing component. 
Mean averaged subcomponent score used in the imputation described in step 3 are derived 
from the averaged subcomponent scores before step 1 imputation among the group of patients 
who were randomized to placebo in the parent study. 
Note that these components are not used in the nerve conduction component of the modified 
+7, therefore Group B only includes the NCT component of the NIS+7 and not the NCT 
component of the mNIS+7. 
Group C: The two components, HRDB and vibration tests, have only one subcomponent. 
Missing data for these averaged subcomponents score will be imputed as follows: 
o For Parent study baseline, the missing averaged subcomponent scores will be set to equal 
to the mean baseline averaged subcomponent score from the parent study Randomized Set 
(across treatment groups). This is the same definition as used in the parent study. 
o For OLE study baseline and CS2 and CS3 post-baseline visits, the missing averaged 
subcomponent scores at that visit will be set equal to the mean averaged subcomponent 
score among the subjects randomized to placebo in the parent study in the Randomized and 
Enrolled set for CS2 and CS3 respectively. If a post-baseline assessment does not fall into the 
scheduled analysis windows, there is no obvious visit on which the mean subcomponent 
scores in the placebo group can be derived. In order to derive the mean scores in the 
placebo group, the following visits will be used: 
 
Timing of Assessment 
Visit used for deriving the mean subcomponent scores in 
the placebo group* 
Before Week 26 
OLE baseline 
Between Week 26 and Week 52 
Week 26 
Between Week 52 and Week 78 
Week 52 
Between Week 78 and Week 104 
Week 78 
Between Week 104 and Week 130 
Week 104 
Between Week 130 and Week 156 
Week 130 
After Week 156 
Week 156 
*Note: the Placebo group refers to the group of patients randomized to placebo in the parent study in the 
Enrolled set for CS3. 
36 


230 
 
 
Composite Score 
The composite scores of mNIS+7, NIS+7, modified +7, +7, and NIS will each be calculated by 
summing the imputed components scores. If any of the component scores after imputation is still 
missing within a composite, the composite score will be set as missing. 
 
Norfolk QOL-DN Domain and Total score 
 
For each patient at a specific visit (defined by the analysis visit window), if at least 50% of the 
questions for a domain (physical functioning/large fiber neuropathy, activities of daily living, 
symptoms, small fiber neuropathy) are not missing or if at least one question is not missing for 
autonomic domain, the missing questions are imputed as follows: 
o For the Parent study baseline, if any question is missing at baseline, the mean value for this 
question at baseline from the parent study Randomized Set (across treatment groups) will be 
used to impute the missing baseline question value, i.e., same with the derivation in the 
parent study. 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. 
o For the OLE study baseline and post-baseline visits: any missing question values will be 
imputed using the last observed or imputed question value (including parent study 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. 
o 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 
In the parent study, 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. In this present OLE study, 
two independent assessments of NSC are planned at the Week 78 and 156 visit. A single NSC 
assessment is planned at the Week 26, 52, 104 and 130 visit. The mean of the two replicate 
assessments within a visit will be used for analysis of the parent study baseline, the parent study 
Week 66 visits (provided both visits fall in the visit window and are within 52 days of the last dose of 
medication), the OLE study Week 78 and 156 visit (provided both visits fall in the visit window and 
 
37 


231 
 
 
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 the parent study baseline and Week 66 visits and the OLE study Weeks 78 and 156 visit, in the 
event that only one question has been performed, the single question will be used in place of the 
mean value for that visit for the averaged question score. If both of the questions are missing, the 
averaged question score is missing. At the parent study Week 35 visit, the OLE study Week 26, 52, 
104 and 130 visit only one assessment is performed, therefore the single question 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 
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% 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 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. 
Imputation of Missing/Partial Dates The imputation of partial or missing dates for adverse events 
and concomitant medications are detailed in Section 3.3.1. The imputations of partial or missing 
dates for duration of disease from diagnosis and duration from onset of symptoms for FAP/FAC are 
detailed in Section 3.2.3. 
Replicated Data, Unscheduled Visits, and Early Termination Visits 
 
38 


232 
 
 
When change from baseline is assessed at a post-baseline visit, 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 for a patient, then the change from baseline will be set to 
missing. 
For patients who withdraw from the OLE study, 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 value of the patient 
will be used 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. 
Analysis Visit Windows 
 
The efficacy and PD data will be assigned to a visit according to the visit windows in the table 1 
of Appendix 3 Analysis Visit Windows. Because mNIS+7 may be implemented over several days, 
window definitions are based on the study day the assessment was initiated. Efficacy 
assessments (except BMI and mBMI) that occurred more than 52 days after the last dose of 
Study Drug in either parent study or the OLE study will not be included in the efficacy 
analysis/summaries during the efficacy on-treatment period, even if they occurred within one of 
the visit windows. PD assessments, as well as BMI and mBMI, that occurred more than 28 days 
after the last dose of Study Drug in either parent study or the OLE study will not be included in 
the PD analyses/summaries during the PD on-treatment period, even if they occurred within 
one of the visit windows. For patients who have multiple visits within a window the visit nearest 
the target day will be used unless two visits are equally near, in which case the average will be 
used. Note that if there are multiple visits within a window with some being from the post- 
treatment evaluation period of either the parent study or the OLE study, the visits from the 
post-treatment evaluation period will not be used. For mNIS+7 at baseline and Week 66 of the 
parent study or at Week 78 and 156 of the OLE study, the two assessments are averaged 
(provided both assessments are within the visit window and are within 52 days of the last dose 
of medication). 
Efficacy and PD data collected during the post-treatment period will be summarized with 
respect to the elapsed time from last dose. Assessments will be slotted into follow-up visit 
windows according to elapsed time from last dose based on the scheduled assessments during 
the post-treatment evaluation period of the study. The planned windows for this investigation 
are shown in the table 2 of Appendix 3 Analysis Visit Windows. 
Visit based safety assessments (scheduled and unscheduled) will be assigned to a visit according 
to analysis visit windows in the table 3 of Appendix 3 Analysis Visit Windows, even if they 
occurred within one of the visit windows. Except for platelet assessments from the local 
laboratory, local laboratory assessment will not be assigned to a visit and the nominal visit only 
will be presented in the listings. Safety assessments that occurred during the safety post- 
treatment period (i.e., more than 7 days after the last dose of study drug) will not be included in 
 
39 


233 
 
 
the visit based safety analyses during the safety treatment period. If there are multiple visits 
within a window, the visit nearest the target day will be used unless two visits are equally near, 
in which case the average will be used. Note that safety assessments that are not utilized in the 
visit based summary tables will appear in listings and be used in the determination of treatment- 
emergent shifts or abnormalities. 
• 
To assess the impact of treatment discontinuation on safety parameters, data from visit based 
safety assessment in the post treatment phase may also be summarized with respect to the 
elapsed time from last dose. Assessment will be slotted into follow-up visit windows according 
to elapsed time from last dose based on the scheduled assessments during the post-treatment 
evaluation period of the study. The planned windows for this investigation are shown in the 
table 4 of Appendix 3 Analysis Visit Windows. 
3.2.1.4 Data Summary Plan 
 
The table below details what data will be included in the summary and analysis output by endpoint 
type. Data summarized or analyzed at each interim analysis will be based on data collected up to the 
data cut date. It is possible that on-treatment data and post-treatment data available for each 
interim analysis is different from the final analysis at the end of study because data collected after 
each interim analysis data cut may slot into different treatment period. Outputs will be updated for 
each interim analysis and for the final analysis. 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 below; such 
exceptions will be noted in this document. 
 
Endpoint type 
Output type 
Comment/definition 
Efficacy 
-Listings 
-On-treatment (CS2&CS3) 
summary/analysis tables 
-Post-treatment summary 
tables 
-On-treatment (CS2 period):The CS2 Study Day 1 S Date 
of assessment s Last dose date in parent study+ 52 days 
-On-treatment (CS3 period): CS3 STUDY DAY 1 $ Date of 
assessment s Last dose date of OLE study+ 52 days 
- showing both CS2 visits and CS3 visits. Note the results 
of the analyses at the CS2 visits will not be the same as 
the results from the CS2 study as this table only includes 
patients in the CS3 FAS.-Post-treatment: Date of 
assessment > last dose date of OLE study + 52 days 
-Visit defined by analysis visit window 
PD, BMIand 
mBMI 
-Listings 
-On-treatment (CS2&CS3) 
summary/analysis tables 
-Post-treatment summary 
tables 
-On-treatment (CS2 period): The CS2 Study Day 1 S Date 
of assessment s Last dose date in parent study+ 28days 
-On-treatment (CS3 period): CS3 STUDY DAY 1 s Date of 
assessment s Last dose date of OLE study+ 28days 
- showing both CS2 visits and CS3 visits. Note the results 
of the analyses at the CS2 visits will not be the same as 
the results from the CS2 study as this table only includes 
patients in the CS3 FAS. 
 
40 


234 
 
 
Endpoint type 
Output type 
Comment/definition 
-Post-treatment: Date of assessment> last dose date+ 
28days 
-Visit defined by analysis visit window 
Safety 
Endpoints: ECG, 
Lab, vitals sign 
(including body 
weight) 
-Listings 
-On-treatment summary 
tables (CS3) 
-Post-treatment summary 
tables 
-On-treatment (CS3 period): CS3 Study Day ls Date of 
assessment 5 Last dose date + 7 days 
-Post-treatment: Date of assessment> last dose date+ 7 
days 
-Visit defined by analysis visit window 
Safety 
Endpoints: ERG 
and 
ophthalmology 
examinations 
-Listings 
-On-treatment summary 
tables (CS3) 
-Post-treatment summary 
tables 
-On-treatment (CS3 period): CS3 Study Day ls Date of 
assessment 5 Last dose date+ 28 days 
-Post-treatment: Date of assessment> last dose date+ 
28 days 
-Visit defined by analysis visit window 
Safety 
Endpoints: 
abnormal lab, 
worst ECG, 
meeting 
Stopping rule 
-Listings 
-On-study summary tables 
(CS3) 
-Abnormal lab analyses described in Sections 3.3.4.1 to 
3.3.4.3 include post-baseline data collected from CS3 
Study Day 1 up to the day of the patient's last contact 
date within the study 
Safety 
Endpoints: AE 
-Listings 
-On-treatment (CS3) 
summary tables 
-On-study (CS3) summary 
tables 
-On-treatment: CS3 Study Day ls Date of assessment 5 
Last dose date + 7 days 
-On-study summary tables includes all treatment 
emergent adverse event (TEAE) in the OLE study, 
including those with onset dates> last dose date + 7 days 
Selected Safety 
Endpoints: 
abnormal lab 
and AEs 
- Longitudinal safety 
summary for overall parent 
study and OLEstudy 
- Longitudinal safety summary for overall parent study 
and OLE study include data collected from the first dose 
of ISIS 420915 in the parent study and ends on the day of 
the patient's last contact date within the study, (1) for 
subjects who enrolled in the OLE study, it is the last 
contact date within the OLE study; (2) for subjects who 
are not enrolled in the OLE study but had been 
administered ISIS 420915 in the parent study, it is the last 
contact date within the parent study. 
Concomitant 
medications 
-Listings 
-On-treatment (CS3) 
summary tables 
-On-study (CS3) summary 
table 
-On-treatment: CS3 Study Day ls Date of assessment s 
Last dose date + 7 days 
-On-study summary tables includes all concomitant 
medication in the OLE study, including those with onset 
dates > last dose date+ 7 days 
lmmunogenicity 
-Listings 
-On-study (CS2 and CS3) 
-On-study summary/analysis tables include data 
collected from the CS2 Study Day 1 up to the day of the 
 
41 


235 
 
 
Endpoint type 
Output type 
Comment/definition 
summary/ analysis tables 
patient's last contact date within the study (showing both 
CS2 visits and CS3 visits) 
-Visit defined by analysis visit window. 
PK 
-Listings 
-On-study (CS3) summary/ 
analysis tables 
-Summary/analysis tablesinclude data collected from 
CS3 Study Day 1 up to the day of the patient's last 
contact date within the study 
-PK concentration will be summarized based onnominal 
scheduled visits (showing CS3 visits) 
3.2.1.5 Multicenter Studies 
 
Approximately 135 patients are planned for the parent study may be eligible to enroll into this OLE 
study. Adjustment for investigative site in multivariable analyses is not planned. 
 
3.2.2 
Patient Populations Analyzed 
The following analysis populations are defined for this present OLE study: 
 
• 
Screened patients will be defined as patients who signed an informed consent form. 
 
• 
Enrolled patients will be defined as patients who signed an informed consent form and were not 
screen failures. 
• 
The FAS will include all enrolled patients who received at least 1 injection of ISIS420915 in the 
OLE study and who have at least one post-baseline efficacy assessment for the mNIS+7 score or 
Norfolk QOL-DN questionnaire total score collected after CS3 Study Day 1 in this OLE study. This 
will be the primary population for analysis of efficacy and PD outcomes. 
• 
The Safety Set (SS) will include all enrolled patients who received at least 1 injection of ISIS 
420915 in the OLE study. This population will beused for analyses of all safety measures 
collected in this OLE study. Results will be summarized under the treatment which the patients 
received in the parent study. 
• 
The Longitudinal Safety Set (LSS): will include all patients who received at least 1 injection of ISIS 
420915 in the parent study. This population will beused for the longitudinal safety analysis for 
either the parent study or this OLE study. Results will besummarized under the treatment which 
the patients received in the parent study. Note that this population will include patients who 
receive ISIS 420915 in the parent study but did not enter this OLE. It does not include patients 
who took placebo in CS2. 
• 
The PPS will include the subset of the Full Analysis Set that have received at least 70% of the 
prescribed doses of ISIS 420915 in this OLE study and that have no significant protocol 
deviations in the OLE study that would be expected to affect efficacy assessments. Prescribed 
doses of ISIS420915 mentioned above is defined as the total assigned dose in mg from the 
Week 1 to the last dose within this study up to week 156 (first three years), i.e. 300mg*156 
doses= 46800mg. Patients in FAS of this OLE study but excluded from PPS in the parent study 
will be excluded from the PPS in this OLE study as well. This will be a secondary population for 
42 


236 
 
 
efficacy and PD analyses. The detailed criteria and definitions for major protocol violations will 
be specified. Results will be summarized under the treatment which the patients received in the 
parent study. 
The PK Set will include all enrolled patients who received at least one dose of ISIS 420915 in the 
OLE study and have at least one evaluable PK sample collected and analyzed with reportable 
result in the OLE study. This population will be used for PK analyses. Results will be summarized 
under the treatment which the patients received in the parent study. 
The ECHO subgroup in the parent study will include the subset of the Randomized Set that 
qualified and consented for the ECHO sub study in the parent study. The ECHO subgroup in this 
OLE study will include the ECHO subgroup patients who are enrolled in this OLE study. Results 
will be summarized under the treatment to which patients were randomized in the parent 
study. 
The CM-ECHO set in the parent study will include the subset of the Randomized Set that meet at 
least one of the following criteria, 1) diagnosis of TTR cardiomyopathy at study entry, or 2) 
eligible to participate in the ECHO Subgroup in the parent study (whether consented or not). 
The CM-ECHO set in this OLE study will include the CM-ECHO set patients from the parent study 
who are enrolled in this OLE study. Results will be summarized under the treatment to which 
patients were randomized in the parent study. 
The CS3 ECHO Set will include the subset of the CS3 Enrolled Set who were not in the CM-ECHO 
Set in the parent study, and were randomized to placebo in the parent study and had an OLE 
 
 
All efficacy and PD endpoints (except ECHO parameters) will be assessed on the FAS and PPS. All 
safety assessments for this OLE study will be performed on the Safety Set. The longitudinal safety 
analysis will be performed on the Longitudinal Safety Set. PK endpoints will be assessed in the PK Set 
as applicable. 
 
