Conditions: FAP Familial Amyloid Polyneuropathy TTR Transthyretin Amyloidosis
Keywords: FAP Familial Amyloid Polyneuropathy TTR Transthyretin Amyloidosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 173
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of inotersen given for 65 weeks in participants with Familial Amyloid Polyneuropathy (FAP).

Detailed description:
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.

Inotersen (also known as ISIS 420915) is an antisense drug that was designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein would result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.

The purpose of this study is to determine if inotersen can slow or stop the nerve damage caused by TTR deposits. This study will enroll late Stage 1 and early Stage 2 FAP participants. Participants will receive either inotersen or placebo for 65 weeks.

Arms:
arm 1: 300 mg inotersen administered subcutaneously (SC) 3 times on alternate days in the first week and then once-weekly for 64 weeks arm 2: Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks

Interventions: intervention 1: Inotersen intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ISIS 420915-CS2 
 
A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study 
to Assess the Efficacy and Safety of ISIS 420915 in Patients with 
Familial Amyloid Polyneuropathy 
 
Protocol Amendment 9 – 13 May 2016 
 
EudraCT No: 2012-001831-30 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 


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ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 420915-CS2 
Protocol Title: 
A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Safety of ISIS 420915 in Patients with Familial 
Amyloid Polyneuropathy 
Amendment: 
Amendment 9 
Date:  
 
13 May 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A 
Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and 
Safety of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy”, dated 13 May 2016, 
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 Isis Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................................14 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................19 
STUDY GLOSSARY ...................................................................................................................20 
1. 
OBJECTIVES .......................................................................................................................22 
1.1 
Primary Objectives .........................................................................................................22 
1.2 
Secondary Objectives .....................................................................................................22 
1.3 
Tertiary Objectives .........................................................................................................22 
1.4 
Exploratory Objectives ..................................................................................................22 
2. 
BACKGROUND AND RATIONALE ................................................................................23 
2.1 
Overview of Disease ......................................................................................................23 
2.1.1 Transthyretin Amyloidosis .........................................................................................23 
2.1.2 Current Therapies .......................................................................................................24 
2.2 
Therapeutic Rationale ....................................................................................................25 
2.3 
ISIS 420915 ...................................................................................................................26 
2.3.1 Mechanism of Action .................................................................................................26 
2.3.2 Chemistry ...................................................................................................................26 
2.3.3 Preclinical Experience ................................................................................................27 
2.3.4 Clinical Experience ....................................................................................................28 
2.4 
Rationale for Dose and Schedule of Administration .....................................................28 
3. 
EXPERIMENTAL PLAN ...................................................................................................29 
3.1 
Study Design ..................................................................................................................29 
3.2 
Number of Study Centers ...............................................................................................30 
3.3 
Number of Patients ........................................................................................................30 
3.4 
Overall Study Duration and Follow-up ..........................................................................30 
3.4.1 Screening and Baseline Assessment ...........................................................................30 
3.4.2 Treatment and EOT Efficacy Assessment ..................................................................31 
3.4.3 Post-Treatment ...........................................................................................................31 
3.5 
End of Study ..................................................................................................................31 
3.6 
Data Safety and Monitoring Board ................................................................................31 
4. 
PATIENT ENROLLMENT ................................................................................................31 
4.1 
Screening........................................................................................................................31 
4.2 
Randomization ...............................................................................................................32 
4.3 
Replacement of Patients .................................................................................................32 
4.4 
Unblinding of Treatment Assignment ...........................................................................32 
5. 
PATIENT ELIGIBILITY ....................................................................................................33 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
6 
5.1 
Inclusion Criteria ...........................................................................................................33 
5.2 
Exclusion Criteria ..........................................................................................................33 
5.3 
Additional Eligibility Criteria for Patients Participating in the ECHO Subgroup .........35 
6. 
STUDY PROCEDURES ......................................................................................................35 
6.1 
Study Schedule...............................................................................................................35 
6.1.1 Screening and Baseline Assessment Period ...............................................................35 
6.1.2 Treatment Period ........................................................................................................36 
6.1.3 EOT Efficacy Assessment Period ..............................................................................38 
6.1.4 Post-Treatment Period ................................................................................................38 
6.2 
Additional Study Assessments .......................................................................................38 
6.2.1 Laboratory Assessments .............................................................................................38 
6.2.2 Congestive Heart Failure ............................................................................................38 
6.2.3 Arrhythmias ................................................................................................................39 
6.2.4 Myocardial Ischemia ..................................................................................................39 
6.2.5 Event-Specific Supplemental CRF Pages ..................................................................39 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................39 
6.3.1 Contraception Requirements ......................................................................................39 
6.3.2 Other Requirements ....................................................................................................41 
7. 
STUDY DRUG ......................................................................................................................41 
7.1 
ISIS 420915 or Placebo .................................................................................................41 
7.2 
Packaging and Labeling .................................................................................................41 
7.3 
Study Drug Accountability ............................................................................................41 
8. 
TREATMENT OF PATIENTS ...........................................................................................41 
8.1 
Study Drug Administration ............................................................................................41 
8.2 
Other Protocol-Required Drugs .....................................................................................42 
8.3 
Other Protocol-Required Treatment Procedures ............................................................42 
8.4 
Treatment Precautions ...................................................................................................42 
8.5 
Safety Monitoring Rules ................................................................................................42 
8.5.1 Safety Monitoring Rules for Liver Chemistry Tests ..................................................43 
8.5.2 Safety Monitoring Rules for Renal Function .............................................................43 
8.5.3 Safety Monitoring Rules for Ocular Effects ...............................................................44 
8.5.4 Safety Monitoring Rules for Platelet Count Results ..................................................45 
8.6 
Stopping Rules ...............................................................................................................45 
8.6.1 Stopping Rules for Liver Chemistry Elevations .........................................................45 
8.6.2 Stopping Rules for Renal Function Test Results ........................................................46 
8.6.3 Stopping Rule for Platelet Count Results ...................................................................46 
8.6.4 Stopping Rule for Ocular Effects ...............................................................................47 
8.6.5 Stopping Rule for QTc Prolongation ..........................................................................47 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
7 
8.7 
Adjustment of Dose and/or Treatment Schedule ...........................................................48 
8.8 
Discontinuation of Study Treatment ..............................................................................48 
8.9 
Withdrawal of Patients from the Study ..........................................................................49 
8.10 
Concomitant Therapy and Procedures ...........................................................................49 
8.10.1 Concomitant Therapy .................................................................................................49 
8.10.2 Concomitant Procedures .............................................................................................50 
8.11 
Treatment Compliance ...................................................................................................50 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ............................50 
9.1 
Sponsor Review of Safety Information..........................................................................50 
9.2 
Regulatory Requirements ...............................................................................................50 
9.3 
Definitions......................................................................................................................51 
9.3.1 Adverse Event ............................................................................................................51 
9.3.2 Adverse Reaction and Suspected Adverse Reaction ..................................................51 
9.3.3 Serious Adverse Event (SAE) ....................................................................................51 
9.4 
Monitoring and Recording Adverse Events ...................................................................52 
9.4.1 Serious Adverse Events ..............................................................................................52 
9.4.2 Non-Serious Adverse Events ......................................................................................52 
9.4.3 Evaluation of Adverse Events (Serious and Non-Serious) ........................................53 
9.4.3.1 
Relationship to the Study Drug ......................................................................... 53 
9.4.3.2 
Severity ............................................................................................................. 53 
9.4.3.3 
Action Taken with Study Drug ......................................................................... 53 
9.4.3.4 
Treatment Given for Adverse Event ................................................................. 54 
9.4.3.5 
Outcome of the Adverse Event ......................................................................... 54 
9.5 
Procedures for Handling Special Situations ..................................................................54 
9.5.1 Abnormalities of Laboratory Tests .............................................................................54 
9.5.2 Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................55 
9.5.3 Dosing Errors .............................................................................................................55 
9.5.4 Contraception and Pregnancy .....................................................................................55 
10. STATISTICAL CONSIDERATIONS ................................................................................56 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................56 
10.1.1 Primary Endpoints ......................................................................................................56 
10.1.2 Secondary Endpoints ..................................................................................................56 
10.1.2.1 
Secondary Efficacy Endpoints ...................................................................... 56 
10.1.2.2 
Pharmacodynamic Endpoint ......................................................................... 56 
10.1.2.3 
Safety Endpoints ........................................................................................... 57 
10.1.2.4 
Pharmacokinetic Endpoints .......................................................................... 57 
10.1.3 Tertiary Endpoint .......................................................................................................57 
10.1.4 Exploratory Endpoints ................................................................................................58 
10.2 
Sample Size Considerations ...........................................................................................58 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
8 
10.3 
Populations .....................................................................................................................58 
10.4 
Interim Analysis .............................................................................................................59 
10.5 
Planned Methods of Analysis ........................................................................................59 
10.5.1 Demographic and Baseline Characteristics ................................................................59 
10.5.2 Safety Analysis ...........................................................................................................59 
10.5.3 Efficacy Analysis .......................................................................................................60 
10.5.4 Pharmacokinetic Analysis ..........................................................................................62 
10.5.5 Pharmacodynamic Analysis .......................................................................................62 
10.5.6 Exploratory Analysis ..................................................................................................62 
11. INVESTIGATOR'S REGULATORY OBLIGATIONS ..................................................62 
11.1 
Informed Consent...........................................................................................................62 
11.2 
Ethical Conduct of the Study .........................................................................................63 
11.3 
Independent Ethics Committee/Institutional Review Board ..........................................63 
11.4 
Patient Confidentiality ...................................................................................................63 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ......................................................64 
12.1 
Protocol Amendments ....................................................................................................64 
12.2 
Study Termination .........................................................................................................64 
12.3 
Study Documentation and Storage.................................................................................64 
12.4 
Study Monitoring ...........................................................................................................65 
12.5 
Language ........................................................................................................................66 
12.6 
Compensation for Injury ................................................................................................66 
13. REFERENCES .....................................................................................................................67 
14. APPENDICES ......................................................................................................................70 
Appendix A 
Schedule of Procedures ......................................................................................71 
Appendix B 
List of Laboratory Analytes ...............................................................................78 
Appendix C 
PK Sampling Schedule ......................................................................................80 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ................................................................................... 41 
 
TABLE OF FIGURES 
Page 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides   
(MOE-Gapmer).  The sequence of ISIS 420915 is shown ................................... 27 
 
 


ISIS 420915-CS2 
CONFIDENTIAL
Amendment 9
Protocol 
13 May 2016
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
 
ISIS 420915-CS2 
Protocol Title: 
A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study 
to Assess the Efficacy and Safety of ISIS 420915 in Patients with 
Familial Amyloid Polyneuropathy 
Amendment Number: 
9 
Amendment Date: 
13 May 2016 
 
The main purpose of this amendment is to increase the frequency of platelet monitoring from 
every 2-3 weeks, to every week throughout the treatment period and for a minimum of 6 weeks 
after the last dose of Study Drug.  This change was made in response to a recently reported case 
of severe thrombocytopenia in this study and in consultation with the independent DSMB.  
Previous to this recent case, two other patients in this study have developed severe 
thrombocytopenia, one of whom experienced a fatal intracranial bleed. 
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: 
Protocol Section 
Description of Change 
Rationale 
3.4.3 
Post-Treatment 
Was: 
The post-treatment evaluation period is 6 months 
and consists of 3 Study Center visits on Weeks 71, 
77 and 91.  The final study visit is Week 91. 
 
Is: 
The post-treatment evaluation period is 6 months 
and consists of Study Center visits and additional 
safety testing.  The final study visit is Week 91. 
Language with regard to the visit 
schedule and laboratory safety 
testing has been updated to 
reflect the new schedule of 
procedures. 
6.1.2 
Treatment Period 
Was: 
Patients will report to the Study Center for Study 
Drug administration, evaluations, and tests 24 times 
during Weeks 2-65 (see Schedule of Procedures in 
Appendix A). 
 
Is: 
Patients will report to the Study Center for Study 
Drug administration, evaluations, and tests regularly 
throughout the treatment period and will have 
weekly safety testing according to the schedule of 
procedures in Appendix A. 
Language with regard to the visit 
schedule and laboratory safety 
testing has been updated to 
reflect the new schedule of 
procedures. 
 
 


ISIS 420915-CS2 
CONFIDENTIAL
Amendment 9
Protocol 
13 May 2016
 
10 
Protocol Section 
Description of Change 
Rationale 
6.1.2 
Treatment Period 
Continued 
Was: 
To help reduce patient travel burden, 13 clinic visits 
may be done as non-clinic visits during the treatment 
period.  For non-clinic visits, collection of vital signs 
and labs (as indicated in the Schedule of 
Procedures) can be performed by the Sponsor’s 
home healthcare service or by a local laboratory with 
prior Sponsor approval.  The selected visits are at 
Weeks 10, 15, 20, 23, 26, 32, 38, 41, 44, 50, 56, 59, 
and 62.  At Weeks 23, 41 and 59, adverse events 
should be collected by the site personal through a 
phone contact with the patient. 
 
Is: 
To help reduce patient travel burden, some clinic 
visits and weekly safety testing between visits 
may be done as non-clinic visits.  For non-clinic 
visits, collection of vital signs and labs (as indicated 
in the Schedule of Procedures) can be performed by 
the Sponsor’s home healthcare service or by a local 
laboratory with prior Sponsor approval. 
Language with regard to the visit 
schedule and laboratory safety 
testing has been updated to 
reflect the new schedule of 
procedures. 
6.1.4 
Post-Treatment Period 
Was: 
After completion of the EOT efficacy assessment, 
patients will enter the 6-month post-treatment 
evaluation period.  This period consists of 8 Study 
Center visits on Weeks 67, 69, 71, 74, 77, 80, 83, 
and 91 as outlined in the schedule of procedures 
(Appendix A).  Weeks 67, 69, 71, 74, 80 and 83 may 
be done as a non-clinic visit where collection of vital 
signs and labs may be collected by the Sponsor’s 
home healthcare service or by a local laboratory with 
prior Sponsor approval.  At Week 71, adverse events 
should be collected by the site personal through a 
phone contact with the patient. 
Alternatively, after completion of the EOT efficacy 
assessment, eligible patients may elect to receive 
ISIS 420915 in an OLE study, pending study 
approval by the IRB/IEC and the appropriate 
regulatory authority.  In this case, patients will not 
participate in the post-treatment evaluation period. 
 
Is: 
After completion of the EOT efficacy assessment, 
patients will enter the 6-month post-treatment 
evaluation period and will report to the study 
center and have weekly platelet monitoring for a 
minimum of 6 weeks after the last dose of Study 
Drug which may be collected by the clinic, 
Sponsor’s home healthcare service or by a local 
laboratory as outlined in the schedule of procedures 
(Appendix A).  At Week 71, adverse events should 
be collected by the site personal through a phone 
contact with the patient if a clinic visit was not 
conducted. 
Language with regard to the visit 
schedule and laboratory safety 
testing has been updated to 
reflect the new schedule of 
procedures. 
 
 


ISIS 420915-CS2 
CONFIDENTIAL
Amendment 9
Protocol 
13 May 2016
 
11 
Protocol Section 
Description of Change 
Rationale 
6.1.4 
Post-Treatment Period 
Continued 
Is: Continued 
Alternatively, after completion of the EOT efficacy 
assessment, eligible patients may elect to receive 
ISIS 420915 in an OLE study (ISIS 420915-CS3), 
pending study approval by the IRB/IEC and the 
appropriate regulatory authority.  In this case, 
patients will not participate in the post-treatment 
evaluation period but weekly platelet monitoring 
should continue between the last dose of Study 
Drug in CS2 and the first dose of Study Drug in 
CS3.  If this period extends beyond 6 weeks, the 
frequency will be determined by the Study 
Medical Monitor. 
Language with regard to the visit 
schedule and laboratory safety 
testing has been updated to 
reflect the new schedule of 
procedures. 
6.2.1 
Laboratory 
Assessments 
Deleted: 
Each time a hematology lab is collected a duplicate 
sample (e.g., local lab) should also be collected in 
parallel.  If both the central and local platelet value is 
uninterpretable (e.g., due to clumping, hemolysis or 
quantity not sufficient) a repeat hematology lab must 
be collected as soon as possible (within 7 days after 
the unreportable value). 
Because platelet counts will be 
monitored more frequently, the 
requirement to collect a local lab 
sample at the same time as the 
samples for the central lab has 
been removed. 
8.5.4 
Safety Monitoring 
Rules for Platelet 
Count Results 
Was: 
If a patient’s platelet count falls by 30% or greater 
from baseline or the absolute platelet count is 
100,000/mm3 or less, then the patient’s platelet 
counts should be monitored more frequently.  The 
frequency of monitoring and additional lab tests will 
be determined by the Investigator in consultation 
with the Study Medical Monitor.  Additional details on 
monitoring platelets are described in the Safety 
Management Plan. 
 
Is: 
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 65-week treatment 
period).  For patients participating in the Post-
Treatment Evaluation Period, frequency of 
testing after the Week 71 visit will be determined 
by the Investigator in consultation with the Study 
Medical Monitor.  For patients participating in the 
ISIS 420915-CS3 study, weekly monitoring 
should continue between the last dose of Study 
Drug in CS2 and first dose of Study Drug in CS3.  
If this period extends beyond 6 weeks, the 
frequency of monitoring will be determined by 
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. 
The monitoring rule has been 
updated to reflect the weekly 
platelet monitoring and to 
indicate that dosing must be 
held if there is more than 
14 days between interpretable 
platelet values. 
 
 


ISIS 420915-CS2 
CONFIDENTIAL
Amendment 9
Protocol 
13 May 2016
 
12 
Protocol Section 
Description of Change 
Rationale 
8.5.4 
Safety Monitoring 
Rules for Platelet 
Count Results 
Continued 
Is: Continued 
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. 
The monitoring rule has been 
updated to reflect the weekly 
platelet monitoring and to 
indicate that dosing must be 
held if there is more than 
14 days between interpretable 
platelet values. 
8.6.3 
Stopping Rule for 
Platelet Count Results 
Was: 
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 Study Drug (ISIS 420915 or 
placebo) must be held until the platelet count returns 
to at least 100,000/mm3.  In addition, platelet counts 
should be monitored weekly (or more frequently as 
determined by the Study Medical Monitor) until they 
return above 75,000/mm3. 
 
Is: 
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 Study Drug (ISIS 420915 or 
placebo) 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. 
Platelet stopping rule has been 
updated to indicate daily platelet 
monitoring is required if the 
platelet value is < 50,000/mm3 
and that the Investigator is 
required to inform the Study 
Medical Monitor within 24 hours 
if a local platelet value is  
< 50,000/mm3. 
Appendix A Schedule 
of Procedures 
Deleted: 
To accommodate scheduling, visit windows may be 
used, however hematology collections must be 
collected no more than 2-3 weeks apart. 
+ Each time a hematology lab is collected a 
duplicate sample (e.g., local lab) should also be 
collected in parallel.  If both the central and local 
platelet value is uninterpretable (e.g., due to 
clumping, hemolysis or quantity not sufficient) a 
repeat hematology lab must be collected as soon as 
possible (within 7 days after the unreportable value). 
The schedule of procedures was 
updated to reflect the weekly 
platelet monitoring and removal 
of duplicate platelet collection. 
 
 


ISIS 420915-CS2 
CONFIDENTIAL
Amendment 9
Protocol 
13 May 2016
 
13 
Protocol Section 
Description of Change 
Rationale 
Appendix A Schedule 
of Procedures 
Continued 
Added: 
Weekly platelet monitoring was added throughout 
the treatment period and up to Week 71 in the post-
treatment evaluation period. 
 
Footnote to weekly platelet monitoring added: 
Weekly platelet 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 65-week treatment period).  For patients 
participating in the Post-Treatment Evaluation 
Period, frequency of testing after the Week 71 visit 
will be determined by the Study Medical Monitor in 
consultation with the Investigator.  For patients 
participating in the ISIS 420915-CS3 study, weekly 
monitoring should continue between the last dose of 
Study Drug in CS2 and first dose of Study Drug in 
CS3.  If this period extends beyond 6 weeks, the 
frequency will be determined by the Study Medical 
Monitor. 
The following visits to collect platelet values are 
required in addition to the visits shown in the table. 
These visits do not have specified windows to allow 
flexibility of scheduling but with the intent that 
platelets are assessed each calendar week.  Visits 
may be completed in clinic, by home healthcare 
service, or by a local laboratory: 
Week 2, 4, 6, 7, 9, 11, 12, 14, 16, 17, 19, 21, 22, 24, 
25, 27, 28, 30, 31, 33, 34, 36, 37, 39, 40, 42, 43, 45, 
46, 48, 49, 51, 52, 54, 55, 57, 58, 60, 61, 63, 64, 66, 
68, and 70 
The schedule of procedures was 
updated to reflect the weekly 
platelet monitoring and removal 
of duplicate platelet collection. 
Appendix B 
List of Laboratory 
Analytes 
Added: 
Total IgG 
Total IgM 
Added two new laboratory 
analytes. 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title  
A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Efficacy and Safety of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy 
(FAP) 
Study Phase 
Phase 2/3 
Indication 
Familial Amyloid Polyneuropathy 
Primary Objectives 
To evaluate the efficacy of ISIS 420915 as compared to placebo, given for 
65 weeks, as measured by the change from baseline in the modified Neuropathy 
Impairment Score +7 (mNIS+7) and in the Norfolk Quality of Life-Diabetic 
Neuropathy (Norfolk QOL-DN) questionnaire total score, in patients with FAP 
Secondary Objectives 
To evaluate the efficacy of ISIS 420915 as compared to placebo, based on the 
change from baseline in the following measures: 
1. 
Norfolk QOL-DN questionnaire symptoms domain score in Stage 1 patients 
and Norfolk QOL-DN questionnaire physical functioning/large fiber neuropathy 
domain score in Stage 2 patients 
2. 
Modified body mass index (mBMI) and body mass index (BMI) 
3. 
NIS and modified +7 
4. 
NIS+7 
5. 
Global longitudinal strain (GLS) by echocardiogram (ECHO) in the ECHO 
subgroup and in the Cardiomyopathy-ECHO (CM-ECHO) Set 
To evaluate the pharmacodynamic (PD) effect of ISIS 420915 as compared to 
placebo, based on the change from baseline in transthyretin (TTR) and retinol 
binding protein 4 (RBP4). 
To evaluate the safety and tolerability of ISIS 420915. 
To evaluate the plasma trough levels of ISIS 420915 in all patients and to evaluate 
the plasma pharmacokinetic parameters of ISIS 420915 in a subset of patients. 
Tertiary Objectives 
To evaluate the change from baseline as compared to placebo in the following 
measures: 
• 
SF-36 questionnaire 
• 
Individual components of NIS, modified +7, and +7 
• 
+7 
• 
Individual domain scores of the Norfolk QOL-DN questionnaire 
Exploratory Objectives 
To evaluate the change from baseline as compared to placebo in the following 
exploratory measures: 
• 
ECHO parameters (except GLS) in the ECHO subgroup and in the CM-ECHO 
Set 
• 
Plasma N-terminal prohormone of brain natriuretic peptide  
(NT-proBNP) 
• 
Polyneuropathy disability score (PND) 
• 
Neuropathy symptoms and change (NSC) score 
 
 


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Protocol Synopsis Continued 
Study Design 
Multicentre, randomized, double-blind, placebo-controlled study.  Approximately 
135 patients will be randomized in a 2:1 ratio (90 ISIS 420915 and 45 PBO) to 
receive 300 mg ISIS 420915 or placebo.  Study Drug (ISIS 420915 or placebo) will 
be administered 3 times on alternate days during Week 1 (Days 1, 3 and 5), and 
then once weekly during Weeks 2-65 (for a total of 67 doses).  Patients will also 
receive daily supplemental doses of the recommended daily allowance of vitamin A.  
The end of treatment (EOT) efficacy assessment is conducted at Week 66.  
Following treatment and the EOT efficacy assessment, eligible patients (including 
patients that received placebo), may elect to enroll in an open-label extension (OLE) 
study pending study approval by the IRB/IEC and the appropriate regulatory 
authority.  All participating patients in the OLE study will receive 300 mg ISIS 420915 
once weekly.  Patients not participating in the OLE will enter the 6-month 
post-treatment evaluation portion of this study after completing the EOT efficacy 
assessment. 
Number of Patients 
Approximately 135 patients will be enrolled into this study 
Study Population 
Inclusion Criteria: 
1. 
Stage 1 and Stage 2 FAP patients with the following: 
a. 
NIS score ≥ 10 and ≤ 130 
b. 
Documented transthyretin variant by genotyping 
c. 
Documented amyloid deposit by biopsy 
2. 
Willingness to take vitamin A supplements 
3. 
Aged 18 to 82 years old at the time of informed consent 
4. 
Satisfy the following: 
a. 
Females:  non-pregnant and non-lactating; surgically sterile, post-
menopausal, abstinent, or if engaged in sexual relations of child-bearing 
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 Study Drug 
b. 
Males:  Surgically sterile, abstinent, or if engaged in sexual relations of 
child-bearing potential, patient is utilizing an acceptable contraceptive 
method (refer to Section 6.3.1) during and for 3 months after the last dose 
of Study Drug 
5. 
Must have given written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all study 
requirements 
Exclusion Criteria: 
1. 
Unwillingness to comply with study procedures, including follow-up, as 
specified by this protocol, or unwillingness to cooperate fully with the 
Investigator 
2. 
Screening laboratory results as follows, or any other clinically-significant 
abnormalities in screening laboratory values that would render a patient 
unsuitable for inclusion: 
a. 
ALT/AST > 1.9 x ULN 
b. 
Bilirubin ≥ 1.5 x ULN (patients with bilirubin ≥ 1.5 x ULN may be allowed 
on study following discussion with the Study Medical Monitor if indirect 
bilirubin only is elevated, ALT/AST is not greater than the ULN and genetic 
testing confirming Gilbert’s disease) 
c. 
Platelets < 125 x 109/L 
d. 
Positive (≥ trace) for protein on urine dipstick.  In the event of a positive 
test eligibility may be confirmed by a quantitative total urine protein 
measurement of < 1.0 g/24 hours 


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Protocol Synopsis Continued 
Study Population Continued Exclusion Criteria: Continued 
e. 
Positive (≥ trace) for blood on urine dipstick.  In the event of a positive test 
eligibility may be confirmed with urine microscopy showing ≤ 5 red blood 
cells per high power field.  If > 5 red blood cells per high power field and 
there is a clearly identifiable benign cause for the microscopic hematuria 
(for example chronic urinary tract infection secondary to neurogenic 
bladder) eligibility should be determined by discussion with the 
Study Medical Monitor 
f. 
TSH values outside normal range (unless approved by the Study 
Medical Monitor) 
3. 
Retinol level at Screen < LLN 
• For patients with a TTR mutation at position 84 (e.g., Ile84Ser or Ile84Asn) 
and retinol < LLN the exclusion criterion is signs or symptoms of vitamin A 
deficiency (such as evidence of vitamin A deficiency on ERG) 
4. 
Uncontrolled hypertension (blood pressure > 160/100) 
5. 
Positive test result for HIV, hepatitis B, or hepatitis C 
6. 
Karnofsky performance status ≤ 50 
7. 
Renal insufficiency as defined by estimated creatinine clearance calculated 
according to the formula of CKD-EPI < 60 mL/min/1.73 m2 at Screen.  If the 
calculated creatinine clearance is thought to be artificially low, a 24-hour urine 
creatinine clearance can be completed with prior Sponsor approval 
8. 
Presence of known type 1 or type 2 diabetes mellitus 
9. 
Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune 
disease) 
10. Treatment with another investigational drug, biological agent, or device within  
3 months of Screening, or 5 half-lives of study agent, whichever is longer 
11. If previously treated with Vyndaqel®, must have discontinued treatment for 
2 weeks prior to Study Day 1.  If previously treated with Diflunisal, must have 
discontinued treatment for 3 days prior to Study Day 1 
12. Previous treatment with any oligonucleotide or siRNA within 6 months of 
Screening.  Subjects that have been previously treated with oligonucleotides 
should be approved by the Study Medical Monitor 
13. Prior liver transplant or anticipated liver transplant within 1-yr of Screening 
14. New York Heart Association (NYHA) functional classification of ≥ 3 
15. Acute coronary syndrome or major surgery within 3 months of Screening 
16. Known Primary Amyloidosis 
17. Known Leptomeningeal Amyloidosis 
18. Anticipated survival less than 2 years 
19. Active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed prior to Study Day 1 
20. Malignancy within 5 years, except for basal or squamous cell carcinoma of the 
skin or carcinoma in situ of the cervix that has been successfully treated. 
Patients with a history of other malignancies that have been curatively treated 
may be eligible but must be discussed and approved by the Sponsor Medical 
Monitor 
21. Have any other conditions, which, in the opinion of the Investigator would 
make the patient unsuitable for inclusion, or could interfere with the patient 
participating in or completing the study 
22. Known Monoclonal Gammopathy of Undetermined Significance or Multiple 
Myeloma 
 


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Protocol Synopsis Continued 
Study Population Continued Exclusion Criteria: Continued 
Additional eligibility criteria for patients participating in the ECHO subgroup: 
1. 
Must have left ventricular wall thickness of ≥ 13 mm on transthoracic 
echocardiogram at Baseline 
2. 
No known history of persistent hypertension ≥ 150 mm Hg within 12 months 
prior to Screening 
3. 
Baseline ECHO is evaluable as ascertained by Sponsor central reader 
Treatment Groups 
Patients will be randomized 2:1 to receive 300 mg ISIS 420915 or placebo 
Study Drug Product Dosage 
and Administration 
Study Drug (ISIS 420915 300 mg or placebo) will be administered as subcutaneous 
(SC) injections in the abdomen, thigh or upper arm 
Rationale for Dose and 
Schedule Selection 
300 mg administered 3 times during Week 1 and then once weekly was chosen 
based on the pharmacokinetic, pharmacodynamic and safety analysis of the 
ISIS 420915 Phase 1 study in healthy volunteers 
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following periods: 
• 
A ≤ 6-week screening and baseline assessment period 
• 
A 65-week treatment period during which Study Drug will be administered as 
a once weekly SC injection (except during Week 1 where 3 SC injections will 
be given on alternate days) 
• 
A 1-week EOT efficacy assessment period, and 
• 
A 6-month post-treatment evaluation period 
Collection and measurement of vital signs, clinical laboratory parameters (including 
hematology, serum chemistry, and urinalysis), adverse events, concomitant 
medication/procedure information, PD parameters (TTR and RBP4), ISIS 420915 
plasma trough concentrations, and immunogenicity testing will be performed 
according to the schedule of procedures in Appendix A.  The following assessments 
will also be performed at specified visits during the study:  mNIS+7, Norfolk QOL-DN 
questionnaire, SF-36 questionnaire, physical examination, PND score, mBMI/BMI, 
Columbia-Suicide Severity Rating Scale (C-SSRS) questionnaire, ophthalmology 
examination, electroretinogram (ERG), and electrocardiogram (ECG).  All patients 
will also have a baseline transthoracic ECHO conducted in the screening and 
baseline assessment period and Week 65 and patients participating in the ECHO 
subgroup will have a Week 41 ECHO.  In addition, approximately 30 patients will 
have additional pharmacokinetic, ECG, complement, coagulation, hematology, and 
inflammatory testing at specified visits according to the schedule of procedures 
(Appendix A). 
Study Drug will be administered at the Study Center during scheduled clinic visits as 
outlined in the schedule of procedures (Appendix A).  Otherwise, administration of 
Study Drug may be given by either the Study Center personnel or at home by the 
patient/caregiver.  Dosing instructions and training on injection technique will be 
provided to the patient where applicable. 
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 Monitoring 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, ERG examination, and C-SSRS questionnaire. 
 
 
 


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Protocol Synopsis Continued 
Efficacy Evaluations 
Efficacy evaluations include change from baseline in mNIS+7, Norfolk QOL-DN 
questionnaire, mBMI, BMI, and individual components of mNIS+7, NIS+7, and 
change in GLS by ECHO  
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 and Appendix C.  In a 
subset of patients, more frequent assessment of pharmacokinetic parameters of 
ISIS 420915 will be determined as detailed in Appendix A and Appendix C. 
Pharmacodynamic 
Evaluations 
Circulating levels of TTR and RBP4 will be determined throughout the study 
according to schedule of procedures (Appendix A). 
Statistical Considerations 
The sample size for this study was estimated using published natural history data 
(Adams et al. 2015) and efficacy data (Berk 2013; Adams 2015) reported in a similar 
patient population as that targeted in this protocol.  The calculations assume an 
effect size of 9.6 points and standard deviation of 14 in the mNIS+7 score, an effect 
size of 10.7 and standard deviation of 18 in the Norfolk QOL-DN total score, and a 
drop-out rate of 25%.  One hundred thirty-five (135) patients will give at least 90% 
and 80% power in the mNIS+7 and Norfolk QOL-DN endpoints, respectively, using a 
two-sided t-test with an alpha level of 0.05. 
Eligible patients will be randomized 2:1 (ISIS 420915 : PBO) and stratified for: 
• 
Previous treatment with Vyndaqel® (tafamidis) or Diflunisal versus no known 
previous treatment 
• 
Stage 1 versus Stage 2 disease 
• 
V30M TTR mutation versus non-V30M TTR mutation 
The study will enroll approximately 50% Stage 1 and 50% Stage 2 patients. 
An interim analysis of reduction in TTR level will be performed by an independent 
statistician and presented to the independent DSMB after approximately 45 patients 
have completed the Week 13 visit.  Details of the analysis and controlled access to 
the unblinded data are outlined in the Statistical Analysis Plan (SAP) and DSMB 
Charter. 
The primary endpoints are the change in the mNIS+7 score and the change in the 
Norfolk QOL-DN questionnaire total score from baseline to Week 66.  The 2 primary 
endpoints will be analyzed using a ranking strategy with the mNIS+7 tested first and 
the Norfolk QOL-DN questionnaire total score tested second.  Interpretation will be 
made in a stepwise approach, i.e. should the null hypothesis for the mNIS+7 be 
rejected, then the null hypothesis for the Norfolk QOL-DN will be tested.  However, if 
the null hypothesis for the mNIS+7 is not rejected, testing for the Norfolk QOL-DN 
will be considered exploratory.  No adjustment will be made for multiple testing (both 
endpoints will be tested at an alpha of 0.05). Various sensitivity analyses will be 
conducted to assess the impacts of the stratification factors and the missing values. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
 
 
 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
A 
An exception to the 6-week period given to perform the screening evaluations and baseline assessments is the 
TTR genotyping and amyloid biopsy tests.  These tests may be conducted up to 10 weeks prior to Study Day 1.  
They are only conducted if appropriate documentation is not already available.  In addition, ERG and 
ophthalmology examinations may be conducted up to 1-week after Study Day 1 if needed for scheduling 
purposes (except for Ile84 patients that fall under exclusion criteria 3 and should have eye examinations 
performed to determine eligibility). 
B 
Patients that terminate treatment early should have the early termination visit and EOT efficacy assessments 
conducted ideally within 14 days from the last dose of Study Drug.  They should then enter the post-treatment 
evaluation period.  
Patients that discontinue treatment due to liver transplantation should return to the clinic for the EOT efficacy 
assessment as soon as feasible after the transplant procedures (if possible within 6 weeks).  After the early 
termination and EOT efficacy assessment procedures are complete, the patient should be withdrawn from the study. 
TREATMENT PERIOD 
Week 1 to 65 
• Week 1:  3 SC doses of 
Study Drug (Days 1, 3 and 5) 
• Weeks 2-65:  Once weekly SC 
dose of Study Drug 
END OF TREATMENT EFFICACY 
ASSESSMENT 
Week 66 
POST-TREATMENT 
EVALUATION PERIOD 
6 months 
SCREEN and BASELINE 
ASSESSMENT PERIOD 
Week -6 to -1A 
EARLY TERMINATION 
VISIT 
END OF TREATMENT EFFICACY 
ASSESSMENTB 
Treatment terminated but 
consent not withdrawn 
Patient 
terminates 
treatment 
early 
OPEN LABEL EXTENSION 
(OLE) STUDY 
 
Eligible patients only and 
pending study approval by the 
IRB/IEC and appropriate 
regulatory authority 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
+7 
Sum 7 test.  Includes measurements of nerve conduction, vibration 
threshold and heart rate to deep breathing 
Alb/C ratio 
Albumin/Creatinine ratio (performed on urine sample) 
aPTT 
Activated partial thromboplastin time 
ASO 
Antisense oligonucleotide 
AUC 
Area under the curve 
BMI 
Body mass index 
CM 
Cardiomyopathy 
CM-ECHO Set 
Patients with a diagnosis of TTR cardiomyopathy at study entry 
who are not in the ECHO subgroup, plus the patients in the ECHO 
subgroup 
C-SSRS 
Columbia-suicide severity rating scale 
DSMB 
Data and safety monitoring board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECHO Subgroup 
The subgroup of patients meeting protocol-specified ECHO criteria 
and having an additional echocardiogram assessment 
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 
IXRS 
Interactive voice/web-response system 
LLN 
Lower limit of normal 
mBMI 
Modified body mass index (requires determination of plasma 
albumin levels; mBMI = BMI x serum albumin g/L) 
MMRM model 
Mixed effect model with repeated measures 


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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 
NIS 
Neuropathy impairment score 
NIS-LL 
Neuropathy impairment score-lower limb 
NIS+7 
Neuropathy impairment score +7 
Norfolk QOL-DN 
Norfolk quality of life-diabetic neuropathy questionnaire 
NT-proBNP 
N-terminal prohormone of brain natriuretic peptide 
OLE 
Open label extension 
OLTX 
Orthotopic liver transplantation 
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 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
Study Day 1 
Defined as the first day Study Drug is administered to the patient 
Study Drug 
ISIS 420915 or placebo 
SUSARs 
Suspected unexpected serious adverse reactions 
TTR 
Transthyretin 
TUCA 
Tauroursodeoxycholic acid 
ULN 
Upper limit of normal 
UTR 
Untranslated region 
 
 


