Conditions: TTR-mediated Amyloidosis Amyloidosis, Hereditary Amyloid Neuropathies, Familial Familial Amyloid Polyneuropathies Amyloid Neuropathies Amyloidosis, Hereditary, Transthyretin-Related
Keywords: RNAi therapeutic FAP Familial Amyloid Polyneuropathy TTR Transthyretin Amyloidosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 225
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of patisiran (ALN-TTR02) in patients with transthyretin (TTR) mediated amyloidosis. An open-label, single-arm, long-term follow-up extension study NCT02510261 (ALN-TTR02-006) was initiated to provide participants who completed this study with continued patisiran-LNP (lipid nanoparticle) treatment.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: patisiran (ALN-TTR02) intervention 2: Sterile Normal Saline (0.9% NaCl)
Intervention descriptions: intervention 1: administered by intravenous (IV) infusion intervention 2: administered by intravenous (IV) infusion

Protocol document:
Prot_000.pdf: 
 
 
Official Title:    
APOLLO: A Phase 3 Multicenter, Multinational, Randomized, Doubleblind, 
Placebo‐controlled Study to Evaluate the Efficacy and Safety of 
ALN‐TTR02 in Transthyretin (TTR)‐Mediated Polyneuropathy 
(Familial Amyloidotic Polyneuropathy‐FAP) 
 
NCT Number:    
NCT01960348 
Document Date:   
Protocol Version 6, 08 September 2015 


 
 
 
 
 
CLINICAL STUDY PROTOCOL  
ALN-TTR02-004 
 
APOLLO:  A Phase 3 Multicenter, Multinational, Randomized, Double-
blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of 
Patisiran (ALN-TTR02) in Transthyretin (TTR)-Mediated 
Polyneuropathy (Familial Amyloidotic Polyneuropathy-FAP) 
 
Protocol Version 
Version 6.0 (Incorporating Amendment 5) 
Protocol Date 
08 September 2015 
IND Number 
117395 
EudraCT Number 
2013-002987-17 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142  USA 
Sponsor Contact: 
  
 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without expressed 
written authorization of Alnylam Pharmaceuticals, Inc. 
The study will be completed according to guidelines of Good Clinical Practice.  
Compliance with this practice provides public assurance that the rights, safety, and 
well-being of study patients are protected consistent with the principles that have their 
origin in the Declaration of Helsinki. 
 


Patisiran (ALN-TTR02) 
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AUTHORIZED SIGNATORIES 
INVESTIGATOR'S STATEMENT: I agree to conduct this study as outlined in the 
protocol and in accordance with the guidelines and all applicable government regulations. 
I have read all parts of the protocol. 
Principal Investigator 
Signature 
Name (print) 
Sponsor 
Signature 
Name (print) 
 
 
 
Version History: 
Version Number 
Date 
1.0 (Original) 
15 August 2013 
2.0 
18 October 2013 
3.0 
21 March 2014 
4.0 
24 April 2014 
5.0 
04 August 2014 
6.0 
08 September 2015 
Final Protocol (Version 6.0) 
Page 2 of 109 
Date 
Date 
Comment 
Initial Release 
Incorporating Global Amendment 1 
Incorporating Global Amendment 2 
Incorporating Global Amendment 3 
Incorporating Global Amendment 4 
Incorporating Global Amendment 5 
Confidential 


 
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Table of Contents 
 
Table of Contents ...............................................................................................................3 
List of Tables ......................................................................................................................7 
List of Appendices ..............................................................................................................7 
PROTOCOL Synopsis .......................................................................................................8 
1 
Introduction ..........................................................................................................32 
1.1 
Background and Rationale ........................................................................ 32 
1.1.1 Disease Overview ......................................................................... 32 
1.1.2 RNA Interference .......................................................................... 33 
1.1.3 PATISIRAN .................................................................................. 34 
1.1.4 Therapeutic Hypothesis ................................................................ 34 
1.2 
Summary of Patisiran Nonclinical Data ................................................... 34 
1.3 
Summary of Clinical Data with Patisiran ................................................. 35 
1.4 
Study Design Rationale............................................................................. 36 
1.5 
Dose Selection and Dosing Schedule Rationale ....................................... 37 
1.6 
Risk-Benefit Assessment .......................................................................... 37 
2 
Study Objectives...................................................................................................40 
2.1 
Primary Objective ..................................................................................... 40 
2.2 
Secondary Objectives................................................................................ 40 
2.3 
Exploratory Objectives ............................................................................. 40 
3 
Study Plan .............................................................................................................42 
3.1 
Overall Design .......................................................................................... 42 
3.2 
Efficacy Assessments................................................................................ 44 
3.3 
Safety Assessments ................................................................................... 44 
3.4 
Pharmacodynamic Assessments ............................................................... 44 
3.5 
Pharmacokinetic Assessments .................................................................. 44 
3.6 
Other Assessments .................................................................................... 45 
4 
Patient Population ................................................................................................46 
4.1 
Eligibility of Patients ................................................................................ 46 
4.2 
Inclusion Criteria ...................................................................................... 46 
4.3 
Exclusion Criteria ..................................................................................... 47 
4.4 
Assignment to Treatment Group/Patient Number .................................... 48 
4.4.1 Randomization Procedures ........................................................... 48 
4.4.2 Patient Numbering ........................................................................ 48 
4.4.3 Blinding Procedure ....................................................................... 48 
4.4.4 Breaking the Blind ........................................................................ 49 
4.5 
Early Patient Discontinuation or Withdrawal ........................................... 49 
4.5.1 Reasons for Treatment Discontinuation or Withdrawal ............... 50 
4.5.2 Handling of Withdrawals or Patients who Discontinue from 
Treatment ...................................................................................... 50 
4.5.3 Replacements ................................................................................ 51 
4.6 
Discontinuation Due to Rapid Disease Progression ................................. 51 
4.7 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements51 
5 
Study Medication .................................................................................................53 