3.2.3 
Patient Characteristics 
Patients disposition, including reasons for permanent discontinuation from ISIS 420915 or 
withdrawal from follow-up, and number of patients in each analysis population (FAS, PPS, SS, LSS, 
PKS, ECHO Subgroup, CM-ECHO Set), will be summarized by treatment group of the parent study 
and overall for all enrolled patients. 
Patient allocation by investigative site will be tabulated by parent study treatment group and 
overall for the all enrolled patients. 
Protocol deviations in OLE study will be listed and summarized by deviation category. 
The following patient demographic characteristics will be summarized by treatment group of the 
parent study and overall for the SS, FAS, PPS, PKS, CM-ECHO Set and ECHO subgroups: 
Sex, race, ethnicity, TTR genotype 
 
43 


237 
 
 
Age at the parent study screening and age at the OLE study screening 
Duration derived from the informed consent form signed date in the OLE study, including 
duration of disease from FAP diagnosis (months) and duration from onset of FAP symptoms 
(months) 
Number and percent of enrolled patients within each of the 3 randomization strata from the parent 
study (previous treatment with Vyndaqel® or Diflunisal; disease stage; V30M TTR mutation) will be 
summarized by treatment group of the parent study and overall for the SS, FAS, PPS, PKS, CM-ECHO 
Set and ECHO subgroups. 
The following will be provided for both parent study baselines and OLE study baselines defined in 
section 3.2.1.1 and for the SS, FAS, PPS, PKS, CM-ECHO Set and ECHO subgroups: 
Baseline severity of illness, including the NIS score, NIS+7, mNIS+7, PND score, mBMI, BMI, weight, 
height, and NT-proBNP will be summarized by parent study treatment group and overall. Measures 
of quality of life and level of functioning, including the baseline Norfolk QOL-DN total score and pre- 
dose SF-36 will also be included. Disease history collected in the parent study will be summarized for 
analysis sets defined above: Information on familial amyloid cardiomyopathy (FAC) will be 
summarized, including FAC diagnosis (Y/N) at parent study screening, duration of disease from FAC 
diagnosis (months), duration from onset of FAC symptoms (months), and clinical or laboratory 
criteria used to document the diagnosis of TTR cardiomyopathy. 
Missing/partial dates (month and year) for the duration of disease from diagnosis for FAP/FAC and 
duration from onset of symptoms for FAP/FAC will be imputed as follows: since CRF only collects 
year and month for FAP and FAC Diagnosis and onset of symptoms, for calculating the duration, a 
day of 15th will be used if only day is missing. JUL01 will be used if both day and month are missing. 
If the imputed date is after the date of informed consented at CS2, use the informed consented at 
CS2 as the imputed date. Calculate as following 
(a) Duration (month) = number of month (date of informed consented at CS3- date of FAP or FAC 
diagnosis + 1) 
(b) Duration (month) = number of month (date of informed consented at CS3- date of onset of FAP 
or FAC symptoms + 1) 
Exposure to Study Drug in OLE study will be summarized by treatment group of the parent study for 
the SS by durations of drug exposure in OLE study (days), total number of dose received, and total 
dose administered (in milligrams). Across all visits, number of subjects with dose pauses and 
reasons for dose pause will be tabulated. A listing presenting for each subject the number of dose 
reductions (frequency of administered dose < protocol defined dose, i.e. 300 mg) and missed doses 
(injection not givens) will be provided. Doses that were not given because the patient discontinued 
will not be summarized. 
Overall drug exposure from the start of the parent study to the end of the OLE study will be 
summarized for patients who took ISIS 420915 in the parent study, i.e. LSS. 
Medical history and baseline physical examination findings collected in the OLE study will be listed 
depending on the data availability. 
44 


238 
 
 
Medications will be coded using WHO Drug Dictionary. The final version used will be designated in 
the clinical study report. Concomitant medications used will be summarized by treatment group 
for the SS and the CM-ECHO Set. 
All medications including concomitant medications will also be listed in a by patient listing. In the 
listing, medications which are started before the CS3 Study Day 1 will be marked. 
Patients with any anti-platelet or anti-coagulant medication taken at any time during this study will 
be presented in a listing. 
A concomitant medication is defined as any medication taken whilst investigational product is being 
taken in this study. 
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 on-treatment and on-study concomitant medication defined relative to use of 
the investigational product are shown schematically in the diagram below. 
 
CM 
Scenario 
On-treatment 
Post-treatment 
On-treatment 
On-study 
1 
2 
3 
4 
5 
6 
7 
x ---------- x 
Y 
Y 
x ---------------------------------------- x 
x---- x 
? ---------- x 
? -------------------------- x 
Y 
Y 
N 
Y 
Y 
Y 
Y 
Y 
x ------------- ? 
x ----- ? 
Y 
Y 
N 
Y 
CM concomitant medication 
x = start/stop date/time 
? = missing date/time 
 
 
 
 
45 


239 
 
 
3.3 Safety Analyses 
All safety endpoints will be summarized for the OLE study SS. In patient listings, ISIS 420915 
baseline values and information collected in the OLE study will be displayed. In addition, 
longitudinal safety analysis of selected safety endpoints for LSS will be performed for patients on 
ISIS 420915 in the parent study. 
Safety endpoints include the following: 
Adverse events 
Vital signs and weight 
Physical examination 
Clinical laboratory tests 
ECG 
Ophthalmology and ERG examinations 
 
3.3.1 
Imputation of Missing/Partial Dates 
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. 
Note: Treatment start date mentioned above is CS3 Study Day 1 in general. In addition, special 
considerations should be given to AEs which started in the parent study but continued at the time 
the patient enrolled in the OLE study. If the AE was originally recorded in the CS2 database, the 
treatment start date mentioned above is from CS2 but not CS3 Study Day 1. 
 
3.3.2 
Adverse Events (AEs) 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). The final 
version used will be designated in the clinical study report. For each AE, the severity level of the 
event (mild, moderate, or severe) will be determined by physician opinion. 
TEAEs are defined as adverse events that first occurred or worsened after the first dose of Study 
Drug (ISIS 420915 or Placebo). This is the general definition of TEAEs. A detailed definition of TEAEs 
for safety analysis of the OLE study or for the longitudinal safety analysis will be discussed in section 
3.3.2.6 or in section 3.3.2.7, respectively. 
 
 
46 


240 
 
 
In this section, whenever first dose of ISIS 420915 is used, it refers to CS3 Study Day 1 for OLE study 
analysis and Day 1 of ISIS 420915 for longitudinal safety analysis. 
An AE with a completely missing start date will be assumed to be treatment emergent. 
If the maximum severity of the adverse event is greater than the baseline severity, i.e. severity prior 
to the first dose of ISIS 420915, or if the onset date/time is the same as or after the date/time of the 
first dose of ISIS 420915, then the event is considered to be treatment emergent. 
In the situation where change in severity (but no change in seriousness) occurs for an adverse event, 
study sites are instructed to enter an end date and start a new record for the adverse event. In the 
new record, the changed severity is to be recorded and the start date will be set to be the end date 
of the previous record. Data linking those records are collected in the database. Consider three 
scenarios: 
 
The first AE record occurs prior to the first dose of ISIS 420915, the second AE record occurs on 
or after the first dose of ISIS 420915, and the severity increases: Only the second record will be 
counted as treatment-emergent. 
The first AE record occurs prior to the first dose of ISIS 420915, the second AE record occurs on 
or after the first dose of ISIS 420915, and the severity decreases: Neither record will be counted 
as treatment-emergent. 
Both records occur on or after the first dose of ISIS 420915: If the AE severity on the second 
record is worse than the severity on the first record, then count both records as treatment- 
emergent. But, if the severity improves, then only count the first record as treatment- 
emergent. 
Of note, when counting the total number of treatment-emergent events, events linked through 
change in severity will still be counted as separate events. 
In addition, special considerations should be given to AEs which started in the parent study but 
continued at the time the patient enrolled in the OLE study. These situations may occur if the 
in the parent study. Records for these 
AEs will be created in the OLE study database with a different AE index number so that they can be 
updated with information collected in the OLE study, e.g. stop date and treatment. The following 
rules describe how these AEs will be handled in the OLE study analysis for SS and the longitudinal 
safety analysis for LSS: 
 
For AEs with the same Lower level term (LLT), complete start date and severity recorded in both 
the parent study and the OLE study: keep the record in the OLE Analysis Data Model (ADaM) 
dataset, but this record is not considered treatment emergent in CS3. In the longitudinal safety 
analysis, this record will be counted once (it is considered treatment emergent in CS2 and 
therefore considered treatment emergent in the longitudinal safety analysis). 
Note that an event which started during the gap period between the parent study and the OLE study 
will not be considered treatment emergent in the CS3 analysis, unless the severity of the event has 
increased after the first dose in CS3. Such events will be regarded as treatment emergent in the 
 
47 


241 
 
 
longitudinal safety analysis (see below) conducted on the LSS. Since subjects randomized to placebo 
in the parent study are not included in the LSS, if a placebo subject from the parent study 
experiences such an event, that event will not be summarized in any of the CS2, CS3 or longitudinal 
safety analyses. 
A listing will be provided stating which patients reported each preferred term. Adverse events in 
the following categories will be summarized separately: 
 
• Adverse events of special interest 
 
• Other adverse events of interest 
 
Summary tables of the number and percentage of patients with these adverse events will be 
displayed split by AEcategory and treatment group. TEAEs of special interest and other TEAEs of 
interest will also be summarized for patients in the CM-ECHO Set. 
3.3.2.1 Adverse Events of Special Interest (AES/) 
 
Adverse events of special interest (AESI) are those that require special collection and/or reporting. 
They are not necessarily those expected to be related to study drug or those most frequently 
occurring. 
The following adverse events have been identified as an important medical risk: 
 
AESI 
Definition 
Ocular adverse events related 
to vitamin A deficiency 
• AE with Higher level term (HLT): Fat soluble vitamin deficiencies and 
disorders; or 
• AE with PT: Vitamin A decreased; or 
• AE with PT: Vitamin A abnormal; or 
• AE within the Structured MedDRA query (SMQ): Optic nerve disorders; or 
• AE within the SMQ: Corneal disorders; or 
• AE within the SMQ: Retinal disorders. 
Thrombocytopenia 
• AE with HLT: Thrombocytopenias; or 
• AE with HLT: platelet analyses 
Renal Impairment 
AE within theSMQ: Acute renal failure 
 
 
3.3.2.2 Other Adverse Events of Interest 
The following list includes other adverse events that have been identified to be of interest: 
 
Other AEs of interest 
Definition 
Coagulation abnormalities 
AE with HLT: Coagulopathies 
Abnormal liver function 
AE within the SMQ: Drug related hepatic disorders - comprehensive search 
Adverse events at the injection 
site 
• AE with HLT: Injection site reaction; or 
• AE within HLT: Administration site reaction NEC. 
Flu-like symptoms 
• AE with PT: Influenza like illness; or 
 
48 


242 
 
 
Other AEs of interest 
Definition 
• AEwith PT: Pyrexia (or Feeling hot or Body temperature increased) plus at 
least one of the following symptoms: 
0 
Chills 
0 
Myalgia 
0 
Arthralgia 
0 
Malaise 
0 
Fatigue 
0 
Headache 
0 
Nausea 
Note that only events that start on the day of the injection or the day after 
injection will be included. AEs with partial or missing dates will be handled as 
follows. First establish whether the event is treatment emergent. If yes, then 
establish if the preferred terms match the ones listed in the flu-like symptoms 
definition. If yes, check whether the event onset dates are within the specified 
time frame. If at this stage, onset date is missing or partially missing, the event 
will be considered to have started within the required time frame. 
CNS disorders 
AE within System Organ Class (SOC): Nervous system disorder 
Haemorrhages 
AE within the SMQ: Heamorrhages 
Potential complement 
activation 
AE within SMQ: Hypersensitivity 
Reduced thryroxine 
AE within SMQ: Hypothyroidism 
Results by type of haemorrhagic eventsmay be provided; the type of haemorhagic events and 
respective definitions will bespecified prior to database lock. 
 
3.3.2.3 Local Cutaneous Reactions at Injection Site {LCRIS} 
 
The following MedDRA preferred terms are determined by the Sponsor's Pharmacovigilance 
personnel to represent the local cutaneous reaction at the injection site: 
• 
Injection site erythema 
• 
Injection site swelling 
• 
Injection site pruritus 
• 
Injection site pain 
• Injection site tenderness 
Only 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. AEs with partial or missing dates will be handled as follows. First establish whether the 
event is treatment emergent (Details ofTEAEdefinition see section 3.3.2.6 for TEAEoccurred during 
the OLEstudy and section 3.3.2.7 for TEAEfor overall including the parent study and OLE study). If 
yes, then establish if the preferred terms match the ones listed in the LCRISdefinition. If yes, check 
whether the event onset dates are within the specified time frame. If at this stage, onset date is 
 
49 


243 
 
 
missing or partially missing, the event will be considered to have started within the required time 
frame. 
The number and percent of patients in each treatment group of the parent study experiencing LCRIS 
will be tabulated. 
Percentage of injections leading to local cutaneous reactions at the injection site will also be 
summarized. Percentage of injections leading to local cutaneous reactions 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. 
3.3.2.4 Flu-Like Reactions 
 
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: 
o Chills 
o Myalgia 
o Arthralgia 
Only events that start on the day of injection or the day after injection will be included. AEs with 
partial or missing dates will be handled as follows. First establish whether the event is treatment 
emergent (Details of TEAE definition see section 3.3.2.6 for TEAE occurred during the OLE study and 
section 3.3.2.7 for TEAE for overall including the parent study and OLE study). If yes, then establish if 
the preferred terms match the ones listed in the flu-like reactions definition. If yes, check whether 
the event onset dates are within the specified time frame. If at this stage, onset date is missing or 
partially missing, the event will be considered to have started within the required time frame. 
The number and percentage of patients in each 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 (A/B)*100, where A is the 
number of injections associated with a flu-like reaction, and B is the total number of injections. 
3.3.2.5 Mortality 
Death that occurs after the first dose of ISIS 420915 will be analyzed as follows: 
Time from Day 1 of ISIS 420915 to the date of death for LSS and time from CS3 Study Day 1 to the 
date of death for SS 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. 
3.3.2.6 OLE Study Analysis of TEAEs 
TEAEs which occur during the OLE study include TEAEs which first occurred or worsened on or after 
CS3 Study Day 1. Derivation is described in Section 3.3.2. 
50 


244 
 
 
The following categories of AEs in the OLE study will be summarized by treatment group from the 
parent study: all TEAEs; TEAEs leading to early discontinuation from Study Drug or from the study; 
and serious adverse events. The percentage of patients reporting the adverse event will be 
summarized by MedDRA System Organ Class (SOC) and Preferred Term (PT), and will be sorted by 
SOC alphabetically and then by decreasing frequency of PT within SOC. 
Summaries of drug related TEAEs, TEAEs by maximum severity, TEAEs grouped by duration of 
exposure to the Study Drug at the start of the event (
 
months to < 24 
 months to < 
 
< 1 
will also be provided. Duration of exposure and the 
number of doses is calculated from CS3 Study Day 1 to the start date of event. 
All TEAEs will be summarized for subgroups defined by the following variables: 
Age at parent study screening (<65 years and >=65 years), 
Sex (Female and Male), 
Race (White, non-White), 
Region (North America, Europe and South America /Australasia), 
CM-ECHO Set (Included and Not Included). 
As well as stratification factors at randomization during the parent study, including 
V30M TTR mutation (Yes, No), 
previous treatment with Vyndaqel® or Diflunisal (Yes, No), 
Disease stage (Stage 1 and Stage 2). 
Results will not be provided for a variable if the overwhelming majority of patients are within one 
level of the subgroup. Non-TEAEs reported will be flagged in the all AE listing. 
TEAEs in the following categories will also be summarized in tables and listed separately: 
Adverse events of special interest (defined in section 3.3.2.1) 
Other adverse events of interest (defined in section 3.3.2.2) 
Local cutaneous reactions at injection site (defined in section 3.3.2.3) 
Flu-like reactions (defined in section 3.3.2.4) 
Summary tables of the number and percentage of patients with these adverse events will be 
displayed split by AE category and treatment group received in the parent study. 
Mortality defined in section 3.3.2.5 on SS will be summarized. 
A plot of incidence rates and relative risks for common TEAEs, with an incidence of 5% or more, by 
treatment group assigned in the parent study will be provided. 
 