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1. 
OBJECTIVES 
1.1 
Primary Objectives 
To evaluate the efficacy of ISIS 420915 as compared to placebo, given for 65 weeks, as 
measured by the change from baseline in the modified Neuropathy Impairment Score+7  
(mNIS+7) and in the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) 
questionnaire total score, in patients with Familial Amyloid Polyneuropathy (FAP). 
1.2 
Secondary Objectives 
To evaluate the efficacy of ISIS 420915 as compared to placebo based on the change from 
baseline in the following measures: 
• Norfolk QOL-DN questionnaire symptoms domain score in Stage 1 patients and Norfolk 
QOL-DN questionnaire physical functioning/large fiber neuropathy domain score in 
Stage 2 patients 
• Modified body mass index (mBMI) and body mass index (BMI) 
• NIS and modified +7 
• NIS+7 
• Global longitudinal strain (GLS) by echocardiogram (ECHO) in the ECHO subgroup and 
in the Cardiomyopathy-ECHO (CM-ECHO) Set 
To evaluate the pharmacodynamic (PD) effect of ISIS 420915 as compared to placebo, based on 
the change from baseline in transthyretin (TTR) and retinol binding protein 4 (RBP4). 
To evaluate the safety and tolerability of ISIS 420915. 
To evaluate the plasma trough levels of ISIS 420915 in all patients and to evaluate the plasma 
pharmacokinetic parameters of ISIS 420915 in a subset of patients. 
1.3 
Tertiary Objectives 
To evaluate the change from baseline as compared to placebo in the following measures: 
• SF-36 questionnaire 
• Individual components of NIS, modified +7, and +7 
• + 7 
• Individual domain scores of the Norfolk QOL-DN questionnaire 
1.4 
Exploratory Objectives 
To evaluate the change from baseline as compared to placebo, in the following exploratory 
biomarkers: 
• ECHO parameters (except GLS) in the ECHO subgroup and in the CM-ECHO Set 


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• Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) 
• Polyneuropathy disability score (PND) 
• Neuropathy symptoms and change (NSC) score 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
2.1.1 
Transthyretin Amyloidosis 
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 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, 
GI 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). 
The main clinical manifestations of FAP are progressive peripheral sensorimotor and autonomic 
neuropathy.  Sensory neuropathy starts in the lower extremities with paresthesias and 
hypoesthesias of the feet, followed within a few years by motor neuropathy 
(Sekijima et al. 2009).  Gastrointestinal symptoms, characterized by diarrhea and weight loss can 
also be prominent and reflect autonomic dysfunction (Falk et al. 1997; Ando et al. 2005).  Death, 
on average, occurs within 10 years from symptom onset and is primarily due to malnutrition and 
cachexia, cardiac disease, sudden death or renal failure (Coelho et al. 2008).  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). 
Clinical trials in patients with FAP have used the Neuropathy Impairment Score (NIS), or 
derivatives of this score such as the NIS Lower Limb (NIS-LL) or the NIS+7, to assess 
progression of neuropathy.  The NIS score was originally developed for assessment of diabetic 
neuropathy and is a quantitative score of motor, sensory, and reflex function as judged by the 
clinician (Dyck et al. 1991).  The NIS-LL is a subset of the full NIS and evaluates changes in 
motor, sensory and reflex activity specifically in the lower limbs whereas the full NIS also 
evaluates changes in the upper limbs and cranial nerves.  The NIS or NIS-LL scores are 
sometimes combined with the Sum 7 Test (or +7) to give the NIS+7 or NIS-LL+7 composite 
score (Dyck et al. 1997).  The +7 Test is an objective score of large fiber function that includes 
measurements of nerve conduction, vibration threshold and heart rate to deep breathing (an 
assessment of autonomic function).  Thus the NIS+7 and NIS-LL+7 scores have the advantage of 
combining a subjective assessment scored by the clinician with objective measurements of 
autonomic and sensory nerve function, which are both affected in patients with FAP.  The 


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NIS-LL / NIS-LL+7 score is most appropriate to measure neuropathy progression in early  
Stage 1 FAP patients.  But patients in later Stage 1 and Stage 2 (as is the case for this protocol) 
can reach a ceiling effect on the NIS-LL score, and therefore the full NIS /NIS+7 is a more 
appropriate score for these patients.  However, even the NIS+7 may not be optimally sensitive 
for assessment of progression of neuropathy in the target population of this study because it is 
primarily focused on motor function and on large nerve fibers whereas FAP has a significant 
sensory component and affects both large and small nerve fibers, with a great deal of between 
patient heterogeneity in the degree to which the different nerve fiber types are affected 
(Plante-Bordeneuve et al. 2007).  Therefore in this study progression of neuropathy will be 
assessed using a modified NIS+7 score (mNIS+7), which includes a greater sensory component 
and assesses both large and small nerve fiber function.  During the mNIS+7 assessment, the 
standard NIS+7 assessment will also be collected and the NIS+7 will be analyzed as a secondary 
endpoint.  The NIS score will be used for selection of the target population (inclusion criteria) 
because there is a greater body of data correlating NIS score with stage of disease.  The 
neuropathy symptom and change (NSC) score is a physician administered questionnaire of the 
patient’s neuropathy symptoms.  It is collected during the NIS assessment procedure and will be 
analyzed as an exploratory endpoint. 
The Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire is included 
to assess disease specific changes in the patients’ perceived quality of life.  This instrument is a 
nerve fiber-specific, 5-domain tool that has been validated in FAP patients (Vinik et al. 2011).  
In addition, the SF-36 questionnaire is included as a non-disease specific tool to assess the 
patient’s perceived functional health and well-being. 
In FAC patients, TTR amyloid fibrils infiltrate the myocardium, with resultant diastolic 
dysfunction progressing to restrictive cardiomyopathy and heart failure.  The age of onset in 
FAC patients is between 60 and 70 years and the mean life expectancy from symptom onset is 
5-6 years.  There is no widely accepted method for measuring progression of cardiac disease in 
FAC. However, recent studies have shown that strain imaging with echocardiography or MRI 
can detect changes within a 1-year time frame (Benson et al. 2011; Falk 2011).  In addition, the 
cardiac biomarker N-terminal prohormone of brain natriuretic peptide (NT pro-BNP) has been 
shown to be elevated in patients with cardiac amyloidosis due to Primary Amyloidosis and to 
decline as cardiac function improves following removal of the amyloid forming light chain 
protein with chemotherapy (Palladini et al. 2006).  In this study serum NT-proBNP will be 
assessed as an exploratory endpoint in all patients.  One (1) of the more sensitive ECHO 
parameters, global longitudinal strain, will be assessed as a secondary endpoint.  This analysis 
will be conducted in a subgroup of patients with echocardiographic evidence of cardiac 
amyloidosis (the ECHO subgroup) and in a subset of patients defined as the CM-ECHO Set.  
The CM-ECHO Set includes patients with a diagnosis of TTR cardiomyopathy at study entry 
who are not in the ECHO subgroup, plus the patients in the ECHO subgroup.  Other ECHO 
parameters will be assessed as exploratory endpoints. 
2.1.2 
Current Therapies 
One (1) therapeutic strategy for FAP is orthotopic liver transplantation (OLTX) since most of the 
amyloidogenic mutated TTR is secreted by the liver.  OLTX results in rapid disappearance of 
mutant TTR protein from the serum, although wild-type TTR protein continues to be produced 


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by the donor liver and can continue to deposit in the tissues after transplantation (see 
Section 2.4).  The result is that OLT28 May slow the rate of progression of peripheral and/or 
autonomic neuropathy but usually does not arrest the disease.  OLTX is performed on about 
120 FAP patients worldwide each year (results from the Familial Amyloid Polyneuropathy 
World Transplant Registry).  Based on prognostic data after liver transplant, current practice is 
not to perform OLTX on patients with mBMI < 600 or in patients with cardiac involvement.  
Additionally, it has been observed that poorer prognosis is associated with non-V30M mutations, 
patients with late onset of disease (> 50 years) or disease duration > 7 years.  Therefore, OLTX 
is generally limited to younger patients early in disease with mild symptoms (typically Stage 1) 
(Herlenius et al. 2004; Stangou and Hawkins 2004; Okamoto et al. 2009). 
In November 2011, the first medication for FAP, Vyndaqel® (tafamidis), was approved under 
exceptional circumstances in the EU.  Vyndaqel® is indicated in the EU for the treatment of 
transthyretin amyloidosis in adult patients with Stage 1 symptomatic polyneuropathy to delay 
peripheral neurological impairment (Coelho et al. 2012). 
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).  ISIS 420915 was designed such that 
it would not hybridize to any other known human gene.  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, a primary organ for antisense oligonucleotide (ASO) distribution after systemic delivery.  
It should be noted that ASOs are highly charged hydrophilic molecules that do not cross the 
blood brain barrier (Levin et al. 2008) and thus systemic treatment with 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 OLTX, 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 world-wide.  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.  For these reasons, it is appropriate to utilize a placebo control in this Phase 2/3 study. 
Because TTR binds the retinol-RBP4 complex and prevents its excretion by the kidney, 
decreased plasma TTR levels result in decreased circulating levels of both RBP4 and retinol.  
This has been shown with the naturally occurring TTR Ile84 mutation that disrupts the TTR-
RBP4-retinol complex and results in low plasma levels of retinol (Waits et al. 1995).  Prolonged 
reduction of circulating retinol could result in impaired delivery of retinol to peripheral tissues 
and consequent signs and symptoms of vitamin A deficiency such as night blindness, 
xerophthalmia or retinopathy.  However, chylomicrons are believed to provide an alternative 


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route of delivery of retinyl esters to peripheral tissues (Wei et al. 1995) and chylomicron-
delivered retinyl will not be affected by treatment with ISIS 420915.  Indeed, preclinical studies 
utilizing TTR null mice have shown that although the mice have only 5-7% of circulating retinol 
and RBP4 levels compared to wild-type mice,  they are viable and fertile, and do not show any 
observable symptoms of vitamin A deficiency (Episkopou et al. 1993; Wei et al. 1995).  In 
addition, the levels of retinol within tissues such as the liver, kidney, testis and eye were similar 
in the TTR null mouse compared with wild-type controls (Wei et al. 1995).  Furthermore, the 
retinal anatomy and function in these mice has been examined in detail with little effect found on 
the retinal structure or function (Bui et al. 2001).  This is consistent with the findings in the 
ISIS 420915 chronic monkeys studies where, after 9 months of repeat dosing, no signs of 
vitamin A deficiency were observed during the ophthalmic examination and histological 
evaluation of eyes, which included full view examination of the cornea, lens, sclera with attached 
conjunctiva, anterior and posterior chambers, retina and optic nerve.  In addition, twins have 
been reported in the literature that have a genetic mutation in RBP4 that causes their RBP4 
protein levels to be below the lower limit of quantification and also results in very low plasma 
retinol levels (Biesalski et al. 1999).  Although the twins presented with night blindness their 
symptoms responded to dietary manipulation to ensure adequate dietary vitamin A.  Taken 
together these findings imply that RBP4 is not essential for maintaining adequate tissue retinol 
levels.  To address the potential for impaired retinol delivery to tissues, in this study all patients 
will be required to take oral supplementation of the recommended daily allowance (RDA) of 
vitamin A (approximately 3000 IU vitamin A per day).  In addition, an ophthalmic examination 
will be performed at Baseline, after approximately 7 months of treatment, and at the end of 
treatment.  An electroretinogram (ERG) will also be performed at Baseline and at the end of 
treatment to exclude subclinical tissue retinol deficiency. 
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 
preventing production of the transthyretin protein.  Maximal antisense-mediated reduction of 
target mRNA levels is typically greater than 90% of control levels in sensitive tissues 
(Crooke and Bennett 1996; Zhang et al. 2010).  Furthermore, reduction in target mRNA levels 
using this approach correlates directly with a subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, ISIS 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 complementary to a 20-nucleotide stretch within the 3′UTR region of the 
transthyretin protein mRNA.  Structurally, the oligonucleotide has 3 regions.  Two (2) of them, 
the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are composed of  
2′-O-(2-methoxyethyl) (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) 


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(Geary et al. 2003), and (3) amelioration of some of the high dose toxicities thereby resulting in 
an improved safety profile compared to first generation antisense drugs containing 
phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  The third region, 
the central portion of the oligonucleotide, is composed of 10 oligodeoxynucleotides.  This 
chimeric design is called a MOE-Gapmer, and ISIS 420915 employs this chimeric structure 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 support RNase H catalysis of 
RNA hybridized to 2′-MOE-modified nucleotides (McKay et al. 1999).  This is caused by 
conformational changes induced in the heteroduplex by 2'-alkoxy:RNA hybrids that are not 
recognized by RNase H enzymes (Inoue et al. 1987; Monia et al. 1993).  By limiting the 2′-MOE 
modification to nucleotides flanking the phosphorothioate oligodeoxynucleotide core, the 
beneficial attributes of the 2′-MOE chemistry are preserved while also retaining RNase H 
recognition. 
 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of ISIS 420915 is shown 
 
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 
2′-MOE 
2′-Deoxy 
2′-MOE
(RNase H
-Sensitive) 
T  C  T T G
G  T T A C A T G A A 
A T C C C 
Phosphorothioate 
Backbone 


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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 
Detailed information concerning the 1 clinical study (ISIS 420915-CS1) conducted with 
ISIS 420915 can be found in the Investigator’s Brochure.  A summary 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.  The allocation of 
subjects was 3:1 or 8:2 randomized to ISIS 420915 or placebo in the single-dose or multiple-
dose cohorts, respectively.  Subjects enrolled in the multiple-dose cohorts received a total of 
6 doses of Study Drug administered by 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.  There were no 
serious adverse advents (SAE).  Two (2) discontinuations were considered possibly related to 
ISIS 420915, 1 due to constitutional symptoms (400 mg subject) and 1 due to injection site 
reactions (300 mg subject).  The main safety findings included mild injection site reactions 
characterized most often by pain and erythema.  The duration of the reactions were typically 
24 hours and resulted from some but not all injections.  This injection site reaction profile is 
considered similar to the profile for other 2′-MOE ASOs.  Transient C-reactive protein 
elevations, primarily associated with the first injection, were observed in nearly all treated 
subjects at 200 mg multiple-dose or higher.  The peak elevations were generally observed 2 days 
after the first dose of ISIS 420915 (Study Day 3) and resolved within 2 weeks despite continued 
dosing.  For those subjects with C-reactive protein > 10 mg/L, the peak values at Day 3 had a 
median of 36 mg/L (range from 14 to 169 mg/L).  Retinol reductions below the lower limit of 
normal (LLN) occurred in approximately 50% of subjects treated in the multiple-dose cohorts.  
The minimum retinol value was 0.19 mg/L (range 0.05 to 0.27 mg/L).  Recovery to above the 
LLN occurred approximately 1-month after the final dose of ISIS 420915.  The retinol reduction 
was an expected consequence of TTR reduction. 
2.4 
Rationale for Dose and Schedule of Administration 
The pharmacokinetics and disposition of many drugs in this class have been characterized and 
there are remarkable similarities from sequence to sequence and across species.  Because 
distribution to tissues is the dominant mechanism for plasma clearance, it can be assumed that 
plasma pharmacokinetic similarities translate into similarities in tissue distribution.  This 
assumption is supported by the knowledge that patterns of tissue distribution for oligonucleotides 
are similar in mice, rats, rabbits, dogs and monkeys (and thus are expected to be similar in 
humans).  Additionally, ASOs are hydrophilic and distribute predominantly to the lean body 
mass and in our experience they should be administered as a fixed dose, rather than by total body 
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In FAP (and FAC), both wild-type and mutant TTR protein will deposit in tissue as amyloid.  
However, it is not known what degree of reduction of TTR will be required to optimally 
attenuate progression of disease.  TTR mutant reductions ≥ 90% have been observed post-liver 
transplantation (Adams et al. 2000) and have been shown to have a therapeutic effect.  Therefore, 
the therapeutic goal for ISIS 420915 is to reduce both wild-type and mutant plasma TTR levels 
as much as possible using a dose level that will not cause unacceptable toxicity.  Based on data 
from the TTR knock-out mouse (Episkopou et al. 1993) and from our 9-month chronic 
toxicology studies in non-human primates, significant target related toxicities are not anticipated 
even with near complete reduction of TTR.  In the ISIS 420915 Phase 1 study, the 300 mg dose 
level showed a satisfactory safety profile and a substantial pharmacodynamic effect after 6 doses 
(> 70% mean reduction in plasma TTR levels).  The PD effect observed with the 300 mg dose 
level was also similar to that observed with the 400 mg dose level, and therefore the 300 mg per 
week dose (with additional loading doses in the first week) was selected for this Phase 2/3 study.  
Preliminary PK/PD modeling (based on data from the Phase 1 study and extrapolation to steady-
state) predicts mean total (wild-type and mutant) TTR steady state reductions of ~80% with 
either a 300 mg/wk or 400 mg/wk regimen. 
A 65-week (15-month) treatment period was selected for this study taking into consideration 
(1) the time needed to achieve steady-state TTR reductions with ISIS 420915 (~3 months) and 
(2) data reported for the tafamidis (Vyndaqel®) Phase 3 study, where a clear separation in 
progression of the NIS-LL score was not observed before 12 months of treatment  
(EMA Assessment report for Vyndaqel). 
The safety data obtained in the ISIS 420915-CS1 study as well as the clinical experience with 
several other 2′-MOE-modified ASOs (Sewell et al. 2002; Chi et al. 2005; Kastelein et al. 2006) 
supports the dosing regimen planned for this study.  The dosing schedule (loading with 3 doses 
in Week 1 followed by once weekly SC injections) has been employed safely in previous clinical 
studies with a number of other phosphorothioate oligonucleotides at doses well in excess of the 
300 mg dose utilized in this 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 safety and tolerability of the proposed 65-week dosing 
period is also supported by nonclinical chronic toxicology studies with ISIS 420915. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 2/3 multicenter, double-blind, randomized, stratified, placebo-controlled study of 
ISIS 420915 in Stage 1 and Stage 2 FAP patients with a NIS score ≥ 10 and ≤ 130.  
Approximately 135 patients will be randomized 2:1 (ISIS 420915 : PBO) to receive 300 mg 
ISIS 420915 or placebo.  The study will enroll approximately 50% Stage 1 and 50% Stage 2 
patients.  Patients will be stratified for:  
• Previous treatment with Vyndaqel® (tafamidis) or Diflunisal versus no known previous 
treatment 
• Stage 1 versus Stage 2 disease 
• V30M TTR mutation versus non-V30M TTR mutation 


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Patients will receive 3 SC doses of Study Drug (ISIS 420195 or placebo) during Week 1 on 
alternate days (Days 1, 3 and 5) followed by once-weekly SC administration during Weeks 2-65 
(for a total of 67 doses). 
Approximately 20 patients at selected sites will be enrolled in a pharmacokinetic (PK) subgroup 
and will receive additional sampling for PK, ECG, complement, coagulation, inflammatory, and 
hematology as specified in the schedule of procedures (Appendix A).  In addition, patients that 
are eligible may consent to participate in the ECHO subgroup and will receive an additional 
transthoracic ECHO during the treatment period (Appendix A). 
The end of treatment (EOT) efficacy assessment is conducted at Week 66 after which patients 
will enter the post-treatment evaluation period.  However, following the EOT efficacy 
assessment, eligible patients (including patients that received placebo) may elect to enroll in an 
open-label extension (OLE) study pending study approval by the IRB/IEC and the appropriate 
regulatory authority.  All participating patients in the OLE study will receive once weekly doses 
of 300 mg ISIS 420915. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Approximately 135 patients will be randomized in a 2:1 ratio (90 ISIS 420915 : 45 placebo).  
Any patient who initiated screening and met eligibility criteria at the time of Amendment 7 
submission for applicable approvals may be enrolled into the study, even if 135 patients have 
already been randomized. 
3.4 
Overall Study Duration and Follow-up 
This study will generally consist of the following periods: 
• A ≤ 6-week screening and baseline assessment period 
• A 65-week treatment period 
• A 1-week EOT efficacy assessment period, and 
• A 6-month post-treatment evaluation period 
3.4.1 
Screening and Baseline Assessment 
A period of 6 weeks is given to complete the screening and baseline assessments outlined in the 
schedule of procedures.  The baseline assessments should ideally be conducted after patient 
eligibility has been determined.  An exception to the 6-week screening and baseline assessment 
window is allowed for TTR genotyping and amyloid biopsy which may be conducted up to 
10 weeks prior to Study Day 1.  In addition, ERG and ophthalmology examinations may be 
conducted up to 1-week after Study Day 1 if needed for scheduling purposes (except for Ile84 
patients that fall under exclusion criteria 3 and should have eye examinations performed to 
determine eligibility). 


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3.4.2 
Treatment and EOT Efficacy Assessment 
The treatment and EOT efficacy assessment period comprises approximately 66 weeks in total.  
Eligible patients will report to the Study Center for assessments at regular intervals throughout 
the 65-week treatment period.  During the treatment period, Study Drug is administered by SC 
injections on alternate days during Week 1 (Days 1, 3 and 5), followed by once-weekly SC 
injections during Weeks 2-65. 
After the treatment period is complete, patients will report to the Study Center during Week 66 
for the EOT efficacy assessments.  
3.4.3 
Post-Treatment 
The post-treatment evaluation period is 6 months and consists of Study Center visits and 
additional safety testing.  The final study visit is Week 91. 
Alternatively, after completion of the EOT efficacy assessment period, eligible patients 
(including patients that received placebo) may elect to enroll in an OLE study where they will 
receive weekly doses of 300 mg ISIS 420915, pending study approval by the IRB/IEC and 
appropriate regulatory authority.  In this case, patients will not participate in the post-treatment 
evaluation period. 
3.5 
End of Study 
The end of study is last patient, last visit. 
3.6 
Data Safety and Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be assembled to review safety, tolerability 
and efficacy (as needed) data collected on ISIS 420915 during this study and to review the 
results of the predetermined TTR interim analysis (see Section 10.4).  Based on its ongoing 
assessment of the safety and tolerability of ISIS 420915, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review, meeting schedules and controlled access 
to unblinded data at the TTR interim analysis are outlined in the DSMB Charter and SAP. 
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 and will be assigned a 
unique screening number before any study procedures, including screening procedures, are 
performed.  At the time of randomization patients will be assigned a unique patient identification 
number.  This number will be used to identify the patient throughout the trial and must be used 
on all study documentation related to that patient.  The screening number and patient 
identification number must remain constant throughout the entire trial.  In the event the patient is 


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re-consented and re-screened the patient must be given a new screening number.  Screening 
numbers and patient identification numbers, once assigned, will not be re-used. 
4.2 
Randomization 
Patients will be randomized after all screening and baseline assessments have been completed 
and after the Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  
No patient may begin treatment prior to randomization and assignment of a unique patient 
identification number. 
Using an Interactive Voice/Web-Response System (IXRS), eligible patients will be randomized 
2:1 to receive ISIS 420915 or placebo, respectively.  There will be 2 separate and independent 
randomizations, 1 for patients in the PK subgroup (approximately 20) and 1 for the other patients 
who are not in the PK subgroup (approximately 115).  Within each randomization, patients will 
be stratified for: 
• Previous treatment with Vyndaqel® or Diflunisal versus no known previous treatment 
• Stage 1 versus Stage 2 disease 
• V30M TTR mutation versus non-V30M TTR mutation 
A permuted block schedule will be used in both randomizations.  The Sponsor Quality 
Assurance department or designee will hold a copy of the randomization lists generated by the 
IXRS vendor. 
4.3 
Replacement of Patients 
Patients that withdraw from the study will not be replaced. 
4.4 
Unblinding of Treatment Assignment 
The Sponsor, patients, monitors, and Study Center personnel will be blinded throughout the 
study until all patients have completed the treatment period and the EOT efficacy assessments, 
and the database has been locked.  The DSMB may be unblinded as described in Section 3.6.  In 
order to ensure maintenance of the study blind, TTR, RBP4, and retinol values will not be 
available to the Sponsor, monitors, Investigators, Study Center Personnel, or the patients.  
However, if a patient has suffered a Serious Adverse Event (as defined in Section 9.3.3), and/or 
when knowledge of the treatment assignment will impact the clinical management of the patient, 
the Investigator will have the ability to unblind the treatment assignment for that patient using 
the IXRS.  The Sponsor or designee will be informed of the unblinding of a patient within 
24 hours.  In addition, all suspected unexpected serious adverse reactions (SUSARs) will be 
unblinded by the Sponsor’s Drug Safety and Quality Assurance personnel for the purpose of 
regulatory reporting (see Section 9.2). 
Every reasonable attempt should be made to complete the EOT efficacy assessment and early 
termination study visit procedures and observations (see Appendix A) prior to unblinding, as 
knowledge of the treatment arm could influence patient assessment. 


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5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 6 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Stage 1 and Stage 2 FAP patients with the following: 
a. NIS score ≥ 10 and ≤ 130 
b. Documented transthyretin variant by genotyping 
c. Documented amyloid deposit by biopsy 
2. Willingness to take vitamin A supplements 
3. Aged 18 to 82 years old at the time of informed consent 
4. Satisfy the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile, post-menopausal, 
abstinent, or if engaged in sexual relations of child-bearing 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 Study Drug 
b. Males:  Surgically sterile, abstinent, or if engaged in sexual relations of child-bearing 
potential, patient is utilizing an acceptable contraceptive method (refer to 
Section 6.3.1) during and for 3 months after the last dose of Study Drug 
5. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements 
5.2 
Exclusion Criteria 
1. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
2. Screening laboratory results as follows, or any other clinically-significant abnormalities 
in screening laboratory values that would render a patient unsuitable for inclusion: 
a. ALT/AST > 1.9 x ULN 
b. Bilirubin ≥ 1.5 x ULN (patients with bilirubin ≥ 1.5 x ULN may be allowed on study 
following discussion with the Study Medical Monitor if indirect bilirubin only is 
elevated, ALT/AST is not greater than the ULN and genetic testing confirming 
Gilbert’s disease) 
c. Platelets < 125 x 109/L 


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d. Positive (≥ trace) for protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine protein measurement of 
< 1.0 g/24 hours 
e. Positive (≥ trace) for blood on urine dipstick.  In the event of a positive test eligibility 
may be confirmed with urine microscopy showing ≤ 5 red blood cells per high power 
field.  If > 5 red blood cells per high power field and there is a clearly identifiable 
benign cause for the microscopic hematuria (for example chronic urinary tract 
infection secondary to neurogenic bladder), eligibility should be determined by 
discussion with the Study Medical Monitor 
f. TSH values outside normal range (unless approved by the Study Medical Monitor) 
3. Retinol level at Screen < LLN 
• For patients with a TTR mutation at position 84 (e.g., Ile84Ser or Ile84Asn) and 
retinol < LLN the exclusion criterion is signs or symptoms of vitamin A deficiency 
(such as evidence of vitamin A deficiency on ERG) 
4. Uncontrolled hypertension (blood pressure > 160/100) 
5. Positive test result for human immunodeficiency virus (HIV), hepatitis B or hepatitis C 
6. Karnofsky performance status ≤ 50 
7. Renal insufficiency as defined by estimated creatinine clearance calculated according to 
the formula of CKD-EPI < 60 mL/min/1.73 m2 at Screen.  If the calculated creatinine 
clearance is thought to be artificially low, a 24-hour urine creatinine clearance can be 
completed with prior Sponsor approval 
8. Presence of known type 1 or type 2 diabetes mellitus 
9. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease) 
10. Treatment with another investigational drug, biological agent, or device within 3 months 
of screening, or 5 half-lives of study agent, whichever is longer 
11. If previously treated with Vyndaqel® must have discontinued treatment for 2 weeks prior 
to Study Day 1.  If previously treated with Diflunisal, must have discontinued treatment 
for 3 days prior to Study Day 1 
12. Previous treatment with any oligonucleotide or siRNA within 6 months of screening.  
Subjects that have been previously treated with oligonucleotides should be approved by 
the Study Medical Monitor 
13. Prior liver transplant or anticipated liver transplant within 1 year of screening 
14. New York Heart Association (NYHA) functional classification of ≥ 3 
15. Acute coronary syndrome or major surgery within 3 months of screening 


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16. Known Primary Amyloidosis 
17. Known Leptomeningeal Amyloidosis 
18. Anticipated survival less than 2 years 
19. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
20. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated.  Patients with a history 
of other malignancies that have been curatively treated may be eligible but must be 
discussed and approved by the Sponsor Medical Monitor 
21. Have any other conditions, which, in the opinion of the Investigator would make the 
patient unsuitable for inclusion, or could interfere with the patient participating in or 
completing the study 
22. Known Monoclonal Gammopathy of Undetermined Significance or Multiple Myeloma 
5.3 
Additional Eligibility Criteria for Patients Participating in the ECHO Subgroup 
1. Must have left ventricular wall thickness of ≥ 13 mm on transthoracic echocardiogram at 
Baseline 
2. No known history of persistent hypertension ≥ 150 mm Hg within 12 months prior to 
screening 
3. Baseline ECHO is evaluable as ascertained by the Sponsor central reader 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A and C. 
6.1.1 
Screening and Baseline Assessment Period 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  A 6-week period is given to perform the screening evaluations and 
baselines assessments which must be completed before Study Day 1.  Exceptions are the ERG, 
and ophthalmology examinations that may be conducted up to 1-week after Study Day 1 if 
needed for scheduling purposes (except for Ile84 patients that fall under exclusion criteria 3 and 
should have eye examinations performed to determine eligibility).  In addition, the TTR 
genotyping and amyloid biopsy tests may be conducted up to 10 weeks prior to Study Day 1.  
These tests are only conducted if appropriate documentation is not already available.  The 
baseline assessments should ideally be performed after patient eligibility has been determined.  
An abnormal screening result may be retested for review by the Study Medical Monitor for 
eligibility purposes. 


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A NIS assessment is performed at Screening to determine patient eligibility only.  This 
assessment does not include the +7 components. 
The baseline assessments include mNIS+7 (which is performed twice), Norfolk QOL-DN 
questionnaire, transthoracic ECHO, 24 hour urine collection, ERG exam, ophthalmology exam, 
vital signs, and a blood draw for chemistry. 
The 2 mNIS+7 assessments must be performed on separate days and within 14 days prior to the 
first dose of Study Drug (Day 1).  In addition, every effort should be made to conduct the 
2 assessments < 7 days apart.  If the ERG or ophthalmology examination are to be performed on 
a mNIS+7 assessment day, they must be performed after the mNIS+7 assessment is complete.  
The mNIS+7 assessment procedure includes the NIS, +7, and additional sensory and nerve 
conduction testing.  The NSC score is collected during the NIS assessment procedure, but is 
analyzed separately. 
For a visit where the Norfolk QOL-DN questionnaire is to be administered, it must be the first 
assessment performed at the visit.  Administration of the baseline Norfolk QOL-DN 
questionnaire should be done on the same day as the first mNIS+7 assessment, but prior to the 
mNIS+7 assessment. 
For an individual patient, every effort should be made to ensure the same NIS evaluator performs 
all of the NIS assessments throughout the study.  In addition, the NIS evaluator must be insulated 
from the patient’s general study procedures and knowledge of the patient’s adverse events. 
6.1.2 
Treatment Period 
During Study Week 1, patients will report to the Study Center for evaluations and Study Drug 
administration on Days 1, 3 and 5.  After Week 1, Study Drug will be administered once weekly.  
Patients will report to the Study Center for Study Drug administration, evaluations, and tests 
regularly throughout the treatment period and will have weekly safety testing according to the 
Schedule of Procedures in Appendix A.  During a clinic visit, all blood samples should be drawn 
prior to Study Drug administration (exceptions are the post-dose samples in the PK subgroup).  
For weeks that do not include a clinic visit, Study Drug may be administered by either Study 
Center personnel (in which case additional clinic visits will occur) or at home by the 
patient/caregiver (see Section 8.1).  Every effort should be made to ensure the previous week’s 
dose is given 7 days prior to a scheduled clinic visit.  Dosing instructions and training will be 
provided to the patient where applicable. 
To help reduce patient travel burden, some clinic visits and weekly safety testing between visits 
may be done as non-clinic visits.  For non-clinic visits, collection of vital signs and labs (as 
indicated in the Schedule of Procedures) can be performed by the Sponsor’s home healthcare 
service or by a local laboratory with prior Sponsor approval. 
In addition to Study Drug, patients will also receive daily supplemental doses of the 
recommended daily allowance (RDA) of vitamin A (approximately 3000 IU vitamin A or closest 
approximate dose as available in the region in which 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 period. 


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A mNIS+7 assessment and Norfolk QOL-DN questionnaire are conducted at Week 35 (D239) 
and must be conducted approximately > 24 hours from the previous week’s dose.  The Norfolk 
QOL-DN questionnaire should be administered prior to the mNIS+7 assessment.  The Week 35 
D239 and D240 assessments may be done on the same day. 
For Weeks 3-15 there is a ± 2 day and for Weeks 18-65 there is a ± 5 day visit window.  All 
reasonable attempts should be made to ensure compliance with the visit schedule as outlined in 
the schedule of procedures (Appendix A).  However, in the event that a visit does not occur or is 
delayed, all subsequent visits should be calculated based on the time elapsed since Day 1 rather 
than from the date of the previous visit. 
During the treatment period, an ophthalmology examination will be performed at Week 29 and 
Week 65, and an electroretinogram (ERG) examination will be performed at Week 65.  The 
Week 65 ophthalmology and ERG examinations may be done at Week 59 if needed for 
scheduling purposes.  A window of ± 2 weeks is allowed for the Week 29 and Week 65 (or 
Week 59) eye examinations. 
Patients with a TTR mutation at position 84 and with retinol levels < LLN at Screening, will be 
required to have 2 additional ophthalmology examinations at approximately 3 and 11 months 
after the first dose. 
Echocardiogram (ECHO) Subgroup Only 
In addition to ECHOs conducted at Baseline, early termination, and Week 65 for all patients, 
patients who qualify and consent to participate in the ECHO subgroup will have an additional 
ECHO conducted during the treatment period at Week 41, which can be done at Week 47 if the 
patient elects to have a Home Healthcare visit at Week 41.  All ECHO assessments have a 
window of ± 2 weeks. 
Pharmacokinetic (PK) Subgroup Only 
A subgroup of approximately 20 patients to ensure approximately 15 patients with evaluable PK 
data after early withdrawals (at selected sites only), will participate in the PK subgroup.  Patients 
in this subgroup will have more frequent pharmacokinetic sampling in order to evaluate the 
plasma pharmacokinetic parameters of ISIS 420915.  Patients will also have additional post-dose 
sampling for ECG, inflammatory, coagulation, hematology, and complement.  Patients in this 
subgroup will have additional visits to the clinic to collect a 24-hour post-dose blood draw after 
dosing on Day 1, and a 24 hour, 3 day and 7 post-dose blood draw after dosing on Day 240 
(Week 35) and Day 449 (Week 65).  Alternatively, the additional visits needed to collect the 
24 hour, 3 day and 7 day post-dose blood draw may be collected by the Sponsor appointed home 
healthcare service. 
A patient participating in either the PK or ECHO subgroups may withdraw consent for the 
subgroup specific procedures (e.g., echocardiogram, multiple blood draws for PK) without being 
withdrawn from dosing or from the study.  If a patient withdraws consent from the subgroup 
procedures, he/she should remain on study and continue to follow all the non-subgroup 
assessments and procedures as outlined in Appendix A. 


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6.1.3 
EOT Efficacy Assessment Period 
The EOT efficacy assessment is conducted at Week 66 and consists of a minimum of 2 visits to 
allow for 2 measurements of the mNIS+7.  Both assessments must be performed on separate 
days and within 14 days from the last dose of Study Drug.  The first mNIS+7 assessment must be 
conducted approximately > 24 hours from the last dose of Study Drug.  In addition, every effort 
should be made to conduct the 2 assessments < 7 days apart.  The Norfolk QOL-DN 
questionnaire should be given on the same day as the first mNIS+7 assessment, but prior to the 
mNIS+7 assessment. 
The Week 66 EOT efficacy assessment should also be performed on patients that terminate from 
treatment early.  In this case, the early termination visit and EOT efficacy assessment should be 
performed within 14 days after the last dose of Study Drug.  In the event that this does not occur, 
the early termination visit and EOT assessments should be performed as soon as possible.  The 
2 mNIS+7 assessments must be conducted on separate days.  In addition, every effort should be 
made to conduct the 2 assessments < 7 days apart. 
6.1.4 
Post-Treatment Period 
After completion of the EOT efficacy assessment, patients will enter the 6-month post-treatment 
evaluation period and will report to the study center and have weekly platelet monitoring for a 
minimum of 6 weeks after the last dose of Study Drug which may be collected by the clinic, 
Sponsor’s home healthcare service or by a local laboratory as outlined in the schedule of 
procedures (Appendix A).  At Week 71, adverse events should be collected by the site personal 
through a phone contact with the patient if a clinic visit was not conducted. 
Alternatively, after completion of the EOT efficacy assessment, eligible patients may elect to 
receive ISIS 420915 in an OLE study (ISIS 420915-CS3), pending study approval by the 
IRB/IEC and the appropriate regulatory authority.  In this case, patients will not participate in the 
post-treatment evaluation period but weekly platelet monitoring should continue between the last 
dose of Study Drug in CS2 and the first dose of Study Drug in CS3.  If this period extends 
beyond 6 weeks, the frequency will be determined by the Study Medical Monitor. 
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 that 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 


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In addition the Congestive Heart Failure supplemental CRF pages should be completed in the 
eCRF. 
6.2.3 
Arrhythmias 
Any patient that 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 CRF pages should be completed in the eCRF. 
6.2.4 
Myocardial Ischemia 
Any patient that 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 CRF pages should be completed in the eCRF. 
6.2.5 
Event-Specific Supplemental CRF Pages 
In the event of any of the following, the corresponding supplemental CRF 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 
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 Study Drug. 


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For the purposes of this study, women of childbearing potential are defined as any female who 
has experienced menarche, and that 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: 
1. 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 Study Drug.  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 that are pregnant must use condoms to ensure that the fetus is not exposed to the 
Study Drug. 
For female patients: 
2. 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 
o Intrauterine contraception/device 
o 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 2 can result in either product failing 


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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 
pharmacodynamic and retinol assessments. 
7. 
STUDY DRUG 
7.1 
ISIS 420915 or Placebo 
Study Drug (ISIS 420915 or placebo) characteristics are listed in Table 1. 
The Study Drug is contained in stoppered glass vials and will be provided to the Study Center by 
the Sponsor.  The Study Drug storage and preparation instructions will be provided by the 
Sponsor.  For long term storage at clinical sites, the Study Drug must be stored securely at 2° to 
8° Celsius and be protected from light. 
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 420915 
Placebo 
Strength 
200 mg/mL  
NA 
Volume/Formulation 
1 mL solution per 2 mL vial or 
1.5 mL solution per 3 mL vial  
1 mL solution per 2 mL vial or 
1.5 mL solution per 3 mL vial 
Route of Administration 
SC 1.5 mL  
SC 1.5 mL 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug labeled in accordance with 
specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug 
supplies provided by the Sponsor.  The Study Center must return all used and unused Study Drug 
to the Sponsor or designee. 
8. 
TREATMENT OF PATIENTS 
8.1 
Study Drug Administration 
For each individual patient, Study Drug will be administered subcutaneously as a single 1.5 mL 
injection 3 times in the first week and then once weekly for Weeks 2-65.  For weeks with a clinic 
visit, Study Drug will be administered at the clinic.  For weeks that do not include a clinic visit, 
Study Drug may be administered by either Study Center personnel or at home by the 
patient/caregiver.  Every effort should be made to ensure the previous week’s dose is given 
7 days prior to a scheduled clinic visit.  If Study Drug is to be administered at home, dosing 
instructions and training will be provided to the patient by the Study Center personnel. 
If needed for tolerability reasons, the single 1.5 mL injection may be administered as 
2 noncontiguous injections of smaller volume, but prior discussion with the Study Medical 
Monitor is encouraged. 


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Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
Study Drug 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 vitamin A or the closest approximate dose as available in the region in which the patient 
resides).  Commercially available vitamin A as a single supplement, or as part of a multivitamin, 
will be provided by the Study Center or designee, in accordance with local regulatory 
requirements and availability. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
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 below (refer to Sections 8.6.1 
to 8.6.3) are met and are confirmed, the patient will be permanently discontinued from further 
treatment with Study Drug (ISIS 420915 or placebo), evaluated fully as outlined below and in 
consultation with the Study Medical Monitor or appropriately qualified designee, and will be 
entered into the post-treatment evaluation portion of the study (after completing the early 
termination and EOT efficacy 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 
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. 


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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 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 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.* 


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a. Creatinine clearance by CKD-EPI < 60 mL/min/1.73m2 
b. Creatinine clearance by CKD-EPI decrease from baseline** > 25% 
c. Urine Alb/C 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 Appendix A) 
** baseline is Wk1D1 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 Baseline, after 
approximately 7 months of receiving Study Drug (Week 29) and also at the end of the dosing 
period (Week 65).  An ERG will also be performed at Baseline and the end of the dosing period 
(Week 65).  In addition, any patient that 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 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 the 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 Sponsor Medical Monitor in consultation with the 
Investigator and ophthalmologist. 


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Clear signs of vitamin A deficiency as assessed by ERG include: 
a) Changes 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 65-week treatment period).  For patients participating in the Post-
Treatment Evaluation Period, frequency of testing after the Week 71 visit will be determined by 
the Investigator in consultation with the Study Medical Monitor.  For patients participating in the 
ISIS 420915-CS3 study, weekly monitoring should continue between the last dose of Study Drug 
in CS2 and first dose of Study Drug in CS3.  If this period extends beyond 6 weeks, the 
frequency of monitoring will be determined by 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.  
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 Study Drug (ISIS 420915 or placebo) 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 Study Drug 
(ISIS 420915 or placebo) 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%) 


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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) 
Dosing of a patient with Study Drug (ISIS 420915 or placebo) 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 Study Drug (ISIS 420915 or placebo) will be stopped permanently.  The follow-
up schedule for any 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 Study Drug 
(ISIS 420915 or placebo) 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. 


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Definition 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 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 
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 value (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 


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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 Study Medical Monitor.  Any additional 
monitoring/investigation will also be determined by the Investigator and Study Medical Monitor. 
8.7 
Adjustment of Dose and/or Treatment Schedule 
Adjustments of dose and/or treatment schedule should occur only on rare occasions.  Up to 
2 adjustments in the treatment schedule may be allowed for patients that are unable to tolerate 
the once weekly dose (for example if platelet counts fall below 75,000/mm3 as described in 
Section 8.6.3).  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, they 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 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 adverse event 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 
• The patient experiences an AE that necessitates unblinding of the Investigator to the 
patient’s treatment assignment 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
Patients that discontinue from treatment are encouraged to remain in the study.  Every effort 
should be made to complete the early termination visit and the EOT efficacy assessment 
followed by all post-treatment evaluation visits.  If the patient declines to participate in the post-
treatment evaluation visits, at a minimum, the early termination visit and EOT efficacy 
assessment procedures should be performed at the time of withdrawal (See Appendix A) and 
ideally within 14 days from the last dose of Study Drug.  If early termination assessments are to 
be performed on a day with mNIS+7 EOT assessment, the mNIS+7 assessment should be 
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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 
• Patient receives liver transplant 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
• Administrative decision by the Investigator or Sponsor 
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 CRF. 
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 EOT efficacy assessment and early termination 
study visit at the time of withdrawal (Appendix A). 
For patients who receive a liver transplant, every effort should be made to complete the EOT 
efficacy assessment as soon as feasible after the transplant procedures (if possible within 
6 weeks).  After the EOT efficacy assessment and early termination visit is complete, patients 
should be withdrawn from the study. 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
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 Week 91 visit. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 


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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 their 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 unless approved by the 
Study Medical Monitor.  If a patient is taking doxycycline or TUCA they should discontinue 
treatment at least 4 days prior to Study Day 1. 
Treatment with either Vyndaqel® or Diflunisal is not allowed at any time during the treatment 
period and ideally should not be taken during the post-treatment follow-up period.  If Vyndaqel® 
or Diflunisal are taken in the post-treatment period, the Study Medical Monitor should be 
consulted to determine if an additional mNIS+7 assessment should be collected prior to initiating 
Vyndaqel® or Diflunisal treatment. 
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 
Sponsor 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 Week 91 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 Study Drug 
supplies.  Patients that are self-administering Study Drug at home must record treatment in a 
provided dosing diary that will be reviewed by the Study Center staff and Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the 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 SUSARs per the International Conference on 


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Harmonization (ICH) guidelines E2A and ICH E6.  Country-specific regulatory requirements 
will be followed in accordance with local country regulations and guidelines. 
IRB/IEC will be notified of any SAE according to applicable regulations.  The Data and Safety 
Monitoring Board (DSMB) will be notified of any SAE as specified in the DSMB charter. 
The Sponsor will evaluate the available information and decide if there is a reasonable possibility 
that the Study Drug caused the AE and, therefore, meets the definition of a SUSAR. 
Appropriate personnel at the Sponsor will unblind SUSARs for the purpose of regulatory 
reporting.  The Sponsor will submit SUSARs to Regulatory Agencies in blinded or unblinded 
fashion according to local law.  The Sponsor will submit SUSARs to Investigators in a blinded 
fashion. 
For Study Drug “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 the Study Drug. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  A suspected adverse reaction implies a lesser degree of 
certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening: that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death.  It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE. 


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• 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 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 in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
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 Week 91 visit or the EOT efficacy assessment for 
patients that will enroll into the OLE.  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. 
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 Week 91 visit, 
or the EOT efficacy assessment for patient’s that will enroll into the OLE.  The Investigator will 
monitor each patient closely and record all observed or volunteered AEs on the Adverse Event 
Case Report Form. 


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9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of Study Drug e.g., 
confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and Study Drug administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
Study Drug administration and/or exposure suggests that a causal relationship is unlikely 
(For reporting purposes, Unlikely/Remote will be grouped together with Not Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and Study Drug 
9.4.3.2 
Severity 
The 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). 
9.4.3.3 
Action Taken with Study Drug 
Action taken with Study Drug due to the event is characterized by the following. 
• None:  No changes were made to Study Drug administration and dose 
• Permanently Discontinued:  Study Drug was discontinued and not restarted 
• Temporarily Interrupted, restarted:  Dosing was temporarily interrupted or delayed 
due to the AE and restarted 


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• 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 on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF 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 a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• 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 
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. 


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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 
Study medication 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 on the Dosing Case Report Form.  If the patient takes a dose 
of Study Drug that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported 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 


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withdrawn from treatment with Study Drug.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known  (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records 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 
Primary Endpoints 
The primary endpoints are the change in mNIS+7 score from baseline to Week 66 and the 
change in the Norfolk QOL-DN questionnaire total score from baseline to Week 66. 
10.1.2 
Secondary Endpoints 
10.1.2.1 
Secondary Efficacy Endpoints 
• Change in the Norfolk QOL-DN questionnaire symptoms domain score (Stage 1 patients 
only) and Norfolk QOL-DN questionnaire physical functioning/large fiber neuropathy 
domain score (Stage 2 patients only) from baseline to Week 66 
• Change in the mBMI and BMI from baseline to Week 65 
• Change in NIS and modified +7 from baseline to Week 66 
• Change in NIS +7 score from baseline to Week 66 
• Change in GLS by ECHO from baseline to Week 65 in the ECHO subgroup and in the 
CM-ECHO Set 
10.1.2.2 
Pharmacodynamic Endpoint 
• Change from baseline in TTR level to Week 65 
• Change from baseline in RBP4 level to Week 65 


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10.1.2.3 
Safety Endpoints 
• Adverse events 
• Vital signs and weight 
• Physical examination 
• Clinical laboratory tests 
• ECG 
• Use of concomitant medication 
• Ophthalmology and ERG examinations 
• Columbia-Suicide Severity Rating Scale 
• Thyroid panel 
• Inflammatory panel 
• Coagulation 
• Complement 
• Immunogenicity 
10.1.2.4 
Pharmacokinetic Endpoints 
Selected ISIS 420915 post-distribution plasma concentrations (i.e., trough and various post-
treatment time points) will be measured throughout the study and the estimated plasma terminal 
elimination half-life (t1/2λz) after end of treatment will be calculated (when possible).  In 
evaluable patients from the PK subgroup, additional selected plasma PK parameters (as outlined 
in Section 10.5.4) will also be determined after dosing on Days 1, 240, and 449.  Further details 
of the various planned plasma PK assessments are outlined in Section 10.5.4. 
10.1.3 
Tertiary Endpoint 
• Change from baseline to Week 65 in SF-36 questionnaire domain scores 
• Change from baseline to Week 66 in the individual components of the NIS (cranial, 
muscle weakness, reflexes and sensory), modified +7 (heart rate to deep breathing, nerve 
conduction, heat-pain sensory and touch-pressure sensory testing), and +7 (vibration 
detection threshold and nerve conduction)  
• Change from baseline to Week 66 in +7 
• Change from baseline to Week 66 in individual domain scores of Norfolk QOL-DN 
(physical functioning/large fiber neuropathy, symptoms, activities of daily living, small 
fiber neuropathy and autonomic neuropathy) 


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10.1.4 
Exploratory Endpoints 
• Change from baseline in echocardiogram parameters (except GLS) in the ECHO 
subgroup and in the CM-ECHO Set 
• Change from baseline in NT-proBNP 
• Change from baseline in the PND score 
• Change from baseline in the NSC score 
• Change from baseline in retinol 
• Change from baseline in retinyl palmitate 
10.2 
Sample Size Considerations 
The sample size for this study was estimated using information published from the placebo 
controlled Phase 3 Diflunisal trial (Berk et al. 2013), a retrospective, multinational natural 
history study in 283 FAP patients (Adams et al. 2015), and uncontrolled data using another TTR 
mRNA targeted therapeutic (Adams 2015).  It is estimated that the placebo group will have a  
16 point increase in the mNIS+7 score from baseline to Month 15, and the treated group will 
have a 6.4 point increase in mNIS+7.  The standard deviation of the change from baseline in 
each treatment group is estimated to be 14.  With 135 patients (2:1 allocation ratio) there would 
be at least 90% power to detect a 9.6 point difference in the change from baseline in the mNIS+7 
score between the 2 groups, with a 2-sided t-test of 5% alpha, assuming that the dropout rate is 
approximately 25%. 
For the Norfolk QOL-DN questionnaire total score, it is estimated that the placebo group will 
have a 13.3 point change from baseline to Month 15, the treated group will have a 2.6 point 
change from baseline and the standard deviation of the change from baseline in each treatment 
group will be 18.  With 135 patients, there would be at least 80% power to detect a 10.7 point 
difference in the change from baseline in the Norfolk QOL total score between the 2 groups, 
with a 2-sided 5% alpha, assuming that the dropout rate is approximately 25%. 
10.3 
Populations 
The Full Analysis Set will include all randomized patients who received at least 1 injection of 
Study Drug (ISIS 420915 or placebo) 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 randomized patients who received at least 1 injection of 
Study Drug. 
The Per-Protocol Set will include the subset of the Full Analysis Set that have received at least a 
certain percentage of the prescribed doses of Study Drug and that have no significant protocol 
deviations that would be expected to affect efficacy assessments.  The detailed criteria will be 
specified and finalized prior to conducting the primary analysis (i.e., exact criteria to determine 
inclusion in or exclusion from the Per Protocol Set will be determined for each patient prior to 
conducting the primary analysis). 


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The Pharmacokinetic Set will include the subset of the Safety Set that has at least 1 evaluable PK 
result. 
The ECHO subgroup will include the subset of the Safety Set that has at least 1 evaluable post 
baseline ECHO assessment and participated in the ECHO substudy.  The CM-ECHO Set will 
include the subset of the Safety Set that has at least 1 evaluable post baseline ECHO assessment 
and had a diagnosis of TTR cardiomyopathy at study entry but are not in the ECHO subgroup, 
plus patients who participated in the ECHO subgroup. 
10.4 
Interim Analysis 
A pharmacodynamic interim analysis of reduction in plasma TTR level will be performed by the 
independent statistician and reviewed by the DSMB after approximately 45 patients have 
completed the Week 13 visit.  This interim will be a futility analysis, so there will be no 
statistical penalty assigned.  The results of this interim analysis will result in a decision to 
continue the study as planned or to stop the study.  Details of the analysis and controlled access 
to the unblinded data are outlined in the SAP and DSMB Charter. 
10.5 
Planned Methods of Analysis 
All eCRF data, lab data transfers, mNIS+7 score data, as well as any outcomes derived from the 
data, will be provided in the patient data listings.  Patient data listings will be presented for all 
patients enrolled into the study. 
Descriptive summary statistics including n, mean, median, standard deviation, interquartile range 
(25th percentile, 75th percentile), and range (minimum, maximum) for continuous variables, and 
counts and percentages for categorical variables will be used to summarize most data by 
treatment group.  Where appropriate, p-values will be reported.  All statistical tests will be 
conducted using 2-sided tests with 5% Type I error rates unless otherwise stated. 
All primary, secondary and tertiary efficacy and pharmacodynamic endpoints, except GLS 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.  ECHO endpoints including GLS will be 
assessed in the ECHO subgroup and in the CM-ECHO Set. 
10.5.1 
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. 
10.5.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group, 
as well as reasons for withdrawal from Study Drug. 
All treatment-emergent adverse events (AEs with onset after the first dose of Study Drug) and 
serious adverse events will be summarized for each treatment group using the MedDRATM 
coding system, by system organ class, preferred term, relationship to Study Drug, and severity.  
Narratives of deaths, serious adverse events, including early withdrawals from Study Drug and 
from study due to adverse events, will also be provided. 


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Laboratory tests to ensure patient safety including chemistry panel, complete blood count with 
differential, coagulation panel, and complement, will be summarized by study visits for each 
treatment group.  These safety variables will also be presented as change and percent change 
from baseline over time after Study Drug administration, as appropriate.  
Vital sign, weight, and ECG measures will be summarized by treatment group.  In addition, the 
number of patients who experience abnormalities in clinical laboratory evaluations will be 
summarized by treatment group. 
10.5.3 
Efficacy Analysis 
The 2 primary endpoints (mNIS+7 and Norfolk QOL-DN questionnaire total score) will be 
analyzed using a ranking strategy with the mNIS+7 tested first and the Norfolk QOL-DN tested 
second.  The primary efficacy analyses will be (1) the comparison of change from baseline to 
Week 66 in mNIS+7 between ISIS 420915 300 mg group and placebo group in the Full Analysis 
Set and (2) the comparison of change from baseline to Week 66 in Norfolk QOL-DN 
questionnaire total score between ISIS 420915 300 mg group and placebo group in the Full 
Analysis set.  Interpretation will be made in a stepwise approach, i.e. should the null hypothesis 
for the mNIS+7 be rejected, then the null hypothesis for the Norfolk QOL-DN questionnaire 
total score will be tested.  However, if the null hypothesis for the mNIS+7 is not rejected, testing 
for the Norfolk QOL-DN questionnaire total score will be considered exploratory.  No 
adjustment will be made for multiple testing (both endpoints will be tested at an alpha of 0.05). 
The data will be analyzed using a Mixed Effects Model with Repeated Measures (MMRM 
model) where the treatment group, time, 3 randomization stratification factors, and treatment by 
time interaction will be included in the model as fixed effects; patient will be a random effect.  
The baseline by time interaction will be included if appropriate.  No imputation for missing data 
will be made.  The 2 assessments at each timepoint (except Week 35 that includes only 
1 assessment) will be averaged at component level. 
For each primary endpoint, a cumulative distribution function plot will be used to show the 
distribution of change from baseline to Week 66 in individual patients by treatment group. 
The primary efficacy analyses will take place after all patients have completed the treatment and 
EOT efficacy assessments and the database has been locked.  Evaluation of the model will be 
performed.  The details of model checking and alternative analyses approach will be provided in 
the SAP that will be finalized prior to the final database lock. 
The following sensitivity analyses will be conducted for both of the primary efficacy endpoints, 
and details of the analysis are outlined in the SAP: 
• Comparison of change from baseline to Week 66 in mNIS+7 score and Norfolk QOL-DN 
questionnaire total score between ISIS 420915 300 mg and placebo group in the Per-
Protocol Set 
• A variety of multiple imputation methods will be used to investigate the impact of 
different patterns of missing data 


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• Addition of pooled investigative site to the primary efficacy MMRM model, where 
pooled site will be specified in the SAP prior to unblinding.  The interaction between 
treatment and pooled site will be examined if model convergence permits 
• Responder analysis (for mNIS+7 only) to examine if the improvement in response is 
consistent over a range of response thresholds.  If a patient terminates treatment early due 
to AE or lack of efficacy or other types of treatment failure, then the response of the 
patient is considered as non-responder.  Other missing values are considered as censoring 
o For the set of response thresholds, the proportion of responders will be plotted against 
the responder threshold by treatment group 
Secondary efficacy analyses include: 
• Comparison of change from baseline to Week 66 in the Norfolk QOL-DN questionnaire 
symptoms domain score (Stage 1 patients) and Norfolk QOL-DN questionnaire physical 
functioning/large fiber neuropathy domain score (Stage 2 patients) between ISIS 420915 
300 mg and placebo group in the Full Analysis Set 
• Comparison of change from baseline to Week 65 in mBMI and BMI between 
ISIS 420915 300 mg and placebo group in the Full Analysis Set 
• Comparison of change from baseline to Week 66 in the NIS, modified +7, and NIS+7 
between ISIS 420915 300 mg and placebo group in the Full Analysis Set.  Comparison of 
change from baseline to Week 66 in Norfolk QOL-DN domain scores (symptoms domain 
for Stage 1 patients and physical functioning/large fiber neuropathy domain for Stage 2 
patients), NIS, modified +7 and NIS+7, and change from baseline to Week 65 in mBMI 
and BMI between ISIS 420915 300 mg and placebo group in the Per-Protocol Set 
• Comparison of change from baseline to Week 65 in GLS by ECHO in the ECHO 
subgroup and in the CM-ECHO Set 
Tertiary analyses include: 
Comparisons of change from baseline to Week 65 in SF-36 questionnaire domain scores, and 
change from baseline to Week 66 in individual components of NIS (cranial, muscle weakness, 
reflexes and sensory), modified +7 (heart rate to deep breathing, nerve conduction, heat-pain 
sensory and touch-pressure sensory testing) and +7 (vibration detection threshold and nerve 
conduction), +7, and individual domain scores of Norfolk QOL-DN (physical functioning/large 
fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy and autonomic 
neuropathy) between ISIS 420915 300 mg and placebo group in both Full Analysis Set and Per-
Protocol set.  The secondary and tertiary analyses except GLS will be conducted in the same way 
as for the primary endpoint.  The analysis for GLS by ECHO in the ECHO subgroup and in the 
CM-ECHO Set will be specified in the ECHO SAP. 
 


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10.5.4 
Pharmacokinetic Analysis 
For all patients, pre-dose ISIS 420915 plasma concentrations will be summarized using 
descriptive statistics.  In addition, non-compartmental pharmacokinetic analysis of ISIS 420915 
concentrations will be carried out on each individual patient data set, and the plasma disposition 
half-life (t1/2λz) associated with the apparent terminal elimination phase will be calculated, if 
appropriate, using available data (Day 449 and later), from the equation, t1/2λz = 0.693/λz, where 
λz is the rate constant associated with the apparent terminal elimination phase. 
For patients in the PK subgroup only, non-compartmental pharmacokinetic analysis of 
ISIS 420915 will be carried out on each individual patient data set.  The maximum observed 
drug concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from 
the concentration-time data.  Following single dosing (Day 1), area under the plasma 
concentration-time curve from zero time (pre-dose) to 24 hours after the dose (AUC0-24hr) will be 
calculated using the linear trapezoidal rule.  Following multiple dosing (Days 240 and 449), 
AUC0-24hr and area under the plasma concentration-time curve during the time of each sampled 
dosing interval (tau,τ) at steady-state (AUCτ) will be calculated using the linear trapezoidal rule. 
Other pharmacokinetic parameters, as appropriate, may be determined or calculated at the 
discretion of the pharmacokinetic scientist. 
Plasma pharmacokinetic parameters will be summarized using descriptive statistics.  Additional 
details regarding the pharmacokinetic analysis will be described in the SAP. 
There is no statistical rationale for the selected sample size of the PK subgroup.  The PK 
subgroup size of approximately 20 patients (to give approximately 10 evaluable patients in the 
treated group assuming a dropout rate of 25%) was selected based upon prior clinical PK 
experience with ISIS 420915 and other 2′-MOE-modified ASOs, and expected low-to- moderate 
inter- and intra-patient variability in PK parameter measures. 
10.5.5 
Pharmacodynamic Analysis 
Pharmacodynamic analyses include comparisons of change from baseline in TTR and RBP4 
between ISIS 420915 300 mg and placebo group.  The data will be analyzed in the same way as 
for the primary endpoint and will be assessed in both the Full Analysis and Per-protocol 
populations. 
10.5.6 
Exploratory Analysis 
Exploratory analysis includes the comparisons of change from baseline in ECHO parameters 
except GLS (ECHO subgroup and CM-ECHO Set), NT-ProBNP, PND score and NSC score to 
Week 65 (Week 66 for NSC) between ISIS 420915 300 mg and placebo group.  Details of the 
analysis will be provided in the SAP and ECHO SAP. 
11. 
INVESTIGATOR'S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, from an English version provided by the Sponsor. 


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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 Study Drug products are 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 form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of Study Drug.  A copy of the 
written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
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.  On the case report 
forms 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. 


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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. 
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 case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, 
CRFs 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 case report forms, patient dosing diaries, 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 


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• 
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 Statement, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., case report forms and other pertinent data) provided that 
patient confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the case report forms at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research.  
The monitor should have access to patient medical records and other study-related records 
needed to verify the entries on the case report forms. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing case report forms, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-
related records will occur to evaluate the trial conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the case report form.  These 
signatures will indicate that the principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content. 
 
 


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12.5 
Language 
Case report forms 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. 
 
 


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13. 
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WC500117838.pdf 
Episkopou V, Maeda S, Nishiguchi S, et al. Disruption of the transthyretin gene results in mice with depressed 
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Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. NEJM 1997; 337: 898-909. 
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imaging. VIIIth International Symposium on Familial Amyloidotic Polyneuropathy. Kumamoto, Japan: Nov 20-22, 
2011. 
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. 
Herlenius G, Wilczek HE, Larsson M, et al; and Reporting Members of the Familial Amyloidotic Polyneuropathy 
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polyneuropathy: results from the familial amyloidotic polyneuropathy world transplant registry. Transplantation 
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Inoue H, Hayase Y, Iwai S, et al. Sequence-dependent hydrolysis of RNA using modified oligonucleotide splints 
and RNase H. FEBS Letters 1987; 215: 327-330. 
Kastelein JJ, Wedel MK, Baker BF, et al. Potent reduction of apolipoprotein B and low-density lipoprotein 
cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 2006; 114: 
1729-1735. 
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 
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Levin AA, Yu RZ, Geary RS. Basic principles of the pharmacokinetics of antisense oligonucleotide drugs. In: 
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FL. Taylor and Francis Group 2008; 183-215. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
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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. 
Okamoto S, Wixner J, Obayashi K, et al. Liver transplantation for familial amyloidotic polyneuropathy: impact on 
Swedish patients' survival. Liver Transplantation 2009; 15: 1229-1235. 
Palladini G, Lavatelli F, Russo P, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic 
peptide type B decrease simultaneously in association with improvement of survival in AL. Blood 2006; 107: 
3854-3858. 
Plante-Bordeneuve V, Ferreira A, Lalu T, et al. Diagnostic pitfalls in sporadic transthyretin familial amyloid 
polyneuropathy (TTR-FAP). Neurology 2007; 69: 693-698. 
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. 
Santos R, Duell PB, East C, et al. Long-term safety and efficacy of mipomersen in patients with familial 
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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 
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Pagon RA, et al. editors. Seattle, WA. 
Sewell KL, Geary RS, Baker BF, et al. Phase 1 trial of ISIS 104838, a 2′-methoxyethyl modified antisense 
oligonucleotide targeting tumor necrosis factor-alpha. J Pharmacol Exp Ther 2002; 303: 1334-1343. 
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid polyneuropathy. Curr 
Opin Neurol 2004; 17: 615-620. 
Vinik EJ, Vinik AI, Paulson JF, et al. Validation of Norfolk QOL-DN as a measure of QOL in patients with 
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Waits RP, Yamada T, Uemichi T, et al. Low plasma concentrations of retinol-binding protein in individuals with 
mutations affecting position 84 of the transthyretin molecule. Clin Chem 1995; 41: 1288-1291. 
Wei S, Episkopou V, Piantedosi R, et al. Studies on the metabolism of retinol and retinol-binding protein in 
transthyretin-deficient mice produced by homologous recombination. Journal of Biological Chemistry 1995; 270(2): 
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14. 
APPENDICES 
 
 
 


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Appendix A 
Schedule of Procedures 
 


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Appendix A Schedule of Procedures 
 
 
 
EOT
Efficacy
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
3
5
8
10
13
15
18
20
23
26
29
32
38
41
44
47
50
53
56
59
62
65
66
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
1
3
5
15
29
50
64
85
99
120
134
155
176
197
218
239
240
260
281
302
323
344
365
386
407
428
449
456
Visit Window (+/- Days)
0
0
0
2
2
2
2
2
2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
7
Informed Consent
X
Inclusion/Exclusion
X
Medical History
X
Height
X
HIV, Hepatitis B & C
X
Biopsy for Amyloid3
X
TTR Genotyping3
X
Study Drug Admin.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Vital SignsA
(BP4, HR, RR, temp)
ECG (12-Lead, triplicate)
X
XC
XA
XA
XA
Pregnancy Test5
X
XA
X
X
X
X
X
Chemistry Panel (Fasting) A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Creatinine (Fasting)
X
X
X
X
X
X
Hematology A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weekly Platelet Monitoring10
Urinalysis A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
24 hour Urine
X
Thyroid PanelA
X
X
X
X
X
X
Inflammatory PanelA
X
X
X
X
X
X
X
X
X
PT, aPTT, INRA
X
X
X
X
X
X
X
Complement (C3)A
X
ImmunogenicityA
X
X
X
X
X
X
AE & Conmeds & 
Concomitant Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weekly Platelet Monitoring
X
X
X
X
X
X
X
X
Study Day
S-42 to S-1
X
Study Week
W -6 to -11
W
1
W
35
Screen
Baseline 
Assess-
ments
Treatment (65 Wks)


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
73 
Appendix A Schedule of Procedures Continued 
 
 
EOT
Efficacy
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
3
5
8
10
13
15
18
20
23
26
29
32
38
41
44
47
50
53
56
59
62
65
66
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
1
3
5
15
29
50
64
85
99
120
134
155
176
197
218
239
240
260
281
302
323
344
365
386
407
428
449
456
Visit Window (+/- Days)
0
0
0
2
2
2
2
2
2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
7
NIS6
X
mNIS+7 Assessment7
2X
X
2X
Norfolk QOL-DN7
X
X
X
SF-36 QuestionnaireA
X
X
X
PND Score
X
X
X
Body Weight (Fasting)
X
X
X
X
X
X
PD Panel (Fasting)A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK TroughA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Transthoracic ECHO8
X
X
X
NT-proBNPA
X
X
X
X
Retinol (Fasting)A
X
X
X
X
X
X
X
ERG Exam9
X
X
Ophthalmology Exam9
X
X
X
C-SSRS
XA
X
X
X
X
PK AUC/Trough Blood
XB
XA
XA
XA
XA
XA
XA
XA
XA
XA
XF
XA
XA
XA
XA
XF
ECG (12-Lead, triplicate)
X
XC
XC
XC
Complement (C5a, Bb)
XC
XA
XA
XA
XA
XC
XC
PT, INR, aPTT
XD
XA
XA
XA
XA
XD
XD
Inflammatory Panel
XA
XA
XA
XA
XA
XA
XA
XE
XE
Hematology
X
XA
XA
XA
XA
XA
XA
XA
XA
XA
XA
XA
XA
XA
XA
XA
XE
XA
XA
XA
XA
XA
XA
XA
XA
XA
XE
Additional Tests for PK Subgroup Only (n = 20)
Study Week
W
-6 to -11
W
1
W
35
Study Day
S-42 to S-1
Screen
Baseline 
Assess-
ments
Treatment (65 Wks)


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
74 
Appendix A Schedule of Procedures Continued 
 
Post Treatment Evaluation Period 
 
 
W
W
W
W
W
W
W
W
67
69
71
74
77
80
83
91
D
D
D
D
D
D
D
D
463
477
491
512
533
554
575
631
Visit Window (+/- Days)
7
7
7
7
7
7
7
7
Informed Consent
Inclusion/Exclusion
Medical History
Height
HIV, Hepatitis B & C
Biopsy for Amyloid3
TTR Genotyping3
Study Drug Admin.
Physical Exam
X
X
Vital SignsA
(BP4, HR, RR, temp)
ECG (12-Lead, triplicate)
X
X
Pregnancy Test5
X
X
X
Chemistry Panel (Fasting) A
X
X
X
X
Serum Creatinine (Fasting)
X
X
X
X
X
Hematology A 
X
X
X
X
X
X
X
X
X
Weekly Platelet 
Monitoring10
Urinalysis A
X
X
24 hour Urine
Thyroid PanelA
X
X
Inflammatory PanelA
X
X
X
PT, aPTT, INRA
X
X
Complement (C3)A
ImmunogenicityA
X
X
X
AE & Conmeds & 
Concomitant Procedures
X
X
X
X
Weekly Platelet Monitoring
Post-Treatment Evaluation Period
Early 
Term
(6 Mo)2
X
X
X
X
Study Week
Study Day


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
75 
Appendix A Schedule of Procedures Continued 
 
Post Treatment Evaluation Period 
 
Note:  If not specifically labeled, “X” means anytime.  Shaded columns represent visits with the option to be completed in clinic, by a home healthcare service, or by a local 
laboratory with prior Sponsor approval.  
 
W
W
W
W
W
W
W
W
67
69
71
74
77
80
83
91
D
D
D
D
D
D
D
D
463
477
491
512
533
554
575
631
Visit Window (+/- Days)
7
7
7
7
7
7
7
7
NIS6
mNIS+7 Assessment7
X
EOT
Norfolk QOL-DN7
X
EOT
SF-36 QuestionnaireA
X
X
PND Score
X
X
Body Weight (Fasting)
X
X
X
PD Panel (Fasting)A
X
X
X
X
PK TroughA
X
X
X
X
Transthoracic ECHO8
X
NT-proBNPA
X
X
X
Retinol (Fasting)A
X
X
X
X
ERG Exam9
X
Ophthalmology Exam9
X
C-SSRS
X
X
PK AUC/Trough Blood
X
X
X
X
ECG (12-Lead, triplicate)
X
X
Complement (C5a, Bb)
X
X
PT, INR, aPTT
X
X
Inflammatory Panel
X
X
X
Hematology
XA
XA
X
XA
X
XA
XA
X
X
Post-Treatment Evaluation Period
Early 
Term
Study Week
Additional Tests for PK Subgroup Only (n = 20)
(6 Mo)2
Study Day


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
76 
Appendix A Schedule of Procedures Continued 
1 
A 6-week period is given to complete the screening/baseline assessments.  Ideally, the baseline assessments should be conducted after patient eligibility is 
determined. 
2 
After completing the Week 66 efficacy assessments, patients will enter the post-treatment evaluation period.  However, eligible patients may elect to enroll in 
an OLE study pending study approval by the IRB/IEC and the appropriate regulatory authority. In this case, patients will not participate in the post-treatment 
evaluation period. 
3 
For determination of patient eligibility only if appropriate documentation is not available. In this case the tests may be conducted up to ten weeks prior to 
Day 1.  For biopsy, location per local practice. 
4 
Blood pressure should be taken after patient has been sitting for ≥ 5 min. 
5 
For females of child-bearing potential only, by serum βhCG except on Day 1 were urine hCG is tested pre-dose. 
6 
At Screening for determination of eligibility only (+7 not needed).  For an individual patient, every effort should be made to use the same NIS evaluator 
throughout the study and the NIS evaluator must be insulated from the patient’s general study procedures and knowledge of the patient’s adverse events. 
7 
The Norfolk QOL-DN questionnaire must be administered prior to any other study procedures. During the baseline and EOT efficacy assessment periods, the 
Norfolk QOL-DN questionnaire should be administered on the same day as the first mNIS+7 assessment.  The mNIS+7 assessment procedure includes the 
NIS, +7, NSC, and additional sensory and nerve conduction testing.  If an ERG or ophthalmology examination are to be conducted on a mNIS+7 assessment 
day, the mNIS+7 assessment must be conducted first. 
• 
Two (2) independent mNIS+7 assessments will be performed at Baseline on separate days.  Both assessments should be performed within 14 days prior 
to the first dose of Study Drug (Day 1).  In addition, every effort should be made to conduct the two assessments < 7 days apart. 
• 
mNIS+7 and Norfolk QOL-DN assessments at Week 35 (D239) must be conducted approximately > 24 hours from the previous weeks dose. 
• 
Two independent mNIS+7 assessments will be performed at Week 66 on separate days.  Both assessments must be performed within 14 days from the 
last dose of Study Drug.  The first mNIS+7 assessment must be conducted approximately > 24 hours from the last dose of Study Drug.  In addition, every 
effort should be made to conduct the two assessments < 7 days apart.  The EOT efficacy assessment should also be performed on patients that 
terminate treatment early, ideally within 14 days of the last dose of Study Drug. 
8 
Transthoracic ECHO 
• 
The baseline, Week 65 and early term ECHOs are conducted on all patients. 
• 
The Week 41 ECHO is only conducted in patients participating in the ECHO subgroup and can be done at Week 47 if the patient elects to have a Home 
Healthcare visit at Week 41. 
• 
There is a window of ± 2 weeks for all ECHOs. 
9 
ERG and ophthalmology examinations 
• 
The Week 29 and Week 65 examinations have a window of ± 2 weeks. The baseline ERG and ophthalmology examinations may be done up to 1-week 
after Study Day 1 if needed for scheduling purposes (except for Ile84 patients that fall under exclusion criteria 3 and should have eye examinations 
performed to determine eligibility).  Week 65 ERG and ophthalmology examinations may be done at Week 59 if needed for scheduling purposes. 
• 
The early termination (Early term) ERG and ophthalmology examinations are only done if the patient discontinues treatment after ≥ 9 mo of dosing. 
 