51 


245 
 
 
Summary of non-serious common TEAEs, with an incidence of 5% or more, will be presented by 
Preferred Term. 
Summary tables of the number and percentage of patients with drug related bleeding TEAEs will be 
presented by bleeding location and Preferred Term. 
3.3.2.7 Longitudinal Safety Analysis of TEAEs 
For this summary TEAEs are defined as those events which first occurred or worsened on or after 
first dose of ISIS in the parent study. 
Adverse events summaries including data from the combined study periods of the parent and OLE 
studies will be provided for subjects in the LSS analysis population. These summaries will include all 
TEAEs which started on or after the first dose of ISIS 420915 in the parent study and before the day 
would be the one obtained from the OLE study. For subjects who are not enrolled in the OLE study 
the last contact date would be the one obtained from the parent study. Note that AEs which started 
during the gap period between the completion of the parent study and the first dose of the OLE 
study and are not considered TEAEs in the OLE study will still be included in these summaries. In 
other words, it is possible that there will be events which are not considered parent study TEAEs or 
OLE study TEAEs, but will be counted towards this analysis. 
These TEAEs will be summarized for subgroups defined by the following variables: Age at parent 
study screening (<65 years and >=65 years), Sex (Female and Male), Race, Region (North America, 
Europe and South America /Australasia), and CM-ECHO Set (Included and Not Included). Results will 
not be provided for a variable if the overwhelming majority of patients are within one level of the 
subgroup. 
Summaries of drug related TEAEs, TEAEs by maximum severity, adverse events leading to early 
withdrawal from Study Drug, TEAEs duration of exposure to Study Drug at the start of event (< 6 
 60 months)and Number of doses at the 
start of event (
 
 
) will also be provided. Duration of exposure and the number of doses is calculated from 
Day 1 of ISIS 420915 to the start date of event. 
TEAEs in the following categories will also be summarized in tables and listed separately: 
Adverse events of special interest (defined in section 3.3.2.1) 
Other adverse events of interest (defined in section 3.3.2.2) 
Local cutaneous reactions at injection site (defined in section 3.3.2.3) 
Flu-like reactions (defined in section 3.3.2.4) 
Summary tables of the number and percentage of patients with these adverse events will be 
displayed split by AE category. 
Mortality defined in section 3.3.2.5 on LSS will be summarized. 
52 


246 
 
 
3.3.3 
Vital Signs, Weight, and Physical Examination Findings 
Vital signs include systolic and diastolic blood pressure, pulse, respiratory rate, and temperature. 
Weight will also be analyzed. Absolute value at each visit, change and percent change from ISIS 
420915 baselines to each visit in vital signs and weight will be summarized by treatment group of 
the parent study. Same summary for weight will also be presented based on the parent study 
baseline and the OLE study baseline. No statistical comparisons between treatments will be 
performed for this summary. 
All vital signs and weight will be listed. Physical examination findings will also be listed. 
 
3.3.4 
Laboratory Measurements 
Laboratory tests to ensure patient safety include chemistry panel, complete blood count with 
differential, thyroid panel, coagulation panel, immunogenicity, inflammatory panel, complement, 
and urinalysis. Absolute value, change and percent change from ISIS 420915 baselines will be 
summarized by visit and treatment group for continuous laboratory tests. No statistical 
comparisons between treatments will be conducted for these summaries. The mean value (and 
associated standard error) will be plotted by treatment group in the parent study or by V30M TTR 
mutation at randomization during the parent study over visits for the following laboratory 
parameters: platelets, creatinine clearance by CKD-EPI, Albumin, urine AC ratio, and urine PC ratio. 
Summary for Albumin will also be presented based on the parent study baseline and the OLE study 
baseline. 
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 ADaM dataset and will include all central lab records. The 
local lab listing will be based on the SDTM dataset. A separate listing for platelets will be provided 
that includes assessment from both the local and central labs. A separate listing will contain only 
values outside of normal ranges. The number and percent of patients that stopped treatment 
because met a protocol-defined stopping rule for liver function, renal function, or platelet counts 
will be tabulated by treatment group of the parent study. 
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 value is based on a consecutive lab value performed on a different day to, but within 7 
days of, the initial value. If that value is in the same or worse category then the initial value is 
confirmed. If the consecutive value is in a better category then the initial value is confirmed using 
the consecutive value category. If there is no retest within 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. 
3.3.4.1 Hepatobiliary Laboratory Abnormalities 
The number and percentage of patients falling in each of the following categories based on all post- 
baseline assessments of the OLE study, including scheduled and unscheduled assessment on-study 
53 


247 
 
 
 
 
within the study, will be provided: 
 
Upper limit of normal (ULN) 
(with both events for any post- 
baseline results) 
 
 
both events for any post-baseline results) 
 
results) 
 
(with both events for post-baseline 
A 
(with all three events for any post- 
baseline results) 
Hepatocellular injury 
Hepatocellular 
(with both events for any post-baseline 
results) 
 
 
AL 
 
 
 
 
 
 
 
- < 5xULN 
- < 10xULN 
- < 20xULN 
 
(ISIS 420915 baseline ALP < 2xULN or ISIS 420915 baseline ALP missing) 
ISIS 420915 baseline 
ISIS 420915 baseline 
 
, the time from CS3 Study Day 1 
3 xULN will be summarized using the following descriptive statistics: mean, standard deviation, 
median, P25, P75, and minimum and maximum. 
Shift tables from baseline for ALT, AST, and total bilirubin based on peak (maximum) and confirmed 
 
will be 
 
A hepatocellular 
 
the ALT and ALP assessments done on the same day. 
 
54 


248 
 
 
Shift tables from baseline will be provided using the nadir value and the confirmed nadir category. 
/L
The categories listed above will also be analyzed using AST instead of ALT. For these analyses the 
definition of hepatocellular injury will not be changed to depend on AST. 
3.3.4.2 Platelets 
The number and percentage of patients falling in each of the following categories (using available 
central and local laboratory assessments combined) based on post-baseline assessments, including 
scheduled and unscheduled assessment on-study period which spans the time drug is administered 
 
Platelet count decrease - Grade 
 
 
Platelet count decrease - 
  
 
Platelet count decrease - 
 
Platelet count decrease - 
 
Platelet count decrease - Grade 4 [< 25 x 10^9/L] 
Confirmed Platelet count decrease - 
 
Confirmed Platelet count decrease - 
 
Confirmed Platelet count decrease - 
 x 10^9/L ] 
Confirmed Platelet count decrease - 
 
Confirmed Platelet count decrease - Grade 4 [< 25 x 10^9/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) 
Value < 140 x 10^9/L 
 the ISIS 420915 baseline 
 the ISIS 420915 baseline 
Confirmed value < 140 x 10^9/L 
Confirmed value < 100 x 10^9/L 
Confirmed value < 75 x 10^9/L 
Confirmed value < 50 x 10^9/L 
Confirmed value < 25 x 10^9/L 
Note that a platelet value of 140 x 10^9/L is the lower limit of normal for the central laboratory and 
will be used as the LLN for all platelet assessments. Furthermore, the platelet counts that define 
platelet count decrease grades are based on interactions with a regulatory authority, and align with 
the definitions from the National Cancer Institute Common Terminology Criteria for Adverse Events 
version 4.03 (except that the CTCAE does not subdivide Grade 1 into Grade 1a and 1b). 
 
 
Time from CS3 Study Day 1 to the onset of each of these events collected in the OLE study will be 
summarized for the patients in SS that met the criterion. Summaries including the following 
descriptive statistics: mean, standard deviation, median, P25, P75, and minimum and maximum. 
 
55 


249 
 
 
2 
Kaplan-Meier plots for time to first event will also be provided for value < 140 x10^9/L, value < 100 
x10^9/L and value < 75 x10^9/L . 
The post-baseline nadir (absolute value, change from the ISIS 420915 baseline, and percent change 
from the ISIS 420915 baseline) of platelet count will be summarized by treatment group of the 
parent study. 
Duration of platelet counts below the 140 x 10^9/L will be summarized, based on the duration (in 
weeks) each patient was below the 140 x 10^9/L. 
The above analyses will be repeated for the subgroups defined by CM-ECHO Set. 
Scatter plots for nadir platlets versus the ISIS 420915 baseline of BMI, mBMI, and weight will be 
provided. 
A listing of patients with dose pause due to Platelet < 75 x10^9/L will also be provided. 
3.3.4.3 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, including scheduled and 
unscheduled assessment on-study period which spans the time drug is administered until the day of 
 
 will be provided: 
Creatinine clearance by CKD-EPI < 90 mL/min/1.73m2 
Creatinine clearance by CKD-EPI < 60 mL/min/1.73m2 
Creatinine clearance by CKD-EPI < 30 mL/min/1.73m2 
Creatinine clearance by CKD-EPI < 15 mL/min/1.73m2 
Creatinine clearance by CKD- 
 the ISIS 420915 baseline 
Creatinine clearance by CKD- 
 the ISIS 420915 baseline 
Urine Alb/C ratio > 5 x ULN 
Urine P/C ratio > 5 x ULN 
Serum creatinine increase > 44.2 umol/l (0.5 mg/dL) from the ISIS 420915 baseline 
Confirmed creatinine clearance by CKD-EPI < 90 mL/min/1.73m2 
Confirmed creatinine clearance by CKD-EPI < 60 mL/min/1.73m2 
Confirmed creatinine clearance by CKD-EPI < 30 mL/min/1.73m2 
Confirmed creatinine clearance by CKD-EPI < 15 mL/min/1.73m2 
Confirmed creatinine clearance by CKD- 
 the ISIS 420915 baseline 
Confirmed creatinine clearance by CKD- 
 the ISIS 420915 baseline 
Confirmed urine Alb/C ratio > 5 x ULN 
Confirmed urine P/C ratio > 5 x ULN 
Confirmed serum creatinine increase > 44.2 umol/l (0.5 mg/dL) from the ISIS 420915 baseline 
Shift tables from baseline for creatinine clearance by CKD-EPI will be provided using the nadir value 
and the confirmed nadir category. Categories for the shift ta 
 
 
56 


250 
 
 
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. 
Shift tables from baseline for hemoglobin will be provided using the nadir value. Categories for the 
shift table will be 
 - 100.0 g/L, Mild), Grade 2 (< 100.0 - 80.0 
g/L, Moderate) and Grade 3 (< 80.0 g/L, Severe). 
The above analyses will be repeated for the subgroups defined by CM-ECHO Set. 
3.3.4.4 Longitudinal Safety Analysis of Laboratory Measurements 
Laboratory measurements summaries including data from the combined study periods of the parent 
and OLE studies will be provided for subjects in the LSS analysis population. These summaries will 
include lab results specified in this section which occurred on or after the first dose of ISIS420915 in 
the parent study and before 
         . For subjects who enrolled in 
the OLE study, the last contact date would be the one obtained from the OLE study. For subjects 
who are not enrolled in the OLE study, the last contact date would be the one obtained from the 
parent study: 
 
Hepatobiliary laboratory abnormalities (defined in section 3.3.4.1); 
 
Platelets (defined in section 3.3.4.2); 
Note: For longitudinal safety analysis, Time to events will be started from Day 1 of ISIS 420915 
instead of Study Day 1. 
 
Renal parameters (defined in section 3.3.4.3) 
Summaries for these abnormal lab test results will be provided for patients on active treatment in 
the parent study in LSS. 
 
3.3.5 
Electrocardiograms 
Absolute value, change and percent change from the ISIS 420915 baseline in ventricular rate and 
ECG intervals (PR, QRS, QT, 
formula [QTcF], QT interval corrected for heart rate int 
[QTcB]) will be presented by treatment group of the parent study and visit. Shift tables from the ISIS 
420915 baseline to the worst (highest) post-baseline value by treatment group of the parent study 
will be used to assess the change in the QTcF interval. The categories for the shift table will be: 450 
msec, >450 msec to 480 msec, >480 msec to 500 msec, and > 500 msec. The number and 
percent of patients experiencing an increase from baseline in QTcF interval of greater than 30 msec 
or 60 msec at any time post-baseline will be summarized by treatment group of the parent study. 
This analysis will be presented overall and also by the subgroup whose QTcF was normal at the ISIS 
420915 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. These analyses will be repeated for patients in the CM-ECHO Set. No statistical 
comparisons between treatments will be performed for these summaries. 
 
57 


251 
 
 
Ventricular rate and ECG intervals (PR, QRS, QT, QTcF, QTcB), as well as treatment-emergent 
abnormalities, will be listed. The number and percent of patients that stopped treatment because 
they met a protocol-defined stopping rule for QT interval corrected for heart rate prolongation will 
be tabulated by treatment group of the parent study. This tabulation will be repeated for patients in 
the CM-ECHO Set. 
The ECG over-read data are used to support medical monitoring and will not be used for the ECG 
summary and analysis. A by-subject listing of ECG over-read data will be provided. 
 
3.3.6 
Electroretinograms (ERG) and Ophthalmology Exam 
Change from the ISIS 420915 baselines in ERG results will be summarized by treatment group of the 
parent study. 
ERG results will be listed. Ophthalmology exam findings will be listed. The number and percent of 
patients reaching protocol defined stopping rules for ocular effects will be tabulated by treatment 
group of the parent study. 
 
3.4 Efficacy Analyses 
All analyses and summaries by visits will be performed based on analysis visits defined in the section 
3.2.1.3 
 
 
3.4.1 
Descriptive Statistics 
For all efficacy endpoints, descriptive summary statistics for absolute values, change or percent 
change from baseline, if applicable, will be provided by analysis visits for FAS and PPS. 
For change or percent change from the parent study baseline, analysis visits are defined for Week 
35 and Week 65 or 66, if applicable, from the parent study and for Week 26, Week 52, Week 78, 
Week 104, Week 130 and Week 156 in the OLE study. Analysis visits of Year 4 Week 52 and Year 5 
Week 52 will also be included for NIS, Norfolk QOL-DN, SF-36 Questionnaire and PND Score. 
For change or percent change from the OLE study baseline, analysis visits are defined for Week 26, 
Week 52, Week 78, Week 104, Week 130 and Week 156 in the OLE study. Analysis visits of Year 4 
Week 52 and Year 5 Week 52 will also be included for NIS, Norfolk QOL-DN, SF-36 Questionnaire and 
PND Score. 
By patient listings for all efficacy endpoints will be provided. 
For the two primary endpoints (mNIS+7 score and Norfolk QOL-DN total score), data collected 
outside the analysis windows in the OLE study, e.g. before Week 26, Week 26 to Week 52, Week 52 
to Week 78, Week 78 to Week 104, Week 104 to Week 130, Week 130 to Week 156, and after Week 
156 will not be summarized. These data will be included in the listings. 
For mNIS+7 score and Norfolk QOL-DN total score, descriptive statistics by subgroup and treatment 
groups of the parent study will also be provided for the following subgroups: 
Stratification factor: V30M TTR mutation (Yes, No) 
 
58 


252 
 
 
 
 
 
Race (White, non-White) 
Sex (Male, Female) 
Region (North America, Europe, South America /Australasia) 
Previous treatment with Vyndaqel® or Diflunisal (Yes, No) prior to the parent study 
Disease stage at the parent study screening (Stage 1, Stage 2) 
CM-ECHO Set (Included, Not included) 
Through the whole OLE study, if the patient took any Vyndaqel® (Yes, No) 
 
3.4.2 
Efficacy Endpoints: mNIS+7 Score and Components, Norfolk QOL-DN Total Score and 
Domain Scores 
The efficacy endpoints that are statistically analyzed are the following 
Change and percent change in the mNIS+7 score from either the parent study baseline or the 
OLE study baseline to Week 78 and Week 156 
Change in the Norfolk QOL-DN questionnaire total score from either the parent study baseline 
or the OLE study baseline to Week 78 and Week 156 
Change in the mNIS+7 components (NIS, heat-pain sensory, touch-pressure sensory, nerve 
conduction and heart rate to deep breathing tests) from either the parent study baseline or the 
OLE study baseline to Week 78 and Week 156 
Change in the Norfolk QOL-DN questionnaire domain scores (symptoms domain score for Stage 
1 patients, and physical functioning/large fiber neuropathy domain score for Stage 2 patients) 
from either the parent study baseline or the OLE study baseline to Week 78 and Week 156 
The maximum mNIS+7 composite score is 346.32 points. It can be broken into two components: the 
NIS component (maximum of 244 points) and the modified +7 component (maximum of 102.32 
points). It can be further divided into the following 8 components: cranial nerves, muscle weakness, 
reflexes, sensory, heart rate deep breathing, nerve conduction, touch-pressure sensory, and heat- 
pain sensory. 
The normal deviates (nds) from heart rate deep breathing and nerve conduction will be used in 
calculation of mNIS+7. 
The mNIS+7 assessment is conducted at the parent study baseline (2 times), Week 35, 66 (2 times), 
the OLE study Week 26, 52, 78 (2 times), 104, 130 and 156 (2 times) visit. For visits where repeated 
assessments are done, the average will be used for analysis. Subcomponent scores will be averaged 
first, and the average composite score will be computed by summing the averaged subcomponent 
scores. 
3.4.2.1 Additional Efficacy Analysis on the Change from the Parent Study Baseline 
The following additional analysis will be done for mNIS+7 score and Norfolk QOL-DN total score: 
59 


253 
 
 
Degree of Progression The degree of progression in the parent study and this OLE study will 
be summarized using the FAS. The degree of progression is defined as the change in the 
endpoint per one month. The degree of progression and corresponding 95% CI will be derived 
separately for each treatment group. A plot of degree of progression over time by treatment 
group assigned in the parent study will also be provided. The degree of progression will be 
derived over the 15 months treatment period of the parent study and then over 12 months 
treatment intervals in the OLE study. The degree of progression will be summariezed described 
in section 3.4.1as follows: 
o Average monthly progression over the first 15 months (i.e. from the first dose administered to 
Week 66 in the parent study) will be derived by dividing the estimated change from parent 
study baseline to Week 66 by 15. 
o Average monthly progression over the first 12 month interval in the OLE study will be 
estimated by dividing the estimated change from Week 66 in the parent study to Week 52 in 
this OLE study by 12. 
o Average monthly progression over the second 12 month interval in the OLE study will be 
estimated by dividing the estimated change from Weeks 52 to Week 104 in this OLE by 12. 
o Average monthly progression over the third 12 month interval in the OLE study will be 
estimated by dividing the estimated change from Weeks 104 to Week 156 in this OLE by 12. 
 