 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
77 
Appendix A Schedule of Procedures Continued 
Legend Continued 
10 Weekly platelet 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 65 week treatment period).  For patients participating in the Post-Treatment Evaluation Period, 
frequency of testing after the Week 71 visit will be determined by the Study Medical Monitor in consultation with the Investigator.  For patients participating in 
the ISIS 420915-CS3 study, weekly monitoring should continue between the last dose of Study Drug in CS2 and first dose of Study Drug in CS3.  If this period 
extends beyond 6 weeks, the frequency will be determined by the Study Medical Monitor.  
The following visits to collect platelet values are required in addition to the visits shown in the table.  These visits do not have specified windows to allow 
flexibility of scheduling but with the intent that platelets are assessed each calendar week.  Visits may be completed in clinic, by home healthcare service, or 
by a local laboratory: 
Week 2, 4, 6, 7, 9, 11, 12, 14, 16, 17, 19, 21, 22, 24, 25, 27, 28, 30, 31, 33, 34, 36, 37, 39, 40, 42, 43, 45, 46, 48, 49, 51, 52, 54, 55, 57, 58, 60, 61, 63, 64, 66, 
68, and 70 
 
Time (time is in reference to Study Drug administration): 
A 
Pre-dose (during treatment period) 
B 
Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24-hour 
C 
Pre-dose, 3-hour 
D 
Pre-dose, 3 and 12-hour 
E 
Pre-dose, 24-hour, 3-day and 7-day 
F 
Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24-hour, 3-day and 7-day.  For both E and F: where applicable, the 7-day blood draw should be taken before the next 
 
weekly dose is given.  The 12-hr blood draw is encouraged but optional. 
 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
78 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 
 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
79 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of ISIS 420915 or other similar 
oligonucleotides 
Clinical Chemistry Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Uric Acid 
• Total bilirubin 
• Direct (conjugated) 
bilirubin 
• Indirect (unconjugated) 
bilirubin 
• ALT 
• AST 
• Alkaline phosphatase 
• Creatine kinase 
• Estimated creatinine 
clearance (CKD-EPI) 
• Total IgM 
• Total IgG 
 
Screening Tests 
• Hepatitis B surface 
antigen 
• Hepatitis C antibody 
• HIV antibody 
• Serum βhCG 
• Urine hCG 
• FSH 
 
Coagulation 
• aPTT (sec) 
• PT (sec) 
• INR 
 
Complement1 
• C3 
• C5a 
• Bb 
 
PD Panel1 
• Transthyretin 
• Retinol binding 
protein 4 (RBP4) 
 
24 hour Urine1 
• Creatinine 
• Protein 
• Albumin 
 
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• Platelets 
• White blood cells 
• WBC Differential (% and 
absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Pharmacokinetics2 
• ISIS 420915 levels in 
plasma 
 
Thyroid Panel 
• Thyroid stimulating 
hormone (TSH) 
• Free T4 (FT4) 
Urinalysis1 
• Color 
• Appearance 
• Specific gravity 
• pH 
• Protein 
• Blood 
• Ketones 
• Urobilinogen 
• Glucose 
• Leukocyte 
esterase 
• Nitrate 
• Microscopic 
examination3 
• P/C and Alb/C 
ratio 
 
Inflammatory 
Panel1 
• hsCRP 
 
Others 
• Retinol 
• Retinyl Palmitate 
• NT-proBNP 
• Immunogenicity 
1 
Other biomarkers may be measured, as needed; at the discretion of the Sponsor.  Back-up samples will be 
collected and stored.  For transthyretin, back-up samples may be analyzed in more sensitive transthyretin assays 
at the discretion of the Sponsor.  Back-up urine samples may be analyzed for additional renal biomarkers. 
2 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, immunogenicity testing, or 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) 
 
 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
80 
 
 
 
 
 
 
 
Appendix C 
PK Sampling Schedule 
 


ISIS 420915-CS2 
CONFIDENTIAL 
Amendment 9 
Protocol 
 
13 May 2016 
 
81 
Appendix C PK Sampling Schedule 
PK Sampling Schedule (All Patients except PK Subgroup) 
D1 
(Wk 1) 
D15 
(Wk3) 
D29 
(Wk 5) 
D50 
(Wk 8) 
D85 
(Wk 13) 
D120 
(Wk 18) 
D155 
(Wk 23) 
D197 
(Wk 29) 
D240 
(Wk 35) 
D281 
(Wk 41) 
D323 
(Wk 47) 
D365 
(Wk 53) 
D407 
(Wk 59) 
D449 
(Wk 65) 
D491 
(Wk 71) 
D533 
(Wk 77) 
D631 
(Wk 91) 
Blood: 
Predose 
Blood:  
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Predose 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
 
Extensive PK Sampling Schedule – (PK Subgroup Only)1 
D1 
(Wk 1) 
D3 
(Wk 1) 
D5 
(Wk 1) 
D15 
(Wk 3) 
D29 
(Wk 5) 
D50 
(Wk 8) 
D85 
(Wk 13) 
D120 
(Wk 18) 
D155 
(Wk 23) 
D197 
(Wk 29) 
D240 
(Wk 35) 
D281 
(Wk 41) 
D323 
(Wk 47) 
D365 
(Wk 53) 
D407 
(Wk 59) 
D449 
(Wk 65) 
D491 
(Wk 71) 
D533 
(Wk 77) 
D631 
(Wk 91) 
Blood: 
Predose, 
0.5, 1, 
1.5, 2, 3, 
4, 6, 8, 
12, 24 
hours 
Post SC 
Injection 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre- 
Dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Predose
0.5, 1, 
1.5, 2, 3, 
4, 6, 8, 
12, 24 
hours, 
3 days, 
7 days 
Post SC 
Injection 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Predose
0.5, 1, 
1.5, 2, 3, 
4, 6, 8, 
12, 24 
hours, 
3 days, 
7 days 
Post SC 
Injection 
Blood: 
Any-time 
Blood: 
Any-time 
Blood: 
Any-time 
1 
The 12-hr time-point is encouraged but optional 

SAP_001.pdf: 
Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
April 21, 2017 
Statistical Analysis Plan 
ISIS 420915-CS2 
 
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 Isis Pharmaceuticals, Inc. 
1 
 
 
 
 
 
Statistical Analysis Plan 
 
 
ISIS 420915-CS2 
A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study 
to Assess the Efficacy and Safety of ISIS 420915 in Patients with 
Familial Amyloid Polyneuropathy  
 
 
Date:  April 21, 2017 
Version:  3.1 
 


 
2  
St atistic al A n al ysis Pl a n Si g n at ur e P a g e  
Io nis  P h ar m ac e utic als, I nc.  
2 8 5 5 G az ell e C o urt  
C arls b a d, C A 9 2 0 1 0  
 
Pr ot oc ol:   
 
I SI S 4 2 0 9 1 5 -C S 2  
St u dy Titl e:   
A P h as e 2/ 3 R a n d o miz e d, D o u bl e -Bli n d, Pl ac e b o -C o ntr oll e d St u dy t o Ass ess 
t h e Effic ac y a n d S af ety of ISI S 4 2 0 9 1 5 i n P ati e nts wit h F a mili al A m yl oi d 
P oly n e ur o p at h y  
Iss u e D at e:   
M a y   1 3 , 2 0 16  ( A m e n d m e nt 9 )  
 
Si g n at ur e:   
 
 
 
 
 
 
 D at e:    
 
 
, P h. D.  
, Bi o m etrics  
I o nis P h ar m ac e utic als, I nc.  
2 8 5 5 G az ell e C o urt  
C arls b a d, C A 9 2 0 1 0  
 
Si g n at ur e:   
 
 
 
 
 
 
 D at e:    
 
 
, P h. D.  
, Bi o m etrics  
I o nis P h ar m ac e utic als, I nc.  
2 8 5 5 G az ell e C o urt  
C arls b a d, C A 9 2 0 1 0  
 
Si g n at ur e:   
 
 
 
 
 
 
 D at e:    
 
 
, P h. D. 
, 
, Cli nic al D e v el o p m e nt  
I o nis P h ar m ac e utic als, I nc.  
2 8 5 5 G az ell e C o urt  
P P D
C arls b a d, C A 9 2 0 1 0
P P D
P P D
P P D
P P D
P P D
P P D


 
3 
Table of Contents 
Abbreviations ..............................................................................................................................7 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study Overview ......................................................................................................... 10 
1.2 
Objectives.................................................................................................................. 11 
1.2.1 
Primary Objective ......................................................................................................................... 11 
1.2.2 
Secondary Objectives ................................................................................................................... 11 
1.2.3 
Tertiary Objectives ........................................................................................................................ 12 
1.2.4 
Exploratory Objectives .................................................................................................................. 12 
1.3 
Hypotheses ................................................................................................................ 12 
1.4 
Endpoints .................................................................................................................. 13 
2 
Procedures ......................................................................................................................... 13 
2.1 
General Overview of Procedures ................................................................................ 13 
2.2 
Randomization & Treatment Allocation ...................................................................... 14 
2.3 
Conduct ..................................................................................................................... 14 
2.4 
Data Monitoring ........................................................................................................ 14 
2.4.1 
Safety Data Monitoring ................................................................................................................ 14 
2.4.2 
Data and Safety Monitoring Board ............................................................................................... 15 
2.5 
Data Management ..................................................................................................... 15 
2.5.1 
Case Report Form Data ................................................................................................................. 15 
2.5.2 
Laboratory Data ............................................................................................................................ 16 
2.5.3 
Pharmacokinetics Data ................................................................................................................. 16 
2.5.4 
Echocardiogram (ECHO) Data ....................................................................................................... 16 
2.5.5 
Electrocardiogram (ECG) Data ...................................................................................................... 16 
2.5.6 
mNIS+7 and Neuropathy Symptoms and Change Score (NSC) ..................................................... 17 
2.6 
Blinding ..................................................................................................................... 17 


 
4 
3 
Analytical Plan ................................................................................................................... 17 
3.1 
Statistical Design Summary ........................................................................................ 17 
3.2 
General Overview of Analyses .................................................................................... 18 
3.2.1 
Analysis Conventions .................................................................................................................... 18 
3.2.1.1 
Definitions and Computational Formulas ........................................................................... 20 
3.2.1.2 
Scoring of Assessment Instruments .................................................................................... 22 
3.2.1.3 
Handling of Missing or Replicated Data, Unscheduled Visits, and Early Termination Visits
 
26 
3.2.1.4 
Data Summary Plan ............................................................................................................. 41 
3.2.1.5 
Multicenter Studies ............................................................................................................. 42 
3.2.2 
Subject Populations Analyzed ....................................................................................................... 43 
3.2.3 
Patient Characteristics .................................................................................................................. 44 
3.3 
Primary Analysis ........................................................................................................ 47 
3.3.1 
Primary Endpoint Definition ......................................................................................................... 47 
3.3.2 
Primary Efficacy Analysis .............................................................................................................. 48 
3.3.3 
Additional Analyses of Primary Endpoints .................................................................................... 50 
3.3.3.1 
Description of the Missing Data .......................................................................................... 51 
3.3.3.2 
Multiple Imputation Methodology ..................................................................................... 52 
3.3.3.3 
Sensitivity Analysis Using Data at Withdrawal Visit ............................................................ 53 
3.3.4 
Subgroup Analyses of Primary Endpoints ..................................................................................... 55 
3.4 
Secondary Analyses ................................................................................................... 55 
3.4.1 
Secondary Efficacy Endpoint Definitions ...................................................................................... 55 
3.4.2 
Pharmacodynamic Endpoint Definitions ...................................................................................... 56 
3.5 
Tertiary Analyses ....................................................................................................... 56 
3.6 
Exploratory Analyses .................................................................................................. 57 
3.7 
Analysis of the PD and Primary Efficacy Endpoints Relationship .................................. 58 
3.8 
Pharmacokinetic (PK) and Immunogenicity (IM) Analysis ............................................ 58 


 
5 
3.8.1 
Plasma Pharmacokinetics ............................................................................................................. 59 
3.8.1.1 
Plasma Concentration Data ................................................................................................. 59 
3.8.1.2 
Plasma Pharmacokinetic Parameters .................................................................................. 60 
3.8.2 
Immunogenicity (IM) Analyses ..................................................................................................... 61 
3.9 
Safety Analyses .......................................................................................................... 63 
3.9.1 
Imputation of Missing/Partial Dates for Adverse Event ............................................................... 64 
3.9.2 
Adverse Events ............................................................................................................................. 64 
3.9.2.1 
Adverse Events of Special Interest (AESI) ............................................................................ 65 
3.9.2.2 
Other Adverse Events of Interest ........................................................................................ 66 
3.9.2.3 
Local Cutaneous Reactions at Injection Site (LCRIS) ........................................................... 67 
3.9.2.4 
Flu-Like Reactions................................................................................................................ 67 
3.9.3 
Vital Signs, Weight, and Physical Examination Findings ............................................................... 68 
3.9.4 
Laboratory Measurements ........................................................................................................... 68 
3.9.4.1 
Hepatobiliary Laboratory abnormalities ............................................................................. 69 
3.9.4.2 
Platelets............................................................................................................................... 70 
3.9.4.3 
Renal parameters ................................................................................................................ 71 
3.9.5 
Electrocardiograms ....................................................................................................................... 71 
3.9.6 
Electroretinograms (ERG) and Ophthalmology Exam ................................................................... 72 
3.9.7 
Columbia Suicide Severity Rating Scale (C-SSRS) .......................................................................... 72 
4 
Sample Size ........................................................................................................................ 74 
5 
Interim Analyses ................................................................................................................ 74 
5.1 
Interim Analysis of TTR .............................................................................................. 74 
5.2 
Unblinded efficacy analysis requested by the DSMB ................................................... 75 
6 
Study Conduct to Minimize Bias .......................................................................................... 75 
7 
References ......................................................................................................................... 78 
8 
Appendix ........................................................................................................................... 80 


 
6 
8.1 
Appendix 1 Components and Subcomponents of the mNIS+7, and NIS+7 .................... 81 
8.2 
Appendix 2 Scoring of Assessment Instruments .......................................................... 87 
8.3 
DSMB SAP ................................................................................................................. 89 


 
7  
A b b r e vi ati o n s  
A b br e vi ati o n/ Acr o n y m  
D efi niti o n  
+ 7  
S u m 7 t est. I ncl u d es m e as ur e m e nts of n erv e c o n d ucti o n, vi br ati o n 
t hr es h ol d, a n d h e art r at e t o d e e p br e at hi n g 
 
 
A D A  
A nti -I SI S 4 2 0 9 1 5  a nti b o di es  
A E  
A dv ers e ev e nt  
A E SI  
A dv ers e ev e nt of s p eci al i nt er est  
A N C O V A  
A n al ysis of c o v ari a nc e  
A S O  
A ntis e ns e oli g o n ucl e oti d e  
A U C  
Ar e a u n d er t h e c urv e 
B MI  
B o dy m ass i n d ex  
C m ax  
M axi m u m o bs er v e d pl as m a c o nc e ntr ati o n; o bt ai n e d dir ectl y fr o m t h e 
pl as m a c o nc e ntr ati o n-ti m e pr ofil e 
C M -E C H O  
C ar di o my o p at h y -E C H O  
CI  
C o nfi d e nc e i nt erv al  
CI CL  
C ar di ac I m a gi n g C or e L a b or at ory  
CI R  
C o py I ncr e m e nt fr o m R ef er e nc e  
CL  
Pl as m a Cl e ar a nc e  
C R F  
C as e r e p ort f or m  
C R O  
C o ntr act r es e arc h or g a niz ati o n  
C -S S R S  
C ol u m bi a S uici d e  S ev erity R ati n g Sc al e  
C V  %  
C o effici e nt of v ari ati o n , ex pr ess e d as a p erc e nt 
DI C  
Diss e mi n at e d i ntr a v asc ul ar c o a g ul ati o n  
D S M B  
D at a a n d s af ety m o nit ori n g b o ar d 
E C G  
El ectr oc ar di o gr a m  
E C H O  
Ec h oc ar di o gr a m  
E C H O S u b gr o u p  
T h e s u b gr o u p of p ati e nts h a vi n g a d diti o n al ec h oc ar di o gr a m ass ess m e nts  
e C R F  
El ectr o nic c as e r e p ort f or m  
E D C  
El ectr o nic d at a c a pt ur e  
E O S  
E n d of st u dy  
E O T  
E n d of tr e at m e nt  
E R G  
El ectr or eti n o gr a m  
F A C  
F a mili al a m yl oi d c ar di o m y o p at h y
P P D
 
P P
D


 
8  
F A P  
F a mili al a m yl oi d p oly n e ur o p at h y  
F A S  
F ull A n al ysis  S et  
G C P  
G o o d Cli nic al Pr actic e  
GL S  
Gl o b al l o n git u di n al str ai n  
HL T  
Hi g h er l e v el t er m  
h A T T R -C M  
H er e dit ar y tr a ns thy reti n a m yl oi d osis wit h c ar di o my o p at h y  
h A T T R -P N  
H er e dit ar y tr a ns thy reti n a m yl oi d osis wit h p oly n e ur o p at h y  
H P  
H e at P ai n  
H R D B  
H e art R at e t o D e e p Br e at hi n g  
I C H 
I nt er n ati o n al c o nf er e nc e o n h ar m o niz ati o n 
I E C 
I n d e p e n d e nt et hics c o m mitt e e 
I M 
I m m u n o g e nicity 
I R B 
I nstit uti o n al r e vi e w b o ar d 
I V R S 
I nt er activ e v oic e-r es p o ns e s yst e m 
J 2 R 
J u m p t o R ef er e nc e 
L C RI S 
L oc al c ut a n e o us r e acti o n at t h e i nj ecti o n sit e 
LL Q 
Lo w er li mit of q u a ntific ati o n  
M A R  
Missi n g at R a n d o m  
m B MI  
M o difi e d b o dy m ass i n d ex (r e q uir es d et er mi n ati o n of s er u m al b u mi n 
l e v els; m B MI = B MI x s er u m al b u mi n g/L) 
 
 
M e d D R A  
M e dic al Dicti o n ary f or R e g ul at or y Activiti es  
M M R M  
Mix e d eff ects m o d el wit h r e p e at e d m e as ur es  
m NI S + 7  
M o difi e d n e ur o p at h y i m p air m e nt Sc or e + 7. St a n d ar d NI S b ut wit h 
m o dific ati o ns m a d e t o t h e + 7 c o m p o n e nt  
M o difi e d + 7  
+ 7 t est wit h m o dific ati o ns m a d e  t o t h e s e ns or y a n d n er v e c o n d ucti o n 
t esti n g 
M R T  
M e a n r esi d e nc e ti m e  
N C T  
N er v e C o n d ucti o n T est  
NI S  
N e ur o p at h y i m p air m e nt sc or e  
NI S + 7  
N e ur o p at h y i m p air m e nt sc or e + 7  
NI S -C  
N e ur o p at h y i m p air m e nt sc or e –  Cr a ni al N er v es  
NI S -R  
N e ur o p at h y i m p air m e nt sc or e –  R efl ex es  
NI S -S  
N e ur o p at h y i m p air m e nt sc or e –  S e ns ati o n  
NI S -W  
N e ur o p at h y i m p air m e nt sc or e –  M uscl e W e ak n ess
P P D
 
P P D


 
9 
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 
QTc 
QT interval corrected for heart rate 
QTcF 
QTc interval calculated using Fridericia’s formula 
RBP4 
Retinol binding protein 4 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SF-36 
Short Form (36) Health Survey 
SMQ 
Standardized MedDRA query 
SOC 
System Organ Class 
SS 
Safety set 
Study Day 1 
Defined as the first day Study Drug is administered to the patient 
Study Drug 
ISIS 420915 or placebo 
SUSARs 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment emergent adverse event 
Tmax 
Time to reach Cmax; obtained directly from the plasma concentration-
time profile 
TP 
Touch Pressure 
TTP 
Thrombotic thrombocytopic purpura 
TTR 
Transthyretin 
ULN 
Upper limit of normal  
VDT 
Vibration Detection Threshold 
WMA 
World Medical Association 


 
10 
1 Introduction 
This statistical analysis plan describes the final reporting for study ISIS 420915-CS2 as per protocol 
amendment #9.  It also describes the interim reporting to support the Data Safety Monitoring Board 
(DSMB) reviews and the interim analysis.  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.  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 it to aggregate and deposit as insoluble 
fibril deposits in multiple tissues.  These deposits 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). In the literature FAP has been referred to as 
hereditary transthyretin amyloidosis  with polyneuropathy (hATTR-PN) and FAC as hereditary 
transthyretin amyloidosis  with cardiomyopathy (hATTR-CM). 
The main clinical manifestations of FAP are progressive peripheral sensorimotor and autonomic 
neuropathy.  Death, on average, occurs within 10 years from symptom onset and is primarily due to 
malnutrition and cachexia, cardiac disease, sudden death or renal failure (Coelho et al. 2008).  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 or 
bed 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 is a randomized, double-blind, placebo-controlled, multicenter study of 
approximately 15 months treatment duration and 6 months follow-up.  Approximately 135 patients 
will be randomized in a 2:1 ratio (90 ISIS 420915 and 45 placebo) to receive 300 mg ISIS 420915 or 
placebo.  Study Drug (ISIS 420915 or placebo) will be administered three times on alternate days 
during Week 1 (Days 1, 3 and 5), and then once weekly during Weeks 2–65 (for a total of 67 doses).  
The end-of-treatment (EOT) efficacy assessment is conducted at Week 66.  Following treatment and 
the EOT efficacy assessment, eligible patients (including patients who received placebo) may elect to 
enroll in an open-label extension (OLE) study pending study approval by the IRB/IEC and the 
appropriate regulatory authority.  All participating patients in the OLE study will receive 300 mg 
ISIS 420915 once weekly.  Otherwise, patients will enter the 6 month post-treatment evaluation 
portion of the study.  


 
11 
Patients in the study will be Stage 1 (approximately 50%) and Stage 2 (approximately 50%) FAP 
patients with the following characteristics: 
a. Neuropathy impairment score (NIS) score ≥ 10 and ≤ 130 
b. Documented transthyretin variant by genotyping 
c. Documented amyloid deposition by biopsy  
Interim safety data will be reviewed regularly by the ISIS 420915-CS2 DSMB.   
A pharmacodynamic interim analysis of reduction in plasma TTR level will be performed by an 
independent statistician and reviewed by the DSMB after approximately 45 patients have completed 
the Week 13 visit.  This interim will be a futility analysis and will result in a decision to continue the 
study as planned or to stop the study.   
1.2 Objectives 
1.2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of ISIS 420915 as compared to placebo, 
given for 65 weeks, as measured by the change from baseline in the modified Neuropathy 
Impairment Score +7 (mNIS+7) and in the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-
DN) questionnaire total score in patients with Familial Amyloid Polyneuropathy. 
1.2.2 
Secondary Objectives 
To evaluate the efficacy of ISIS 420915 as compared to placebo based on the change from baseline 
in the following measures:   
• 
Norfolk QOL-DN questionnaire symptoms domain score in Stage 1 patients and Norfolk 
QOL-DN questionnaire physical functioning / large fiber neuropathy domain score in Stage 2 
patients 
• 
Modified body mass index (mBMI) and body mass index (BMI) 
• 
Neuropathy impairment score (NIS) and modified +7 
• 
Neuropathy impairment score +7 (NIS+7) 
• 
Global longitudinal strain (GLS) by echocardiogram (ECHO) in the ECHO subgroup and in the 
Cardiomyopathy-ECHO (CM-ECHO) Set  
To evaluate the pharmacodynamic (PD) effect of ISIS 420915 as compared to placebo, based on the 
change from baseline in TTR and retinol binding protein 4 (RBP4) 
To evaluate the safety and tolerability of ISIS 420915 
To evaluate the plasma trough levels of ISIS 420915 in all patients and to evaluate the plasma 
pharmacokinetic (PK) parameters of ISIS 420915 in a subset of patients. 


 
12 
1.2.3 
Tertiary Objectives 
The tertiary objectives are to evaluate the change from baseline, as compared to placebo, in the 
following measures: 
• 
SF-36 questionnaire 
• 
Individual components of NIS, modified +7, and +7 
• 
+7 
• 
Individual domain scores of the Norfolk QOL-DN. 
1.2.4 
Exploratory Objectives 
The exploratory objectives are to evaluate the change from baseline, as compared to placebo, in the 
following exploratory biomarkers: 
• 
 ECHO parameters (except GLS) 
• 
Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) 
• 
Polyneuropathy disability score (PND) 
• 
Neuropathy symptoms and change (NSC) score. 
1.3 Hypotheses 
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, a primary organ for antisense oligonucleotide (ASO) 
distribution after systemic delivery. 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 (as measured by 
the mNIS+7) and maintain or improve quality of life (as measured by the Norfolk QOL-DN). 
The two primary endpoints (mNIS+7 and Norfolk QOL-DN questionnaire total score) will be tested 
using a ranking strategy with the mNIS+7 tested first and the Norfolk QOL-DN tested second. The 
null hypothesis is that there is no difference between ISIS 420915 and placebo in the change from 
baseline to Week 66 on the mNIS+7, as evaluated by a repeated measures mixed model analysis. 
Since the Norfolk QOL-DN will not be tested unless the mNIS+7 is significant, the Norfolk QOL-DN is 
not involved in formulating the null hypothesis (since under the null, it will not be tested). Should 
the null hypothesis for the mNIS+7 be rejected, then the null hypothesis for the Norfolk QOL-DN 
questionnaire total score will be tested. However, if the null hypothesis for the mNIS+7 is not 
rejected, testing for the Norfolk QOL-DN questionnaire total score will be considered exploratory. 
No adjustment will be made for multiple testing; both endpoints will be tested at an alpha of 0.05. 
The primary study hypotheses will be formally evaluated at the time of the end of treatment lock 
(EOT analysis), occurring after all patients have completed the EOT assessments, the database is 
locked and treatment code is unblinded. 


 
13 
1.4 Endpoints 
The primary efficacy endpoints are the change from baseline to Week 66 in the modified 
Neuropathy Impairment Score +7 (mNIS+7) and in the Norfolk Quality of Life-Diabetic Neuropathy 
(Norfolk QOL-DN) questionnaire total score. Details describing the mNIS+7 endpoint and scoring can 
be found in the mNIS+7 Quality Manual.  Other study endpoints are described in Sections 3.4 
through 3.8. 
2 Procedures 
2.1 General Overview of Procedures 
The study consists of the following periods: 
• 
<6 week screening and baseline assessment period 
• 
65 week treatment period 
• 
1 week EOT efficacy assessment period 
• 
6 month post-treatment evaluation period (unless patients elect to enroll in an OLE study in 
which case they will not participate in the post-treatment evaluation period) 
Screening assessments include safety and specialty labs, physical exam, vital signs, 
electrocardiogram (ECG), and body weight.  A NIS assessment is also performed that is used solely 
for patient eligibility purposes. 
The primary endpoints (mNIS+7 and Norfolk QOL-DN questionnaire) are measured at baseline, 
Week 35, and Week 66 (EOT efficacy assessment).  Patients who do not enroll in the OLE will also 
have efficacy assessments measured at Week 91 in the post-treatment evaluation period.  The 
mNIS+7 assessments at baseline and Week 66 are performed twice and the duplicates averaged.  
The duplicates cannot be performed on the same day.  In addition, patients who terminate 
treatment early for any reason will have the mNIS+7 (2x) and Norfolk QOL-DN questionnaire 
conducted within 14 days from the last dose of Study Drug. 
Other secondary and exploratory efficacy measurements (including the pharmacodynamic measures 
TTR and RBP4, BMI, mBMI, and NT-proBNP) are measured at baseline, at the end of treatment 
(Week 65) and periodically throughout the treatment period.  The SF-36 questionnaire and PND 
score are measured at baseline, Week 35, and Week 65. 
In addition to ECHOs conducted at Baseline, early termination, and Week 65 for all patients, patients 
who qualify and consent to participate in the ECHO subgroup will have an additional ECHO 
conducted during the treatment period at Week 41, which can be done at Week 47 if the patient 
elects to have a Home Healthcare visit at Week 41. All ECHO assessments have a window of ± 2 
weeks.  


 
14 
Patients participating in the PK subgroup will have additional blood draws on Day 1, Week 35, and 
Week 65 to evaluate pharmacokinetic and other safety parameters. PK subgroup patients will also 
have additional visits to collect 24 hr, 3 day, and 7 day post-dose blood draws. 
Safety labs, adverse events (AEs), concomitant medications, ECGs, electroretinograms (ERGs), 
Ophthalmology examination, physical examination, vital signs, and specialty labs, etc. are collected 
periodically throughout the baseline, treatment, and post-treatment evaluation periods.   
2.2 Randomization & Treatment Allocation 
Almac Clinical Technologies is responsible for providing the randomization for this study. Patients 
will be randomized after all screening assessments have been completed and after the Investigator 
has verified that they are eligible. No patient may begin treatment prior to randomization and 
assignment of a unique subject identification number. 
Using an Interactive Voice-Response System (IVRS), eligible patients will be randomized 2:1 to 
receive ISIS 420915 or placebo, respectively.  There will be 2 separate and independent 
randomizations, one for patients in the PK subgroup (approximately 20) and one for patients who 
are not in the PK subgroup (approximately 115).  Within each subgroup, randomization will use a 
permuted block schedule using the 8 combinations of the following 3 binary stratification variables:  
• 
Previous treatment with Vyndaqel® or Diflunisal versus no known previous treatment 
• 
Stage 1 versus Stage 2 disease  
• 
V30M TTR mutation versus non-V30M TTR mutation 
A description of the randomization process, including block size and the procedure to follow will be 
provided in a separate document prepared by Almac Clinical Technologies. 
The randomization list will be generated prior to enrollment of any patients. The Sponsor Quality 
Assurance department or designee will hold a copy of the randomization lists generated by the IVRS 
vendor.   
2.3 Conduct 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated October 2002, 
the applicable regulations and guidelines of the current Good Clinical Practice (GCP), 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 will review all AEs and SAEs on an ongoing 


 
1 5  
b asis t hr o u g h o ut t h e st u dy.  I o nis P h ar m ac e utic als, I nc. ( or d esi g n e e) will pr e p ar e a n d s u b mit s af et y 
r e p orts t o t h e h e alt h a ut h oriti es w orl d wi d e i n acc or d a nc e wit h l oc al r e q uir e m e nts.  If it b ec o m es 
n ec ess ary t o c o m m u nic at e n e w s af et y i nf or m ati o n, I o nis P h ar m ac e utic als, I nc. ( or d esi g n e e) will als o 
pr e p ar e a s af ety n otific ati o n l ett er a n d tr a ns mit it t o all a p plic a bl e st u dy sit es. 
2. 4. 2  
D at a a n d S af et y M o nit ori n g B o ar d  
A D at a a n d S af ety M o nit ori n g B o ar d ( D S M B) will b e c o nve n e d f or t h e f oll o wi n g p ur p os es:  
•  
T o r e vi e w s af ety  a n d  t ol er a bilit y d at a c oll ect e d d uri n g t h e tri al (fr e q u e ncy of r evi e w  is 
d e p e n d e nt o n p ati e nt e nr oll m e nt, i nf or m ati o n acc u m ul at e d , a n d s af et y ev e nt r at es b ut will 
occ ur n o l ess t h a n a p pr oxi m at el y e v er y 6  m o nt hs ); a n d  
•  
T o r e vi e w r es ults of t h e pr e d et er mi n e d T T R i nt eri m a n al ysis ( d et ails of t h e a n al ysis a n d 
c o ntr oll e d acc ess t o d at a ar e o utli n e d i n S ecti o ns 5. 1 a n d 6. 0) . 
D at a s u m m ari es a n d listi n gs will pr es e nt by tr e at m e nt gr o u p i n a n u n bli n d e d f as hi o n  a n d  will b e 
pr e p ar e d by a n i n d e p e n d e nt st atistic a n .  N o st atistic al c o m p aris o ns acr oss tr e at m e nt gr o u ps will b e 
pr o vi d e d , a n d n o hy p ot h esis t esti n g will b e d o n e.   
F urt h er d et ail o n t h e D S M B m e eti n g sc h e d ul e , ass ess m e nts  t o b e r e vi e w e d, fl o w di a gr a m f or t h e 
int eri m a n alys is, a n d c o ntr oll e d acc ess t o d at a ar e o utli n e d i n t h e D S M B C h art er.  
2. 5  D at a M a n a g e m e nt  
2. 5. 1  
C as e R e p ort F or m D at a  
 is r es p o nsi bl e f or cr e ati n g t h e El ectr o nic D at a C a pt ur e ( E D C) d at a e ntry scr e e ns, d at a b as e 
a n d e dit c h ecks usi n g d efi niti o ns d ev el o p e d by I o nis P h ar m ac e utic als , I nc..  I o nis P h ar m ac e utic als, 
I nc. is r es p o nsi bl e f or t h e r e vi e w, d at a m a n a g e m e nt q u eryi n g a n d l oc ki n g of t h e d at a b as e . 
D at a ar e si n gl e -e nt er e d i nt o t h e E D C syst e m by t h e i nv esti g at or sit e st aff.  Pr o gr a m m e d e dit c h ec ks 
(c o m p ut er l o gic t h at c h ec ks t h e v ali dit y of t h e d at a e nt er e d a n d als o pr o m pts f or missi n g d at a t h at 
ar e  ex p ect e d t o b e e nt er e d) ar e  r u n a n d a ut o m atic q u eri es ar e g e n er at e d.  I o nis P h ar m ac e utic als , 
I nc. r e vi e ws all d at a f or acc ur ac y a n d v ali dit y a n d g e n er at es a d diti o n al q u eri es i n t h e E D C s yst e m 
w h e n n ec ess ary.  Exc e pti o ns ar e t h e m NI S + 7, N orf ol k Q OL -D N, S F -3 6,  N S C, P N D, a n d b o dy w ei g ht 
i nf or m ati o n t h at is e nt er e d i nt o t h e E D C b ut fir e w all e d fr o m r evi e w by I o nis P h ar m ac e utic als, I nc.  
T h e d at a ar e  c orr ect e d or a n ex pl a n ati o n c o nc er ni n g t h e q u er y is pr ovi d e d i n t h e E D C syst e m .  F or 
t h e p ur p os e of pr e-pr o gr a m mi n g a n d d at a cl e a ni n g, P ar ex el (t h e c o ntr act r es e arc h or g a niz ati o n 
(C R O ) p erf or mi n g t h e st atistic al a n al ysis) a n d a  fir e w all e d d at a m a n a g er w or ki n g at t h e C R O 
c o ntr act e d t o p erf or m d at a m a n a g e m e nt (
) will h av e acc ess t o t h e p ost-
b as eli n e m NI S + 7, N S C, N orf ol k -Q OL -D N, S F -3 6, P N D  a n d b o dy w ei g ht. Aft er all d at a ar e  e nt er e d, 
r e vi e w e d, a n d q u eri e d , t h e d at a b as e is cl os e d a n d s e nt t o t h e st atistics gr o u p f or r e vi e w a n d f or 
i d e ntific ati o n of pr ot oc ol d e vi ati o ns.  Aft er any f urt h er  q u eri es t h at ar os e fr o m t his r e vi e w ar e 
r es olv e d, t h e d at a b as e is l oc k e d.  D at a b as e cl osi n g a n d l oc ki n g will b e d o n e aft er all p ati e nts h a v e 
c o m pl et e d t h e E O T ass ess m e nts (t h e pri m ary a n alysis) a n d a g ai n 
P P D
aft er all s u bj ects c o m pl et e t h e 
P P D


 
1 6  
st u dy, r ef err e d t o as e n d of st u dy ( E O S). T h e st u dy wil l b e u n bli n d e d aft er t h e first l ock ( E O T 
a n al ysis). D et ails c a n b e f o u n d i n t h e D at a M a n a g e m e nt Pl a n.  
2. 5. 2  
L a b or at or y D at a  
I o nis P h ar m ac e utic als , I nc. is r es p o nsi bl e f or t h e f or m at of t h e l a b or at ory el ectr o nic d at a tr a nsf ers 
a n d t h e tr a nsf er sc h e d ul e.  I o nis P h ar m ac e utic als , I nc. is r es p o nsi bl e f or t h e r evi e w of t h e cli nic al 
l a b or at or y d at a.  C e ntr al l a b or at or y  d at a ar e  n ot st or e d i n t h e E D C syst e m.  I nv esti g at or sit es h a v e 
acc ess t o t h e d at a vi a l a b r e p orts s e nt dir ectly fr o m t h e l a b or at ory  or t hr o u g h t h e l a b or at or y’s w e b 
p ort al (i n w hic h c as e I nv esti g at ors o nl y h a v e acc ess t o d at a fr o m t h eir sit e) .  I n or d er to e ns ur e 
m ai nt e n a nc e of t h e st u dy bli n d, p ost -tr e at m e nt T T R  ( als o c all e d pr e-al b u mi n) , R B P 4, r eti n ol ( als o 
c all e d vit a mi n A), hs C R P, a n d N T-pr o B N P  v al u es will n ot b e a v ail a bl e t o t h e S p o ns or, m o nit ors, 
I nv esti g at ors, St u dy C e nt er P ers o n n el, or t h e p ati e nts u ntil aft er E O T d at a b as e l oc k a n d t h e bli n d is 
br o k e n .   
2. 5. 3  
P h ar m ac o ki n etics  D at a  
I o nis P h ar m ac e utic als , I nc. is r es p o nsi bl e f or t h e m a n a g em e nt a n d r evi e w of t h e P K d at a.   T his 
pr oc ess i n v ol v es  r e vi e wi n g t h e p ati e nt a n d visit i d e ntifi ers wit h t h e cli nic al d at a c oll ect e d i n t h e E D C 
s yst e m.  T h e P K d at a ar e  n ot st or e d i n t h e E D C syst e m.   Pri or t o u n bli n di n g  of t h e fi n al a n al ysis , a n y 
I SI S 4 2 0 9 1 5 c o nc e ntr ati o n d at a s ets pr ovi d e d t o I o nis by t h e bi o a n al ytic al l a b will b e pr ovi d e d 
wit h o ut r ef er e nc e t o act u al p ati e nt i d e ntifi ers t o a v oi d i n a dv ert e nt or acci d e nt al u n bli n di n g.   T h e 
bi o a n al ytic al l a b m a y pr ovi d e I o nis wit h d at a s ets c o nt ai ni n g f als e p ati e nt i d e ntifi ers u nr el at e d t o 
t h e act u al i d e ntifi ers t o all o w r e vi e w of t h e P K d at a. 
2. 5. 4  
Ec h oc ar di o gr a m ( E C H O ) D at a  
T h e E C H O d at a will b e c oll ect e d, a n alyz e d a n d st or e d i n a s ec ur e d at a b as e by a n i n d e p e n d e nt C R O 
(
 
  T h e sit es will u pl o a d t h e E C H O d at a o n a s ec ur e w e b-p ort al f or a n al ysis b y  
.  F or 
t h e p ur p os e of pr e-pr o gr a m mi n g a n d d at a cl e a ni n g, P ar ex el a n d a  fir e w all e d d at a m a n a g er w or ki n g 
at t h e C R O c o ntr act e d t o p erf or m d at a m a n a g e m e nt (
) will h av e acc ess t o t h e 
p ost -b as eli n e E C H O d at a.    
2. 5. 5  
El ectr oc ar di o gr a m ( E C G) D at a  
All E C G d at a ( m ac hi n e r e a d) ar e e nt er e d i nt o t h e  
 E D C b y t h e sit es.  T h e  
 d at a will 
b e us e d f or E C G s u m m ary a n d a n alysis.  
All tri plic at e E C G w a v ef or ms will b e c oll ect e d a n d st or e d i n a s ec ur e d at a b as e by a n i n d e p e n d e nt 
C R O (
).  S el ect e d E C Gs will b e a n alyz e d b y  
 a n d t h e r es ulti n g 
d at a  c a pt ur e d i n t h e  
 d at a b ase.  T h e 
 d at a is us e d t o s u p p ort m e dic al m o nit ori n g a n d will n ot 
b e us e d f or t h e E C G s u m m ar y a n d a n alysis.  
P P D
 
P P D
P P D
P P
D
P P D
P P D
P P
D
P P
D
P P
D


 
1 7  
2. 5. 6  
m NI S + 7 a n d N e ur o p at h y S y m pt o ms a n d C h a n g e Sc or e  ( N S C) 
T h e pri m ar y effic acy ass ess m e nt, m NI S + 7 sc or es, will  b e c oll ect e d a n d st or e d by a n i n d e p e n d e nt 
c o ntr act r es e arc h gr o u p, 
 t h at 
is u n d er t h e dir ecti o n of 
.  T h e N S C sc or e is o bt ai n e d d uri n g t h e NI S ass ess m e nt 
pr oc e d ur e a n d is al s o c oll ect e d a n d st or e d b y  
.  T h e m NI S + 7 r es ults fr o m e ac h sit e will b e 
f ax e d t o  
 f or pr oc essi n g a n d q u alit y ass ur a nc e.  F ax e d c o pi es will b e m ai nt ai n e d i n s ec ur e 
r o o ms wit hi n l oc k e d c a bi n ets.  T h e NI S a n d N S C  d at a ar e st or e d i n t h e  
 ( a  d at a b as e).  T h e 
ot h er c o m p o n e nts of t h e m NI S + 7 ( n erv e c o n d ucti o n, s e ns ory t esti n g a n d h e art r at e t o d e e p 
br e at hi n g) ar e e nt er e d b y t h e  
 i nt o a fir e w all e d p orti o n of t h e st u dy E D C s yst e m.   
 
o nl y h as acc ess t o t his p orti o n of t h e E D C s yst e m a n d t h e S p o ns or a n d cli nic al sit es d o n ot h a v e 
acc ess t o t h e  
 p orti o n of t h e E D C.   T h e m NI S + 7 s u m m at e d sc or e will n ot b e s h ar e d wit h t h e 
sit es.  U p u ntil t h e E O T  d at a b as e l oc k  a n d u n bli n di n g , t h e S p o ns or will o nly h a v e acc ess t o p ati e nt 
b as eli n e v al u e s of t h e m NI S + 7.   
2. 6  Bli n di n g  
T h e S A P will b e fi n ali ze d pri or t o u n bli n di n g.  T h e  E O T  a n a lysis will b e p erf or m e d aft er all p ati e nts 
h a v e c o m pl et e d t h e E O T ass ess m e nts, t h e d at a b as e is l oc k e d a n d tr e at m e nt c o d e is u n bli n d e d.  All 
of t h e s af et y a n d effic acy o ut p uts will b e pr o d uc e d f or t his fi n al a n al ysis.  H o w ev er, at t h e e n d of t h e 
st u dy aft er all of t h e p ati e nts c o mpl et e d t h eir p ost -tr e at m e nt ev al u ati o n p eri o d or e nr oll e d i nt o 
o p e n l a b el ext e nsi o n st u dy , all d at a listi n gs a n d a p plic a bl e o ut p uts will b e u p d at e d.    
F or t h e p ur p os e of pr e -pr o gr a m mi n g a n d d at a cl e a ni n g,  
 a n d a  fir e w all e d d at a m a n a g er 
w or ki n g at t h e C R O c o ntr act e d t o p erf or m d at a m a n a g e m e nt (
) will h a v e 
acc ess t o t h e p ost -b as eli n e m NI S + 7, N S C, N orf olk -Q OL -D N, S F -3 6, P N D, E C H O a n d b o dy w ei g ht.  All 
st aff at 
 will b e bli n d e d t o tr e at m e nt assi g n m e nt. At 
a s m all t e a m 
r es p o nsi bl e f or pr ovi di n g t h e D S M B u n bli n d e d s u m m ar y st atistics f or effic ac y e n d p oi nts w er e 
u n bli n d e d t o tr e at m e nt assi g n m e nts. D et ails of t h e u n bli n d e d a n al ysis of effic ac y e n d p oi nts 
i ncl u di n g s af e g u ar ds t o e ns ur e st u dy i nt e grity ar e d et ail e d  i n S ecti o n 5. 2.  
3  A n al yti c al  Pl a n  
3. 1  St atistic al D esi g n S u m m ar y  
T his St atistic al A n al ysis Pl a n ( S A P) s p ecifi es t h e st u dy e n d p oi nts t o b e a n al yz e d, t h e st u dy 
p o p ul ati o ns, a n d t h e m et h o ds of a n al ysis.   S ecti o n  3. 2 pr o vi d es g e n er al g ui d eli n es t o b e f oll o w e d f or 
all a n alys es, a n d c o v ers t h e a n alysis p o p ul ati o ns, h a n dli n g of missi n g d at a, a n d ot h er g e n er al t o pics.   
A n al ys es of b as eli n e c h ar act eristics ar e als o c o v er e d i n t his s ecti o n.   S ecti o n  3. 3 disc uss e s t h e 
pri m ar y effic acy a n alysis a n d t h e s e nsiti vity a n alys es t o b e c o n d uct e d o n t h e pri m ar y effic ac y 
e n d p oi nt.  S ecti o n  3. 4 s p ecifi es t h e s ec o n d ar y effic ac y e n d p oi nts a n d m et h o ds of a n alysis f or t h es e 
e n d p oi nts.  S ecti o n s 3. 5  t hr o u g h 3. 8 c o v er t erti ar y effic ac y e n d p oi nts, p h ar m ac o dy n a mic e n d p oi nts, 
p h ar m ac o ki n etic a n al ys es, a n d a n alysis of s af et y e n d p oi nts, r es p ecti v el y.  
P P D
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
18 
Section 4 provides the sample size justification.  Section 5 presents details on the interim analysis to 
be conducted for this study: an early review of the reduction in TTR levels with possible stopping for 
futility. 
The SAP concludes with a references section and appendix. 
3.2 General Overview of Analyses 
This analysis plan describes the reporting of data at the end of the study (unless specified 
otherwise).  Additionally, some of these data will also be reported for the purposes of the DSMB 
and/or the TTR interim analysis.   
3.2.1 
Analysis Conventions 
All reporting will be performed in SAS version 9.1.3 or higher.   
Efficacy results will be summarized under the treatment to which patients were randomized. Safety 
and PK results will be summarized under the treatment which patients actually received. Should 
there be any cases after unblinding in which a patient received treatment other than what was 
randomized, such cases will be discussed in the study report and noted in footnotes where 
applicable. 
All electronic case report form (eCRF) data, lab data transfers, echocardiogram, 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 study, and will be 
sorted by treatment group, subject 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 is 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 and/or subgroup (where 
appropriate) and will indicate the number of subjects with non-missing data and the denominators 
for percentages.    
Descriptive summary statistics including n, mean, percentiles (e.g., median, P25, 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.  Summaries of 
pharmacokinetic parameters will also present geometric mean, standard deviation of log-
transformed data, and 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 stated.  
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. 
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 two more 


 
19 
decimal places than measured values. The minimum, maximum and confidence intervals 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.  Confidence intervals (CIs) will be 
presented using a comma separator rather than a dash. 
All primary and secondary efficacy and pharmacodynamic endpoints, except GLS will be assessed on 
the Full Analysis Set and Per-Protocol Set, with the former being the basis for the primary efficacy 
analysis.  Tertiary efficacy endpoints will be assessed only on the Full Analysis Set (Note that the 
study protocol specified these endpoints would additionally be assessed in the Per-Protocol Set). All 
safety assessments will be performed on the Safety Set.  PK endpoints will be assessed in the PK Set 
as applicable.  ECHO endpoints including GLS will be assessed in the All Randomized Set, the ECHO 
subgroup and in the CM-ECHO Set.  All analyses will take place after all patients have completed 
treatment and their EOT efficacy assessments and the database has been locked.   
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. 
   
Should the randomization stratum recorded from IVRS be different from the actual data recorded in 
eDC, the randomization stratum recorded from IVRS will be used in the analysis.   


 
20 
Treatment effects for the primary, secondary, teritiary, and select exploratory endpoints will be 
evaluated based on a 2-sided significance level of 0.05.  All other endpoints will be evaluated in an 
exploratory manner. 
All tables and figures containing efficacy and pharmacodynamic endpoints will indicate whether 
they present raw data or adjusted results from the statistical model, with footnotes indicating the 
model used and covariates included in the model.   
3.2.1.1 
Definitions and Computational Formulas 
• 
Day 1 will refer to the day of the first dose of Study Drug.  
• 
The baseline for efficacy, PD and safety assessments will be defined as follows: 
o Baseline mNIS+7 and its individual components 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 baseline mNIS+7 assessment(s) (or a subset of this 
assessment) will have been completed early in the treatment period rather than pre-
treatment.  These will be considered protocol deviations.  These assessments will be 
included in the analysis as valid baseline assessments provided they are taken within 
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 patient’s data to be 
included in the primary analysis.  A sensitivity analysis will be conducted excluding these 
assessments.  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. 
o Baseline NSC and individual components 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. 
Because NSC score is collected during the NIS assessment procedure, it is possible it 
could be completed early in the treatment period rather than pre-treatment.  These will 
be considered protocol deviations.  These assessments will be included in the analysis as 
valid baseline assessments provided they are taken within one week after the first dose. 
o The baseline ECG will be defined as the average of the triplicate taken on Day 1 Pre-
dose. If only one or two assessments are available, the single assessment or average of 
the two assessments will be used. If the case that Day 1 Pre-dose ECG is missing, 
screening visit results will be used as baseline.  
o The protocol permitted baseline ERG and ophthalmology examinations can be done up 
to one week after Study Day 1. Assessments done within one week of first dose will be 
included in the analysis as valid baseline assessments.  
o The baseline laboratory assessment including PD will be defined as the average of all 
non-missing pre-dose assessments.  


 
21 
o The baseline for all other assessments will be defined as the last non-missing value prior 
to the first dose of Study Drug.  
• 
For efficacy endpoints except for BMI and mBMI: 
o  The efficacy on-treatment period spans the time during which the study treatment 
is administered until 52 days after the last dose of medication.   
o The efficacy post-treatment period starts on the day after the efficacy on-treatment 
period and ends on the day of the patients’s last contact date within the study. 
• 
For BMI, mBMI and PD endpoints: 
o The on-treatment period spans the time during which the study treatment is 
administered until 28 days after the last dose of medication.  
o The on-post-treatment period starts on the day after the on-treatment period and 
ends on the day of the patient’s last contact date within the study. 
• 
For safety endpoints except ERG: 
o The safety on-treatment period spans the time during which the study treatment is 
administered until 7 days after the last dose of medication.  
o The safety post-treatment period starts on the day after the safety treatment period 
and ends on the day of the patient’s last contact date within the study. 
o The safety on-study period spans the time drug is first administered until the day of 
the patient’s last contact date within the study. 
• 
For ERG: 
o The on-treatment period spans the time during which the study treatment is 
administered until 28 days after the last dose of medication.  
o The post-treatment period starts on the day after the on-treatment period and ends 
on the day of the patient’s last contact date within the study. 
 
• 
The PK and Immunogenicity (IM) on-study period spans the time drug is administered until 
the day of the patient’s last contact date within the study.  
• 
Note: Assessments for mNIS+7, NSC, ERG, and ophthalmology done early in the treatment 
period that are used for baseline cannot also be used as an on-treatment assessment.  
• 
Body mass index (BMI) will be computed using the formula: 
                      BMI = (weight in kilograms) / [height in cm / 100]2 
• 
Modified BMI (mBMI) will be computed from BMI and serum albumin levels by: 
                      mBMI = BMI * serum albumin (g/L). 


2 2  
•
D ur ati o n of st u dy dr u g ex p os ur e will b e d eri v e d as t h e diff er e nc e b et w e e n t h e d at e of t h e
l ast d os e of st u dy dr u g a n d t h e d at e of t h e first d os e pl us o ne.
•
St u dy dr u g will b e a d mi nist er e d as 1. 5 mL s u bc ut a n e o us  ( S C) i nj ecti o ns.  F or p ati e nts
r ec eivi n g I SI S 4 2 0 9 1 5, t h e d os e f or e ac h a d mi nistr ati o n will b e 3 0 0 m g.  T h e t ot al d os e of
st u dy dr u g d uri n g t h e tr e at m e nt p eri o d will b e c o m p ut e d f or s u bj ects r ec eivi n g I SI S 4 2 0 9 1 5
by s u m mi n g t h e a d mi ni st er e d d os e b et w e e n t h e first d os e of st u dy dr u g o n D ay  1 a n d t h e
E O T d at e or d at e of pr e m at ur e t er mi n ati o n.   T ot al d os e will b e s u m m ariz e d i n m g.
3. 2. 1. 2  Sc ori n g of Ass ess m e nt I nstr u m e nts  
m NI S + 7  
T h e m NI S + 7 c o nsists of t w o c o m p osit e sc or es: t h e NIS c o m p osit e sc or e ( m axi m u m of 2 4 4 p oi nts) 
a n d t h e m o difi e d + 7 c o m p osit e sc or e ( m axi m u m of 1 0 2. 3 2 p oi nts).    
NI S  
T h e NI S c o m p osit e sc or e c o nsist s of 4  c o m p o n e nts: 
•
Q u esti o ns t h at m ak e u p e ac h c o m p osit e ar e list e d i n t h e t a bl e b el o w . 
NI S c o m p osit e 
Q u esti o n n u m b er 
 
 
 
 
 
 
 
 
M o difi e d + 7  
T h e m o difi e d + 7 c o m p osit e sc or e c o nsists of 4 c o m p o n e nts:  
•
•
•
C CI
 
C CI
C CI
C CI
C CI
C CI


 
2 3  
o  
  
 
 
 
 
 
 
   
D u e t o t h e t esti n g al g orit h m a n d t h e M C C or e d at a e ntr y c o nv e nti o n s, r a w m o difi e d + 7 d at a  n e e d 
t o u n d er g o a pr e-pr oc essi n g st e p b ef or e t h e sc or es c a n b e d eriv e d . T h e diff er e nt pr e-pr oc essi n g 
st e ps a r e s u m m ariz e d i n t h e t a bl e b el o w. 
C o m p o n e nt  
D at a  e ntr y c o n v e nti o n / C o m m e nt  
Pr e -pr oc essi n g st e p  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
C CI
C CI


 
2 4  
 
 
  
 
 c alc ul at e d b y m ulti ply i n g 
t h e s u m of t h e 1 0 av er a g e d su bc o m p o n e nt  sc or es ( d efi n e d b el o w) b y 2. 
NI S + 7   
T h e NI S + 7 c o nsists of t w o c o m p osit e sc or es: t h e NI S c o m p osit e sc or e  ( a b ov e) a n d t h e + 7 c o m p osit e 
sc or e ( m axi m u m of 2 6. 0 4  p oi nts).  
+ 7  
T h e + 7 c o m p osit e sc or e c o nsists of 3  c o m p o n e nts: 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
C o m p o n e nt  
D at a e ntr y c o n v e nti o n / C o m m e nt  
Pr e -pr oc essi n g st e p  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
C CI
C CI
C CI


 
2 5  
 
 
 
 
  
 
 
 
  
  
 
 
 
  
 
N orf ol k Q OL -D N  
T h e N orf ol k Q OL -D N (
) c o nsists of o n e c o m p osit e sc or e ( T ot al Q OL) a n d fi v e s u b -
d o m ai n  sc or es ( p hysic al f u ncti o ni n g/l ar g e fi b er n e ur o p at h y, acti viti es of d ail y li vi n g, s y m pt o ms, 
s m all fi b er n e ur o p at h y, a n d a ut o n o mic n e ur o p at h y).  T h e sc ori n g of t h e N orf ol k Q OL -D N will b e 
c o n d uct e d acc or di n g t o t h e sc ori n g m a n u al d ev el o p e d at t h e E ast er n Vir gi ni a M e dic al Sc h o ol  a n d is 
s u m m ariz e d b el o w. 
Q u esti o ns t h at m ak e u p e ac h d o m ai n ar e list e d i n t h e t a bl e b el o w  
N orf ol k Q OL -D N D o m ai n  
Q u esti o n n u m b er  
 
 
 
 
 
 
 
 
 
 
All s y m pt o ms ( Q u esti o ns 1 t o 7 ) ar e a si m pl e i n v e nt ory of s y m pt o ms of n e ur o p at hy . E ac h of t h es e 
q u esti o n s ar e ass ess e d f or t h e f e et, l e gs, h a n ds a n d ar ms, wit h pr es e nc e of a sy m pt o m sc or e d as a 1 
a n d a bs e nc e as a 0 . T h e Qu esti o n S c or e is c alc ul at e d by s u m mi n g t h e sc or es f or t h e i n di vi d u al sit es 
f or t h e Q u esti o n, wit h t h e Q u esti o n Sc or e r a n gi n g fr o m 0 ( n o s y m pt o ms) t o 4 (s y m pt o ms i n t h e f e et, 
l e gs, h a n ds, an d ar ms) . T h e ot h er Q u esti o ns, exc e pt Q u esti o ns 3 1 a n d 3 2, ar e sc al e d o n a 5 p oi nt 
Li k ert sc al e, r a n gi n g fr o m 0 (“ N ot a pr o bl e m”) t o 4 (“ S e v er e Pr o bl e m”). I n Q u esti o n 3 1 , “ G o o d” is 
sc or e d as 0, “ V ery G o o d” is sc or e d as -1, “ Exc ell e nt” is sc or e d as -2 , “ F air” is sc or e d as 1, a n d “ P o or”  
is sc or e d as 2 . I n Q u esti o n 3 2, “ A b o ut t h e s a m e” is sc or e d a 0, “ S o m e w h at b ett er” is sc or e d a -1, 
“ M uc h b ett er” is sc or e d a -2, “ S o m e w h at w ors e” is sc or e d a 1, a n d “ M uc h w ors e” is sc or e d a 2.  
S F -3 6  
T h e S F -3 6 (v ersi o n 2) co nsists of t w o c o m p osit e sc or es, t h e P hysic al C o m p o n e nt S u m m ary sc or e a n d 
t h e M e nt al C o m p o n e nt S u m m ar y sc or e, as w ell as ei g ht d o m ai n sc or es ( p hysic al f u ncti o n, r ol e-
p hysic al, b o dily p ai n, g e n er al h e alt h, vit ality, s oci al f u ncti o ni n g, r ol e -e m oti o n al, a n d m e nt al h e alt h).   
T h e sc ori n g of t h e S F -3 6 will b e c o n d uct e d usi n g Q u ality M etrics C ertifi e d Sc ori n g S oft w ar e v 4. 5.    
N S C  
T h e N S C (v ersi o n: 0 4J a n 2 0 0 9) q u esti o n n air e c o nsists of o n e t ot al sc or e a n d fi v e d o m ai ns  (m uscl e 
w e a k n ess , s e ns ory (hy p o/l oss  of s e ns ati o n ),  s e ns or y (p ar est h esi a, h y p er s e ns ati o n ), a ut o n o mic 
(g astr o i nt esti n al ( GI) a n d uri n ar y i nc o nti n e nc e ), a n d a ut o n o mic ( n o n-GI /n o n -uri n ar y i nc o nti n e nc e )
C CI
). 
C CI
C CI


 
26 
The muscle weakness domain is divided in to four sub-domains (head and neck, chest, upper limbs, 
and lower limbs). The scoring of the NSC questionnaire is described in the Appendix. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Scoring of the C-SSRS questionnaire will be done following the scoring and data analysis guidelines 
provided by the Center for Suicide Risk Assessment at Columbia University Medical Center. 
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.  In a Mixed Model for 
Repeated Measures (MMRM) , missing data are not explicitly imputed.  Instead, all available post-
baseline assessments (within the scheduled visit windows) of the endpoint during the treatment 
period are utilized and via modelling of the within subject correlation structure, the endpoint 
treatment differences (which are adjusted to take account of missing data) are derived.  In addition 
several ‘Missing not at random’ methods are described in Section 3.3.3.2 of the statistical analysis 
plan which will be used as sensitivity analyses to impute missing visit level data. 
Missing data imputation strategies for missing assessment level data 
Two independent assessments of the primary efficacy endpoint, mNIS+7, are planned at the 
baseline visit and the Week 66 visit, and the early termination visit (for patients that terminate 
treatment early). A single mNIS+7 assessment is also planned at the Week 35 visit.  The mean of the 
two replicate assessments within visit will be used for analysis of both the baseline and Week 66 
visits (provided both visits fall in the visit window and are within 52 days of the last dose of 
medication) .  Subcomponent scores will be averaged first.  These will be referred to as the averaged 
subcomponent scores.   
At baseline and Week 66, 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 Week 35, only one assessment is performed, therefore the single subcomponent will be 
used as the averaged subcomponent score for that visit.  These values will be used in the summary 
and analysis of averaged subcomponent scores. 
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. 


 
27 
The component scores will be computed by summing the averaged subcomponent scores and the 
composite scores will be computed by summing the component scores.   
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 
missing averaged subcomponent scores will be set to equal to the mean of the patient’s other 
non-missing averaged subcomponent scores in that component.  The component score is then 
calculated. 
• 
Step 2 (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.  
• 
Step 3 (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 Randomized Set at that visit.  The component score is 
then calculated.  
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 Visit  
Imputation rule 
Before Week 35 
Randomized Set mean at baseline 
Between Week 35 and Week 66 
Week 35 placebo mean 
After Week 66 
Week 66 placebo mean 
 
Note: when imputing missing subcomponents based on placebo mean at a specific visit, the placebo 
mean is derived from on-treatment assessments only (i.e., those that were done within 52 days of 
last dose). 


 
28 
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: 
• 
Group A:  For components with multiple subcomponents except the NCT component of +7, 
imputation steps 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.  
 
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 component may be “not evaluable” 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).  These nerve conduction attributes 
are not evaluable when the tibial or fibular nerve amplitude is 0, therefore, these “not 
evaluable” results are 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) if the recorded response was classified “not 
evaluable.” After this, imputation step 1 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 Randomized Set at that visit.  
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. 


 
29 
• 
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 baseline,  the missing averaged subcomponent scores will be set to equal to the mean 
baseline averaged subcomponent score from the Randomized Set (across treatment 
groups).  
o For 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 Randomized Set at that visit. 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 Visit  
Imputation rule 
Before Week 35 
Randomized Set mean at baseline 
Between Week 35 and Week 66 
Week 35 placebo mean 
After Week 66 
Week 66 placebo mean 
 
Composite Score 
The composite scores of mNIS+7, NIS+7, modified +7, +7, and NIS will each be calculated by 
summing the imputed component scores.  If any of the component scores after imputation are 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: If any question 
is missing at baseline, the mean value for this question at baseline from the study 
population (across all treatment groups) will be used to impute the missing baseline 
question value.  For post-baseline visits during the treatment period, any missing question 
values will be imputed using the last observed or imputed question value (including baseline 
value). For the symptom domain, in the case that a patient responded on a particular 
question (Questions 1- 7) as not a having the symptom but also marked presence of the 
symptom in their feet, legs, hands, or arm, the question will be set to missing and the 
imputation rules will be followed.  
• 
Otherwise,  the total for that domain will be set to missing  
The Norfolk QOL-DN total score will be calculated by summing the imputed domain scores.  If any 
domain score after imputation is still missing, then the Norfolk QOL-DN total score will be set to 
missing. 


 
30 
The Norfolk QOL-DN individual domain and total scores will only be calculated for visits where the 
patient had a Norfolk QOL-DN assessment.  The individual domain and total scores are set to be 
missing if a patient misses the visit or does not have a Norfolk QOL-DN assessment at that visit.   
NSC Domain and Total score 
Two independent assessments of NSC are planned at the baseline visit and the Week 66 visit. A 
single NSC assessment is planned at the Week 35 visit. The mean of the two replicate assessments 
within a visit will be used for analysis of both the baseline and Week 66 visits (provided both visits 
fall in the visit window and are within 52 days of the last dose of medication). The individual 
questions scores will be averaged first. These will be referred to as the averaged question scores.  
 
At baseline and Week 66, in the event that only one NSC assessment has been performed, the single 
NSC assessment will be used in place of the mean value for that visit for the averaged question 
score.   If both of the NSC assessments are missing, the averaged question score is missing. At Week 
35, only one assessment is performed, therefore the single NSC assessment will be used as the 
averaged question score for that visit. The sub-domain and domain scores will be computed using 
the averaged question scores.  
 
Imputing Missing Assessment Averaged Question Scores   
The following imputation rule will be applied at the domain level for the sensory (hypo / loss of 
sensation), sensory (paresthesia, hyper sensation), autonomic (GI and urinary incontinence) and the 
autonomic (other than GI/urinary incontinence) domains 
• 
If at least 50% of the averaged question scores in the domain are available, the missing 
questions will be set to be equal to the mean of the non-missing averaged question scores in 
the domain. The total domain score is then calculated from the sum of the non-missing and 
imputed averaged question scores  in the domain. 
• 
Otherwise, the domain score will be considered to be missing 
 
Note for the imputation of the autonomic (other than GI/urinary incontinence) component in 
women, questions 35 and 36 are ignored and are not included in the imputation procedure 
 
The following imputation rule will be applied at the sub-domain level for the four muscle weakness 
sub-domains (head and neck, chest, upper limb, lower limb): 
• 
If at least 50% of the averaged question scores in the sub-domain are available, the missing 
averaged question scores will be set to be equal to the mean of the non-missing questions in 
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 


 
31 
Pattern of missing data For mNIS+7 and Norfolk QOL-DN composite scores, the pattern of missing 
data will be explored (see section 3.3.3.1).  Multiple imputation methods will be used to impute 
missing data in the sensitivity analyses of the primary efficacy endpoint.  Details of these methods 
are presented in Section 3.3.3.2. 
Imputation of Missing/Partial Dates The imputation of partial or missing dates for adverse events 
and prior/concomitant medications are detailed in Section 3.9.1. The imputation 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  
When change from baseline is assessed, unless otherwise specified, only patients with both baseline 
and post-baseline measurements will be included in the analyses.  If baseline or post-baseline value 
is missing, then the change from baseline will be set to missing.   
For patients who withdraw, all data will be reported prior to the point of withdrawal in line with the 
population definitions and the specified analysis.   
For data that are scheduled to be measured in duplicate or triplicate, the mean will be presented in 
tables and figures, while all measured values will appear in the listings. 
If more than the scheduled number of measurements is taken, the mean will include all replicate 
measurements. 
Analysis Visit Windows 
The efficacy and PD data will be assigned to a visit according to the visit windows in the table below.   
Efficacy assessments that occurred more than 52 days after the last dose of Study Drug will not be 
included in the efficacy analyses/summaries during the efficacy on-treatment period, even if they 
occured within one of the visit windows. PD assessments, as well as body weight, BMI, and mBMI, 
that occurred more than 28 days after the last dose of Study Drug will not be included in the PD 
analyses/summaries during the PD on-treatment period, even if they occured 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 
the study, the visits from the post-treatment evaluation period will not be used.  For mNIS+7 the 
assignment of assessments to a visit is done subcomponent by subcomponent according to the date 
the component was assessed. As long as the component is completed within the analysis window 
and within 52 days of last dose it is eligible to be used for the efficacy analyses/summaries during 
the efficacy on-treatment period. If, after subcomponents have been assigned to visit windows, 
there are two or more subcomponents of the same type within a window, the subcomponent that 
was assessed closer to the target day will be used (or the average of the two, if they are equally 
close). For  baseline and Week 66 the two assessments are averaged (provided both assessments 
are within the visit window and are within 52 days of the last dose of medication). In case of 


 
3 2  
a v er a g e d s u bc o m p o n e nts, f or t h e p ur p os e of d et er mi ni n g pr oxi mit y t o t h e visit wi n d o w t ar g et d a y , 
t h e d at e of t h e s ec o n d ass ess m e nt will b e us e d.   
Effic ac y/ P D m e as ur e  
N o mi n al Visit  ( T ar g et D a y) 
A n al ysis Visit Wi n d o w  ( D a y) 
m NI S + 7 a n d i n di vi d u al 
c o m p o n e nts, N S C, 
N orf ol k Q OL -D N  a n d 
in di vi d u al c o m p o n e nts  
 
 
 
 
 
 
S F -3 6 Q u esti o n n air e, 
P N D Sc or e  
 
 
 
 
 
B MI a n d m B MI  
 
 
 
 
 
 
 
 
 
 
 
P D P a n el ( T T R a n d 
R B P 4)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N T -pr o B N P  
 
 
 
 
 
 
 
 
 
Effic ac y a n d P D d at a c oll ect e d d uri n g t h e p ost -tr e at m e nt p eri o d will b e s u m m ariz e d wit h r es p ect t o 
t h e el a ps e d ti m e fr o m l ast d os e. Ass ess m e nts will b e sl ott e d i nt o visit wi n d o ws acc or di n g t o el a ps e d 
ti m e fr o m l ast d os e b as e d o n t h e sc h e d ul e d ass ess m e nts duri n g t h e p ost -tr e at m e nt ev al u ati o n 
p eri o d of t h e st u dy. T h e pl a n n e d wi n d o ws f or t his i nv esti g ati o n ar e s h o w n i n t h e t a bl e b el o w. 
C CI
 
C CI
C CI
C CI
C CI


 
3 3  
Effic ac y/ P D m e as ur e  
W e e ks fr o m l ast d os e  
( D a ys fr o m l ast d os e) 
A n al ysis Visit Wi n d o w ( D a y s fr o m l ast d os e) 
m NI S + 7 a n d i n di vi d u al 
c o m p o n e nts, N S C, 
N orf ol k Q OL -D N a n d 
in di vi d u al c o m p o n e nts  
 
 
 
 
 
 
 
 
S F -3 6 Q u esti o n n air e, 
P N D Sc or e  
 
 
B MI a n d m B MI  
 
 
 
 
 
P D P a n el ( T T R a n d 
R B P 4)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N T -pr o B N P  
 
 
 
 
 
 
V isit b as e d s af ety ass ess m e nts (sc h e d ul e d a n d u nsc h e d ul e d) will b e assi g n e d t o a visit acc or di n g t o 
a n al ysis visit wi n d o ws  i n t h e t a bl e b el o w, e v e n if t h ey occ ur e d wit hi n o n e of t h e visit wi n d o ws . 
Exc e pt f or pl at el et ass ess m e nts fr o m t h e l oc al l a b or at or y, l oc al l a b or at ory ass ess m e nt will n ot b e 
assi g n e d t o a visit. S af et y ass ess m e nts t h at occ urr e d d uri n g t h e s af et y p ost -tr e at m e nt p eri o d (i. e., 
m or e t h a n 7  d ays aft er t h e l ast d os e of st u dy d r u g) will n ot b e i ncl u d e d i n t h e visit b as e d s af et y 
a n al ys es  d uri n g t h e s af et y tr e at m e nt p eri o d . If t h er e ar e m ulti pl e visits wit hi n a wi n d o w, t h e visit 
n e ar est t h e t ar g et d ay will b e us e d u nl ess t w o visits ar e e q u ally n e ar, i n w hic h c as e t h e a v er a g e will 
b e us e d. N ot e t h at s af et y ass ess m e nts t h at ar e n ot utiliz e d i n t h e visit b as e d s u m m ar y t a bl es will 
a p p e ar i n listi n gs a n d b e us e d i n t h e d et er mi n ati o n of tr e at m e nt -e m er g e nt s hifts or a b n or m aliti es.   
 
S af et y e n d p oi nt  
N o mi n al Visit ( T ar g et D a y)  
A n al ysis Visit Wi n d o w ( D a y)  
Vit al Si g ns  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI


 
3 4  
S af et y e n d p oi nt  
N o mi n al Visit ( T ar g et D a y)  
A n al ysis Visit Wi n d o w ( D a y)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E C G  
 
 
 
 
 
 
 
 
R eti n ol a n d R eti n yl 
p al mit at e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C h e mistr y P a n el  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S er u m Cr e ati ni n e  
 
 
C CI
C CI
C CI
C CI
C CI


 
3 5  
S af et y e n d p oi nt  
N o mi n al Visit ( T ar g et D a y)  
A n al ysis Visit Wi n d o w ( D a y)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H e m at ol o g y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI


 
3 6  
S af et y e n d p oi nt  
N o mi n al Visit ( T ar g et D a y)  
A n al ysis Visit Wi n d o w ( D a y)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pl at el ets ( w e e kl y)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI


 
3 7  
S af et y e n d p oi nt  
N o mi n al Visit ( T ar g et D a y)  
A n al ysis Visit Wi n d o w ( D a y)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


 
3 8  
S af et y e n d p oi nt  
N o mi n al Visit ( T ar g et D a y)  
A n al ysis Visit Wi n d o w ( D a y)  
Uri n al ysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T h yr oi d P a n el  
 
 
 
 
 
 
 
 
 
 
 
I nfl a m m at or y P a n el 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P T, a P T T, I N R  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o m pl e m e nt  
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI


 
3 9  
S af et y e n d p oi nt  
N o mi n al Visit ( T ar g et D a y)  
A n al ysis Visit Wi n d o w ( D a y)  
 
 
 
 
 
 
 
 
 
I m m u n o g e nicit y 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E R G  
 
 
O p ht h al m ol o g y  
 
 
 
 
 
C -S S R S  
 
 
 
 
 
 
 
 
 
 
 
B o d y W ei g ht  
 
 
 
 
 
 
 
 
 
 
 
 
T o ass es s t h e i m p act of tr e at m e nt disc o nti n u ati o n o n s af et y p ar a m et ers, d at a fr o m visit b as e d 
s af et y ass ess m e nt m ay als o b e s u m m ariz e d wit h r es p ect t o t h e el a ps e d ti m e fr o m l as t d os e. 
Ass ess m e nt will b e sl ott e d i nt o visit wi n d o ws acc or di n g t o el a ps e d ti m e fr o m l ast d os e  b as e d o n t h e 
sc h e d ul e d ass ess m e nts d uri n g t h e p ost-tr e at m e nt e v al u ati o n p eri o d of t h e st u dy.  T h e pl a n n e d 
wi n d o ws f or t his i nv esti g ati o n ar e s h o w n i n t h e t a bl e b el o w.  Aft er 6 w e e ks of f oll o w -u p i n t h e p ost -
tr e at m e nt ev al u ati o n pl at el ets  will b e c oll ect e d as p art of t h e h e m at ol o gy p a n el. 
S af et y e n d p oi nt  
W e e ks fr o m l ast d os e  
( D a ys fr o m l ast d os e) 
A n al ysis Visit Wi n d o w ( D a y s fr o m l ast d os e) 
Vit al Si g ns  
 
 
 
 
 
 
 
 
B o d y W ei g ht  
 
 
 
 
 
E C G  
 
 
R eti n ol a n d R eti n yl 
p al mit at e  
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


 
4 0  
S af et y e n d p oi nt  
W e e ks fr o m l ast d os e  
( D a ys fr o m l ast d os e) 
A n al ysis Visit Wi n d o w ( D a y s fr o m l ast d os e) 
 
 
 
C h e mistr y P a n el  
 
 
 
 
 
 
 
 
S er u m Cr e ati ni n e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H e m at ol o g y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pl at el ets  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri n al ysis  
 
 
T h yr oi d P a n el  
 
 
I nfl a m m at or y P a n el 
 
 
 
 
 
P T, a P T T, I N R  
 
 
C o m pl e m e nt  
 
 
I m m u n o g e nicit y  
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


 
4 1  
S af et y e n d p oi nt  
W e e ks fr o m l ast d os e  
( D a ys fr o m l ast d os e) 
A n al ysis Visit Wi n d o w ( D a y s fr o m l ast d os e) 
 
 
 
C -S S R S  
 
 
 
3. 2. 1. 4  D at a S u m m ar y Pl a n  
T h e t a bl e b el o w d et ails w h at d at a will b e i ncl u d e d i n t h e s u m m ary  a n d a n alysis o ut p ut by e n d p oi nt 
t y p e, a n d w h at o ut p ut is pl a n n e d f or t h e E O T a n d w h at  o ut p ut will b e u p d at e d f or t h e E O S. D at a 
s u m m ariz e d/ a n alyz e d at E O T will b e b as e d o n  d at a c oll ect e d u p t o t h e d at e of t h e d at a c ut. It is 
p ossi bl e t h at t h e o n -tr e at m e nt s et of d at a av ail a bl e at E O S will b e diff er e nt t o t h e o n e t h at w as 
a v ail a bl e at E O T b ec a us e d at a c oll ect e d aft er t h e E O T d at a c ut m ay sl ot i nt o t h e o n -tr e at m e nt 
p eri o d. O n -tr e at m e nt o ut p ut pr ovi d e d at t h e E O T will b e u p d at e d at E O S if t h e d at a i n t h e o n -
tre at m e nt p eri o d  h as c h a n g e d  fr o m E O T. I n s el ect i nst a nc es t h e d at a f or a t y p e of e n d p oi nt t h at is 
s u m m ariz e d or a n al yz e d m a y n ot b e c o nsist e nt wit h t h e r ul es i n t h e T a bl e; s uc h exc e pti o ns will b e 
n ot e d  i n t his d oc u m e nt. N ot e: ass ess m e nts f or m NI S + 7, N S C, E R G, a n d o p ht h al m ol o gy d o n e e arly i n 
t h e tr e at m e nt p eri o d t h at ar e us e d f or b as eli n e c a n n ot als o b e us e d as a n o n-tr e at m e nt ass ess m e nt.  
E n d p oi nt t y p e  
Pr o vi d e at E O T  
U p d at e at E O S  
C o m m e nt/ d efi niti o n  
Effic ac y  
-Listi n gs 
-O n -tr e at m e nt 
s u m m ar y/ a n al ysis 
t a bl es 
-P ost -tr e at m e nt 
s u m m ar y t a bl es 
 
-Listi n gs 
-O n -tr e at m e nt 
s u m m ar y/ a n al ysis 
t a bl es 
-P ost -tr e at m e nt 
s u m m ar y t a bl es 
 