Responder Analysis for mNIS+7 score 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 using the OLE study FAS. A responders is defined as a patient 
whose mNIS +7 score change from the parent study baseline to the respective post-baseline 
visit in the OLE study, i.e. Weeks 26, 52, 78, 104, 130, 156 from the OLE study, is less than or 
equal to the threshold value. Threshold values to be tested will include 0, 2, 4, 6, 8, 10, 15, 20, 
30 points above the baseline values. For each response threshold, the response rates at each 
post-baseline visit in the OLE study for both the treated group and the placebo group will be 
calculated and plotted against the response threshold. Evaluable patients that terminate 
treatment early irrespective of the reason or had missing the respective post-baseline visit in the 
OLE study data will be considered a non-responder. Because a patient may not be followed in 
the OLE long enough to contribute data at a visit, the analysis at a visit is limited to evaluable 
patients, defined as patients who are in the study longer than the upper bound of analysis visit 
window for that visit (see Table 1 of Appendix 3 Analysis Visit Windows). For example, the week 
26 window extends up to day 206, and a patient would be considered evaluable at Week 26 if 
(data cut date first dose date) was more than 206 days. 
The efficacy analyses described in this section will be repeated using the OLE study PPS. 
3.4.2.2 Additional Efficacy Analysis on the Change from the OLE Study baseline 
 
The following additional analysis will be done for mNIS+7 score: 
 
Responder Analysis for mNIS+7 score described in section 3.4.2.1 based on the change in 
mNIS +7 score from the OLE study baseline will be performed. 
 
60 


254 
 
 
The efficacy analyses described in this section will be repeated using the OLE study PPS. 
 
3.4.3 
Other Efficacy Endpoints 
Descriptive statistics, as described in section 3.4.1 (but without stratification by subgroup) will also 
be provided for the following efficacy endpoints: 
Change and percent change in mBMI and BMI from either the parent study baseline or the OLE 
study baseline to Week 78 and Week 156 in the FAS and PPS 
Shift table from either the parent study baseline or the OLE study baseline in PND score from 
to Week 78 and Week 156 in the FAS and PPS 
Change and percent change from either the parent study baseline or the OLE study baseline in 
NT-proBNP in the FAS, PPS, ECHO subgroup and CM-ECHO Set. Change in log-transformed NT- 
proBNP from either the parent study baseline or the OLE study baseline to Week 78 and Week 
156 in the FAS, PPS, ECHO subgroup and in the CM-ECHO Set 
Change and percent change in the SF-36 questionnaire domain scores, including Physical 
Component Summary Score, Mental Component Summary Score, and Mental Health Domain 
Score from either the parent study baseline or the OLE study baseline to Week 78 and Week 
156 in the FAS and PPS 
Change and percent change from either the parent study baseline or the OLE study baseline to 
Week 78 and Week 156 in NSC in the FAS and PPS 
Change and percent change from either the parent study baseline or the OLE study baseline to 
Week 78 and Week 156 in the NSC individual domain scores (muscle weakness, sensory 
[hypo/loss of sensation], sensory [paresthesia, hyper sensation], autonomic [GI/urinary 
incontinence], and autonomic [other than GI//urinary incontinence]) in the FAS and PPS. 
Analysis for ECHO will be included in a separate SAP for the following endpoints: 
Change and percent change in GLS by ECHO from either the parent study baseline or the OLE 
study baseline to Week 78 and Week 156 in the parent study ECHO subgroup, OLE ECHO set 
and in the Cardiomyopathy-ECHO (CM-ECHO) Set 
Change and percent change in the ECHO parameters (except GLS) in the parent study ECHO 
subgroup, OLE ECHO set and in the CM-ECHO Set from either the parent study baseline or the 
OLE study baseline to Week 78 and Week 156 
Note that the 7 point change score (-3, -2, -1, 0, 1, 2, 3) that is recorded on the NSC questionnaire 
will be listed but not summarized or analyzed. Similarly for questions 20-29 the location is only 
listed. Questions 31-34 are of particular interest and therefore the number and percentage of 
patients responding 0 (No), 1 (slight +), 2 (moderate ++) or 3 (severe +++) will be presented. 
 
3.5 Pharmacodynamic (PD) Analyses 
Descriptive statistics as described in section 3.4.1 (but without stratification by subgroup) will also 
be provided the following PD endpoints: 
61 


255 
 
 
Change and percent change in TTR level from either the parent study baseline or the OLE study 
baseline to Week 78 and Week 156 
Change and percent change in RBP4 level from either the parent study baseline or the OLE 
study baseline to Week 78 and Week 156. 
In addition the proportion of patients with percentage decrease from either the parent study 
baseline or the OLE study baseline in plasma transthyretin (TTR) 60% will be summarized by 
parent study treatment group at each visit. 
As not all subjects will get to year 4 and 5 of the study, data from year 4 and 5 will be summarized as 
described in section 3.4.1. 
 
3.6 Pharmacokinetic (PK) and Immunogenicity (IM) Analyses 
PK endpoints include the following: 
Plasma trough and post-treatment levels of ISIS 420915 in all evaluable patients in the OLE study 
PK set 
IM endpoints include the following: 
IM status [confirmed positive/negative or unevaluable and, when applicable, titer of anti-ISIS 
420915 antibodies (ADA)] in all patients in the OLE study SS 
 
peak titer, time to reach peak titer, etc.) in the OLE study SS 
Plasma samples will be collected at protocol designated times for ISIS 420915 plasma PK and IM 
assessments. 
 
3.6.1 
Plasma Pharmacokinetics 
Plasma concentrations of ISIS 420915 will be summarized at interim analyses and final analysis at 
EOS of the OLE study. 
Plasma concentrations of ISIS 420915, along with the scheduled (nominal) and actual sampling 
times (i.e., time from subcutaneous dosing) will be listed for each evaluable patient by treatment 
group of the parent study, actual dose, gender, patient immunogenicity (IM) status, and study day. 
Percent differences between nominal and actual dose, as well as between scheduled and actual 
sampling times will also be listed for all patients. 
ISIS 420915 plasma trough (predose) concentrations will be summarized using descriptive statistics 
by dose, study day, and scheduled time point, without and with stratification by prior treatment in 
the parent study and patient IM status (see Section 3.6.2). For the purpose of calculating typical 
summary descriptive statistics (n, mean, SD, %CV, geometric mean, geometric %CV, percentiles 
(e.g., median, P25, and P75), 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, and %CV will be reported as not applicable. Other stratifications may also be 
62 


256 
 
 
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, ISIS 420915 plasma trough (predose) concentrations versus time (actual) 
profiles 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 prior treatment in the parent study and patient immunogenicity 
status (see Section 3.6.2). 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. 
 
3.6.2 
Immunogenicity (IM) Analyses 
Samples collected during treatment and post-treatment period, including early termination and 
unscheduled samples for IM assessment as specified in the study protocol will be analyzed for ADA. 
However, plasma samples collected at other time points (or for PK purposes) may also be potentially 
evaluated if deemed of further interest and warranted by the pharmacokinetic scientist. Samples 
that are confirmed IM positive are subjected for titering, which may include but not limited to the 
samples collected on Days 85, 176, 358, 540, 722, or 1086 during treatment period. 
 
confirmation assay results (i.e., confirmed positive result); otherwise, the 
 
and when applicable, titer of anti-ISIS 420915 antibodies) during and after treatment with study 
drug (ISIS 420915 
 
study, dose, and study day. 
Patient IM status: 
positive sample result at any time during the treatment or post-treatment evaluation periods. Study 
 
and post-treatment evaluation periods are IM negative and they have at least one evaluable IM 
 
status. Subject IM results will be listed by treatment group of the parent study and dose for all 
evaluable patients, which will include but may not be limited to: patient IM status (positive, negative 
or unknown), the day associated with the first positive IM status emerged since receiving ISIS 
420915 treatment (Tfirst, i.e., onset of ADA development as described below), the last positive IM 
status observed (Tlast), the last evaluable IM sample collected (Tlast sampling), peak titer, and time to 
reach peak titer. 
 
 
 
63 


257 
 
 
Onset of immunogenicity: The onset (Tfirst) of anti-ISIS 420915 antibodies for OLE study will be 
derived as the difference between the date when first immunogenicity sample becomes confirmed 
positive (i.e., positive sample IM status) and Day 1 of ISIS 420915 plus one. 
If a patient has confirmed positive IM samples detected on or prior to Day 1 of ISIS 420915, e.g., 
pre-existing antibodies cross-react with ISIS 420915, the onset in the OLE study for that patient 
Other immunogenicity data analysis (e.g. classification as persistent or transient status, etc.) may 
be performed as described below (Shankar et al, 2014) if deemed warranted at the discretion of the 
pharmacokineticist, medical monitor, and/or biostatistician. 
Transient ADA response will be defined as: 
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 ought to 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 
of any 
 
sampling time point is ADA-negative. 
Persistent ADA response will be defined as: 
Treatment-induced ADA detected at two or more sampling time points during the treatment 
(Including follow-
    -positive samples (irrespective of any 
negative samples in between) are separated by a period of 16 weeks or longer or 
Treatment-induced ADA incidence only in the last sampling time point of the treatment study 
period or at a sampling time point with less than 16 weeks before an ADA-negative last sample. 
The sample IM incidence (number) and incidence rate (percent) at each evaluated study time point, 
and for the overall treatment and post-treatment evaluation period, as well as subject IM incidence 
and incidence rate, will be determined and appropriately summarized by treatment group of the 
parent study, as the total number of and percentage of evaluated subjects with IM negative, 
positive, and unknown status. Subjects with positive IM status may further be classified as transient 
or persistent status if applicable, with incidence and incidence rate being transient or persistent 
appropriately summarized. Furthermore, onset, titer over time, peak titer of the ADA response, and 
time to reach peak titer, if applicable, will be also appropriately summarized (using descriptive 
statistics) as median, quartiles (25% and 75%), and range and presented graphically, if deemed 
appropriate, by treatment group of the parent study (e.g., summarized at each evaluated study time 
point and overall; summarized by observed peak titer values from the individual IM positive 
patients; etc.). 
 - Day 1 of ISIS 420915 
+1; 
Time to reach peak titer in days = The date of peak titer observed- Day 1 of ISIS 420915 +1; 
64 
(Including follow- 
-positive samples (irrespective 


258 
 
 
In addition to PK assessments (Section 3.6.1), selected efficacy (Sections 3.4 to 3.5) and safety 
(Section 3.3) assessments will also be further stratified by patient IM status (i.e., patient IM status 
being positive, negative, or unknown) and presented in tables and/or graphically, as deemed 
appropriate or warranted by the designated study pharmacokineticist, medical monitor, and/or 
biostatistician. Efficacy measures to be stratified by patient IM status will include, but may not be 
limited to, TTR level, mNIS+7, and Norfolk QOL-DN score. Safety measures to be stratified by 
patient IM status will include, but may not be limited to, AEs, and lab tests for hematology and 
kidney functions. 
Other stratifications (e.g., based on antibody titer, onset of 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. Sample Size 
No sample size calculations were performed as this is an extension study to the double-blind, 
placebo-controlled ISIS 420915-CS2 study. Approximately 135 patients were planned to be eligible 
to enroll into this present OLE study. 
 
5. Interim Analyses 
Database closing and locking will be done at the following milestones: 
1. When all patients in the parent study have completed the EOT assessments, the OLE study 
database will be cleaned and will be unblinded according to CS2 unblinding plan. Therefore, 
all treatment information is available for this OLE study to the team specified in the CS2 
unblinding plan. This interim analysis will be used to support the FAP regulatory file. For this 
interim analysis the data cut-off date utilized was prior to the last subject completing EOT 
assessments in the parent study CS2 to allow sufficient time for data cleaning prior to 
closing the database for analysis. 
2. After all patients complete the study (at EOS). This will be considered the final analysis of 
this OLE study. 
Additional closing and locking may be done to support additional interim analyses, with the timing 
of the database closing and locking coinciding with regulatory requirements or study milestones. 
 
5.1 Interim Analysis at EOT of the Parent Study 
A planned interim analysis of the OLE study based on cleaned database will be performed after all 
patients in the parent study have completed EOT assessments and the parent study is unblinded 
according to CS2 unblinded plan. 
The following will not be performed as part of this interim analysis: 
 
Summaries using PPS 
The review of protocol deviations to identify those leading to exclusion from the PPS 
65 


259 
 
 
The table below lists what data will be included in the summary output by endpoint type and what 
output is planned for this interim analysis at the parent study EOT. 
 