 
-O n -tr e at m e nt: First d os e d at e ≤ D at e of 
ass ess m e nt  ≤ L ast d os e d at e + 5 2 d a ys   
-P ost -tr e at m e nt: D at e of ass ess m e nt >  l ast 
d os e d at e + 5 2 d a y s 
-Visit d efi n e d b y a n al ysis visit wi n d o w  
-T h e pri m ar y i nf er e nc e f or m NI S + 7 a n d 
N orf ol k Q OL -D N will b e m a d e at E O T, e v e n if 
d at a sl ott e d i n t h e o n -tr e at m e nt p eri o d h as 
c h a n g e d b y E O S  
P D , B MI a n d 
m B MI , E R G 
-Listi n gs 
-O n -tr e at m e nt 
s u m m ar y/ a n al ysis 
t a bl es 
-P ost -tr e at m e nt 
s u m m ar y t a bl es 
-Listi n gs 
-O n -tr e at m e nt 
s u m m ar y/ a n al ysis 
t a bl es 
 -P ost -tr e at m e nt 
s u m m ar y t a bl es 
-O n -tr e at m e nt: First d os e d at e ≤ D at e of 
ass ess m e nt  ≤ L ast d os e d at e + 2 8 d a ys   
-P ost -tr e at m e nt: D at e of ass ess m e nt >  l ast 
d os e d at e + 2 8 d a ys  
-Visit d efi n e d b y a n al ysis visit wi n d o w  
 
E C G, L a b, vit al  
si g ns (i ncl u di n g 
b o d y w ei g ht) ,  
-Listi n gs 
-O n -tr e at m e nt 
su m m ar y t a bl es  
-P ost -tr e at m e nt 
s u m m ar y t a bl es 
 
-Listi n gs 
-O n -tr e at m e nt 
su m m ar y t a bl es  
-P ost -tr e at m e nt 
s u m m ar y t a bl es 
 
-O n -tr e at m e nt: First d os e d at e ≤ D at e of 
ass ess m e nt  ≤ L ast d os e d at e + 7  d a ys  
-P ost -tr e at m e nt: D at e of ass ess m e nt >  l ast 
d os e d at e + 7  d a ys  
-Visit d efi n e d b y a n al ysis visit wi n d o w  
-A b n or m al l a b a n al ys es d escri b e d i n S ecti o ns 
3. 9. 4. 1  t o 3. 9. 4. 3  i ncl u d e p ost-b as eli n e  d at a 
C CI
C CI


 
42 
Endpoint type 
Provide at EOT 
Update at EOS 
Comment/definition 
collected up to the day of the patient’s last 
contact date within the study  
AE  
-Listings 
-On-treatment 
summary tables 
-On-study summary 
tables 
-Listings 
-On-treatment 
summary tables 
-On-study summary 
tables 
-On-treatment summary tables include TEAE 
with onset dates up to the last dose date + 7 
days  
-On-study summary tables includes all TEAE in 
the study, including those with onset dates > 
7 days after last dose  
Concomitant/ 
Prior  
medications 
-Listings 
-On-treatment 
summary tables 
-On-study summary 
table 
-Listings 
-On-treatment 
summary tables 
-On-study summary 
table 
-On-treatment summary tables include 
medications taken on or after the study drug 
first dose date and up to the study drug last 
dose date +7 days  
- On study summary tables include 
medications taken after the study drug first 
dose date 
- Medications taken before the first dose date 
will be considered prior.  
Immunogenicity 
-Listings 
-On-study summary/ 
analysis tables 
-Listings 
-On-study summary/ 
analysis tables 
 
-On-study summary/analysis tables include 
post-baseline data collected up to the day of 
the patient’s last contact date within the 
study  
-Visit defined by analysis visit window 
PK 
-Listings 
-On-study summary/ 
analysis tables 
-Listings 
-On-study summary/ 
analysis tables 
 
-Summary/analysis tables include post-
baseline data collected include data collected 
up to the day of the patient’s last contact 
date within the study  
-PK parameters will be derived based data 
collected up to the patient’s last contact date 
within the study  
-PK concentration will be summarized based 
on nominal scheduled visits  
-All PK parameters will be recalculated using 
all available data at EOS 
 
 
3.2.1.5 
Multicenter Studies 
This study expects to enroll approximately 135 patients from 30 to 35 investigative sites.  For 
analyses that include investigative site, the analysis will use pooled sites.  All sites with fewer than 
two randomized patients per treatment group with non-missing baseline and Week 66 mNIS+7 
composite scores will be pooled together within country and considered a single site for analysis.  If 


 
43 
this results in any site with fewer than two randomized patients per pooled site, the smallest site 
will be pooled with the next smallest site within the same geographic region (North America, 
Europe, or South America/Australasia).  If there are no other sites in the region, no further pooling 
will be conducted. 
3.2.2 
Subject Populations Analyzed 
The following analysis populations are defined for this study: 
• 
Screened patients will be defined as those patients who signed an informed consent form. 
• 
The Randomized Set will be defined as those screened patients who received a 
randomization assignment. Results will be summarized under the treatment to which 
patients were randomized. 
• 
The Full Analysis Set (FAS) will include all randomized patients who received at least 1 
injection of Study Drug (ISIS 420915 or placebo) and who have a baseline and at least one 
post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire 
total score.  This will be the primary population for analysis of efficacy and PD outcomes. 
Results will be summarized under the treatment to which patients were randomized. 
• 
The Safety Set (SS) will include all randomized patients who received at least 1 injection of 
Study Drug.  This population will be used for analyses of all safety measures. Results will be 
summarized under the treatment which the patients received. 
• 
The Per-Protocol Set (PPS) will include the subset of the Full Analysis Set who have received 
at least 80% of the prescribed doses of Study Drug and who have no major protocol 
violations that would be expected to affect efficacy assessments. Prescribed doses of Study 
Drug mentioned above is defined as the total assigned dose in mg from the Week 1 to the 
last dose within this study, i.e. 300mg*67doses = 20100mg.   This will be a secondary 
population for efficacy and PD analyses and will be used for sensitivity purposes.  The 
detailed criteria and definitions for major protocol violations will be specified and finalized 
prior to unblinding; individual subjects will be identified as meeting the violation criteria or 
not after locking the database and prior to unblinding. Results will be summarized under the 
treatment which the patients received. 
• 
PK Set will include all subjects who are randomized and receive at least one dose of active 
Study Drug (ISIS 420915) and have at least one evaluable PK sample collected and analyzed 
with reportable result. Results will be summarized under the treatment which the patients 
received.  
• 
The Pharmacokinetic subgroup (PKS) will include the patients that participated in the PK 
subgroup who have at least one evaluable PK result.  This population will be used for 
pharmacokinetic analyses. Results will be summarized under the treatment which the 
patients received. 


 
44 
• 
The ECHO subgroup will include the subset of the Randomized Set that and qualified and 
consented for the ECHO substudy. Results will be summarized under the treatment to which 
patients were randomized.    
• 
The CM-ECHO Set 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 (whether consented or not). Results will be summarized 
under the treatment to which patients were randomized. 
• 
The TTR subgroup will consist of the subset of the Safety Set who have completed their 
Week 13 visit and are included in the interim analysis of TTR. Results will be summarized 
under the treatment to which patients were randomized. 
All primary, secondary (except GLS), and PD endpoints will be assessed on the Full Analysis Set and 
Per-Protocol Set, with the former being the basis for the primary efficacy analysis.  All safety 
assessments will be performed on the Safety Set.  PK endpoints will be assessed in the PK Set as 
applicable. 
3.2.3 
Patient Characteristics 
Patient disposition, including reasons for premature discontinuation of treatment or follow-up, 
number of patients in each analysis population (FAS, PPS, SS, PKS, ECHO Set, CM-ECHO Set), number 
and percent of randomized patients within each of the 3 randomization strata (previous treatment 
with Vyndaqel® or Diflunisal; disease stage; V30M TTR mutation) will be summarized by treatment 
group and overall for all randomized patients.  
Patient allocation by investigative site will be tabulated by treatment group and overall for the all 
screened patients. 
Protocol deviations will be listed and summarized by deviation category.   
Patient demographic characteristics, including age, sex, race, ethnicity, TTR genotype, duration of 
disease from FAP diagnosis (months), and duration from onset of FAP symptoms (months) will be 
summarized by treatment group and overall for the SS, FAS, PPS, and CM-ECHO Set and for the PK 
and ECHO subgroups. 
Baseline severity of illness, including the NIS score, mNIS+7, PND score, mBMI, BMI, weight, height, 
and NT-proBNP will be summarized by treatment group and overall for the SS, FAS, and PPS 
populations.  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. Information on familial amyloid 
cardiomyopathy (FAC) will be summarized, including FAC diagnosis (Y/N), 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. Note that the day for 
these variables will not be imputed as this was not collected on the CRF. If year is missing no 


 
45 
imputation will be performed. If month is missing and the recorded year is before the year in 
informed consent date, the missing month will be imputed to be December, otherwise it will be 
imputed as the month from the informed consent date.  
Exposure to Study Drug will be summarized for the SS by treatment duration (weeks), total volume 
(mL) and total dose administered (in milligrams, for the ISIS 420915 group only).  The reason for 
dose pause will be tabulated.  A listing summarizing for each subject the number of dose reductions 
(frequency of administered dose < protocol defined dose) and missed doses (injection not givens) 
will be provided. Doses that were were not given because the patient discontinued will not be 
summarized.  
Medical history and baseline physical examination findings will be listed. 
Medications will be coded using WHO Drug Dictionary.  The final version used will be designated in 
the clinical study report.  Prior medications, concomitant medications used while on-treatment and 
during the study  will be summarized by treatment group for the SS and the CM-ECHO Set.    
Prior and concomitant medications will be defined using the start and stop dates, and ongoing fields 
recorded in the CRFs relative to the first and last dose dates of randomised investigational 
product.   A prior medication is defined as any medication taken up to, but not including the start 
date of investigational product.  A concomitant medication is defined as any medication taken whilst 
investigational product is being taken.  A concomitant medication is started during the post-
treatment period (more than 7 days after last dose) will be considered an on-study medication but 
not on-treatment. 
Note that if either of the start dates or stop dates of prior/concomitant medication are missing, the 
worst, or most conservative, case will be considered when slotting medications (i.e. the medications 
should slot into all possible phases).  If a medication is administered pre-treatment or after first dose 
of investigation produce and no stop date/time is recorded then usage will be assumed to be 
ongoing for the remainder of the data collection periods. If a medication is stopped on-treatment or 
or after first dose and no start date/time is recorded it will be assumed that the medication was 
ongoing from prior to the start of investigational product.  If a medication has no start or stop date it 
will be assumed that the medication was ongoing from prior to the start of investigational product.  
 
If a partial date is recorded in the CRF, the following convention will be used to assign the 
medication: 
• 
if the partial date is a start date, a '01' will be used for the day and 'Jan' will be used for the 
month 
• 
if the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent on the 
month and year) and 'Dec' will be used for the month. 
The recorded partial date will be displayed in listings. 
The definitions for prior, and on-treatment and on-study concomitant medication defined relative to 
use of the investigational product are shown schematically in the diagram below.  


 
46 
 
 


 
47 
 
 
                                          On-Study 
 
CM 
Scenario 
Pre-treatment                On-treatment                                    Post-
treatment 
PM 
On-
trt 
On-
study 
1 
       x------------x  
 
Y 
N 
N 
2 
       x--------------------------------------------x 
Y 
Y 
Y 
3 
       x--------------------------------------------------------------------x 
Y 
Y 
Y 
4 
                                        x------------x  
 
N 
Y 
Y 
5 
                                        x--------------------------------------------x 
N 
Y 
Y 
6 
                                                                                                   x-----x 
N 
N 
Y 
7 
       ?------------x  
 
Y 
N 
N 
8 
                                        ?------------x  
 
 
Y 
Y 
Y 
9 
                         ?----------------------------------------------------x 
Y 
Y 
Y 
10 
 ? ---------------------------------------? 
Y 
Y 
Y 
11 
 x---------------? 
Y 
Y 
Y 
12 
                                                x---------------? 
N 
Y 
Y 
13 
                                                                                                     x------? 
N 
N 
Y 
PM = prior medication; CM – concomitant medication 
x = start/stop date/time 
? = missing date/time 
 
3.3 Primary Analysis 
3.3.1 
Primary Endpoint Definition 
There are two primary endpoints.  The primary efficacy endpoints are the change from baseline to 
Week 66 in the mNIS+7 score and in the Norfolk QOL-DN questionnaire total score. 
The mNIS+7 composite score has a maximum of 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 for the primary analysis.  
The mNIS+7 assessment is conducted at baseline (2 times), Week 35, Week 66 (2 times), and 
Week 91 (post-treatment).  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.  Visits occurred after 52 days from 
the last dose of study medication are considered part of the post-treatment evaluation period, the 
data collected in the those visits will not be included in the efficacy analysis. 


 
4 8  
T h er e ar e t w o sc h e d ul e d visits  f or e ac h of t h e t w o pri m ar y e n d p oi nts:  W e e k 3 5 a n d W e ek 6 6.  T h e 
d at a will b e assi g n e d t o W e e k 3 5 or W e e k 6 6  acc or di n g t o t h e visit wi n d o ws d efi n e d i n s ecti o n  
3. 2. 1. 3 .  
3. 3. 2  
Pri m ar y Effic ac y A n al ysis  
T h e t w o pri m ary e n d p oi nts, t h e m NI S + 7 a n d t h e N orf ol k Q OL-D N q u esti o n n air e t ot al sc or e, will b e 
t est e d usi n g a r a nki n g str at e g y wit h t h e m NI S + 7 t est e d first a n d t h e N orf ol k Q OL -D N t est e d s ec o n d.   
T h e pri m ar y effic acy a n alys es will b e t h e c o ntr ast b et w e e n t h e I SI S  4 2 0 9 1 5 3 0 0 m g gr o u p  a n d t h e 
pl ac e b o gr o u p at W e e k 6 6 fr o m a Mix e d Eff ects M o d el wit h R e p e at e d M e as ur es ( M M R M) of c h a n g e 
fr o m b as eli n e i n e ac h of t h es e t w o e n d p oi nts d uri n g t h e tr e at m e nt p eri o d .  T h e pri m ar y a n alysis will 
b e c o n d uct e d usi n g t h e F ull A n al ysis S et ( F A S).   I nt erpr et ati o n will b e m a d e i n a st e p wis e a p pr o ac h; 
s h o ul d t h e n ull hy p ot h esis, b as e d o n t h e m NI S + 7, b e r ej ect e d at a 2 -si d e d 0. 0 5 si g nific a nc e l ev el, 
t h e n t h e N orf ol k Q OL-D N q u esti o n n air e t ot al sc or e will b e t est e d.   H o w e v er, if t h e n ull h y p ot h esis 
f or t h e m NI S + 7 is n ot r ej ect e d, t esti n g f or t h e N orf ol k Q OL-D N q u esti o n n air e t ot al sc or e will b e 
c o nsi d er e d ex pl or at or y.   N o a dj ust m e nt is t h er ef or e r e q uir e d f or m ulti pl e hy p ot h esis t esti n g.  T h is 
s e q u e nti al t esti n g pr oc e d ur e f or t h e t w o pri m ar y o bj ecti v es c o ntr ols t h e ov er all Ty p e I err or r at e at 
a 2 -si d e d 0. 0 5 l ev el a n d is b as e d o n t h e m et h o d ol o gy d e v el o p e d i n D mitri e n k o, T a m h a n e a n d Wi e ns 
( 2 0 0 8). T h e pri m ary st u dy hy p ot h es es will b e f or m ally e v al u at e d at t h e ti m e of t h e e n d of tr e at m e nt 
l oc k, occ urri n g aft er all p ati e nts h a v e c o m pl et e d t h e E O T ass ess m e nts, t h e d at a b as e is l oc k e d a n d 
tr e at m e nt c o d e is u n bli n d e d. 
T h e M M R M  m et h o d will i ncl u d e fix e d c at e g oric al eff ects f or tr e at m e nt (t w o l e v els), ti m e (t w o 
l e v els), tr e at m e nt-b y -ti m e i nt er acti o n, a n d e ac h of t h e 3 r a n d o miz ati o n str atific ati o n f act ors ( e ac h 
wit h t w o l e v els).  T h e b as eli n e v al u e of t h e e n d p oi nt a n d t h e b as eli n e -by -ti m e i nt er acti o n will b e 
i ncl u d e d as fix e d c ov ari at es i n t h e m o d el.  M o d el p ar a m et ers a n d tr e at m e nt eff ects c o ul d b e 
esti m at e d by t h e f oll o wi n g ex a m pl e S A S c o d e:  
I n t his m o d el, missi n g d at a ar e n ot ex plicitl y i m p ut e d ( exc e pt f or t h e ass ess m e nt l e v el d at a 
i m p ut ati o n s p ecifi e d i n S ecti o n 3. 2. 1. 3 ).  I nst e a d, all av ail a bl e  p ost -b as eli n e ass ess m e nts of t h e 
e n d p oi nt d uri n g t h e tr e at m e nt p eri o d (w hic h f all i n t h e W e e k 3 5 a n d W e e k 6 6 visit wi n d o ws) f or 
s u bj ects i n t h e F A S ar e utilize d a n d vi a m o d elli n g of t h e wit hi n s u bj ect c orr el ati o n str uct ur e, t h e 
e n d p oi nt tr e at m e nt diff er e nc es ( w hic h ar e a dj ust e d t o t ak e acc o u nt of missi n g d at a) ar e d eriv e d.  
T h e esti m ati o n of tr e at m e nt diff er e nc es is b as e d u p o n t h e ass u m pti o n t h at t h e missi n g d at a f oll o ws 
a missi n g  at r a n d o m m ec h a nis m (i. e. t h e missi n g n ess of t h e o bs erv ati o ns m a y b e d e p e n d e nt o n t h e 
o bs erv e d o utc o m es or c ov ari at es, b ut n ot o n u n o bs erv e d o utc o m es).  
T h e u nstr uct ur e d ( 2x 2) c o v ari a nc e m o d el will b e us e d t o m o d el t h e wit hi n p ati e nt err ors, s h ar e d 
acr oss tr e at m e nts 
C CI
a n d s m all s a m pl e a dj ust m e nts t o st a n d ar d err ors a n d t ests will b e m a d e f oll o wi n g 


 
49 
the Kenward-Roger approach (Kenward, M. G. and Roger, J. H. (1997).  In the unlikely circumstance 
that there are convergence problems with the repeated measures mixed model, this will be 
explored.  For example the SCORING=4 option could be used in the PROC MIXED statement in SAS.  
This makes SAS use Fisher scoring for the first 4 iterations.  If the convergence problem cannot be 
resolved the unstructured covariance matrix will be replaced by the restricted unstructured 
covariance matrix (Type=UNR in SAS).  This also specifies an unstructured covariance matrix but with 
a different parameterization.  
The treatment contrast for both Week 35 and Week 66 will be estimated by the model, with the 
Week 66 estimate considered primary. The normality assumptions for the MMRM models will be 
formally tested using a Shapiro-Wilks test at the 0.01 significance level and assessed by inspection of 
the following plots: 
• 
Histogram of marginal studentized residuals derived from the MMRM model. 
• 
Normal probability plot. 
If the Shapiro-Wilks test assessing normality of the MMRM residuals from week 66 is statistically 
significant at the 0.01 level, formal hypothesis testing for that endpoint will be done at the 0.025 
one-sided significance level using a non-parameteric rerandomization test. Thus, the null hypothesis 
for the endpoint will only be tested using the results from the MMRM if the p-value from the 
Sharpio-Wilks test is > 0.01. 
Steps for the rerandomization test are: 
1. The MMRM detailed above will be fit using the randomized treatment and the estimated 
treatment effect (difference in least squares means between the treatment arms) at week 
66 from this analysis will be stored and will be denoted by t*. 
2. Assignment to ISIS 420915 and Placebo is randomly shuffled within each of the eight study 
strata. Note that the shuffling will be done for all patients in the FAS irrespective of whether 
their post-baseline data falls within an analysis window. The MMRM is refit but now uses 
the shuffled treatment assignment (instead of the actual assigned treatment) and the 
estimated treatment effect at week 66 from the analysis is stored. This step will be repeated 
in the event that the MMRM does not converge. 
3. Step 2 is repeated 50,000 times, where the collection of the estimated treatment effects 
under the shuffled treatment assignment defines the randomization distribution. Denote 
the treatment effect from the ith permutation of the data by ti.  
4. The p-value or the probability of observing a treatment effect as extreme as or more 
extreme than t* under the null hypothesis of no treatment difference is estimated by  
1+ ∑
𝐼(𝑡𝑖≤𝑡∗)
50,000
𝑖=1
1+50,000
, 
where I(A) is an indicator function that equals one if argument A is true, and 0 otherwise. If 
this one-side p-value is less than 0.025, the null hypothesis of no treatment difference will 
be rejected. The number of shuffled datasets may be increased depending if the simulation 
error in the estimated p-value is considered large.  


 
50 
If the rerandomization test is implemented, 95% CIs obtained by bootsrapping the data will be 
presented, with the resampling being done at the patient and not at the assessment level. A total of 
10,000 bootstrap samples will be drawn, with the CI being defined as the 2.5th and 97.5th percentile 
from the empirical distribution of the treatment effect.  
3.3.3 
Additional Analyses of Primary Endpoints 
In addition to the primary efficacy analysis, the following sensitivity analyses will be conducted on 
the FAS except where noted for each of the two primary efficacy endpoints: 
• 
Sensitivity Analysis 1 (Non-Parametric Analysis) – The non-parametric Van-Elteren test will 
also be performed for the two primary study endpoints as the sensitivity analysis.  Hodges-
Lehmann estimates of the differences between ISIS 420915 300 mg group and the placebo 
group as well as distribution-free CIs based on the Wilcoxon Rank Sum Test will also be 
provided.   
• 
Sensitivity Analysis 2 (Conservative Assessment Level Imputation) – To examine whether 
the primary analysis results are robust to the strategy for imputing missing assessment level 
data, an alternative strategy that results in a conservative estimate of the treatment effect 
will be implemented. Patients without an assessment at a visit will not have their score 
imputed for that visit. Imputation of missing baseline assessment level data will follow the 
approach detailed in Section 3.2.1.3. For patients with at least one  non-missing post-
baseline subcomponent score missing data will be imputed as follows. Missing post-baseline 
assessment level data will be imputed for the placebo group using their observed or 
imputed baseline value. Missing post-baseline assessment level data will be imputed for the 
ISIS 420915 group using the placebo mean in the Randomized population for that 
subcomponent at that visit (done after the placebo imputation).  
• 
Senstivity Analysis 3 (Excluding Assessments done at Early Termination Visits) – In order to 
examine the robustness of the primary analysis to the inclusion of premature termination 
data, the primary efficacy analysis will be repeated excluding data collected at early 
termination visits which are included in the primary analysis.  
• 
Sensitivity analyses will be performed to investigate the impact of alternative missing data 
assumptions (see sections 3.3.3.2 and 3.3.3.3). These analyses will be done on the Safety Set  
and will be labeled as: 
o Sensitivity  Analysis 4 – Multiple Imputation assuming Missing at Random 
o Sensitivity Analysis 5 – Multiple Imputation assuming Copy Increments from 
Reference 
o Sensitivity Analysis 6 – Multiple Imputation assuming Jump to Reference 
o Sensitivity Analysis 7 – Data at Withdrawal Visit Included 
• 
Sensitivity Analysis 8 (Per Protocol Set) – The primary efficacy analysis will be repeated, 
using the PPS population. 


 
51 
• 
Sensitivity Analysis 9 (Adjustment for Pooled Site) – The primary efficacy analysis will be 
repeated, but with the addition of pooled investigative site as a fixed categorical effect in 
the model. In the event that there are model convergence issues, results from this analysis 
will not be provided and will be noted in the study report. The interaction between 
treatment and pooled site will also be examined if model convergence permits. 
• 
Sensitivity Analysis 10 (Responder Analysis) – A responder analysis based on the change in 
mNIS +7 score will be conducted to examine whether improvement in response is consistent 
over a range of response thresholds.  A responder is defined as a patient whose mNIS +7 
score change from baseline to Week 66 is less than or equal to the threshold value. The 
relationship between response rate and thresolds will be summarized using a cumulative 
distribution plot. In addition, comparison of response rates for specific threshold values will 
be done. Thresholds that will be tested will include 0, 2, 4, 6, 8, 10, 15, 20, 30 points above 
the baseline value.   For each of these specific response thresholds, the response rates at 
Week 66 for both the treated group and the placebo group will be calculated and plotted 
against the response threshold.  Patients that terminate treatment early irrespective of the 
reason or had missing Week 66 data will be considered a non-responder.  The difference in 
the estimated response rate and associated 95% CI based on the Mantel-Haenszel approach 
will be presented for each threshold.  
• 
Sensitivity Analysis 11 (HRDB and Nerve Conductions Scored Using Points and NIS-Sensation 
Excluded) – Additional sensitivity analysis on mNIS+7 composite score will be performed 
using the points (instead of Normal Dev) from heart rate deep breathing and nerve 
conduction and also removing the sensation part of the NIS.  
• 
Sensitivity Analysis 12 (HRDB Component Excluded) – Additional sensitivity analysis on 
mNIS+7 composite score will be performed, with HRDB not included as a component. HRDB 
will also be descriptively summarized for the group that has least one non-imputed HRDB 
score during efficacy treatment period and a non-imputed score at baseline.  
• 
Sensitivity Analysis 13 (Modified mNIS+7 Baseline Definition) – As outlined in Section 
3.2.1.1, the primary efficacy analysis for mNIS+7 will be repeated using a modified baseline 
definition, defined as the average of two assessments taken within 60 days prior to the first 
dose of Study Drug.   
Descriptive statistics will be provided for absolute values and change from baseline for Norfolk QOL-
DN questionnaire total score by study visit. For mNIS+7 descriptive statistics by visit will be provided 
for absolute values, change from baseline and percent change percent from baseline. Data collected 
outside the analysis windows will be summarized.      
3.3.3.1 
Description of the Missing Data 
To examine the nature of missing data, cohorts of subjects will be defined based on the scheduled 
assessments that were completed.   


 
52 
For each of the primary endpoints there will be 3 cohorts of based on the FAS (based on the post-
baseline data included in the primary analysis): 
1. Subjects who have a Week 35 assessment only 
2. Subjects who have a Week 66 assessment only 
3. Subjects who have Weeks 35 and 66 assessments 
For each endpoint plots will be produced, illustrating the mean change from baseline over time in 
each of the cohorts.  These will be based on the observed data for each of the cohorts.  The trends 
over time will be visually compared across cohorts to explore patterns of missing data. Of particular 
interest is  the group that has complete follow-up data available (i.e. have Weeks 35 and 66 
assessments) and the group with a Week 35 assessment only.  This can help indicate if subjects 
show any sign of decline in their efficacy prior to dropping out from the study.   
3.3.3.2 
Multiple Imputation Methodology 
For each of the primary endpoints, sensitivity analyses will be performed in the Safety Set using 
multiple imputation methods based on pattern mixture models.  First, a repeated measures 
Gaussian model will be fitted to the data using a Bayesian approach, with non-informative priors for 
the mean and variance-covariance matrix to provide a joint posterior for the parameters in this 
model.  The repeated measures Gaussian model will include separate mean profiles for each 
treatment group and the same covariates as those in the primary MMRM analysis. 
Independent samples will then be drawn from the posterior distributions for the mean and variance-
covariance matrix to provide inputs into an imputation model.  For each subject with missing data, 
these sampled values of the parameters for mean vectors and the variance- covariance matrices 
specify a joint distribution for their observed and unobserved outcome data. 
The post-withdrawal part of each pattern-specific distribution will be modelled using three different 
approaches discussed below.  This imputation model will have the same covariates as those in the 
primary MMRM analysis. 
Based on this imputation model, a single set of data will be sampled for the missing data based on 
the distribution for the subject’s missing data conditional upon their observed data. 
The post-withdrawal part of each pattern-specific distribution will be modelled using these three 
approaches: 
1. Missing at Random (MAR) approach.  
The means and variance-covariances following withdrawal are chosen to reflect the subject’s 
own treatment group.  This approach should provide similar numerical results to the primary 
analysis. 
2. Copy Increment from Reference (CIR) approach.  
The CIR approach is detailed in Carpenter et al. (2013) and addresses a potential pattern of 
informative missingness where the assumption is that the active Study Drug halts or slow 


 
53 
disease progression, and the disease progresses after treatment is discontinued. In CIR 
missing data in the placebo group will be imputed under a within treatment arm MAR 
assumption. For a patient in the active treatment group their mean profile (i.e. mean 
increments) will track that of the placebo group, but starting from the benefit obtained. 
3. Jump to reference (J2R) approach. 
The J2R approach is detailed in Carpenter et al. (2013) and is an extemely conservative 
imputation approach that assumes that a patient receiving active Study Drug does not sustain 
benefit after discontinuing study treatment. In J2R missing data in the placebo group will be 
imputed under a within treatment arm MAR assumption. For a patient with missing data in 
the active treatment group their mean response distribution is set to equal that of the 
placebo group.  
For each imputation method used, at least 5000 imputed datasets will be generated. The imputed 
observations in each dataset will be checked to ensure they are within the possible change from 
baseline range for the particualr subject they belong to. If a dataset contains out-of-range values, it 
will be discarded and a new dataset will be generated until there are 5000 datasets which contain 
no out-of-range values.  Each of 5000 imputed data set will then be analyzed using simple analysis of 
covariance (ANCOVA) model at Week 66 and the resulting treatment differences and their standard 
errors will be combined using Rubin’s rules.  The ANCOVA model will include fixed effects for 
treatment (two levels), and each of the 3 randomization stratification factors (each with two levels) 
with baseline value of the endpoint as the covariate.  Note that in these analyses efficacy 
assessment that are within the analysis window but more than 52 days after last dose will be 
included. This is different from the primary analysis, where data after 52 days from last dose is 
excluded.The number of imputed datasets may be increased after review of results if the simulation 
error is considered large.  
A random seed to be used by a random number generator with value of 2855 will be used to initiate 
data imputation for all three methods.  
3.3.3.3 
Sensitivity Analysis Using Data at Withdrawal Visit 
The primary outcome variable, modified Neuropathy Impairment Score +7 (mNIS+7) score, is 
measured on treatment at baseline, Week 35 and Week 66.  The primary analysis is the difference 
between the active treatment and placebo at week 66 based on a repeated measures model for 
Week 35 and Week 66 data using treatment-by-time 2*2 factorial, baseline-by-time and strata 
covariate fixed effects, and an unstructured 2*2 covariance matrix shared across treatments.  The 
analyzed response is difference from baseline in mNIS+7, but the treatment difference will be the 
same as if the absolute value of mNIS+7 were analyzed instead, since baseline-by-time covariate is 
included in the model. 
In order to include the values of mNIS+7 at withdrawal visit in the analysis the following model is 
fitted as a sensitivity analysis in the Safety Set.  Care needs to be taken with its interpretation as 
these withdrawal visit measurements may be extreme.  The absolute value of mNIS+7, and not 
change from baseline, will be used as response.  This is done for simplicity of expression of the 


 
5 4  
m o d el a n d m a k es n o diff er e nc e t o t h e r es ults.  T h e f oll o wi n g m o d el is e q ui v al e nt t o t h e pr evi o us 
pri m ar y a n alysis m o d el w h e n t h er e ar e n o wit h dr a w al visit d at a.   T h e o nl y diff er e nc e will c o m e fr o m 
t h e i ncl usi o n of t h e a d diti o n al d at a fr o m exit visits.  If str at a h a d b e e n cr oss e d wit h ti m e or str at a 
excl u d e d fr o m t h e pri m ary a n al ysis t h e n t h ey w o ul d b e al g e br aic ally i d e ntic al.  T h e m o d el is si m pl y a 
r e-ex pr essi o n of t h e pri m ary a n al ysis m o d el t h at all o ws o n e t o i ncl u d e d at a m e as ur e d at ti m es ot h er 
t h a n W e e ks 3 5 a n d 6 6.  
T o i m pl e m e nt t his m o d el, 3 ti m e p ar a m et ers s h o ul d b e d efi n e d as f oll o ws: 
C CI
 
C CI
C CI


 
55 
The other primary endpoint, Norfolk QOL-DN, will also be analyzed using the methods described in 
this section. 
3.3.4 
Subgroup Analyses of Primary Endpoints 
Subgroup analyses will be conducted for each of the two primary efficacy endpoints in the FAS.  
Subgroups defined by the following variables will be evaluated: 
• 
V30M TTR mutation (Yes, No) 
• 
Age (< 65 years old, ≥ 65 years old) 
• 
Race (White, non-White) 
• 
Sex (Male, Female) 
• 
Region (North America, Europe, South America/Australasia)  
• 
Previous treatment with Vyndaqel® or Diflunisal (Yes, No) 
• 
Disease stage (Stage 1, Stage 2) 
• 
CM-ECHO Set (Included, Not included) 
The MMRM for the change from baseline with include fixed categorical effects for treatment (two 
levels), time (two levels), each of the 3 randomization stratification factors (each with two levels), 
treatment-by-time interaction, treatment-by-subgroup interaction, and treatment-by-time-by-
subgroup interaction.  The baseline value of the endpoint and the baseline-by-time interaction will 
be included as covariates in the model.  The treatment-by-subgroup interaction at each timepoint 
will be tested at the significance level of 0.10.  Treatment group differences will be evaluated within 
each category of the subgroup, regardless of whether the interaction is statistically significant.   
3.4 Secondary Analyses 
Secondary analyses include the analysis of secondary endpoints and pharmacodynamic analyses. 
3.4.1 
Secondary Efficacy Endpoint Definitions 
Secondary efficacy endpoints are: 
• 
Change from baseline to Week 66 in the Norfolk QOL-DN questionnaire symptoms domain 
score (Stage 1 patients only) and the Norfolk QOL-DN questionnaire physical 
functioning/large fiber neuropathy domain score (Stage 2 patients only) 
• 
Change from baseline to Week 65 in the Modified Body Mass Index (mBMI) 
• 
Change from baseline to Week 65 in the Body Mass Index (BMI)  
• 
Change from baseline to Week 66 in the NIS 
• 
Change from baseline to Week 66 in the modified +7 


 
56 
• 
Change from baseline to Week 66 in the NIS+7 
• 
Change in GLS by ECHO from baseline to Week 65 in the Randomized Set, ECHO subgroup 
and in the CM-ECHO Set  
Treatment group differences will be evaluated using the same method as the primary efficacy 
analysis (MMRM described in Section 3.3.2).  These analyses will be conducted on both the FAS and 
the PPS populations.  The analysis for GLS will be specified in the ECHO SAP. 
The normality assumptions for the MMRM will be assessed for each of the secondary endpoints by 
inspecting the following plots: 
• 
Histogram of marginal studentized residuals derived from the MMRM model. 
• 
Normal probability plot. 
The non-parametric Van-Elteren test may be performed as a sensitivity analysis, if deemed 
necessary.  Hodges-Lehmann estimates of the differences between ISIS 420915 300 mg group and 
the placebo group as well as distribution-free confidence intervals based on the Wilcoxon Rank Sum 
Test will also be provided.   
3.4.2 
Pharmacodynamic Endpoint Definitions  
Pharmacodynamic endpoints are: 
• 
Change and percent change from baseline to Week 65 in TTR level 
• 
Change and percent change from baseline to Week 65 in RBP4 level. 
Analyses of the pharmacodynamic endpoints will be evaluated using the same method as the 
primary efficacy analysis (MMRM  described in Section 3.3.2).  All pharmacodynamic analyses will be 
conducted on both the FAS and the PPS. 
In addition the proportion of subjects with percentage decrease from baseline in plasma 
transthyretin (TTR)  60% will be summarized by treatment group at each visit. 
3.5 Tertiary Analyses 
The tertiary efficacy analyses will assess whether ISIS 420915 is superior to placebo as measured by 
the following endpoints: 
• 
Change from baseline to Week 65 in the SF-36 in the Physical Component Summary score, 
the Mental Component Summary score, and mental health domain score.   
• 
Change from baseline to Week 66 in the individual components of the NIS score (cranial 
nerves, muscle weakness, reflexes, and sensory) 
• 
Change from baseline to Week 66 in individual components of the modified +7 score (heart 
rate to deep breathing, nerve conduction, heat-pain sensory, and touch-pressure sensory)   


 
57 
• 
Change from baseline to Week 66 in individual components of the +7 score (heart rate to 
deep breathing, nerve conduction and vibration detection threshold) 
• 
Change from baseline to Week 66 in the +7 score  
• 
Change from baseline to Week 66 in individual domain scores of the Norfolk QOL-DN 
(physical functioning/large fiber neuropathy, symptoms, activities of daily living, small fiber 
neuropathy, and autonomic neuropathy) 
Analyses of the tertiary endpoints will utilize the MMRM described in Section 3.3.2.  All tertiary 
analyses will be conducted on the FAS (Note that the study protocol specified these endpoints 
would additionally be assessed in the PPS). 
Similar to the primary endpoints, by-visit descriptive statistics will be provided for the individual 
mNIS+7 components, Norfolk QOL-DN questionnaire domain scores, PD assessments, and SF-36 
domain scores.  At the end of study, the summaries will be updated to include the Post-Treatment 
follow-up visits if supported by adequate data. 
3.6 Exploratory Analyses 
Exploratory endpoints include the following: 
• 
Change from baseline in echocardiogram parameters (except GLS) in the Randomized Set, 
ECHO subgroup and in the CM-ECHO Set 
• 
Change and percent change from baseline in NT-proBNP in the FAS, ECHO subgroup and in 
the CM-ECHO Set 
• 
Change from baseline in the log-transformed NT-proBNP values in the FAS, ECHO subgroup 
and in the CM-ECHO Set 
• 
Shift table from baseline in PND score in the FAS and in the PPS 
• 
Change from baseline in NSC total score in the FAS and in the PPS 
• 
Change from baseline 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 in the 
PPS 
• 
Proportion of patients with at least 60% reduction in TTR in the FAS and in the PPS 
Echocardiogram parameters, NSC (total and individual domains), and NT-proBNP (log-transformed) 
will be summarized and statistically analyzed using the MMRM described in Section 3.3.2.  Summary 
statistics will be used to summarize the other exploratory endpoints.   
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 summarised or analysed. Similarly for questions 20-29 the location is only 
listed. Questions 31-34 are of particular intereste and therefore the number and percentage of 
patients responding 0 (No), 1 (slight +), 2 (moderate ++) or 3 (severe +++) will be presented. 


 
58 
The ECHO data analysis will be conducted by CICL. 
Note: retinol and retinyl palmitate are specified as exploratory endpoints in the protocol. These 
endpoints are considered safety endpoints and therefore will be summarized with safety laboratory 
paratemers. 
3.7 Analysis of the PD and Primary Efficacy Endpoints Relationship 
The relationship between TTR and both primary endpoints will be explored in the FAS and the PPS 
among the subset with an assessment within the Week 66 analysis window. For each of the primary 
endpoints, a scatterplot will be provided with change from baseline to Week 66 in the primary 
endpoint on the y-axis and change from baseline in TTR on the x-axis. Change from baseline in TTR 
will be represented by the area under the curve (AUC), and calculated using the following formula 
∑[(𝑦𝑣+ 𝑦𝑣−1)×(𝑡𝑣−𝑡𝑣−1)×0.5] −𝑦0×(𝑡𝑉−𝑡0)
𝑉
𝑣=1
 
where 𝑦𝑣 is the TTR concentration from baseline to visit 𝑣 on day 𝑡𝑣,, 𝑣= 0, … 𝑉, with 𝑣= 0 
corresponding to baseline. 
 A four parameter Emax model will be fit to this data to characterize the relationship. If the Emax 
model does not converge, other models will be explored.   
An additional investigation will be performed based on the categorization of the AUC TTR data. 
There will be a total of five categories. The first category will include patients in the placebo group. 
The other categories is for the ISIS 420915 group, where categories are defined based on quartiles 
of the AUC for change from baseline in TTR. Change for baseline to Week 66 for both primary 
endpoints will be summarized by TTR category. An analysis of covariance model will be fit with the 
change from baseline in the efficacy endpoint as the dependent variable, and TTR category, baseline 
value of the primary endpoint, and randomization factor as explanatory variables. The estimated LS 
difference between the separate ISIS 420915 TTR categories and the placebo category will be 
presented.  
3.8 Pharmacokinetic (PK) and Immunogenicity (IM) Analysis 
Pharmacokinetic endpoints include the following: 
• 
To evaluate the plasma trough levels of ISIS 420915 in all evaluable patients  
• 
To evaluate the plasma pharmacokinetic parameters of ISIS 420915 in a subset of evaluable 
patients (PK subgroup). 
Immunogenicity endpoints include the following: 
• 
To evaluate sample IM status [confirmed positive, negative or unevaluable and, when 
applicable, titer of anti-ISIS 420915 antibodies (ADA)] before, during, and after treatment 
with ISIS 420915 or placebo in all evaluable patients 


 
59 
• 
To evaluate subject IM status (positive, negative or ‘unknown’) and its characteristics if 
applicable (onset, duration, peak titer, etc.) 
Plasma samples will be collected at protocol designated times for ISIS 420915 plasma 
pharmacokinetic and immunogenicity assessments from patients receiving either ISIS 420915 300 
mg or placebo treatment.   
3.8.1 
Plasma Pharmacokinetics 
Pharmacokinetic analysis will be performed on two separation occasions: after all patients have 
completed treatment of ISIS 420915 (EOT) and at the end of the study (EOS). 
3.8.1.1 
Plasma Concentration Data 
Plasma concentrations of ISIS 420915, along with the scheduled (nominal) and actual sampling times 
(i.e., time from SC dosing) will be listed for each evaluable patient by treatment, actual dose, 
gender, subject immunogenicity (IM) status, and study day.  Plasma concentrations below the lower 
limit of quantification (LLOQ) will be indicated by “BLQ”.  Percent differences between nominal and 
actual dose, as well as between scheduled and actual sampling times will also be listed for all 
patients.   
For all patients who receive ISIS 420915 treatment, ISIS 420915 plasma trough and post-treatment 
concentrations will be summarized using descriptive statistics by dose, study day, and scheduled 
time point, without and with stratification by IM status (see Section 3.8.2).  ISIS 420915 plasma 
concentrations from the PK subgroup will also be similarly summarized.  For the purpose of 
calculating typical summary descriptive statistics (n, mean, standard deviation (SD), standard error 
(SE), %CV, geometric mean, geometric %CV, median, minimum, and maximum) for plasma 
concentrations, all BLQ values will be set to zero.  Mean plasma concentrations that are below the 
LLOQ  will be presented as BLQ, and the SD, SE, and %CV will be reported as not applicable.  Other 
stratifications may also be performed if deemed warranted to properly interpret the 
pharmacokinetic analysis. Samples will be excluded from descriptive statistics if there are large 
deviations between scheduled and actual sampling times (percent difference between scheduled 
and actual sampling time greater than 30%), or large deviations between actual dose and nominal 
dose (percent difference between nominal and actual dose greater than 30%).  Any samples 
excluded from the summary descriptive statistics, if deemed necessary, will be listed separately 
along with the reason for exclusion. 
For all evaluable patients, ISIS 420915 plasma trough (predose) and post-treatment concentrations 
versus time (actual) profiles from Study Day 1 to 631 for each individual patient, as well as 
corresponding mean (±SD) plasma concentration versus time (scheduled) profiles will be presented 
graphically on linear and semilogarithmic scales, without and with stratification by subject 
immunogenicity status (see Section 3.8.2).    For the PK subgroup only, ISIS 420915 plasma 
concentration versus time (actual) profiles from Study Day 1 to 3, from Study Day 240 to 247, and 
from Study Day 449 to 456, for each patient, as well as corresponding mean (±SD) plasma 
concentration versus time (scheduled) profiles (by treatment), will be presented graphically on 


 
60 
linear and semilogarithmic scales, without and with stratification by subject immunogenicity status 
(see Section 3.8.2).  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. 
3.8.1.2 
Plasma Pharmacokinetic Parameters 
For ISIS 420915 treated patients only, non-compartmental pharmacokinetic analysis of ISIS 420915 
will be carried out on each evaluable individual patient data using Phoenix WinNonlin version 6.3 or 
higher (Pharsight Corporation, Mountain View, CA) to determine plasma pharmacokinetic 
parameters.  For calculation of PK parameters, all BLQ values will be set to zero.   
For the PK subgroup (ISIS 420915 treated) only, the following plasma PK parameters will be 
calculated (when applicable and possible) based on actual sampling times: 
• 
Cmax (µg/mL):  the maximum observed drug concentration in plasma.  Calculated for dosing 
on Study Days 1, 240, and 449. 
• 
Tmax (hr):  the time at which Cmax occurs.  Calculated for dosing on Study Days 1, 240, and 
449. 
• 
AUC0-24hr (µg•hr/mL):  areas under the plasma concentration-time curve from zero time (pre-
dose) to 24 hours after the SC administration will be calculated using the linear trapezoidal 
rule for dosing on Study Days 1, 240, and 449.  
• 
AUC0-48hr (µg•hr/mL):  areas under the plasma concentration-time curve from zero time (pre-
dose) to 48 hours after the SC administration will be calculated using the linear trapezoidal 
rule for dosing on Study Day 1 only. 
• 
AUC0-72hr (µg•hr/mL):  areas under the plasma concentration-time curve from zero time (pre-
dose) to 72 hours after the SC administration will be calculated using the linear trapezoidal 
rule for dosing on Study Days 240 and 449 only. 
• 
AUC0-168hr (AUC0-) (µg•hr/mL): partial AUC from time zero to 168 hr (dosing interval) will be 
calculated using the linear trapezoidal rule.  This parameter will only be calculated for 
dosing on Study Days 240 and 449 only. 
• 
MRT0-24hr (hr): mean residence time (MRT) from time zero to 24 hours after the SC 
administration will be calculated from the equation, MRT0-24hr = AUMC0-24hr /AUC0-24hr where 
AUMC0-24hr is the area under the first moment plasma concentration-time curve from time 
zero to 24 hours after the SC administration.  This parameter will be calculated for dosing on 
Study Day 1, 240, and 449.  This parameter will be calculated and reported mainly as an 
index measure to reflect the expected initial rapid disposition of ISIS 420915 from plasma to 
tissues shortly after dosing.  
• 
CL0-24hr /F (L/hr):  Plasma clearance will be calculated from CL0-24hr/F= Actual Dose/AUC0-24hr 
for dosing on Study Day 1, 240, and 449. 


 
61 
• 
CLss/F (L/hr):  Plasma clearance at steady-state will be calculated from CLss/F = Actual 
Dose/AUC0-168hr for dosing on Study Days 240 and 449 only. 
• 
Vz/F (L):  Apparent volume of distribution in the terminal phase will be calculated from Vz/F 
= CLss/F/ λz  for dosing on Study Day 449 only.  Note:  calculation of this parameter may not 
be possible in any ISIS 420915 treated patients rolling into an open label extension study. 
For all evaluable patients (including subjects participating in the PK subgroup) receiving active study 
drug (ISIS 420915), the following plasma PK parameters may be calculated (when applicable and 
determinable) based on actual sampling times at the discretion of the pharmacokineticist:  
• 
t½λz (day):  the plasma disposition half-life associated with the apparent terminal elimination 
phase may be calculated from the equation, t1/2λz = 0.693/λz, based on any evaluable post-
treatment data with scheduled collections on Days 491, 533, and 631.  A minimum of three 
data points in the elimination phase will be used to define z, and the correlation of 
determination values (r2) have to be at or greater than 0.8 for the estimate to be accepted.  
Note: if quantifiable data is only available from just 2 time points or r2< 0.8, this parameter 
may still be determined at the discretion of the pharmacokineticist and will be flagged as 
such in the clinical study report.  Note:  calculation of this parameter may not be possible in 
any ISIS 420915 treated patients rolling into an open label extension study. 
• 
Ctrough ave, Day 29-85 (ng/mL): average plasma trough concentrations between Days 29 to 85 
(Weeks 5 to 13). 
• 
Ctrough ave, Day 155-240 (ng/mL):  average plasma trough concentrations between Days 155 to 240 
(Weeks 23 to 35). 
• 
Ctrough ave, Day 365-449 (ng/mL):  average plasma trough concentrations between Days 365 to 449 
(Weeks 53 to 65). 
Plasma pharmacokinetic parameters will be listed by dose, subject ID, gender, subject IM status, and 
study day; and appropriately summarized (separately for the PK subgroup and all evaluable ISIS 
420915 treated patients) using descriptive statistics (n, mean, SD, SE, %CV, geometric mean, 
geometric %CV, median, minimum, and maximum) by study day.  Additionally, subject IM status 
stratified (see Section 3.8.2) plasma pharmacokinetic parameters will be similarly summarized (again 
separately for the PK Subgroup and all evaluable ISIS 420915 treated patients).  Other stratifications 
may also be performed if deemed warranted at the discretion of the pharmacokineticist and/or 
biostatistician. 
Exposure-response relationships between selected pharmacodynamic (including but not limited to 
TTR level, mNIS+7 and Norfolk QOL-DN score) and pharmacokinetic measures (including but not 
limited to plasma trough concentrations) may also be explored (including with and without 
stratification by IM status), where appropriate. 
3.8.2 
Immunogenicity (IM) Analyses 
Samples collected at predose on Days 1, 29, 85, 197, 323, and 449 and anytime on Day 631, 
including early termination and unscheduled samples for IM assessment will be analyzed for anti-
ISIS 420915 antibodies (ADA).    However, plasma samples collected at other time points (for PK 


 
62 
purposes) may also be potentially evaluated if deemed of further interest and warranted by the 
pharmacokinetic scientist.  An evaluable sample will be designated ‘IM positive’ based on both 
positive screening and confirmation assay results (i.e., confirmed positive result), and otherwise will 
be deemed ‘IM negative’.  Sample IM results (screen positive/negative, confirmed positive/negative 
or unevaluable, and when applicable, titer of anti-ISIS 420915 antibodies) before, during, and after 
treatment with study drug (ISIS 420915 or placebo) (sample IM status) will be listed by treatment 
and dose.   
Study subjects will be given ‘IM positive’ status if they have at least one confirmed positive sample 
result at any time during the treatment or post-treatment evaluation periods.  Study subjects will be 
given ‘IM negative’ status if all evaluated IM sample results during the treatment and post-
treatment evaluation periods are IM negative and they have at least one evaluable IM result 
collected post study drug treatment.  Otherwise, a study patient will be given ‘unknown’ IM status.   
Subject IM results will be listed by treatment and dose for all evaluable patients, which will include 
but may not be limited to: subject IM status (positive, negative or unknown), the study day 
associated with the first positive IM status emerged (Tfirst, i.e., onset of ADA development), the last 
positive IM status observed (Tlast), the time of last evaluable IM sample collected (Tlast sampling), peak 
titer, and time to reach peak titer. The onset of ADA and time to reach peak titer will be calculated 
by: 
• 
Onset in days = The date of first sample has “positive” sample IM status - first dose date +1;  
• 
Time to reach peak titer in days = The date of first peak titer observed- first dose date +1;  
Other immunogenicity data analysis (e.g. classification as transient  or persistent status for IM 
positive subjects) if there is sufficient number of patients with transient IM status. Transient and 
Persistent ADA definitions are defined below and based on Shankar et al. (2014). 
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 will be 
considered persistent unless shown to be undetectable at a later time) or 
• 
Treatment-induced ADA detected at two or more sampling time points during the treatment 
(including follow-up period if any), where the ﬁrst and last ADA-positive samples 
(irrespective of any negative samples in between) are separated by a period less than 16 
weeks, and the subject’s last sampling time point is ADA-negative. 
Persistent ADA response will be defined as: 
• 
Treatment-induced ADA detected at two or more sampling time points during the treatment 
(including follow-up period if any), where the ﬁrst and last ADA-positive samples 
(irrespective of any negative samples in between) are separated by a period of 16 weeks or 
longer or 
• 
Treatment-induced ADA detected only at the last sampling time point of the study 
treatment period or at a sampling time point with less than 16 weeks before an ADA-
negative last sample. 


 
63 
 
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, 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, and incidence and incidence rate for being transient or persistent will be appropriately 
summarized. Furthermore, onset, titer over time, and peak titer of the ADA response, 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 at the discretion of 
the designated study pharmacokineticist and/or statistician (e.g., summarized at each evaluated 
study time point and overall; summarized by observed peak titer values from the individual IM 
positive subjects; etc.).    
In addition to PK assessments (Section 3.8.1), selected efficacy (Sections 3.3 to 3.6) and safety 
(Section 3.8) assessments will also be further stratified by subject IM status (i.e., subject 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.  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.   
Efficacy measures to be stratified by subject 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 subject IM status will 
include but may not be limited to AEs, and lab tests for hematology and kidney functions. 
3.9 Safety Analyses 
All safety analyses will use the Safety Set unless otherwise specified.   
Safety endpoints include the following: 
• 
Adverse events 
• 
Vital signs and weight 
• 
Physical examination 
• 
Clinical laboratory tests 
• 
Urinalysis 
• 
ECG 
• 
Ophthalmology and ERG examinations 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Thyroid panel 


 
64 
• 
Inflammatory panel 
• 
Coagulation 
• 
Complement 
• 
Immunogenicity.  
For the analysis that will be performed after all patients have completed their EOT assessment,  AE 
tables will include events with onset date up to seven days after last doset. An additional summary 
table of events while on-study  (“summary of all TEAEs by PT and SOC”) will be created including all 
AEs recorded, even if onset date is more than 7 days after last dose. Unless noted otherwise, 
denominators for all tables will be number of subjects in the SS.  
 
For visit based safety endpoints including laboratory assessments and vital signs, the analyses will 
use analysis visit windows.  
3.9.1 
Imputation of Missing/Partial Dates for Adverse Event 
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. 
3.9.2 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as adverse events that first occurred or 
worsened after the first dose of Study Drug. An AE with a completely missing start date will be 
assumed to be treatment emergent. 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 TEAE, the severity level of the event (mild, moderate, or severe) will be determined 
by physician opinion.  If the maximum severity of the adverse event is greater than the baseline 
severity, or if the onset date/time is the same as or after the date/time of the first dose of Study 
Drug, 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: 
 


 
65 
• 
The first AE record occurs prior to the first dose, the second AE record occurs on or after the 
first dose, and the severity increases: Only the second record will be counted as treatment-
emergent.  
• 
The first AE record occurs prior to the first dose, the second AE record occurs on or after the 
first dose, and the severity decreases: Neither record will be counted as treatment-
emergent. 
• 
Both records occur on or after the first dose: 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.  
The following categories of AEs will be summarized by treatment group: all TEAEs; TEAEs leading to 
early discontuation from Study Drug or from study; and serious adverse events.  The percentages of 
patients reporting the adverse event will be summarized by MedDRA System Organ Class (SOC) and 
Preferred Term (PT), sorted by SOC alphabetically and then by decreasing frequency of PT within 
SOC.   
Summaries of related TEAEs, TEAEs by maximum severity, TEAEs during the safety treatment period, 
and TEAEs grouped by time from first dose to event onset (< 6 months, ≥ 6 months to < 12 months, 
≥ 12 months) will also be provided.   
All TEAEs will be summarized for subgroups defined by the following variables: Age, Sex, Race, 
Region, CM-ECHO Set, V30M TTR mutation, previous treatment with Vyndaqel® or Diflunisal, 
disease stage. 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.   
A listing will be provided stating which subjects 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 subjects with these adverse events will be 
displayed split by AE category and treatment group.  TEAEs of special interest and other TEAE of 
interest will also be summarized for patients in the CM-ECHO Set. Statistical comparison between 
treatment groups will be done for AEs of special interest and other AEs of interest using the risk 
difference (ISIS 420915 – Placebo) and associated 95% CI.   
3.9.2.1 
Adverse Events of Special Interest (AESI) 
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: 


 
66 
AESI 
Definition 
Ocular adverse events 
related to vitamin A 
deficiency 
AE with 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 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 the SMQ: Acute renal failure 
 
3.9.2.2 
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 with HLT:  Administration site reaction NEC 
Flu-like symptoms 
• AE with PT Influenza like illness; or 
• AE with PT Pyrexia (or Feeling hot or Body temperature increased) plus at 
least one of the following symptoms: 
1. Chills 
2. Myalgia 
3. Arthralgia 
4. Malaise 
5. Fatigue 
6. Headache 
7. 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 with SOC:   Nervous system disorders 
Haemorrhages 
AE within the SMQ: Heamorrhages 
Complement activation 
AE within SMQ: Hypersensitivity 


 
67 
Other AEs of interest 
Definition 
Reduced thryroxine 
AE within SMQ: Hypothyroidism 
For haemorrhages results will be further classified by type of event, using the following categories: 
actual bleeds, hematomas/subdermal bleeds, investigations SOC (test result), and DIC, TTP. Events 
classified as actual bleeds or hematomas/subdermal bleeds will be further categorized by whether 
the event occurred at injection site or not at injection site.  
3.9.2.3 
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. If yes, then establish if the preferred terms match the ones listed in 
the LCRIS 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 percent of patients in each treatment group 
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. 
3.9.2.4 
Flu-Like Reactions  
The following MedDRA preferred terms are determined by the Sponsor’s Pharmacovigilance 
personnel to be the flu-like reactions: 
• 
Influenza like illness 
• 
Pyrexia (or Feeling hot or Body temperature increased) plus at least two of the following 
symptoms: 
1. Chills 
2. Myalgia 
3. Arthralgia 


 
68 
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. 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 percent of patients in each treatment experiencing flu-like reactions will be 
tabulated.  
Percentage of injections leading to flu-like reactions will also be summarized. 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.  
3.9.3 
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 values at each visit, change and percent change from 
baseline to each visit in vital signs and weight will be summarized by treatment group.  No statistical 
comparisons between treatments will be performed for this summary. 
All vital signs and weight will be listed.  Physical examination findings will also be listed. 
3.9.4 
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 values, change and percent change from baseline 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 over visits for the following laboratory parameters: platelets, 
eGFR,  urine A/C ratio, and urine P/C ratio. 
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 they met a protocol-defined stopping rules for liver function, renal function, or platelet 
counts will be tabulated by treatment group. 
Additional investiagation of heptobiliary 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.  


 
69 
A confirmed laboratory value is based on consecutive  lab values within 7 days. If that value is in the 
same or worse category the initial value is confirmed. If the consecutive value is in a better category 
then the initial value is confirmed using 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. 
 
3.9.4.1 
Hepatobiliary Laboratory abnormalities 
The number and percentage of patients falling in each of the following categories based on post-
baseline assessements will be provided: 
• 
ALT ≥ 3xULN and total bilirubin ≥ 2xULN 
• 
Confirmed ALT ≥ 3xULN and confirmed total bilirubin ≥ 2xULN 
• 
ALT ≥ 3xULN and international normalized ratio > 1.5 
• 
ALT ≥ 3xULN and total bilirubin ≥ 2xULN and ALP < 2xULN 
• 
Hepatocellular injury 
• 
Hepatocellular injury and total bilirubin ≥ 2xULN 
• 
ALT ≥ 3xULN 
• 
ALT ≥ 5xULN 
• 
ALT ≥ 8xULN 
• 
ALT ≥ 10xULN 
• 
ALT ≥ 20xULN 
• 
Confirmed ALT ≥ 3xULN 
• 
Confirmed ALT ≥ 5xULN 
• 
Confirmed ALT ≥ 8xULN 
• 
Confirmed ALT ≥ 10xULN 
• 
Confirmed ALT ≥ 20xULN 
• 
ALT ≥ 3xULN - < 5xULN 
• 
ALT ≥ 5xULN - < 10xULN 
• 
ALT ≥ 10xULN - < 20xULN 
• 
Total bilirubin ≥ 2xULN 
• 
ALP ≥ 2xULN and baseline ALP < 2xULN or baseline ALP missing 
• 
ALT ≥ 3x ULN or ALT ≥ 2 x baseline 
• 
Confirmed ALT ≥ 3x ULN or confirmed ALT ≥ 2 x baseline 
For patients that had ALT elevation ≥ 3 xULN, the time from first dose to first ALT elevation ≥ 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 
peak category will also be provided. Categories for the ALT and AST shift tables will be < 3 x ULN, ≥ 3 


 
70 
x ULN to < 5 x ULN, ≥ 5 x ULN to < 8 x ULN, and ≥ 8 x ULN. Categories for the total bilirubin shift table 
will be < 2 x ULN and ≥ 2 x ULN.  
A heptocellular injury event is defined as (ALT/ALT ULN)/(ALP/ALP ULN) ≥ 5 and ALT ≥ 3xULN, with 
the ALT and ALP assessments done on the same day. The categories listed above will also be 
analyzed using AST in place of ALT. For these analyses the definition of hepatocellular injury will not 
be changed to depend on AST. 
3.9.4.2 
Platelets 
The number and percentage of patients falling in each of the following categories (using available 
central and local laboratory assessments) based on post-baseline assessements will be provided: 
• 
Platelet count decrease - Grade 1a [≥ 100 10^9/L to < 140 x 10^9/L]  
• 
Platelet count decrease- Grade 1b [≥ 75 10^9/L to < 100 x 10^9/L]  
• 
Platelet count decrease- Grade 2 [≥ 50 10^9/L to < 75 x 10^9/L] 
• 
Platelet count decrease- Grade 3 [≥ 25 10^9/L to < 50 x 10^9/L] 
• 
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 
• 
Confirmed ≥ 30% decrease from baseline 
• 
Confirmed ≥ 50% decrease from 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. 
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 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).  
Shift tables from baseline will be provided using the nadir value and the confirmed nadir category. 
Categories for the shift table will be ≥ 140 x 10^9/L, ≥ 100 x 10^9/L to < 140 x 10^9/L, ≥ 75 x 10^9/L 
to < 100 x 10^9/L, ≥ 50 x 10^9/L to < 75 x 10^9/L, ≥ 25 x 10^9/L to < 50 x 10^9/L, and < 25 x 10^9/L. 
For each of the platelet categories investigated, time from first dose to the onset will be 
summarized for the patients that met the criterion using the following descriptive statistics: mean, 
standard deviation, median, P25, P75, and minimum and maximum. Kaplan-Meier plots for time to 
first event will be provided for value < 140 x10^9/L and value < 100 x10^9/L. 


 
71 
The post-baseline nadir (absolute value, change from baseline, and percent change from baseline) of 
platelet count will be summarized by treatment group.  
Duration of platelet counts below the 140 x 10^9/L will be summarized, based on the duration (in 
weeks) each subject was below the 140 x 10^9/L .  
The above analyses will be repeated for the subgroups defined by CM-ECHO Set.  
3.9.4.3 
Renal parameters 
The number and percentage of patients falling in each of the following categories (using available 
central laboratory assessments) based on post-baseline assessements 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-EPI ≥ 25% decrease from baseline 
• 
Creatinine clearance by CKD-EPI ≥ 50% decrease from baseline 
• 
Urine Alb/C ratio > 5 x ULN 
• 
Urine P/C ratio > 5 x ULN 
• 
Serum creatinine increase > 44.2 umol/l (0.5 mg/dL) from 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-EPI ≥ 25% decrease from baseline 
• 
Confirmed creatinine clearance by CKD-EPI ≥ 50% decrease from baseline 
• 
Confirmed urine Alb/C ratio > 5 x ULN 
• 
Confirmed urine P/C ratio > 5 x ULN 
• 
Confirmed serum creatinine increase > 44.2 umol (0.5 mg/dL) from baseline  
Shift tables from baseline for creatinine clearance by CKD-EPI will be provided usng the nadir value 
and the confirmed nadir category. Categories for the shift table will be ≥ 90 mL/min/1.73m2, ≥ 60 
mL/min/1.73m2 to < 90 mL/min/1.73m2, ≥ 30 mL/min/1.73m2 to < 60 mL/min/1.73m2, ≥ 15 
mL/min/1.73m2 to < 30 mL/min/1.73m2,  and < 15 mL/min/1.73m2. 
The above analyses will be repeated for the subgroups defined by CM-ECHO Set.  
3.9.5 
Electrocardiograms 
Absolute values, change and percent change from baseline in ventricular rate and ECG intervals (PR, 
QRS, QT, QTcF, QTcB) will be presented by treatment and visit.  Shift table from baseline to the 
worst (highest) post-baseline value by treatment group will be used to assess the change in the QTcF 


 
72 
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.  This analysis will be presented overall and also by the subgroup 
whose QTcF was normal at baseline.  Normal QTcF will be defined as 450 msec for males or 470 
msec for females.  The number and percent of patients with overall qualitative ECG abnormalities 
will also be summarized.  These analyses will be repeated for patients in the CM-ECHO Set.  No 
statistical comparisons between treatments will be performed for these summaries. 
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 rules for QTc prolongation will be tabulated by treatment 
group. 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-patient listing of ECG over-read data will be provided.  
3.9.6 
Electroretinograms (ERG) and Ophthalmology Exam 
The change from baseline in ERG results will be summarized by treatment group.  
ERG results will be listed.  Ophthalmology exam findings will be listed.  The number and percent of 
patients that stopped treatment because they met a protocol defined stopping rules for ocular 
effects will be tabulated by treatment group. 
3.9.7 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS collects binary responses to 11 categories: five subtypes of suicidal ideation, five 
subtypes of suicidal behavior, and self-injurious behavior without suicidal intent.  Specifically, the 
following outcomes are C-SSRS categories and have binary (Yes/No) responses.  (The categories have 
been re-ordered from the actual scale to facilitate the definitions of the composite endpoints and to 
enable clarity in the presentation of the results.) 
Suicidal Ideation: 
Category 1 – Wish to Be Dead 
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Suicidal Behavior: 
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt 


 
73 
Category 8 – Interrupted Attempt 
Category 9 – Actual Attempt (non-fatal) 
Category 10 – Completed Suicide 
Other 
Category 11 – Non-suicidal Self-injurious Behavior 
In addition, a numerical score, the Suicidal Ideation Score, will be defined as the highest suicide 
ideation category (1–5) at which the patient responded “Yes” for the given visit.  If the patient did 
not respond “Yes” to any of these categories, the score will be set to zero. 
For each of the 11 categories above, the number and percent of patients with a “Yes” response at 
any time post-baseline (regardless of baseline response) will be summarized by treatment group.  
In addition, treatment-emergent suicidal ideation or behavior will be summarized.  Treatment 
emergence will be identified when the event was reported at any post-baseline visit but was not 
present at any baseline visit.  The binary categories above and the Suicidal Ideation Score will be 
used to identify the following 8 composite endpoints: 
• 
Suicidal Ideation: A “Yes” answer at any time post-baseline to any one of the five suicidal 
ideation questions (Categories 1–5), regardless of the baseline response 
• 
Suicidal behavior: A “Yes” answer at any time post-baseline to any one of the five suicidal 
behavior questions (Categories 6–10), regardless of the baseline response 
• 
Suicidal Ideation or Behavior: A “Yes” answer at any time post-baseline to any one of the 
ten suicidal ideation or behavior questions (Categories 1–10), regardless of the baseline 
response 
• 
Treatment-Emergent Suicidal Ideation compared to recent history: An increase in the 
maximum suicidal ideation score post-baseline from the baseline suicidal ideation score 
• 
Treatment-Emergent Serious Suicidal Ideation compared to recent history: An increase in 
the maximum suicidal ideation score to 4 or 5 post-baseline from not having serious suicidal 
ideation (scores of 0–3) at baseline.  Only patients with a baseline score of 0–3 will be 
considered evaluable for this outcome. 
• 
Emergence of Serious Suicidal Ideation compared to recent history: An increase in the 
maximum suicidal ideation score to 4 or 5 post-baseline from no suicidal ideation (score of 
0) at baseline.  Only patients with a baseline score of 0 will be considered evaluable for this 
outcome. 
• 
Improvement in Suicidal Ideation compared to baseline: A decrease in the suicidal ideation 
score at the patient’s last C-SSRS assessment compared to the baseline assessment. 


 
74 
• 
Emergence of Suicidal Behavior compared to all prior history: The occurrence of suicidal 
behavior (a “Yes” response to one or more of Categories 6–10) post-baseline from not 
having suicidal behavior at baseline. 
Each of the composite endpoints will be summarized by treatment group.  For each treatment-
emergent outcome listed, only those patients with the specified baseline condition will be 
considered evaluable. In addition, patients who discontinue from the study with no post-baseline C-
SSRS assessment will be considered unevaluable for analyses of suicidality.  Percents will be based 
on the number of evaluable patients for each outcome.     
C-SSRS results will be listed.   
4 Sample Size 
The planned sample size for this study was revised from 195 to 135 using information published 
from the placebo controlled Phase 3 Diflunisal trial (Berk et al. 2013), a retrospective, multinational 
natural history study in 283 FAP patients (Adams et al. 2015), and uncontrolled data using another 
TTR mRNA targeted therapeutic (Adams 2015). It is estimated that the placebo group will have a 16 
point increase in the mNIS+7 score from baseline to Month 15, and the treated group will have a 6.4 
point increase in mNIS+7. The standard deviation of the change from baseline in each treatment 
group is estimated to be 14. With 135 patients (2:1 allocation ratio) there would be at least 90% 
power to detect a 9.6 point difference in the change from baseline in the mNIS+7 score between the 
2 groups, with a two-sided t-test of 5% alpha, assuming that the dropout rate is approximately 25%. 
For the Norfolk QOL-DN questionnaire total score, it is estimated that the placebo group will have a 
13.3 point change from baseline to Month 15, the treated group will have a 2.6 point change from 
baseline and the standard deviation of the change from baseline in each treatment group will be 18. 
With 135 patients, there would be at least 80% power to detect a 10.7 point difference in the 
change from baseline in the Norfolk QOL total score between the 2 groups, with a two-sided 5% 
alpha level, assuming that the dropout rate is approximately 25%.    
5 Interim Analyses 
5.1 Interim Analysis of TTR 
An unblinded interim analysis of reduction in plasma transthyretin (TTR) level is planned after 
approximately the first 45 patients (total drug and placebo treated) have completed the Week 13 
visit.  The purpose of this analysis is futility as measured by effect on plasma TTR levels, so there will 
be no statistical penalty.  The DSMB will inform the Sponsor whether at least 50% of patients 
treated with ISIS 420915 achieved either a 60% reduction in plasma TTR level or plasma TTR level 
below the limit of quantification (BLQ) following 13-weeks of treatment.  Only a binary answer (Yes 
or No, this is the futility criteria) will be communicated to the Sponsor Primary Contact.  
Independent of the answer being communicated to the Sponsor, a separate evaluation will be 
performed.   