Provided at interim of OLE study (at parent study EOT) 
Comment 
Patient Characteristics 
• Summaries of patient disposition, protocol deviations, 
analysis sets. 
- For all enrolled patients 
• Summary of demographic characteristics and baseline 
characteristics and exposure to Study Drug. 
- For SS 
• Concomitant medication. 
- On-study summary for SS 
• The longitudinal safety analysis of exposure to Study 
Drug. 
- For LSS 
• Corresponding listings. 
Efficacy and PD 
• By visit summary table for each endpoint, Include 
summary statistics (absolute, change and/or percent 
change from baselines) based on both the parent study 
baseline and the OLE study baseline. 
-  On-treatment summary for FAS 
• Boxplot of Absolute Value, Change from Baseline, and/or 
Percent Change from Baseline over Time based on both 
the parent study baseline and the OLE study baseline. 
- On-treatment summary for FAS 
- Only plot time points where at least 
20% of the CS3 population have data 
• Summary table and figure for Response Rate byThreshold 
Value by Visit. 
- On-treatment summary for FAS 
• Corresponding listings. 
- All results collected in CS3 before IA 
data cut 
Safety Endpoint 
• Summary tables for AE. 
- On-Treatment and On-Study for SS 
• Summary tables of safety lab, vital sign, ECG, ERG by visit. 
- On-Treatment+ Post-Treatment for 
ss 
• Summary table and shift table of abnormal safety lab 
results, ECG worst values and stopping rules. 
- Abnormal safety lab is on-study for 
ss 
• The longitudinal safety analysis of AE and abnormal safety 
lab results, including hepatobiliary, platelets and renal 
parameters. 
- For LSS 
• Corresponding listings. 
- All results collected in CS3 before IA 
data cut 
lmmunogenicity 
 
66 


260 
 
 
Provided at interim of OLE study (at parent study EOT) 
Comment 
• Summary table for sample IM status, anti-lSIS 420915 
antibody titer values, patient IM status, onset and peak 
titer of the ADA, time to reach peak titer. 
• Box Plot of Titer over Time. 
- On-study summary for SS 
• mNIS+7, Norfolk total score and TTR summary by patient 
IM status. 
• Box plot for mNIS+7 and Norfolk totalscore by patient IM 
status. 
- Efficacy is on-treatment for FAS 
- Patient IM status ison-study for SS 
• Summary table of AE by patient IM status. 
- AE is on-treatment and On-Study for 
ss 
- Patient IM status is on-study for SS 
• Summary table and shift table of abnormal safety lab 
results by patient IM status. 
- Abnormal safety lab is on-study for 
ss 
- Patient IM status ison-study for SS 
• Corresponding listings. 
- All results collected in CS3 before IA 
data cut 
PK 
• Summary table of ISIS 420915 Trough Plasma 
Concentrations (ng/mL) with and without Stratification by 
prior treatment in the parent study and Subject 
lmmunogenicity Status 
- On-study for PK set 
• Figure of Mean (±SD) of ISIS 420915 Plasma Trough 
Concentrations (ng/mL) over Time by prior treatment in 
the parent study and Subject lmmunogenicityStatus 
- On-study for PK set 
- plot time points where at least 20% 
of the CS3 population have data 
• Corresponding listings 
- All results collected in CS3 before IA 
data cut 
 
5.2 Interim Analysis for Day-90 Updates 
 
The CS3 safety resuIts for 90-day safety update are based on the data as of the data cutoff date of 
15-Sep-2017. lmmunogenicity results are based on a data cutoff date of 08-Jul-2017 due to timing of 
sample collection, batch sizes, and processing schedules. The following data were included in the 
interim analyses: dispositions, demographics, concomitant medications, exposure, adverse events 
(AEs), laboratory results, vital signs, physical examinations, electrocardiograms (ECGs), 
electroretinograms (ERGs), and immunogenicity {IM). 
The following will not be performed as part of this interim analysis: 
 
• 
Summaries using PPS, FAS, ECHO subgroup, OLEECHO set and Longitudinal analysis set 
 
67 


261 
 
 
• 
The review of protocol deviations to identify those leading to exclusion from the PPS 
• 
Descriptive summary for efficacy and PD endpoints 
 
In addition, listings will be provided for patients who will be found with following conditions after 
Feb. 28th 2017. A note: Feb. 28th 2017 is the data cut for supporting CS2 EOT submission: 
• 
Platelet count <100 X 10"9/L; 
• 
Platelet count confirmed value <100 X 10"9/L; 
• 
Confirmed Nadir Creatinine Clearance by CKD-EPI (ml/min/1.73m2) shift from ISIS 420915 
Baseline to category 2 or above; 
• 
Confirmed nadir creatinine clearance by CKD-EPI decreasing 25% from ISIS 420915 Baseline or 
more in which percent change= (post-baseline - baseline)/baseline; 
• 
Confirmed nadir creatinine clearance by CKD-EPI decreasing 50% from ISIS 420915 Baseline or 
more in which percent change= (post-baseline - baseline)/baseline. 
The table below lists what data will be included in the summary output by endpoint type and what 
output isplanned for this interim analysis for Day-90 updates. 
 
Provided at interim of OLE study (Day-90 updates) 
Comment 
Patient Characteristics 
• Summaries of patient disposition, protocol deviations, 
analysis sets. 
- For all enrolled patients 
• Summary of demographic characteristics and baseline 
characteristics (excluding efficiacy endpoints) and 
exposure to Study Drug. 
- For SS 
• Concomitant medication. 
- On-study summary for SS 
• Corresponding listings. 
Safety Endpoint 
• Summary tables for AE. 
-  On-Study for SS 
• Summary tables of safety lab, vital sign, ECG, ERG by visit. 
-  On-Treatment+ Post-Treatment for 
ss 
• Summary table and shift table of abnormal safety lab 
results, ECG worst values and stopping rules. 
- Abnormal safety lab is on-study for 
ss 
• Corresponding listings. 
- All results collected in CS3 before IA 
data cut 
lmmunogenicity 
• Summary table for sample IM status, anti-lSIS 420915 
antibody titer values, patient IM status, onset and peak 
titer of the ADA, time to reach peak titer. 
• Box Plot of Titer over Time. 
- On-study summary for SS 
 
68 


262 
 
 
Provided at interim of OLE study (Day-90 updates) 
Comment 
• Summary table of AE by patient IM status. 
- AE is On-Study for SS 
- Patient IM status ison-study for SS 
• Summary table and shift table of abnormal safety lab 
results by patient IM status. 
- Abnormal safety lab is on-study for 
ss 
- Patient IM status ison-study for SS 
• Corresponding listings. 
- All results collected in CS3 before IA 
data cut 
PK 
• Summary table of (SIS 420915 Trough Plasma 
Concentrations (ng/ml) with and without Stratification by 
Subject lmmunogenicity Status 
- On-study for PK set 
• Figure of Mean (±SD) of (SIS 420915 Plasma Trough 
Concentrations (ng/ml) over Time Subject 
lmmunogenicity Status 
- On-study for PK set 
- plot time points where at least 20% 
of the CS3 population have data 
• Corresponding listings 
- All results collected in CS3 before IA 
data cut 
 
 
 
 
5.3 
Interim Analysis II 
 
CS3 lniterim analysis II are based on the data as of the data cutoff date of 31-MAY-2018. The 
following data were included in the interim analyses: dispositions, demographics, concomitant 
medications, exposure, adverse events (AEs), laboratory results, ECHO, mNIS+7, NIS, NIS-LL, Norfolk 
SF36, and PND score. 
The table below lists what data will be included in the summary output by endpoint type and what 
output is planned for this interim analysis II. 
 
Provided at interim II 
Comment 
Patient Characteristics (for CS3 and ISS) 
• Summary of demographic characteristics and 
baseline characteristics (excluding efficiacy 
endpoints) and exposure to Study Drug. 
- For SS 
• Concomitant medication. 
- On-study summary for SS 
• Listings for exposure, dropouts and dose pause 
69 


263 
 
 
Provided at interim II 
Comment 
Safety Endpoint (for CS3 and ISS) 
• Summary tables for AE. 
-  On-Study for SS 
• Summary tables of safety lab (Hematology, 
Chemistry) by visit. 
-  On-Treatment+ Post-Treatment for SS 
• Summary table and shift table of abnormal safety 
lab results and stopping rules. 
- Abnormal safety lab is on-study for SS 
• Survival plot for time from first ISIS dose to death 
or discontinuation 
- On-Study for SS 
• Listing of adverse events and medication occurred 
or took 30 days prior to platelet value <50x109/L 
• Listing of platelet values and anticoagulants or 
antiplatelets medication for subjects with grade 3 
thrombocytopenia 
Efficacy (for CS3) 
• Summary table of mNIS+7, NIS, NIS-LL, SF-36 and 
PND score, NT-proBNP and Log-Transformed NT- 
proBNP 
- On-treatment for FAS 
• Listing of NSC domain, subdomain and totalscore 
-  CS3 Enrolled Patients 
PD Parameters (for CS3) 
• Summary of TTR and RBP4 by visit. 
-  On-treatment for FAS 
ECHO (for CS3) 
• Global Longitudinal Strain and Global Left 
Ventricular Size and Function - LV Mass 
- On-treatment for Enrolled Patients and 
CM-ECHO Set 
 
 
Interim II also create Topline efficacy/safety tables by subgroup/subset for CS3 (both efficacy and safety 
outputs) and ISS (safety outputs). The subgroup/subset are: 
• 
Stage 3 patients (PND score=V at BL) 
• 
V30M TTR Mutation (IVRS) 
• 
Disease Stage (IVRS) 
• 
Previous Treatment (IVRS) 
• 
CM-ECHO Set 
70 


264 
 
 
NT-proBNP>650 pg/nL at BL 
NYHA 1 vs 2 at BL 
IVS>15 mm at BL 
Paitents who Diagnosed as TTR Cardiomyopathy at BL 
 
 (for primary endpoints only) 
Patients on lower dose which is subjects with dose <=150 for more than 12 weeks in CS2 and CS3 (for 
primary endpoints only ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
71 


265 
 
 
6. Study Conduct to Minimize Bias 
The sponsor recognizes the importance of confidentiality of interim results before the parent study 
is unblinded. To minimize any potential risk to the integrity of the study, the first interim analysis 
will be conducted only after the database of the parent study is locked and unblinded. 
The ISIS 420915 CS2/CS3 DSMB will conduct regular safety reviews throughout the study. Until the 
parent study is unblinded, the outputs will be prepared by an independent statistician who is 
independent from the sponsor. 
The independent statistician who supports DSMB will be an employee of a CRO (InVentiv), one that 
is independent from a second CRO conducting the trial (ICON) and a third CRO (PAREXEL) who will 
be performing the final statistical analysis. InVentiv will also provide programming support for the 
DSMB, handle all DSMB related analyses, independent of the Sponsor and independent of ICON and 
PAREXEL. The independent statistician from InVentiv will maintain secure custody of blinded and 
unblinded data to ensure the integrity of the data. Additionally, the independent statistician will 
maintain all unblinded data in electronic form in a secure area. All transfer of data/reports by the 
independent statistician to the DSMB, which includes patient data will be by secure, trackable 
courier and/or secure electronic means. The independent statistician will provide all of the 
unblinded data to the DSMB as outlined in the DSMB Charter. 
All DSMB members will sign a Confidentiality Agreement with the Sponsor. In addition, all DSMB 
members will treat as confidential the reports, meeting discussions, minutes and recommendations 
of the DSMB. Strict rules for DSMB communication with the Sponsor have been put in place for the 
purpose of minimizing the potential for bias, as outlined in the DSMB Charter. All written 
communication described in the DSMB Charter will be by secure, trackable courier and/or secure 
electronic means. This includes dissemination of DSMB recommendations, and review of minutes of 
open and closed sessions between the DSMB and, as appropriate, other DSMB members and/or, the 
Sponsor contacts (primary, CMO and statistics). 
During the conduct of this OLE study and before unblinding of the parent study, the Sponsor will not 
have access to any efficacy, PD or exploratory data, except for parent study baseline values and data 
collected after the Week 13 visit for the following endpoints: plasma retinol, plasma TTR, plasma 
RBP4 and plasma NT-proBNP . The efficacy data will be collected and stored by independent CROs 
as detailed below. All CROs will maintain secure custody of their databases. The CROs will not 
transfer any efficacy data other than baseline data or post-Week 13 data for certain endpoints to 
the Sponsor until after all patients in the parent study have completed the treatment period and the 
database of the parent study has been locked and unblinded. The efficacy or PD data includes the 
following: mNIS+7, NIS+7, Norfolk QOL-DN, BMI/mBMI, plasma retinol, plasma retinyl palmitate, 
plasma TTR, plasma RBP4, plasma NT-proBNP, SF-36 questionnaire, ECHO efficacy parameters, NSC 
and PND scores. Derived mNIS+7 and the components including NIS, +7 and modified +7, as well as 
NSC, Norfolk QOL-DN, PND, body weight and ECHO will be available before the parent study is 
unblinded to PAREXEL who are preparing this SAP and are performing statistical analysis. 
 
 
 
72 


266 
 
 
For the purpose of data cleaning, an independent data manager at Trennic Data Services will also 
have access to post-baseline data for the following endpoints: mNIS+7, NIS+7, Norfolk QOL-DN, 
BMI/mBMI, SF-36 questionnaire, ECHO efficacy parameters, NSC and PND scores. 
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) that 
is under the direction of Dr. 
. 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 
faxed to MC Core for processing and quality assurance. Faxed copies will be maintained in secure 
rooms within locked cabinets. The NIS and NSC data are stored in the RedCap (a database). The 
other components of the mNIS+7 (nerve conduction, sensory testing and heart rate to deep 
breathing) are entered by the MC Core into a firewalled portion of the study EDC system. MC Core 
only has access to this portion of the EDC system and 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. Up until the parent study database lock, the Sponsor will only have access to patient baseline 
values of the mNIS+7. Post-baseline values will be available for PAREXEL who are preparing this SAP 
and are performing statistical analysis. 
The Norfolk QOL-DN, body weight (needed to calculate BMI/mBMI), SF-36 questionnaire and PND 
scores will be entered into the EDC system by each site. The independent CRO BioClinica is 
contracted to develop and maintain secure custody of the EDC database. During the conduct of this 
OLE study before unblinding of the parent study the Sponsor will receive regular data transfers from 
BioClinica but without the above mentioned efficacy data included (except for baseline values). 
Post-baseline values for most endpoints mentioned above except for SF-36 derived scores will be 
available for PAREXEL who are preparing this SAP and are performing statistical analysis. 
The plasma retinol, plasma TTR, plasma RBP4, and plasma NT-proBNP samples will be assayed at 
Medpace, the central laboratory contracted for this study. The results will be maintained in 
 
 from the 
above mentioned tests (except for baseline values) prior to week 13. During the conduct of this OLE 
study before unblinding of the parent study the Sponsor will receive regular lab data transfers from 
Medpace to perform safety assessments. The above mentioned data collected prior to Week 13 will 
not be available to PAREXEL or the sponsor. 
The ECHO data will be collected, analyzed and stored in a secure database by CICL. The sites will 
upload the ECHO data on a secure web-portal for analysis by CICL. Up until the parent study 
database lock, the Sponsor will only have access to patient baseline ECHO values. ECHOs conducted 
for safety assessment purposes will be available to the DSMB, Sponsor, and Investigator. Post- 
baseline ECHO data will be available for PAREXEL who are preparing this SAP and are performing 
statistical analysis. 
Prior to the parent study unblinding, any ISIS 420915 concentration data sets and IM data sets 
provided to Ionis Pharmaceuticals, Inc. by the respective bioanalytical labs will not include results 
for samples collected prior to Week 13, nor will they include results for unscheduled or early term 
(ET) samples to prevent the potential unblinding of the parent study. 
 
73 


267 
 
 
In conclusion, the unblinding process before the parent study unblinding for periodic safety reviews 
has been clearly defined and detailed roles and responsibilities to the independent statistician, 
DSMB, Partner Firewalled Staff and Sponsor, such that the potential for bias to enter into the 
conduct of the study will be minimized. Additional steps to ensure the data for the primary and 
secondary endpoints remain blinded, such as housing the primary and secondary efficacy data in 
databases to which the Sponsor has no access, further safeguards the potential for Sponsor bias. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
74 


268 
 
 
7. References 
Coelho T, Ericzon B, Falk R, Grogan DR, Ikeda S, Maurer M, Planté-Bordeneauv, Suhr OB, Trigo P. A 
physician's guide to transthyretin amyloidosis. Amyloidosis Foundation 2008: 1-16. 
Coutinho P, Martins da Silva A, Lopas Lima J. Resende Barbosa A. Forty years of experience with type 
1 amyloid neuropathy. Review of 483 cases. In: Glenner GG, Pinho e Costa P, Falcao de Freitas A, 
editors. Amyloid and Amyloidosis. Amsterdam, the Netherlands 1980. 
Dmitrienko A, Tamhane A, Wiens B. 2008. General multistage gatekeeping procedures. Biometrical 
Journal 50:667-677. 
Faraway, J.J. (2002). Practical regression and anova using R. Unpublished manuscript. Retrieved from 
http://cran.r-project.org/doc/contrib/Faraway-PRA.pdf. 
Kenward, M. G. and Roger, J. H. (1997), "Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood," Biometrics, 53, 983-997. 
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. 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0 3 
Ionis document: QOL-DN Scoring Manual--updated 2006.pdf 
Ionis document: mNIS+7_Quality_Manual_Version 2_final_03Sept2014.pdf 
Ionis document: SF36-detailed score.pdf 
Ionis document: 420915 CS2 unblinding plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
75 


269 
 
 
8. Appendices 
8.1 Appendix 1 Components and Subcomponents of the mNIS+7, and NIS+7 
 
 
Figure 1 
Components and Subcomponents of the mNIS+7 
 
Note that only two of the five subcomponents for Nerve Conduction Total are shared in modified + 7 and + 7, which are 
fibular CMAP amplitude and sural SNAP amplitude. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
76 


Figure 2 
Components and Subcomponents of the NIS+7 
270 
 
 
 
 
 
Note that only two of the five subcomponents for Nerve Conduction Total are shared in modified + 7 and + 7, which are 
fibular CMAP amplitude and sural SNAP amplitude. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
77 


Table 1: Neuropathy Impairment Score 
271 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
78 


272 
 
 
 