 
7 5  
At t h e r e q u est of t h e S p o ns or’s I SI S 4 2 0 9 1 5 d e v el o p m e nt p art n er, 
, a n 
u n bli n d e d e v al u ati o n of effic ac y a n d s af ety will b e p erf or m e d b y t h e i n d e p e n d e nt st atistici a n a n d 
r e vi e w e d by t h e D S M B a n d a s m all gr o u p of fir e w all e d st aff at  
 (
).  T h e 
e v al u ati o n wil l i ncl u d e u n bli n d e d pl as m a T T R d at a f oll o wi n g 1 3-w e eks of tr e at m e nt a n d c u m ul ativ e 
s af et y a n d effic ac y d at a o n all p ati e nts c urr e ntly e nr oll e d at t h e ti m e of t h e a n alysis.  T his d at a will 
b e us e d b y  
 f or b usi n ess d ecisi o n m a ki n g.  T his d at a will n ot b e c o m m u nic at e d t o a ny ot h er G S K 
e m pl o y e es n or t o a ny m e m b er of t h e S p o ns or c o m p a ny.  Strict m e as ur es h a v e b e e n p ut i n pl ac e t o 
m ai nt ai n c o nfi d e nti ality of t h e D S M B a n d 
 (s e e S ecti o n 6. 0 a n d D S M B 
C h art er ).   
D et ails of c o ntr oll e d acc es s t o t h e u n bli n d e d d at a ar e o utli n e d i n t h e D S M B C h art er. 
5. 2  U n bli n d e d effic ac y a n al ysis r e q u est e d b y t h e D S M B  
W hil e t h e st u dy w as o n g oi n g t h e D S M B r e q u est e d t h at I o nis P h ar m ac e utic als pr o vi d e u n bli n d e d 
s u m m ar y st atistics f or t h e pri m ar y effic acy d at a s o t h at t h ey c o ul d b ett er e v al u at e b e n efit:risk . T h e 
r e q u est w as f ulfill e d by  
, a c o ntr act r es e arc h or g a niz ati o n ( C R O) t h at is r es p o nsi bl e f or pr e-
pr o gr a m mi n g d at as ets a n d TL Fs f or t h e St u dy. Strict m e as ur es w er e p ut i n pl ac e t o e ns ur e t his 
a n al ysis  di d n ot c o m pr o mis e t h e i nt e grity of t h e o n g oi n g S t u dy, i ncl u di n g t h e f or m ati o n of t w o  
 
t e a ms f ulfil t his r e q u est ( u n bli n d e d a n d bli n d e d t e a m). D et ails a b o ut t h e a n al ysis a n d s af e g u ar ds t o 
e ns ur e t h e st u dy i nt e grity w as n ot c o m pr o mis e d ar e d et ail e d  i n th e S A P g e n er at e d t o s u p p ort t h e 
D S M B r e q u est, av aili a bl e i n S ecti o n  8. 3 . T h e D S M B p ack a g e i ncl u d e d o nl y d escri pti v e st atistics. As n o 
f or m al c o m p aris o ns of effic ac y e n d p oi nts w er e p erf or m e d n o a dj ust m e nt t o t h e o v er all st u dy-wis e 
t y p e I err or is n e e d e d.  
6  St u d y C o n d u ct t o Mi ni mi z e Bi a s  
T h e s p o ns or r ec o g niz es t h e i m p ort a nc e of c o nfi d e nti alit y of i nt eri m r es ults .  T o mi ni miz e a ny 
p ot e nti al d a m a g e t o t h e  i nt e grit y of t h e cli nic al tri al, t h e m et h o d b y w hic h t h e S p o ns or will c o n d uct 
t h e i nt eri m a n alysis is t hr o u g h t h e I SI S 4 2 0 9 1 5-C S 2 D S M B ( w hic h i ncl u d es a st atistici a n m e m b er) a n d 
a n i n d e p e n d e nt st atistici a n w h o is disti nct fr o m t h e D S M B.  
T h e i n d e p e n d e nt s t atistici a n w h o s u p p orts D S M B a n d first i nt eri m a n alysis will b e a n e m pl oy e e of a 
C R O 
, o n e t h at is i n d e p e n d e nt fr o m a s ec o n d C R O c o n d ucti n g t h e tri al ( 
) a n d a t hir d 
C R O 
 w h o will b e p erf or mi n g t h e fi n al st atistic al a n al ysis .  I n V e nti v will als o pr o vi d e 
pr o gr a m mi n g s u p p ort f or t h e D S M B , h a n dl e all D S M B r el at e d a n alys es, i n d e p e n d e nt of t h e S p o ns or 
a n d i n d e p e n d e nt of 
 a n d 
  T h e I n d e p e n d e nt St atistici a n fr o m I n V e ntiv will m ai nt ai n 
s ec ur e c ust o dy of bli n d e d a n d u n bli n d e d  d at a t o e ns ur e t h e i nt e grity of t h e d at a.  A d diti o n ally, t h e 
i n d e p e n d e nt st atistici a n will m ai nt ai n all u n bli n d e d d at a i n el ectr o nic f or m i n a s ec ur e ar e a.  All 
tr a nsf er of d at a/r e p orts b y t h e i n d e p e n d e nt st atistici a n t o t h e D S M B, w hic h i ncl u d es p ati e nt dat a 
will b e by s ec ur e, tr ac k a bl e c o uri er a n d/ or s ec ur e el ectr o nic m e a ns.  T h e i nd e p e n d e nt st atistici a n 
will pr ovi d e all of t h e u n bli n d e d d at a t o t h e D S M B a s o utli n e d i n t h e D S M B C h art er. U n bli n d e d 
s u m m ar y st atistics f or effic ac y e n d p oi nts w as r e q u est e d fr om t h e D S M B w hil e t h e st u dy w as 
o n g oi n g  (s e e a b o v e). 
w as r es p o nsi bl e f or pr o d uci n g t h e o ut p ut, w hic h w as distri b
P P D
ut e d t o 
P P D
P P D
P P D
P P D
P P D
P P
D
P P
D
P P D
P P D
P P
D
P P D
P P D


 
7 6  
I nv e nti v f or distri b uti o n t o t h e D S M B. S ecti o n 5. 2. d et ails t h e strict m e as ur es i n pl ac e t o e ns ur e 
f ulfilli n g t h e D S M B r e q u est did n ot c o m pr o mis e t h e i nt e grit y of t h e st u dy.   
All D S M B m e m b ers will si g n a C o nfi d e nti alit y A gr e e m e nt wit h t h e S p o ns or.  I n a d diti o n, all D S M B 
m e m b ers will tr e at as c o nfi d e nti al t h e r e p orts, m e eti n g disc ussi o ns, mi n ut es a n d r ec o m m e n d ati o ns 
of t h e D S M B.  St rict r ul es f or D S M B c o m m u nic ati o n wit h t h e S p o ns or a n d 
 
h a v e b e e n p ut i n pl ac e f or t h e p ur p os e of mi ni mizi n g t h e p ot e nti al f or  bi as, as o utli n e d i n t h e D S M B 
C h art er .  All writt e n c o m m u nic ati o n d escri b e d i n t h e D S M B C h art er will b e by s ec ur e, tr ac k a bl e 
c o uri er a n d/ or s ec ur e el ectr o nic m e a ns.  T his i ncl u d es diss e mi n ati o n of D S M B r ec o m m e n d ati o ns, 
a n d r e vi e w of mi n ut es of o p e n a n d cl os e d s essi o ns b et w e e n t h e D S M B a n d, as a p pr o pri at e, ot h er 
D S M B m e m b ers, t h e S p o ns or c o nt acts ( pri m ar y, C M O  a n d st atistics) a n d/ or 
.   
T h e 
 is li mit e d t o u p t o t hr e e 
e m pl oy e es wit h t h e s e ni orit y t o m a k e 
b usi n ess d ecisi o ns c o nti n g e nt o n t h e st u dy d at a.  T h e 
 will n ot disc uss t h e 
u n bli n d e d d at a/r e p orts wit h ot h er  
 st aff a n d t h e S p o ns or St u dy T e a m u ntil aft er fi n al d at a b as e 
l oc k.   
N o S p o ns or st aff will n or m ally p artici p at e i n t el ec o nf er e nc es b et w e e n t h e D S M B/I n d e p e n d e nt 
St atistici a n a n d 
.  H o w ev er, as o utli n e d i n t h e D S M B C h art er, s uc h 
p artici p ati o n m ay occ ur i n t h e f oll o wi n g circ u mst a nc es: ( 1) if t h e D S M B d et er mi n es t h at a d e q u at e 
disc ussi o n of t h e iss u es(s) c o nc er n e d r e q uir es i n p ut fr o m t h e S p o ns or t h e n t h e S p o ns or C M O ( w h o is 
t h e S p o ns or c o nt act f or disc ussi o ns i nv olvi n g u n bli n d e d d at a) m a y b e ask e d b y t h e D S M B C h air t o 
p artici p at e i n a t el ec o nf er e nc e wit h P art n er e d Fir e w all e d St aff a n d ( 2) if it h as b e e n n ec ess ar y f or 
t h e D S M B t o s h ar e d at a wit h t h e S p o ns or C M O t h e n t h e S p o ns or C M O m ay c o nv e n e a 
t el ec o nf er e nc e bet w e e n t h e D S M B a n d P art n er Fir e w all e d St aff.   
D uri n g t h e c o n d uct of t h e st u dy, t h e S p o ns or will n ot h a v e acc ess t o a n y effic ac y, p h ar m ac o dy n a mic 
or ex pl or at ory d at a, exc e pt f or b as eli n e v al u es.  T h e effic ac y d at a will b e c oll ect e d a n d st or e d b y 
i n d e p e n d ent C R Os as d et ail e d b el o w.  All C R Os will m ai nt ai n s ec ur e c ust o dy of t h eir d at a b as es.  T h e 
C R Os will n ot tr a nsf er a ny effic ac y d at a ot h er t h a n b as eli n e d at a t o t h e S p o ns or u ntil aft er all 
p ati e nts h av e c o m pl et e d t h e tr e at m e nt p eri o d a n d t h e d at a b as e h as b e e n l oc k e d  a n d t h e st u dy is 
u n bli n d e d .  T h e effic ac y d at a i ncl u d es t h e f oll o wi n g:  m NI S + 7, NI S + 7, N orf ol k Q OL-D N, B MI/ m B MI, 
pl as m a r eti n ol, pl as m a r eti nyl p al mit at e, pl as m a T T R, pl as m a R B P 4, pl as m a N T -pr o B N P, S F -3 6 
q u esti o n n air e, E C H O effic ac y p ar a m et ers, N S C a n d P N D sc or es.  
F or t h e p ur p os e of pr e -pr o gr a m mi n g a n d d at a cl e a ni n g, P ar ex el a n d a n i n d e p e n d e nt d at a m a n a g er 
at Tr e n nic D at a S ervic es  will r ec eiv e p ost -b as eli n e d at a f or t h e f oll o wi n g e n d p oi nts: m NI S + 7, NI S + 7, 
N orf ol k Q OL -D N, B MI/ m B MI,  S F -3 6 q u esti o n n air e, E C H O effic ac y p ar a m et ers, N S C a n d P N D sc or es.  
T h e pri m ar y effic acy ass ess m e nt, m NI S + 7 sc or es, will b e c oll ect e d a n d st or e d by a n i n d e p e n d e nt 
c o ntr act r es e arc h gr o u p, 
 t h at 
is u n d er t h e dir ecti o n of 
.  T h e N S C sc or e is o bt ai n e d d uri n g t h e NI S ass ess m e nt 
pr oc e d ur e a n d is als o c oll ect e d a n d st or e d b y 
.  T h e m NI S + 7 r es ults fr o m e ac h sit e will b e 
f ax e d t o 
 f or pr oc essi n g a n d q u alit y ass ur a nc e.  F ax e d c o pi es will b e m ai nt ai n e d i n s ec ur e 
r o o ms wit hi n l oc k e d c a bi n ets.  T h e NI S a n d N S C  d at a ar e st or e d i n t h e 
 ( a d at a b as e )
P P D
. T h e 
P P D
P P D
P P D
P P D
P P
D
P P D
P P D
P P D
P P D
P P D
P P D


 
7 7  
ot h er c o m p o n e nts  of t h e m NI S + 7 ( n erv e c o n d ucti o n, s e ns ory t esti n g a n d h e art r at e t o d e e p 
br e at hi n g) ar e e nt er e d b y t h e  
 i nt o a fir e w all e d p orti o n of t h e st u dy E D C s yst e m.   
 
o nl y h as acc ess t o t his p orti o n of t h e E D C s yst e m a n d t h e S p o ns or a n d cli nic al sit es d o n ot h a v e 
acc ess t o t h e  
 p orti o n of t h e E D C.   T h e m NI S + 7 s u m m at e d sc or e will n ot b e s h ar e d wit h t h e 
sit es.  U p u ntil t h e d at a b as e l oc k, t h e S p o ns or will o nl y h a v e acc ess t o p ati e nt b as eli n e v al u es of t h e 
m NI S + 7.   
T h e N orf ol k Q OL -D N, b o dy w ei g ht ( n e e d e d t o c alc ul at e B MI/ m B MI), S F-3 6 q u esti o n n air e a n d P N D 
sc or es will b e e nt er e d i nt o t h e E D C syst e m b y e ac h sit e.  T h e i n d e p e n d e nt C R O 
 is 
c o ntr act e d t o d e v el o p a n d m ai nt ai n s ec ur e c ust o dy of t h e E D C d at a b as e.  D uri n g t h e c o n d uct of t h e 
st u dy t h e S p o ns or will r ec ei v e r e g ul ar d at a tr a nsf ers fr o m 
 b ut wit h o ut t h e a b ov e 
m e nti o n e d effic acy d at a i ncl u d e d ( exc e pt f or b as eli n e v al u es).   
T h e pl as m a r eti n ol, pl as m a r eti n yl p al mit at e, pl as m a T T R, pl as m a R B P 4, hs C R P, a n d pl as m a N T -
pr o B N P s a m pl e s will b e ass a y e d at 
, t h e c e ntr al l a b or at ory c o ntr act e d f or t his st u dy.  T h e 
r es ults will b e m ai nt ai n e d i n 
’s s ec ur e d at a b as e.  N eit h er t h e S p o ns or n or t h e sit es will 
r ec eiv e t h e r es ults fr o m t h e a b ov e m e nti o n e d t ests ( exc e pt f or b as eli n e v al u es).  D uri n g t h e c o n d uct 
of t h e st u dy t h e S p o ns or will r ec eiv e r e g ul ar l a b d at a tr a nsf ers fr o m 
 t o p erf or m s af et y 
ass ess m e nts, b ut t h e a b ov e m e nti o n e d d at a will n ot b e i ncl u d e d i n t h e tr a nsf ers.  
T h e E C H O d at a will b e c oll ect e d, a n alyz e d a n d st or e d i n a s ec ur e d at a b as e by a n i n d e p e n d e nt C R O 
( 
).  T h e sit es will u pl o a d t h e E C H O d at a o n a s ec ur e w e b-p ort al f or a n al ysis by  
.  U p u ntil t h e 
d at a b as e l oc k, t h e S p o ns or will o nly h a v e acc ess t o p ati e nt b as eli n e E C H O v al u es.  E C H Os c o n d uct e d 
f or s af et y ass ess m e nt p ur p os es will b e a v ail a bl e t o t h e D S M B, S p o ns or, a n d I nv esti g at or.   
Pri or t o u n bli n di n g  of t h e fi n al a n al ysis , a ny I SI S 4 2 0 9 1 5 c o nc e ntr ati o n d at a s ets pr o vi d e d t o I o nis by 
t h e bi o a n alytic al l a b will b e pr o vi d e d wit h o ut r ef er e nc e t o act u al p ati e nt i d e ntifi ers t o a v oi d 
i n a dv ert e nt or acci d e nt al u n bli n di n g.  T h e bi o a n al ytic al l a b m ay pr o vi d e I o nis wit h d at a s ets 
c o nt ai ni n g f als e p ati e nt i d e ntifi ers u nr el at e d t o t h e act u al i d e ntifi ers t o all o w r e vi e w of t h e P K d at a.  
I n c o ncl usi o n, t h e u n bli n di n g pr oc ess f or t h e i nt eri m a n al ysis a n d p eri o dic s af ety r e vi e ws h as b e e n 
cl e arl y d efi n e d a n d d et aile d  ro l es a n d r es p o nsi biliti es t o t h e in d e p e n d e nt st atistici a n, D S M B,  
 
a n d S p o ns or, s uc h t h at t h e p ot e nti al f or bi as t o e nt er i nt o t h e c o n d uct of t h e st u dy 
will b e mi ni miz e d.  A d diti o n al st e ps t o e ns ur e t h e d at a f or t h e pri m ar y a n d s ec o n d ar y e n d p oi nts 
r e m ai n bli n d e d, s uc h as h o usi n g t h e pri m ary a n d s ec o n d ar y effic ac y d at a i n d at a b as e s t o w hic h t h e 
S p o ns or h as  n o  acc ess, f urt h er s af e g u ar ds t h e p ot e nti al f or S p o ns or bi as.  
P P D
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P
D
P P
D


 
78 
7 References 
Adams D, Coelho T, Obici L, et al. Rapid progression of familial amyloidotic polyneuropathy. 
Neurology 2015; 85: 1-8.  
 
Adams D. Phase 2 Open-Label Extension Study of Patisiran – An Investigational RNAi Therapeutic for 
the Treatment of Familial Amyloidotic Polyneuropathy. 67th Annual Meeting of the American 
Academy of Neurology (AAN) being held April 18 – 25, 2015 in Washington, D.C. 
(http://www.alnylam.com/web/assets/PATISIRAN-12MONTHOLE-AAN-FINAL_Capella.pdf) 
 
Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy a 
randomized clinical trial. JAMA 2013: 310(24): 2658-26673. 
 
Carpenter J, Roger J, and Kenward M. (2013), “Analysis of Longitudinal Trials with Protocol 
Deviations: A Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation,” Journal of Biopharmaceutical Statistics, 23, 1352-1371. 
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. 
Craig Mallinckrodt, James Roger, Christy Chuang-stein, Geert Molenberghs, Peter W. Lane, Michael 
O’kelly, Bohdana Ratitch, Lei Xu, Steve Gilbert, Devan V. Mehrotra, Russ Wolfinger & Herbert Thijs 
(2013) Missing Data: Turning Guidance Into Action, Statistics in Biopharmaceutical Research, 5:4, 
369-382. 
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. 
Little, R.J.A. and Rubin, D.B. (2002) Statistical Analysis with Missing Data, Second Edition, New York: 
John Wiley & Sons, Inc.  
Kenward, M. G. and Roger, J. H. (1997), "Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood," Biometrics, 53, 983-997. 
Schafer, J.L. (1997) Analysis of Incomplete Multivariate Data. New York: Chapman and Hall. 
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. 


 
79 
 


 
80 
8 Appendix  


 
8 1  
8. 1  A p p e n di x 1 C o m p o n e nts a n d S u bc o m p o n e nts of t h e m NI S + 7, a n d NI S + 7
C CI
 


 
8 2  
Fi g ur e 2  
C o m p o n e nts a n d S u bc o m p o n e nts of t h e NI S + 7  
 
C CI


 
8 3  
T a bl e 1:  N e ur o p at h y I m p air m e nt Sc or e  
C o m p o n e nt  
S u bc o m p o n e nt  
Ri g ht 
Si d e  
L eft 
Si d e  
M a x 
Sc or e  
M a x S u b -
T ot als  
Missi n g v al u e 
i m p ut ati o n f or 
C o m p o n e nt 
Sc or e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C
CI
C CI


 
8 4  
C o m p o n e nt  
S u bc o m p o n e nt  
Ri g ht 
Si d e  
L eft 
Si d e  
M a x 
Sc or e  
M a x S u b -
T ot als  
Missi n g v al u e 
i m p ut ati o n f or 
C o m p o n e nt 
Sc or e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
 


 
8 5  
T a bl e 2:  M o difi e d + 7 Sc or e  
C o m p o n e nt  
S u bc o m p o n e nt  
M a x 
Sc or e  
S u b -
T ot als  
Missi n g v al u e 
i m p ut ati o n f or 
C o m p o n e nt Sc or e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


 
8 6  
T a bl e 3:  + 7 Sc or e  
C o m p o n e nt  
S u bc o m p o n e nt  
M a x 
Sc or e  
M a x S u b -
T ot als  
Missi n g 
v al u e 
i m p ut ati o n 
f or 
C o m p o n e nt 
Sc or e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
 


 
87 
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 
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. 
 
 


 
88 
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 +++ 
 
 
 


 
89 
8.3 DSMB SAP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
90 
 
 
 
 
 
 
Statistical analysis plan for the unblinded analysis of 
efficacy endpoints - A request from the DSMB  
 
 
ISIS 420915-CS2 
A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study 
to Assess the Efficacy and Safety of ISIS 420915 in Patients with 
Familial Amyloid Polyneuropathy  
 
 
Date:  August 31, 2016 
Version:  1.0 
 


 
9 1  
St atistic al A n al ysis Pl a n Si g n at ur e P a g e  
Io nis  P h ar m ac e utic als, I nc.  
2 8 5 5 G az ell e C o urt  
C arls b a d, C A 9 2 0 1 0  
 
Pr ot oc ol:   
 
I SI S 4 2 0 9 1 5 -C S 2  
St u dy Titl e:   
A P h as e 2/ 3 R a n d o miz e d, D o u bl e -Bli n d, Pl ac e b o -C o ntr oll e d St u dy t o Ass ess 
t h e Effic ac y a n d S af ety of ISI S 4 2 0 9 1 5 i n P ati e nts wit h F a mili al A m yl oi d 
P oly n e ur o p at h y  
Iss u e D at e:   
M a y 1 3 , 2 0 16  ( A m e n d m e nt 9 )  
 
Si g n at ur e:   
 
 
 
 
 
 
 D at e:    
 
 
, Dr .P .H.   
, Bi o m etrics  
I o nis P h ar m ac e utic als, I nc.  
2 8 5 5 G az ell e C o urt  
C arls b a d, C A 9 2 0 1 0  
 
Si g n at ur e:   
 
 
 
 
 
 
 D at e:    
 
 
, P h. D.  
, Bi o m etrics  
I o nis P h ar m ac e utic als, I nc.  
2 8 5 5 G az ell e C o urt  
C arls b a d, C A 9 2 0 1 0  
 
Si g n at ur e:   
 
 
 
 
 
 
 D at e:    
 
 
, P h. D. 
, 
, Cli nic al D e v el o p m e nt  
I o nis P h ar m ac e utic als, I nc.  
2 8 5 5 G az ell e C o urt  
C arls b a d, C A 9 2 0 1 0
P P D
 
C CI
C CI
C CI
C CI
C CI
C CI


 
92 
TABLE OF CONTENTS 
1 
Introduction ....................................................................................................................... 93 
1.1 
Overview .................................................................................................................... 93 
1.2 
Endpoints .................................................................................................................... 93 
2 
Procedures ......................................................................................................................... 93 
2.1 
Analysis and distribution of the output ........................................................................ 93 
2.2 
Data management ....................................................................................................... 94 
3 
Analytical Plan ................................................................................................................... 94 
3.1 
Analysis conventions ................................................................................................... 94 
3.1.1 
Baseline definition ...................................................................................................................... 94 
3.1.2 
Analysis population .................................................................................................................... 95 
3.1.3 
Analysis windows ....................................................................................................................... 95 
3.1.4 
Scoring of assessment instruments ............................................................................................ 95 
3.2 
Analysis ...................................................................................................................... 96 
3.2.1 
Considerations for the interpretation of unblinded efficacy results .......................................... 96 
3.2.2 
Endpoints ................................................................................................................................... 96 
3.2.3 
Sensitivity analysis of the endpoints .......................................................................................... 96 
3.2.4 
Handling of missing assessment level data ................................................................................ 97 
 
 
 


 
9 3  
 
1  I nt r o d u cti o n 
1. 1  O v er vi e w  
 
T his d oc u m e nt d escri b es t h e a n al ysis pl a n f or f ul filli n g t h e D S M B’s r e q u est f or a n u n bli n d e d a n al ysis 
of t h e pri m ary effic acy e n d p oi nts. T h e a n alysis pl a n c ov ers t h e t w o pri m ar y effic ac y e n d p oi nts 
( N orf olk Q OL-D N T ot al sc or e a n d m NI S + 7 C o m p osit e sc or e) a n d NI S C o m p osit e sc or e, a s ec o n d ary 
effic ac y e n d p oi nt t h at w as n ot r e q u est e d by t h e D S M B. NI S C o m p osit e sc or e is pr o vi d e d b ec a us e t h e 
S p o ns or b eli e v es it c a n ai d e i n t h e ev al u ati o n of I SI S 4 2 0 9 1 5; a d diti o n al c o nsi d er ati o ns f or t his 
e n d p oi nt ar e pr ovi d e d b el o w.  
T his a n al ysis pl a n is ali g n e d wit h t h e c urr e nt w or ki n g v ersi o n of t h e I SI S 4 2 0 9 1 5 CS 2 st atistic al 
a n al ysis pl a n ( S A P); d e vi ati o ns fr o m t h e S A P a n d pr ot oc ol ar e n ot e d.  
1. 2  E n d p oi nts  
N orf ol k Q OL -D N, m NI S + 7 a n d NI S ar e m e as ur e d at b as eli n e, W e e k 3 5, a n d W e ek 6 6 ( E O T effic ac y 
ass ess m e nt).  P ati e nts w h o d o n ot e nr oll i n t h e OL E will als o h av e effic acy ass ess m e nts m e as ur e d at 
W e ek 9 1 i n t h e p ost -tr e at m e nt ev al u ati o n p eri o d.  T h e m NI S + 7 ass ess m e nts at b as eli n e a n d W e e k 
6 6 ar e p erf or m e d t wic e a n d t h e d u plic at es a v er a g e d.  T h e d u plic at es c a n n ot b e p erf or m e d o n t h e 
s a m e d a y.   
NI S is pr o vi d e d t o ai d e i n t h e e v al u ati o n of p ot e nti al t h e b e n efit of I SI S 4 2 0 9 1 5 i n p ati e nts wit h F A P. 
T h e S p o ns or h as r es erv ati o n a b o ut t h e m NI S + 7 d at a b ec a us e t h e m + 7 c o m p o n e nt r eli es o n a 
c o m plic at e d sc ori n g al g orit h m a n d c urr e ntl y t h e d at as et is n ot c o m pl et e. F or t his r e as o n t h e 
S p o ns or is pr ovi di n g r es ults f or NI S C o m p osit e sc or e, t h e ot h er m aj or c o m p o n e nt i n t h e m NI S + 7 
C o m p osit e sc or e. T h e S p o ns or b eli e v es t his d at a is m or e c o m pl et e b as e d o n o ur e v al u ati o n of t h e 
b as eli n e d at a, a n d c a n i nf or m t h e ass ess m e nt of t h e b e n efit of I SI S 4 2 0 9 1 5.  
2  P r o c e d u r e s  
2. 1  A n al ysis a n d distri b uti o n of t h e o ut p ut  
T h e S p o ns or is c o m mitt e d t o e ns ur e st u dy i nt e grity will n ot b e c o m pr o mis e d i n f ulfilli n g t h e D S M B 
r e q u est for a n u n bli n d e d a n al ysis of effic ac y d at a fr o m a n o n g oi n g st u dy.  
A n al ysis of t h e u n bli n d e d effic ac y d at a will b e d o n e by 
, a c o ntr act r es e arc h 
or g a niz ati o n ( C R O) t h at is r es p o nsi bl e f or pr e -pr o gr a m mi n g d at as ets a n d TL Fs f or t h e St u dy. T o li mi t 
t h e p ossi bilit y t h at  
 c o m pr o mis es t h e st u dy i nt e grit y, t w o s e p ar at e  
 t e a ms will b e i nv olv e d i n 
f ulfilli n g t h e D S M B r e q u est. O n e t e a m ( U n bli n d e d T e a m) will o nl y b e r es p o nsi bl e f or a n al yzi n g t h e 
effic ac y d at a usi n g t h e r e al r a n d o miz ati o n c o d es. T his t e a m will c o nsist of a n u n bli n d e d st atistici a n 
P P D
a n d at l e ast o n e u n bli n d e d pr o gr a m m er. T h e ot h er t e a m ( Bli n d e d T e a m), w hic h is r es p o nsi bl e f or 
P P
D
P P
D


 
9 4  
s u p p orti n g t h e o n g oi n g st u dy a n d h as r o uti n e c o nt act wit h t h e S p o ns or, will r e m ai n bli n d e d a n d will 
pr e p ar e t h e e n d p oi nts f or t h e U n bli n d e d T e a m t o a n alyz e usi n g d u m my tr e at m e nt c o d es. T h e 
U n bli n d e d T e a m e ns ur es bli n di n g is m ai nt ai n e d a n d pr e v e nts u n a ut h oriz e d acc ess of u n bli n d e d d at a 
t o t h e Bli n d e d T e a m u ntil t h e St u dy is u n bli n d e d. U n bli n di n g i nf or m ati o n is t o b e stor e d a n d 
acc essi bl e i n a r estrict e d ar e a of t h e  
 n et w or k, wit h acc ess r estrict e d t o t h e U n bli n d e d T e a m.  
R e al tr e at m e nt c o d es will b e s e nt fr o m t h e S p o ns or t o t h e u n bli n d e d st atistici a n at  
 by I o nis 
Q A/ C, a n d will b e d o n e i n acc or d a nc e wit h I o nis S O P s. 
O ut p ut g e n er at e d fr o m t h e U n bli n d e d T e a m will b e s e nt t o I nv e ntiv, a C R O t h at w or ks wit h t h e 
D S M B, w h o will t h e n distri b ut e it t o t h e D S M B f or r evi e w. As p art of t h e Q C pr oc ess, t h e Bli n d e d 
T e a m will s e n d b as eli n e c o m p osit e sc or es f or m NI S + 7, N orf olk Q O L-D N a n d NI S t o t h e S p o ns or t o 
v erify t o sc ori n g w as i m pl e m e nt e d c orr ectl y. P ost -b as eli n e c o m p osit e sc or es ar e n ot t o b e s e nt t o 
t h e S p o ns or f or v erific ati o n si nc e t h e S p o ns or is t o b e fir e w all e d fr o m p ost-b as eli n e effic ac y d at a.  
2. 2  D at a m a n a g e m e nt  
T h e S p o ns or is fir e w all e d fr o m p ost -b as eli n e effic acy a n d P D d at a, i ncl u di n g N orf ol k Q OL -D N a n d 
m NI S + 7. U p u ntil t h e  d at a b as e l oc k  a n d u n bli n di n g f or t h e e n d of tr e at m e nt a n alysis , t h e S p o ns or 
will o nly h a v e acc ess t o p ati e nt b as eli n e v al u es . Effic acy d at a w as tr a nsf err e d fr o m t h e diff er e nt 
st u dy v e n d ors t o  
. I nf or m ati o n o n t h e effic acy d at as et is d et ail e d i n t h e t a bl e b el o w.  
 
V e n d or  
D at e P XL r ec ei v e d d at a  
M ost c urr e nt d at e i n 
d at a b as e  
NI S d at a  
 
 
 
m + 7 d at a  
 
 
 
N orf ol k Q OL -D N  
 
 
 
3  A n al yti c al Pl a n  
3. 1  A n al ysis c o n v e nti o ns  
3. 1. 1  
B as eli n e d efi niti o n  
B as eli n e will b e d efi n e d as f oll o ws:  
o  N orf ol k Q OL -D N: L ast n o n -missi n g v al u e pri or t o t h e first d os e of St u dy Dr u g  
o  m NI S + 7 a n d NI S: D efi n e d as t h e av er a g e of t w o ass ess m e nts t a k e n wit hi n 4 5 d a ys pri or t o 
t h e first d os e of St u dy Dr u g.  If o nly o n e ass ess m e nt h as b e e n d o n e, t h e si n gl e ass ess m e nt 
will b e us e d i n pl ac e of t h e a v er a g e.  R ar el y, t h e b as eli n e tr e at m e nt m NI S + 7 ass ess m e nt(s) 
( or a s u bs et of t his ass ess m e nt) will  h a v e b e e n c o m pl et e d e arly i n t h e tr e at m e nt p eri o d 
r at h er t h a n pr e-tr e at m e nt.  
C CI
T h es e ass ess m e nts will b e i ncl u d e d i n t h e a n alysis as v ali d 
C CI
C CI
P P
D
P P
D
P P
D


 
9 5  
b as eli n e ass ess m e nts pr ovi d e d t h e y ar e t a k e n wit hi n o n e w e ek aft er t h e first d os e.   T h e 
r ati o n al e f or t his is t h at t h e p h ar m ac ol o gy of t h e dr u g i n dic at es t h at t h e dr u g will h a v e n o 
eff ect o n m NI S + 7 t his e arl y i n tr e at m e nt, a n d i ncl u di n g t h es e v al u es as t h e b as eli n e 
ass ess m e nts will all o w t h es e p ati e nt’s d at a t o b e i ncl u d e d i n t h e a n alysi s.    
3. 1. 2  
A n al ysis p o p ul ati o n  
U n bli n d e d effic ac y d at a will b e a n al yz e d f or t h e f ull a n al ysis s et ( F A S), d efi n e d as all r a n d o miz e d 
p ati e nts w h o r ec eiv e d at l e ast 1 i nj ecti o n of St u dy Dr u g (I SI S 4 2 0 9 1 5 or pl ac e b o) a n d w h o h av e a 
b as eli n e a n d at l e ast o n e p ost -b as eli n e effic ac y ass ess m e nt f or m NI S + 7 or N orf olk Q OL -D N .  R es ults 
will b e s u m m ariz e d u n d er t h e tr e at m e nt t o w hi c h p ati e nts w er e r a n d o miz e d. 
3. 1. 3  
A n al ysis wi n d o ws   
D at a will b e assi g n e d t o a n o mi n al visit acc or di n g t o t h e visit wi n d o ws i n t h e t a bl e b el o w. B ec a us e 
m NI S + 7 m ay b e i m pl e m e nt e d ov er s ev er al d ays, wi n d o w d efi niti o ns ar e b as e d o n t h e st u dy d a y t h e 
ass ess m e nt w as  i niti at e d. Ass ess m e nts t h at occ urr e d m or e t h a n 5 2 d a ys aft er t h e l ast d os e of 
m e dic ati o n will n ot b e s u m m ariz e d. 
N o mi n al Visit ( T ar g et D a y)  
Wi n d o w ( D a y)  
W e ek 3 5 ( D a y 2 3 9)  
2 0 9 -2 6 9  
W e ek 6 6 ( D a y 4 5 6)  
4 1 1 -5 0 1  
 
3. 1. 4  
Sc ori n g of ass ess m e nt i nstr u m e nts  
N orf ol k Q OL -D N : N orf olk Q OL -D N c o nsists of o n e c o m p osit e sc or e ( T ot al Q OL) a n d fi v e s u b -d o m ai n 
sc or es ( p hysic al f u ncti o ni n g/l ar g e fi b er n e ur o p at h y, acti viti es of d ail y li vi n g, sy m pt o ms, s m all fi b er 
n e ur o p at h y, a n d a ut o n o mic n e ur o p at hy).  T h e sc ori n g of t h e N orf olk  Q OL -D N will b e c o n d uct e d 
acc or di n g t o t h e sc ori n g m a n u al d e v el o p e d at t h e E ast er n Vir gi ni a M e dic al Sc h o ol.  T h e N o rf ol k Q OL-
D N T ot al sc or e  will b e c alc ul at e d b y s u m mi n g t h e d o m ai n sc or es.   
T h e r a n g e f or N orf olk Q OL -D N T ot al sc or e is -4 t o 1 2 4, wit h l ar g e v al u es b ei n g l ess f a v or a bl e t h a n 
s m all er v al u es.  
NI S a n d m NI S + 7 : m NI S + 7 c o nsists of t w o c o m p osit e sc or es: 
 
 
 
 
 
 
 
 
 
 
C CI
 
C CI
C CI


 
9 6  
 
  
3. 2  A n al ysis  
3. 2. 1  
C o nsi d er ati o ns f or t h e i nt er pr et ati o n of u n bli n d e d effic ac y r es ults  
T h e f oll o wi n g s h o ul d b e n ot e d:  
•  
O ut p ut is b as e d o n d at a ( b as eli n e a n d p ost -b as eli n e) t h at h a v e n ot b e e n cl e a n e d a n d will b e 
i nc o m pl et e f or s o m e p ati e nts.   F or ex a m pl e, s o m e p ati e nts h av e n ot y et r e ac h e d t h e W e ek 
6 6 ass ess m e nt, a n d s o m e p ati e nts will h a v e missi n g d at a t h at will ulti m at el y b e e nt er e d 
d uri n g t h e n o r m al d at a b as e cl e a ni n g pr oc ess.  T his is p artic ul arl y r el e v a nt t o t h e m NI S + 7 
e n d p oi nt.   
 d o es n ot e nt er a ny d at a i nt o t h e d at a b as e u ntil all q u eri es h av e b e e n 
r es olv e d.  T h us, t h er e is a si g nific a nt a m o u nt of m NI S + 7 d at a t h at h as b e e n r ec eiv e d b y 
 b ut n ot y et e nt er e d a n d t h er ef or e will b e missi n g f or t his a n al ysis.  T h er e ar e als o 
circ u mst a nc es w h er e t h e t est w as d o n e by t h e sit e, b ut n ot y et s e nt t o  
.  C o ncl usi o ns 
dr a w n fr o m t h e d at a s h o ul d t h er ef or e b e d o n e wit h a p pr o pri at e c a uti o n.  
•  
T h er e will  b e f e w er s u bj ects wit h W e ek 6 6 d at a i ncl u d e d i n t h e u n bli n d e d effic acy a n alysis 
t h a n w h at is a ntici p at e d w h e n t h e e n d of tr e at m e nt a n al ysis is p erf or m e d, m e a ni n g t h at 
t h er e will b e gr e at er d e gr e e of u nc ert ai nty i n c h ar act erizi n g t h e b e n efit of I SI S 4 2 0 9 1 5.  
•  
B ec a us e t h e S p o ns or is fir e w all e d fr o m p ost -b as eli n e effic ac y d at a, t h e S p o ns or c a n n ot 
att est t o t h e acc ur ac y of p ost -b as eli n e c o m p osit e sc or es i ncl u di n g c h a n g e a n d p erc e nt 
c h a n g e fr o m b as eli n e.   
3. 2. 2  
E n d p oi nts  
 
E n d p oi nts t h at will b e s u m m ariz e d i n t h e F A S i ncl u d e: 
•  
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e t o W e e ks 3 5 a n d 6 6 i n N orf olk Q OL -D N T ot al 
sc or e 
•  
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e t o W e e ks 3 5 a n d 6 6 i n m NI S + 7 C o m p osit e sc or e  
•  
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e t o W e e ks 3 5 a n d 6 6 i n NI S C o m p osi t e sc or e 
T h es e e n d p oi nts will b e s u m m ariz e d d escri pti v el y by s a m pl e siz e, m e a n, st a n d ar d d e vi ati o n, d at a 
q u artil es ( 2 5 t h, 5 0t h a n d 7 5 t h), a n d mi n a n d m ax v al u es.  N eit h er t h e M M R M t h at is pr es p ecifi e d f or 
t h e pri m ar y effic acy a n alysis n or ot h er i nf er e nti al st atistic al m et h o ds will b e fit t o t h e i nt eri m d at a. 
3. 2. 3  
S e nsiti vit y a n al ysis of t h e e n d p oi nts  
B ec a us e t h e St u dy is o n g oi n g a n d s o m e p ati e nts h av e n ot b e e n i n t h e St u dy l o n g e n o u g h t o h a v e a 
W e ek 6 6 effic acy ass ess m e nt (t h e pri m ary st u dy visit), effic acy d at a  will b e s u m m ariz e d f or t h e 
s u bs et of t h e F A S t h at ar e W e ek 6 6 e v al u a bl e. A p ati e nt i n t h e F A S is W e e k 6 6 ev al u a bl e if t h ey:  
1.  H a d a W e e k 6 6 ass ess m e nt o n m NI S + 7, NI S or N orf ol k Q OL -D N; or  
2.  Di d n ot h a v e a W e ek 6 6 ass ess m e nt o n m NI S + 7, NI S or N orf olk Q OL -D N b u t eit h er:
C CI
 
P P D
P P D
P P D


 
97 
a. Discontinued from the Study and had their first dose of Study Drug on or before 
28Jun2015; or 
b. Had their first dose of Study Drug on or before 30Mar2015. 
The 28Jun2015 and 30Mar2015 dates are based on the Week 66 analysis window, and the most 
current date in the efficacy dataset analyzed (12AUG2016).  
3.2.4 
Handling of missing assessment level data 
3.2.4.1 
Norfolk QOL-DN  
Missing assessment level data will be imputed according to the following rules: 
• 
For each patient at a specific visit, 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: If any question is missing at baseline, the 
mean value for this question at baseline from the study population (across all treatment 
groups) will be used to impute the missing baseline question value.  For post-baseline visits 
during the treatment period, any missing question values will be imputed using the last 
observed or imputed question value (including baseline value). For the symptom domain, in 
the case that a patient responded on a particular question (Questions 1- 7) as not a having 
the symptom but also marked presence of the symptom in their feet, legs, hands, or arm, 
the question will be set to missing and the imputation rules will be followed.  
• 
Otherwise,  the total for that domain will be set to missing  
The Norfolk QOL-DN Total score will be calculated by summing the imputed domain scores.  If any 
domain score after imputation is still missing, then the Norfolk QOL-DN Total score will be set to 
missing. 
The Norfolk QOL-DN individual domain and Total score will only be calculated for visits where the 
patient had a Norfolk QOL-DN assessment.  The individual domain and Total score are set to be 
missing if a patient misses the visit or does not have a Norfolk QOL-DN assessment at that visit.   
3.2.4.2 
mNIS+7 and NIS 
• 
Missing data imputation strategies for missing assessment level data 
Two independent assessments of the primary efficacy endpoint, mNIS+7, are planned at the 
baseline visit and the Week 66 visit.  A single mNIS+7 assessment is also planned at the 
Week 35 visit.  The mean of the two replicate assessments within visit will be used for 
analysis of both the baseline and Week 66 visits (provided both visits fall in the visit window 
and are within 52 days of the last dose of medication).  Sub-component scores will be 
averaged first.  These will be referred to as the Averaged Sub-component scores.   
At baseline and week 66, in the event that only one sub-component has been performed, 
the single sub-component will be used in place of the mean value for that visit for the 
Averaged Sub-component score.  If both of the sub-component values are missing, the 


 
98 
Averaged Sub-component score is missing.  At week 35, only one assessment is performed, 
therefore the single sub-component will be used as the Averaged Sub-component score for 
that visit.  These values will be used in the summary and analysis of Averaged Sub-
component scores. 
The component scores will be computed by summing the Averaged Sub-component scores 
and the composite scores will be computed by summing the component scores.   
• 
Imputation of missing averaged sub-components 
If a patient has completed at least part of the mNIS+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.  
o If at least 50% of Averaged Sub-component scores within a component are available, the 
missing Averaged Sub-component scores will be set to equal to the mean of the 
patient’s other non-missing Averaged Sub-component scores in the component.  The 
component score is then calculated. 
o Otherwise, the component will be considered to be missing. 
• 
Composite Score 
The composite scores of mNIS+7 and NIS will each be calculated by summing the imputed 
component scores.  If any of the component scores after imputation are still missing within 
a composite, the composite score will be set as missing.