Component 
Assessment 
Right 
Side 
Left 
Side 
Max 
Score 
Max Sub- 
Totals 
Missing value 
imputation for 
Component 
Score 
Cranial Nerves 
(NIS-C) 
1. 3rd Nerve 
0-4 
0-4 
8 
40 
Group A 
2. 6th Nerve 
0-4 
0-4 
8 
3. Facial weakness 
0-4 
0-4 
8 
4. Palate weakness 
0-4 
0-4 
8 
5. Tongue weakness 
0-4 
0-4 
8 
Muscle Weakness 
(NIS-W) 
6. Respiratory 
0-4 
0-4 
8 
152 
Group A 
7. Neck flexion 
0-4 
0-4 
8 
8. Shoulder abduction 
0-4 
0-4 
8 
9. Elbow flexion 
0-4 
0-4 
8 
10. Brachioradialis 
0-4 
0-4 
8 
11. Elbow extension 
0-4 
0-4 
8 
12. Wrist flexion 
0-4 
0-4 
8 
13. Wrist extension 
0-4 
0-4 
8 
14. Finger flexion 
0-4 
0-4 
8 
15. Finger spread 
0-4 
0-4 
8 
16. Thumb abduction 
0-4 
0-4 
8 
17. Hip flexion 
0-4 
0-4 
8 
18. Hip extension 
0-4 
0-4 
8 
19. Knee flexion 
0-4 
0-4 
8 
20. Knee extension 
0-4 
0-4 
8 
21. Ankle dorsiflexors 
0-4 
0-4 
8 
22. Ankle plantar flexors 
0-4 
0-4 
8 
23. Toe extensors 
0-4 
0-4 
8 
 
79 


273 
 
 
Component 
Assessment 
Right 
Side 
Left 
Side 
Max 
Score 
Max Sub- 
Totals 
Missing value 
imputation for 
Component 
Score 
24. Toe flexors 
0-4 
0-4 
8 
Reflexes 
(NIS-R) 
25. Biceps brachii 
0-2 
0-2 
4 
20 
Group A 
26. Triceps brachii 
0-2 
0-2 
4 
27. Brachioradialis 
0-2 
0-2 
4 
28. Quadriceps femoris 
0-2 
0-2 
4 
29. triceps surae 
0-2 
0-2 
4 
Sensation 
(NIS-S) 
30. Index Finger Touch 
pressure 
0-2 
0-2 
4 
32 
Group A 
31. Index Finger Pin- 
prick 
0-2 
0-2 
4 
32. Index Finger 
Vibration 
0-2 
0-2 
4 
33. Index Finger Joint 
position 
0-2 
0-2 
4 
34. Great Toe Touch 
pressure 
0-2 
0-2 
4 
35. Great Toe Pin-prick 
0-2 
0-2 
4 
36. Great Toe Vibration 
0-2 
0-2 
4 
37. Great Toe Joint 
position 
0-2 
0-2 
4 
NIS Score (total) 
244 
 
 
 
 
 
 
 
 
 
 
 
 
80 


274 
 
 
Table 2: Modified +7 Score 
 
Component 
Assessment 
Max 
Score 
Sub- 
Totals 
Missing value 
imputation for 
Component Score 
Heart rate deep 
breathing (HRDB) 
Heart rate decrease with 
deep breathing 
determined with CASE IV 
3.72 
3.72 
Group C 
Nerve 
Conduction Tests 
Fibular CMAP amplitude 
(PMAK) 
3.72 
18.6 
Group A 
Tibial CMAP amplitude 
(TMAK) 
3.72 
Ulnar CMAP amplitude 
(UMAE) 
3.72 
Ulnar SNAPamplitude 
(USAW) 
3.72 
Sural SNAPamplitude 
(SSAB) 
3.72 
Touch-Pressure 
Dorsal toes 
4 
40 
Group A 
Mid-lateral leg 
4 
Mid-anterior thigh 
4 
Anterior lower abdomen 
4 
Mid-upper abdomen 
4 
Anterior subclavicular 
4 
Dorsal finger 
4 
Mid-volar forearm 
4 
Lateral deltoid 
4 
Maxilla of face 
4 
Heat-Pain 
Dorsal toes 
4 
40 
Group A 
Mid-lateral leg 
4 
Mid-anterior thigh 
4 
 
81 


275 
 
 
Component 
Assessment 
Max 
Score 
Sub- 
Totals 
Missing value 
imputation for 
Component Score 
Anterior lower abdomen 
4 
Mid-upper abdomen 
4 
Anterior subclavicular 
4 
Dorsal finger 
4 
Mid-volar forearm 
4 
Lateral deltoid 
4 
Maxilla of face 
4 
Modified +7 
Score (Total) 
102.32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
82 


Table 3: +7 Score 
276 
 
 
 
Component 
Assessment 
Max 
Score 
Max Sub- 
Totals 
Missing 
value 
imputation 
for 
Component 
Score 
Heart rate deep 
breathing (HRDB) 
Heart rate decrease with 
deep breathing determined 
with CASE IV 
3.72 
3.72 
Group C 
Nerve Conduction Tests 
Fibular CMAP amplitude 
(PMAK) 
3.72 
18.6 
Group B 
Fibular MNCV (PMCVK) 
3.72 
Fibular MNDL(PMLA) 
3.72 
Tibial MNDL(TMLA) 
3.72 
Sural SNAPamplitude (SSAB) 
3.72 
Vibration Detection 
Threshold 
Vibration detection 
threshold of the great toe 
determined using CASE IV 
3.72 
3.72 
Group C 
+7 Score (Total) 
26.04 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
83 


Table 4: NIS-LL Score 
277 
 
 
 
Component 
Assessment 
Right 
Side 
Left 
Side 
Max 
Score 
Max Sub- 
Totals 
Missing value 
imputation for 
Component 
Score 
Muscle Weakness 
for NIS-LL 
Calculation 
17. Hip flexion 
0-4 
0-4 
8 
64 
18. Hip extension 
0-4 
0-4 
8 
19. Knee flexion 
0-4 
0-4 
8 
20. Knee extension 
0-4 
0-4 
8 
21. Ankle dorsiflexors 
0-4 
0-4 
8 
22. Ankle plantar flexors 
0-4 
0-4 
8 
23. Toe extensors 
0-4 
0-4 
8 
24. Toe flexors 
0-4 
0-4 
8 
Reflexes for NIS-LL 
Calculation 
28. Quadriceps femoris 
0-2 
0-2 
4 
8 
Group A 
29. triceps surae 
0-2 
0-2 
4 
Sensation 
(NIS-S) 
34. Great Toe Touch 
pressure 
0-2 
0-2 
4 
16 
Group A 
35. Great Toe Pin-prick 
0-2 
0-2 
4 
36. Great Toe Vibration 
0-2 
0-2 
4 
37. Great Toe Joint 
position 
0-2 
0-2 
4 
NIS-LL Score 
(total) 
88 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
84 


Table 5: Sensation Score 
278 
 
 
 
 
 
Component 
Assessment 
Right 
Side 
Left 
Side 
Max 
Score 
Max Sub- 
Totals 
Missing value 
imputation for 
Component 
Score 
Sensation - 
Index 
Finger 
30. Index Finger Touch 
pressure 
0-2 
0-2 
4 
20 
31. Index Finger Pin- 
prick 
0-2 
0-2 
4 
32. Index Finger 
Vibration 
0-2 
0-2 
4 
33. Index Finger Joint 
position 
0-2 
0-2 
4 
29. triceps surae 
0-2 
0-2 
4 
Sensation - 
Great Toe 
34. Great Toe Touch 
pressure 
0-2 
0-2 
4 
16 
35. Great Toe Pin-prick 
0-2 
0-2 
4 
36. Great Toe Vibration 
0-2 
0-2 
4 
37. Great Toe Joint 
position 
0-2 
0-2 
4 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 
Appendix 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 
85 


279 
 
 
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. 
The NSC questionnaire also records a change score for the change in symptoms compared to the 
week before study onset. These are scored as follows 
-3 
=worse --- 
-2 
= worse -- 
-1 
= worse - 
0 
= no change 
+1 
= better + 
+2 
= better ++ 
 
+3 
= better +++ 
86 


280 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
87 


281 
 
 
8.3 Appendix 3 Analysis Visit Windows and Follow-Up Visit Window 
 
8.3.1 
Table 1. Efficacy Endpoints and PD Endpoints (On-Treatment Analysis Visit Wondow): 
Visit window for mNIS+7 and individual components: 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
the Parent 
study 
Week 35 (Day 239) 
209-269 
Week 66 (Day 456) 
411-501 
The OLE study 
Week 26 (Day 176) 
146 - 206 
Week 52 (Day 358) 
328 - 388 
Week 78 (Day 540) 
510 - 570 
Week 104 (Day 722) 
692 - 752 
Week 130 (Day 904) 
874 - 934 
Week 156 (Day 1086) 
1041-1131 
 
 
Visit window for NIS and individual components, NSC, Norfolk QOL-DN and individual components: 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
the Parent 
study 
Week 35 (Day 239) 
209-269 
Week 66 (Day 456) 
411-501 
The OLE study 
Week 26 (Day 176) 
146 - 206 
Week 52 (Day 358) 
328 - 388 
Week 78 (Day 540) 
510 - 570 
Week 104 (Day 722) 
692 - 752 
Week 130 (Day 904) 
874 - 934 
Week 156 (Day 1086) 
1041-1131 
Y4-W52 (Day 1450) 
1420 - 1480 
Y5-W52 (Day 1814) 
1784 - 1844 
 
 
Visit window for SF-36 Questionnaire and PND Score: 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
the Parent 
study 
Week 35 (Day 240) 
210-270 
Week 65 (Day 449) 
397-501 
The OLE study 
Week 26 (Day 176) 
146 - 206 
Week 52 (Day 358) 
328 - 388 
Week 78 (Day 540) 
510 - 570 
 
88 


282 
 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
Week 104 (Day 722) 
692 - 752 
Week 130 (Day 904) 
874 - 934 
Week 156 (Day 1086) 
1041 - 1131 
Y4-W52 (Day 1450) 
1420 - 1480 
Y5-W52 (Day 1814) 
1784 - 1844 
 
 
Visit window for Body Weight, BMI and mBMI: 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
the Parent 
study 
Week 13 (Day 85) 
55-115 
Week 35 (Day 240) 
210-270 
Week 53 (Day 365) 
335-395 
Week 65 (Day 449) 
419-479 
The OLE study 
Week 13 (Day 85) 
55-115 
Week 26 (Day 176) 
146-206 
Week 52 (Day 358) 
328-388 
Week 78 (Day 540) 
510-570 
Week 104 (Day 722) 
692-752 
Week 130 (Day 904) 
874-934 
Week 156 (Day 1086) 
1056-1116 
 
 
Visit window for PD Panel (TTR and RBP4): 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
the Parent 
study 
Week 3 (Day 15) 
2-21 
Week 5 (Day 29) 
22-38 
Week 8 (Day 50) 
39-66 
Week 13 (Day 85) 
67-101 
Week 18 (Day 120) 
102-136 
Week 23 (Day 155) 
137-175 
Week 29 (Day 197) 
176-217 
Week 35 (Day 240) 
218-259 
Week 41 (Day 281) 
260-301 
Week 47 (Day 323) 
302343 
Week 53 (Day 365) 
344-385 
Week 59 (Day 407) 
386-427 
Week 65 (Day 449) 
428-469 
89 


283 
 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 7 (Day 43) 
13-63 
Week 13 (Day 85) 
64-101 
Week 18 (Day 120) 
102-129 
Week 21 (Day 141) 
130-157 
Week 26 (Day 176) 
158-206 
Week 39 (Day 267) 
237-297 
Week 52 (Day 358) 
328-388 
Week 65(Day 449) 
419-479 
Week 78 (Day 540) 
510-570 
Week 91 (Day 631) 
601-661 
Week 104 (Day 722) 
692-752 
Week 117 (Day 813) 
783-843 
Week 130 (Day 904) 
874-934 
Week 143 (Day 995) 
965-1025 
Week 156 (Day 1086) 
1056-1116 
Y4-W13 (Day 1177) 
1147-1207 
Y4-W26 (Day 1268) 
1238-1298 
Y4-W39 (Day 1359) 
1329-1389 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W13 (Day 1541) 
1511-1571 
Y5-W26 (Day 1632) 
1602-1662 
Y5-W39 (Day 1723) 
1693-1753 
Y5-W52 (Day 1814) 
1784-1844 
 
 
Visit window for NT-proBNP: 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
the Parent 
study 
Week 13 (Day 85) 
55-115 
Week 35 (Day 240) 
210-270 
Week 65 (Day 449) 
397-501 
The OLE study 
Week 7 (Day 43) 
13-63 
Week 13 (Day 85) 
64-101 
Week 18 (Day 120) 
102-147 
Week 26 (Day 176) 
148-206 
Week 39 (Day 267) 
237-297 
Week 52 (Day 358) 
328-388 
Week 65(Day 449) 
419-479 
90 


284 
 
 
Nominal Visit (Target Day) 
Analysis Visit Window (Day) 
Week 78 (Day 540) 
510-570 
Week 91 (Day 631) 
601-661 
Week 104 (Day 722) 
692-752 
Week 117 (Day 813) 
783-843 
Week 130 (Day 904) 
874-934 
Week 143 (Day 995) 
965-1025 
Week 156 (Day 1086) 
1041-1131 
Y4-W13 (Day 1177) 
1147-1207 
Y4-W26 (Day 1268) 
1238-1298 
Y4-W39 (Day 1359) 
1329-1389 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W13 (Day 1541) 
1511-1571 
Y5-W26 (Day 1632) 
1602-1662 
Y5-W39 (Day 1723) 
1693-1753 
Y5-W52 (Day 1814) 
1784-1844 
 
8.3.2 
Table 2. Efficacy Endpoints and PD Endpoints (Post-Treatment Analysis Follow-Up Visit 
Wondow): 
 
Efficacy/PD measure 
Weeks from last dose 
(Days from last dose) 
Analysis Visit Window (Days from 
last dose) 
NT-proBNP; 
Follow-up Week 13 (91) 
61-121 
BMI and mBMI; PD 
Panel (TTR and RBP4); 
Follow-up Week 13 (91) 
61-121 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
91 


285 
 
 
8.3.3 
Table 3. Safety Endpoints (On-Treatment Analysis Visit Wondow): 
Vital Signs and Retinol and Retinyl palmitate 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 7 (Day 43) 
22-63 
Week 13 (Day 85) 
64-115 
Week 26 (Day 176) 
146-206 
Week 52 (Day 358) 
328-388 
Week 78 (Day 540) 
510-570 
Week 104 (Day 722) 
629-752 
Week 130 (Day 904) 
874-934 
Week 156 (Day 1086) 
1056-1116 
Y4-W26 (Day 1268) 
1238-1298 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W26 (Day 1632) 
1602-1662 
Y5-W52 (Day 1814) 
1784-1844 
Body Weight 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 13 (Day 85) 
55-115 
Week 26 (Day 176) 
146-206 
Week 52 (Day 358) 
328-388 
Week 78 (Day 540) 
510-570 
Week 104 (Day 722) 
629-752 
Week 130 (Day 904) 
874-934 
Week 156 (Day 1086) 
1056-1116 
ECG 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 26 (Day 176) 
146-206 
Week 52 (Day 358) 
328-388 
Week 78 (Day 540) 
510-570 
Week 104 (Day 722) 
629-752 
Week 130 (Day 904) 
874-934 
Week 156 (Day 1086) 
1056-1116 
Y4-W26 (Day 1268) 
1238-1298 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W26 (Day 1632) 
1602-1662 
92 


286 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Y5-W52 (Day 1814) 
1784-1844 
 
Chemistry Panel, Hematology and Urinalysis 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 4 (Day 22) 
11-31 
Week 7 (Day 43) 
32-52 
Week 10 (Day 64) 
53-73 
Week 13 (Day 85) 
74-91 
Week 15 (Day 99) 
92-108 
Week 18 (Day 120) 
109-129 
Week 21 (Day 141) 
130-147 
Week 23 (Day 155) 
148-164 
Week 26 (Day 176) 
165-185 
Week 29 (Day 197) 
186-227 
Week 39 (Day 267) 
237-297 
Week 52 (Day 358) 
328-388 
Week 65 (Day 449) 
419-479 
Week 78 (Day 540) 
510-570 
Week 91 (Day 631) 
601-661 
Week 104 (Day 722) 
692-752 
Week 117 (Day 813) 
783-843 
Week 130 (Day 904) 
874-934 
Week 143 (Day 995) 
965-1025 
Week 156 (Day 1086) 
1056-1116 
Y4-W13 (Day 1177) 
1147-1207 
Y4-W26 (Day 1268) 
1238-1298 
Y4-W39 (Day 1359) 
1329-1389 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W13 (Day 1541) 
1511-1571 
Y5-W26 (Day 1632) 
1602-1662 
Y5-W39 (Day 1723) 
1693-1753 
Y5-W52 (Day 1814) 
1784-1844 
Serum Creatinine 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 4 (Day 22) 
11-31 
Week 7 (Day 43) 
32-52 
93 


287 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Week 10 (Day 64) 
53-73 
Week 13 (Day 85) 
74-91 
Week 15 (Day 99) 
92-108 
Week 18 (Day 120) 
109-129 
Week 21 (Day 141) 
130-147 
Week 23 (Day 155) 
148-164 
Week 26 (Day 176) 
165-185 
Week 29 (Day 197) 
186-203 
Week 31 (Day 211) 
204-217 
Week 33 (Day 225) 
218-231 
Week 35 (Day 239) 
232-245 
Week 37 (Day 253) 
246-259 
Week 39 (Day 267) 
260-273 
Week 41 (Day 281) 
274-287 
Week 43 (Day 295) 
288-301 
Week 45 (Day 309) 
302-315 
Week 47 (Day 323) 
316-329 
Week 49 (Day 337) 
330-346 
Week 52 (Day 358) 
347-364 
Week 54 (Day 372) 
365-378 
Week 56 (Day 386) 
379-392 
Week 58 (Day 400) 
393-406 
Week 60 (Day 414) 
407-420 
Week 62 (Day 428) 
421-437 
Week 65 (Day 449) 
438-455 
Week 67 (Day 463) 
456-469 
Week 69 (Day 477) 
470-483 
Week 71 (Day 491) 
484-497 
Week 73 (Day 505) 
498-511 
Week 75 (Day 519) 
512-528 
Week 78 (Day 540) 
529-546 
Week 80 (Day 554) 
547-560 
Week 82 (Day 568) 
561-574 
Week 84 (Day 582) 
575-588 
Week 86 (Day 596) 
589-602 
Week 88 (Day 610) 
603-619 
Week 91 (Day 631) 
620-637 
Week 93 (Day 645) 
638-651 
 
94 


288 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Week 95 (Day 659) 
652-665 
Week 97 (Day 673) 
666-679 
Week 99 (Day 687) 
680-693 
Week 101 (Day 701) 
694-710 
Week 104 (Day 722) 
711-728 
Week 106 (Day 736) 
729-742 
Week 108 (Day 750) 
743-756 
Week 110 (Day 764) 
757-770 
Week 112 (Day 778) 
771-784 
Week 114 (Day 792) 
785-801 
Week 117 (Day 813) 
802-819 
Week 119 (Day 827) 
820-833 
Week 121 (Day 841) 
834-847 
Week 123 (Day 855) 
848-861 
Week 125 (Day 869) 
862-875 
Week 127 (Day 883) 
876-892 
Week 130 (Day 904) 
893-910 
Week 132 (Day 918) 
911-924 
Week 134 (Day 932) 
925-938 
Week 136 (Day 946) 
939-952 
Week 138 (Day 960) 
953-966 
Week 140 (Day 974) 
967-983 
Week 143 (Day 995) 
984-1001 
Week 145 (Day 1009) 
1002-1015 
Week 147 (Day 1023) 
1016-1029 
Week 149 (Day 1037) 
1030-1043 
Week 151 (Day 1051) 
1044-1057 
Week 153 (Day 1065) 
1058-1074 
Week 156 (Day 1086) 
1075-1092 
Y4-W2 (Day 1100) 
1093-1106 
Y4-W4 (Day 1114) 
1107-1120 
Y4-W6 (Day 1128) 
1121-1134 
Y4-W8 (Day 1142) 
1135-1148 
Y4-W10 (Day 1156) 
1149-1165 
Y4-W13 (Day 1177) 
1166-1183 
Y4-W15 (Day 1191) 
1184-1197 
Y4-W17 (Day 1205) 
1198-1211 
Y4-W19 (Day 1219) 
1212-1225 
 
95 


289 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Y4-W21 (Day 1233) 
1226-1239 
Y4-W23 (Day 1247) 
1240-1256 
Y4-W26 (Day 1268) 
1257-1274 
Y4-W28 (Day 1282) 
1275-1288 
Y4-W30 (Day 1296) 
1289-1302 
Y4-W32 (Day 1310) 
1303-1316 
Y4-W34 (Day 1324) 
1317-1330 
Y4-W36 (Day 1338) 
1331-1347 
Y4-W39 (Day 1359) 
1348-1365 
Y4-W41 (Day 1373) 
1366-1379 
Y4-W43 (Day 1387) 
1380-1393 
Y4-W45 (Day 1401) 
1394-1407 
Y4-W47 (Day 1415) 
1408-1421 
Y4-W49 (Day 1429) 
1422-1438 
Y4-W52 (Day 1450) 
1439-1456 
Y5-W2 (Day 1464) 
1457-1470 
Y5-W4 (Day 1478) 
1471-1484 
Y5-W6 (Day 1492) 
1485-1498 
Y5-W8 (Day 1506) 
1499-1512 
Y5-W10 (Day 1520) 
1513-1529 
Y5-W13 (Day 1541) 
1530-1547 
Y5-W15 (Day 1555) 
1548-1561 
Y5-W17 (Day 1569) 
1562-1575 
Y5-W19 (Day 1583) 
1576-1589 
Y5-W21 (Day 1597) 
1590-1603 
Y5-W23 (Day 1611) 
1604-1620 
Y5-W26 (Day 1632) 
1621-1638 
Y5-W28 (Day 1646) 
1639-1652 
Y5-W30 (Day 1660) 
1653-1666 
Y5-W32 (Day 1674) 
1667-1680 
Y5-W34 (Day 1688) 
1681-1694 
Y5-W36 (Day 1702) 
1695-1711 
Y5-W39 (Day 1723) 
1712-1729 
Y5-W41 (Day 1737) 
1730-1743 
Y5-W43 (Day 1751) 
1744-1757 
Y5-W45 (Day 1765) 
1758-1771 
Y5-W47 (Day 1779) 
1772-1785 
Y5-W49 (Day 1793) 
1786-1802 
 
96 


290 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Y5-W52 (Day 1814) 
1803-1820 
 
Platelets (weekly) 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 2 (Day 8) 
7-11 
Week 3 (Day 15) 
12-17 
Week 4 (Day 22) 
18-24 
Week 5 (Day 29) 
25-31 
Week 6 (Day 36) 
32-38 
Week 7 (Day 43) 
39-45 
Week 8 (Day 50) 
46-52 
Week 9 (Day 57) 
53-59 
Week 10 (Day 64) 
60-66 
Week 11 (Day 71) 
67-73 
Week 12 (Day 78) 
74-80 
Week 13 (Day 85) 
81-87 
Week 14 (Day 92) 
88-94 
Week 15 (Day 99) 
95-101 
Week 16 (Day 106) 
102-108 
Week 17 (Day 113) 
109-115 
Week 18 (Day 120) 
116-122 
Week 19 (Day 127) 
123-129 
Week 20 (Day 134) 
130-136 
Week 21 (Day 141) 
137-143 
Week 22 (Day 148) 
144-150 
Week 23 (Day 155) 
151-157 
Week 24 (Day 162) 
158-164 
Week 25 (Day 169) 
165-171 
Week 26 (Day 176) 
172-178 
Week 27 (Day 183) 
179-185 
Week 28 (Day 190) 
186-192 
Week 29 (Day 197) 
193-199 
Week 30 (Day 204) 
200-206 
Week 31 (Day 211) 
207-213 
Week 32 (Day 218) 
214-220 
Week 33 (Day 225) 
221-227 
Week 34 (Day 232) 
228-235 
 
97 


291 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Week 35 (Day 240) 
236-242 
Week 36 (Day 246) 
243-248 
Week 37 (Day 253) 
249-255 
Week 38 (Day 260) 
256-262 
Week 39 (Day 267) 
263-269 
Week 40 (Day 274) 
270-276 
Week 41 (Day 281) 
277-283 
Week 42 (Day 288) 
284-290 
Week 43 (Day 295) 
291-297 
Week 44 (Day 302) 
298-304 
Week 45 (Day 309) 
305-311 
Week 46 (Day 316) 
312-318 
Week 47 (Day 323) 
319-325 
Week 48 (Day 330) 
326-332 
Week 49 (Day 337) 
333-339 
Week 50 (Day 344) 
340-346 
Week 51 (Day 351) 
347-353 
Week 52 (Day 358) 
354-360 
Week 53 (Day 365) 
361-367 
Week 54 (Day 372) 
368-374 
Week 55 (Day 379) 
375-381 
Week 56 (Day 386) 
382-388 
Week 57 (Day 393) 
389-395 
Week 58 (Day 400) 
396-402 
Week 59 (Day 407) 
403-409 
Week 60 (Day 414) 
410-416 
Week 61 (Day 421) 
417-423 
Week 62 (Day 428) 
424-430 
Week 63 (Day 435) 
431-437 
Week 64 (Day 442) 
438-444 
Week 65 (Day 449) 
445-451 
Week 66 (Day 456) 
452-458 
Week 67 (Day 463) 
459-465 
Week 68 (Day 470) 
466-472 
Week 69 (Day 477) 
473-479 
Week 70 (Day 484) 
480-486 
Week 71 (Day 491) 
487-493 
Week 72 (Day 498) 
494-500 
 
98 


292 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Week 73 (Day 505) 
501-507 
Week 74 (Day 512) 
508-514 
Week 75 (Day 519) 
515-521 
Week 76 (Day 526) 
522-528 
Week 77 (Day 533) 
529-535 
Week 78 (Day 540) 
536-542 
Week 79 (Day 547) 
543-549 
Week 80 (Day 554) 
550-556 
Week 81 (Day 561) 
557-563 
Week 82 (Day 568) 
564-570 
Week 83 (Day 575) 
571-577 
Week 84 (Day 582) 
578-584 
Week 85 (Day 589) 
585-591 
Week 86 (Day 596) 
592-598 
Week 87 (Day 603) 
599-605 
Week 88 (Day 610) 
606-612 
Week 89(Day 617) 
613-619 
Week 90 (Day 624) 
620-626 
Week 91 (Day 631) 
627-633 
Week 92 (Day 638) 
634-640 
Week 93 (Day 645) 
641-647 
Week 94 (Day 652) 
648-654 
Week 95 (Day 659) 
655-661 
Week 96 (Day 666) 
662-668 
Week 97 (Day 673) 
669-675 
Week 98 (Day 680) 
676-682 
Week 99 (Day 687) 
683-689 
Week 100 (Day 694) 
690-696 
Week 101 (Day 701) 
697-703 
Week 102 (Day 708) 
704-710 
Week 103 (Day 715) 
711-717 
Week 104 (Day 722) 
718-724 
Week 105 (Day 729) 
725-731 
Week 106 (Day 736) 
732-738 
Week 107 (Day 743) 
739-745 
Week 108 (Day 750) 
746-752 
Week 109 (Day 757) 
753-759 
Week 110 (Day 764) 
760-766 
 
99 


293 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Week 111 (Day 771) 
767-773 
Week 112 (Day 778) 
774-780 
Week 113 (Day 785) 
781-787 
Week 114 (Day 792) 
788-794 
Week 115 (Day 799) 
795-801 
Week 116 (Day 806) 
802-808 
Week 117 (Day 813) 
809-815 
Week 118 (Day 820) 
816-822 
Week 119 (Day 827) 
823-829 
Week 120 (Day 834) 
830-836 
Week 121 (Day 841) 
837-843 
Week 122 (Day 848) 
844-850 
Week 123 (Day 855) 
851-857 
Week 124 (Day 862) 
858-864 
Week 125 (Day 869) 
865-871 
Week 126 (Day 876) 
872-878 
Week 127 (Day 883) 
879-885 
Week 128 (Day 890) 
886-892 
Week 129 (Day 897) 
893-899 
Week 130 (Day 904) 
900-906 
Week 131 (Day 911) 
907-913 
Week 132 (Day 918) 
914-920 
Week 133 (Day 925) 
921-927 
Week 134 (Day 932) 
928-934 
Week 135 (Day 939) 
935-941 
Week 136 (Day 946) 
942-948 
Week 137 (Day 953) 
949-955 
Week 138 (Day 960) 
956-962 
Week 139 (Day 967) 
963-969 
Week 140 (Day 974) 
970-976 
Week 141 (Day 981) 
977-983 
Week 142 (Day 988) 
984-990 
Week 143 (Day 995) 
991-997 
Week 144 (Day 1002) 
998-1004 
Week 145 (Day 1009) 
1005-1011 
Week 146 (Day 1016) 
1012-1018 
Week 147 (Day 1023) 
1019-1025 
Week 148 (Day 1030) 
1026-1032 
 
100 


294 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Week 149 (Day 1037) 
1033-1039 
Week 150 (Day 1044) 
1040-1046 
Week 151 (Day 1051) 
1047-1053 
Week 152 (Day 1058) 
1054-1060 
Week 153 (Day 1065) 
1061-1067 
Week 154 (Day 1072) 
1068-1074 
Week 155 (Day 1079) 
1075-1081 
Week 156 (Day 1086) 
1082-1088 
Y4-W1 (Day 1093) 
1089-1095 
Y4-W2 (Day 1100) 
1096-1102 
Y4-W3 (Day 1107) 
1103-1109 
Y4-W4 (Day 1114) 
1110-1116 
Y4-W5 (Day 1121) 
1117-1123 
Y4-W6 (Day 1128) 
1124-1130 
Y4-W7 (Day 1135) 
1131-1137 
Y4-W8 (Day 1142) 
1138-1144 
Y4-W9 (Day 1149) 
1145-1151 
Y4-W10 (Day 1156) 
1152-1158 
Y4-W11 (Day 1163) 
1159-1165 
Y4-W12 (Day 1170) 
1166-1172 
Y4-W13 (Day 1177) 
1173-1179 
Y4-W14 (Day 1184) 
1180-1186 
Y4-W15 (Day 1191) 
1187-1193 
Y4-W16 (Day 1198) 
1194-1200 
Y4-W17 (Day 1205) 
1201-1207 
Y4-W18 (Day 1212) 
1208-1214 
Y4-W19 (Day 1219) 
1215-1221 
Y4-W20 (Day 1226) 
1222-1228 
Y4-W21 (Day 1233) 
1229-1235 
Y4-W22 (Day 1240) 
1236-1242 
Y4-W23 (Day 1247) 
1243-1249 
Y4-W24 (Day 1254) 
1250-1256 
Y4-W25 (Day 1261) 
1257-1263 
Y4-W26 (Day 1268) 
1264-1270 
Y4-W27 (Day 1275) 
1271-1277 
Y4-W28 (Day 1282) 
1278-1284 
Y4-W29 (Day 1289) 
1285-1291 
Y4-W30 (Day 1296) 
1292-1298 
 
101 


295 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Y4-W31 (Day 1303) 
1299-1305 
Y4-W32 (Day 1310) 
1306-1312 
Y4-W33 (Day 1317) 
1313-1319 
Y4-W34 (Day 1324) 
1320-1326 
Y4-W35 (Day 1331) 
1327-1333 
Y4-W36 (Day 1338) 
1334-1340 
Y4-W37 (Day 1345) 
1341-1347 
Y4-W38 (Day 1352) 
1348-1354 
Y4-W39 (Day 1359) 
1355-1361 
Y4-W40 (Day 1366) 
1362-1368 
Y4-W41 (Day 1373) 
1369-1375 
Y4-W42 (Day 1380) 
1376-1382 
Y4-W43 (Day 1387) 
1383-1389 
Y4-W44 (Day 1394) 
1390-1396 
Y4-W45 (Day 1401) 
1397-1403 
Y4-W46 (Day 1408) 
1404-1410 
Y4-W47 (Day 1415) 
1411-1417 
Y4-W48 (Day 1422) 
1418-1424 
Y4-W49 (Day 1429) 
1425-1431 
Y4-W50 (Day 1436) 
1432-1438 
Y4-W51 (Day 1443) 
1439-1445 
Y4-W52 (Day 1450) 
1446-1452 
Y5-W1 (Day 1457) 
1453-1459 
Y5-W2 (Day 1464) 
1460-1466 
Y5-W3 (Day 1471) 
1467-1473 
Y5-W4 (Day 1478) 
1474-1480 
Y5-W5 (Day 1485) 
1481-1487 
Y5-W6 (Day 1492) 
1488-1494 
Y5-W7 (Day 1499) 
1495-1501 
Y5-W8 (Day 1506) 
1502-1508 
Y5-W9 (Day 1513) 
1509-1515 
Y5-W10 (Day 1520) 
1516-1522 
Y5-W11 (Day 1527) 
1523-1529 
Y5-W12 (Day 1534) 
1530-1536 
Y5-W13 (Day 1541) 
1537-1543 
Y5-W14 (Day 1548) 
1544-1550 
Y5-W15 (Day 1555) 
1551-1557 
Y5-W16 (Day 1562) 
1558-1564 
 
102 


296 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
Y5-W17 (Day 1569) 
1565-1571 
Y5-W18 (Day 1576) 
1572-1578 
Y5-W19 (Day 1583) 
1579-1585 
Y5-W20 (Day 1590) 
1586-1592 
Y5-W21 (Day 1597) 
1593-1599 
Y5-W22 (Day 1604) 
1600-1606 
Y5-W23 (Day 1611) 
1607-1613 
Y5-W24 (Day 1618) 
1614-1620 
Y5-W25 (Day 1625) 
1621-1627 
Y5-W26 (Day 1632) 
1628-1634 
Y5-W27 (Day 1639) 
1635-1641 
Y5-W28 (Day 1646) 
1642-1648 
Y5-W29 (Day 1653) 
1649-1655 
Y5-W30 (Day 1660) 
1656-1662 
Y5-W31 (Day 1667) 
1663-1669 
Y5-W32 (Day 1674) 
1670-1676 
Y5-W33 (Day 1681) 
1677-1683 
Y5-W34 (Day 1688) 
1684-1690 
Y5-W35 (Day 1695) 
1691-1697 
Y5-W36 (Day 1702) 
1698-1704 
Y5-W37 (Day 1709) 
1705-1711 
Y5-W38 (Day 1716) 
1712-1718 
Y5-W39 (Day 1723) 
1719-1725 
Y5-W40 (Day 1730) 
1726-1732 
Y5-W41 (Day 1737) 
1733-1739 
Y5-W42 (Day 1744) 
1740-1746 
Y5-W43 (Day 1751) 
1747-1753 
Y5-W44 (Day 1758) 
1754-1760 
Y5-W45 (Day 1765) 
1761-1767 
Y5-W46 (Day 1772) 
1768-1774 
Y5-W47 (Day 1779) 
1775-1781 
Y5-W48 (Day 1786) 
1782-1788 
Y5-W49 (Day 1793) 
1789-1795 
Y5-W50 (Day 1800) 
1796-1802 
Y5-W51 (Day 1807) 
1803-1809 
Y5-W52 (Day 1814) 
1810-1816 
 
Thyroid Panel and Coagulation: PT, aPTT, INR 
 
103 


297 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 7 (Day 43) 
13-63 
Week 13 (Day 85) 
64-115 
Week 26 (Day 176) 
146-206 
Week 52 (Day 358) 
328-388 
Week 78 (Day 540) 
510-570 
Week 104 (Day 722) 
629-752 
Week 156 (Day 1086) 
1056-1116 
Y4-W26 (Day 1268) 
1238-1298 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W52 (Day 1814) 
1784-1844 
ISIS 420915 baseline for patients took placebo in the parent study. 
 
Immunogenicity 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 7 (Day 43) 
13-63 
Week 13 (Day 85) 
64-101 
Week 18 (Day 120) 
102-147 
Week 26 (Day 176) 
148-206 
Week 39 (Day 267) 
237-297 
Week 52 (Day 358) 
328-388 
Week 65(Day 449) 
419-479 
Week 78 (Day 540) 
510-570 
Week 91 (Day 631) 
601-661 
Week 104 (Day 722) 
692-752 
Week 117 (Day 813) 
783-843 
Week 130 (Day 904) 
874-934 
Week 143 (Day 995) 
965-1025 
Week 156 (Day 1086) 
1056-1116 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W52 (Day 1814) 
1784-1844 
 
 
 
 
 
ERG 
 
 
 
104 


298 
 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 78 (Day 540) 
510-570 
Week 156 (Day 1086) 
1056-1116 
 
Ophthalmology 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 26 (Day 176) 
146-206 
Week 52 (Day 358) 
328-388 
Week 78 (Day 540) 
510-570 
Week 104 (Day 772) 
742-802 
Week 130 (Day 904) 
874-934 
Week 156 (Day 1086) 
1056-1116 
Y4-W26 (Day 1268) 
1238-1298 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W26 (Day 1632) 
1602-1662 
Y5-W52 (Day 1814) 
1784-1844 
Inflammatory Panel: Hs-CRP 
 
Safety endpoint 
Nominal Visit (Target 
Day) 
Analysis Visit Window (Day) 
The OLE study 
Week 7 (Day 43) 
22-63 
Week 13 (Day 85) 
64-115 
Week 26 (Day 176) 
146-206 
Week 52 (Day 358) 
328-388 
Week 78 (Day 540) 
510-570 
Week 91 (Day 631) 
601-661 
Week 104 (Day 722) 
692-752 
Week 117 (Day 813) 
783-843 
Week 130 (Day 904) 
874-934 
Week 143 (Day 995) 
965-1025 
Week 156 (Day 1086) 
1056-1116 
Y4-W26 (Day 1268) 
1238-1298 
Y4-W39 (Day 1359) 
1329-1389 
Y4-W52 (Day 1450) 
1420-1480 
Y5-W13 (Day 1541) 
1511-1571 
Y5-W26 (Day 1632) 
1602-1662 
Y5-W39 (Day 1723) 
1693-1753 
Y5-W52 (Day 1814) 
1784-1844 
 
105 


299 
 
 
8.3.4 
Table 4. Safety Endpoints (Post-Treatment Analysis Follow-Up Visit Wondow): 
 
Safety endpoint 
Weeks from last dose 
(Days from last dose) 
Analysis Visit Window (Days from last 
dose) 
Vital Signs; Body 
Weight, ECG; 
Chemistry Panel; 
Hematology; 
Urinalysis; Thyroid 
Panel; Coagulation: PT, 
aPTT, INR; Retinol and 
Retinyl palmitate; 
Inflammatory Panel: 
Hs-CRP; 
Immunogenicity 
Follow-up Week 13 (91) 
61-121 
Serum Creatinine 
Follow-up Week 2 (14) 
8-20 
Follow-up Week 4 (28) 
21-34 
Follow-up Week 6 (42) 
35-65 
Follow-up Week 13 (91) 
66-121 
Platelets 
Follow-up Week 2 (14) 
10-16 
Follow-up Week 3 (21) 
17-23 
Follow-up Week 4 (28) 
24-30 
Follow-up Week 5 (35) 
31-37 
Follow-up Week 6 (42) 
38-65 
Follow-up Week 13 (91) 
66-121 
 
 
 
 
 
 
9. Updates and Additional Analysis in Final Analyses 
CS3 final analysis will perform when OLE study completed. 
 
9.1 Analyses Removed from Final Analyses 
Per protocol set (PPS) flag will not created in final ADaM dataset and Efficacy and PD analysis based 
on PPS will not be performed. 
Efficacy analysese by subgroup will not be performed. 
The degree of progression for mNIS+7 and Norfolk (specified in section 3.4.2.1) will not be 
performed 
106 


300 
 
 
The proportion of patients with percentage decrease from either the parent study baseline or the 
OLE study baseline in plasma transthyretin (TTR) 60% (specified in section 3.5) will not be 
performed. 
 
 
9.2 Additional Analyses added for Final Analyses 
 
9.2.1 
Based on OLE data only 
 
Summary of disposition and protocol deviation associated with COVID-19 based on CS3 
Enrolled Patients 
Summary of ISIS 420915 Trough Plasma Concentrations (On-Study) based on safety set. 
Summary of Complement Results (Complement C3, Complement C4, Complement Split Bb, 
Complement Split C5a) by visit based on safety set 
Summary of TEAE by System Organ Class and Preferred Term and by PND score (On-Study) 
based on safety set 
Lab shift table for Hematology (Hemoglobin, Lymphocyte, Neutrophil, White Blood Cell), 
Chemistry Test, Coagulation Test, Urinalysis test, Urinalysis Results from Central Lab Based 
on 24-hr Urine Collections, Confirmed Peak ALT, Confirmed Peak AST, Confirmed Peak Total 
Bilirubin (On-study) based on safety set. 
Incidence of Post-baseline abnormality, including lab Complement Results, vital signs and 
body weight and QTcF. 
 
Efficacacy endpoints 
 
On-treatment: Add Statistical Analysis of Change from CS2 Baseline to efficacy endpoints: 
 
mNIS+7, NIS+7, NIS, Modified +7, +7, NSC composite and component score, mNIS+7 
composite score, Norfolk QOL-DN, NSC total and domain score and selected questions, SF- 
36 component and Domain Scores. Norfolk QOL-DN Symptoms Domain Score based on 
Stage 1 Patients, Norfolk QOL-DN Physical Functioning/Large Fiber Neuropathy Domain 
Score based on Stage 2 Patients 
 
Post-treatment: 
Show Descriptive statistics of absolute value, change from baseline and percent change 
from baseline in mNIS+7, NIS+7, NIS, Modified +7, +7 Composite and Component, Norfolk 
QOL-DN Total and Domain Scores, SF-36 Scores, NSC score and Select Questions from NSC 
 
 
 
 
 
 
 
107 


301 
 
 
9.2.2 
Based on both CS2 and CS3 data 
CS3 final CRS will include some outputs from 420915 ISS, Please reference 420915 ISS SAP for 
planned statistical analyses and definition in details. Below are updates were added based on CS3 
final CRS additional request 
9.2.2.1 Add More Population Definition 
ISIS 420915 Full Analysis Set (ISIS 420915 FAS) will be subset of CS2 or CS3 FAS patients who 
received at least 1 injection of ISIS 420915 in CS2 or CS3 studies. 
ISIS 420915 ECHO subgroup will be the subset of CS2 ECHO subgroup patients who received at 
least 1 injection of ISIS 420915 in CS2 or CS3 studies. 
ISIS 420915 CM-ECHO Set will be the subset of CS2 CM-ECHO Set patients who received at least 
1 injection of ISIS 420915 in CS2 or CS3 studies. 
ISIS 420915 PK Set will include all patients who received at least one dose of ISIS 420915 and 
have at least one evaluable PK sample collected and analyzed with reportable result in CS2 or 
CS3 studies. 
 
 
9.2.2.2 Study Period Definition (On-Treatment, Post-Treatment and On-Study) 
 
 
On-Treatment 
o For efficacy endpoints except BMI, mBMI and PD, on-treatment period starts from ISIS 
420915 Study Day 1 until 52 days after the last dose of ISIS 420915. 
o For BMI, mBMI, PD and Safety endpoint ERG, on-treatment period is from ISIS 420915 Study 
Day 1 until 28 days after the last dose of ISIS 420915 
o For other Safety endpoints except ERG, on-treatment period is from ISIS 420915 Study Day 
1 until 7 days after the last dose of ISIS 420915 
 
 
Post-Treatment 
o Post-treatment period starts on the day after the on-treatment period and ends on the day 
 
On-Study 
o On-Study starts from ISIS 420915 Study Day 1 
ontact date. 
 
 
Of note, the definition above only apply for CS2 and CS3 combined data summary, which is not 
conflict with section 3.2.1.1.4 
 
108 


302 
 
 
 
9.2.2.3 Itegrated Summary of Efficacy based on CS2 and CS3 data 
 
 
Descriptive summary statistics: 
 
Descriptive summary statistics for absolute values, change or percent change from ISIS 420915 
baseline, if applicable, will be provided by analysis visits for below endpoints based on 420915 FAS, 
unless specify. 
mNIS+7 Composite Score (On-Treatment) 
mNIS+7 Composite Score (On-Treatment) by IM 
Modified +7 and +7 Composite Scores (On-Treatment) 
NIS+7 Composite Scores (On-Treatment) 
NIS Composite and Component Scores (On-Treatment) 
Modified +7 Component Scores (On-Treatment) 
+7 Component Scores (On-Treatment) 
Norfolk QOL-DN Total Score (On-Treatment) 
Norfolk QOL-DN Total Score (On-Treatment) by IM 
Norfolk QOL-DN Symptoms Domain Score (On-Treatment) - Stage 1 Patients 
Norfolk QOL-DN Physical Functioning/Large Fiber Neuropathy Domain Score (On-Treatment) 
- Stage 2 Patients 
Norfolk QOL-DN Domain Scores (On-Treatment) 
NSC Total Score and Domain Scores (On-Treatment) 
Modified Body Mass Index and Body Mass Index (On-Treatment) 
Transthyretin (TTR) and Retinol Binding Protein 4 (RBP4) (On-Treatment) 
Transthyretin (TTR) (On-Treatment) by IM 
SF-36 Component Summary Scores and Domain Scores (On-Treatment) 
NT-proBNP Result (pmol/L) and Log-Transformed NT-proBNP Result (On-Treatment), 
outputs will be repeated based on ISIS 420915 CM-ECHO set 
mNIS+7, NIS+7, NIS, Modified +7, +7 Composite and Component Scores (Post-Treatment) 
Norfolk QOL-DN Total and Domain Scores (Post-Treatment) 
SF-36 Scores (Post-Treatment) 
NSC Score (Post-Treatment) 
Global Longitudinal Strain (%) (On-Treatment) based on ISIS 420915 Enrolled Patients, ISIS 
420915 ECHO Subgroup, and ISIS 420915 CM-ECHO Set 
Assessment of Global Left Ventricular Size and Function - LV Mass (g) (On-Treatment) based 
on ISIS 420915 Enrolled Patients, ISIS 420915 ECHO Subgroup, and ISIS 420915 CM-ECHO Set 
mNIS+7 Composite Score: Response Rate by Threshold Value by Visit (On-Treatment) based 
on ISIS 420915 FAS 
 
109 


303 
 
 
Summary of PND Score Shift from Baseline by Visit (On-Treatment) based on ISIS 420915 
FAS 
Summary of PND Score Change from Baseline by Visit (On-Treatment) based on ISIS 420915 
FAS 
Summary of Select Questions from NSC (On-Treatment) and (Post-Treament) based on ISIS 
420915 FAS 
 
 
 
9.2.2.4 PK and IM Analyses 
Summary of ISIS 420915 Trough Plasma Concentrations (ng/mL) (On-Study) based on ISIS 
420915 PK Set 
Summary of ISIS 420915 Trough Plasma Concentrations (ng/mL) (On-Study) by IM 
based on ISIS 420915 PK Set 
Incidence and Incidence Rate of Sample Immunogenicity Status (On-Study) based on 
ISIS 420915 Safety Set 
Summary of Anti-ISIS 420915 Antibody Titer Values over Time (On-Study) based on ISIS 
420915 Safety Set 
Incidence and Incidence Rate of Subject Immunogenicity Status (On-Study) based on ISIS 
420915 Safety Set 
Summary Statistics of Onset and Peak Titer of the ADA Response by Treatment in Patients 
with Positive Patients Immunogenicity Status (On-Study) based on ISIS 420915 Safety Set 
 
 
9.2.2.5 Patient Characteristics and Population 
Summary of Treatment Discontinuations and Study Withdrawals Associated with COVID-19 
Based on ISIS 420915 Treated Set 
Summary of Patients with Protocol Deviations Based on ISIS 420915 Treated Set 
Summary of Patients with Protocol Deviations Associated with COVID-19 Based on ISIS 
420915 Treated Set 
Summary of Analysis Populations Based on ISIS 420915 Treated Set 
Summary of Concomitant Medications based on ISIS 420915 Safety Set 
 
 
9.2.2.6 ECG QRS Analyses 
Number and percent patient who have post baseline QRS value >160ms and 25% of CS2 
Baseline based on CS2 Safety Set 
Number and percent patient who have post baseline QRS value >160ms and 25% of CS2 or 
CS3 Baseline based on CS3 Safety Set 
110 


304 
 
 
Number and percent patient who have post baseline QRS value >160ms and 25% of ISIS 
420915 Baseline based on ISIS 420915 Safety Set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
111