 
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5.1 
Presentation of Study Drug ....................................................................... 53 
5.2 
Preparation of Study Drug ........................................................................ 53 
5.2.1 Preparation of Patisiran ................................................................. 53 
5.2.2 Preparation of Placebo .................................................................. 53 
5.3 
Drug Administration ................................................................................. 54 
5.3.1 Premedication ............................................................................... 54 
5.3.2 Study Drug Administration ........................................................... 55 
5.4 
Storage of Study Drug .............................................................................. 55 
5.5 
Labeling and Packaging of Study Drug .................................................... 56 
5.6 
Measurement of Patient Compliance ........................................................ 56 
5.7 
Study Drug Accountability ....................................................................... 56 
5.8 
Concomitant Medication / Treatment ....................................................... 57 
5.9 
Suggested Guidelines for Management of Infusion-related Reactions..... 57 
6 
Study Visits ...........................................................................................................59 
6.1 
Screening, Screening/Baseline, and Baseline Visits (Days –42 to Day 0) 59 
6.1.1 Screening....................................................................................... 59 
6.1.2 Screening/Baseline Visit ............................................................... 60 
6.1.3 Baseline Visit ................................................................................ 61 
6.2 
Treatment Visits ........................................................................................ 63 
6.2.1 Day 0 ............................................................................................. 63 
6.2.2 Routine Study Visits ..................................................................... 64 
6.2.3 Efficacy Assessment Visits (9 Months and 18 Months) ............... 65 
6.2.4 Follow-Up Visits ........................................................................... 67 
6.3 
Early Withdrawal Visit and Follow-up Visits for Patients who 
Permanently Discontinue Study Treatment .............................................. 68 
6.3.1 Early Withdrawal Visit ................................................................. 68 
6.3.2 Follow-up Visits for Patients who Permanently Discontinue Study 
Treatment ...................................................................................... 69 
6.4 
Modified Visit Schedule for Patients who Discontinue Study Drug for 
Rapid Disease Progression at Month 9 ..................................................... 70 
6.4.1 Modified Day 273 ......................................................................... 70 
6.4.2 Modified Day 294 ......................................................................... 71 
6.4.3 Modified Day 378 and Day 462 .................................................... 71 
6.4.4 Modified Day 546 ......................................................................... 71 
6.4.5 Modified 18-Month Efficacy Assessment Visit ........................... 72 
6.4.6 Modified Twenty-One-Day Follow-up Visit (End of Study) ....... 73 
6.4.7 Modified Early Withdrawal Visit ................................................. 73 
6.5 
Unscheduled Visits ................................................................................... 74 
7 
Study Assessments ...............................................................................................75 
7.1 
Demographic Data and Medical History .................................................. 75 
7.2 
Efficacy Assessments................................................................................ 75 
7.2.1 Modified Neurological Impairment Score +7 ............................... 75 
7.2.2 Neurological Impairment Score +7 ............................................... 76 
7.2.3 Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy 
Disability Score ............................................................................. 76 


 
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7.2.4 Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber 
Density .......................................................................................... 76 
7.2.5 Modified Body Mass Index .......................................................... 76 
7.2.6 Timed Ten-meter Walk Test ......................................................... 76 
7.2.7 Grip Strength Test ......................................................................... 77 
7.2.8 Composite Autonomic Symptom Score........................................ 77 
7.2.9 Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..... 77 
7.2.10 EuroQoL Quality of Life Questionnaire ....................................... 77 
7.2.11 Rasch-built Overall Disability Scale ............................................. 77 
7.2.12 Echocardiogram and Biomarkers of Cardiac Function ................. 77 
7.3 
Pharmacodynamic Assessments ............................................................... 78 
7.3.1 Transthyretin ................................................................................. 78 
7.3.2 Retinol Binding Protein ................................................................ 78 
7.3.3 Vitamin A...................................................................................... 78 
7.3.4 Exploratory Biomarkers ................................................................ 78 
7.4 
Pharmacokinetic Evaluations .................................................................... 78 
7.4.1 Plasma Pharmacokinetics.............................................................. 79 
7.4.2 Urine Pharmacokinetics ................................................................ 79 
7.5 
Safety Assessments ................................................................................... 79 
7.5.1 Physical Examination.................................................................... 79 
7.5.2 Body Weight and Height .............................................................. 79 
7.5.3 Vital Signs ..................................................................................... 79 
7.5.4 Electrocardiogram ......................................................................... 79 
7.5.5 Clinical Laboratory Tests .............................................................. 80 
7.5.6 Ophthalmology Examination ........................................................ 82 
7.5.7 Adverse Events and Study-Procedure-Related Adverse Events ... 82 
7.5.8 Concomitant Medications and Treatments ................................... 82 
7.6 
Other Assessments .................................................................................... 82 
7.6.1 Pharmacoeconomics Questionnaire .............................................. 82 
7.6.2 Suicidality Questionnaire .............................................................. 82 
7.6.3 Phone Contact for Health Status Update and FAP Treatment ...... 83 
8 
Reporting Adverse Events ...................................................................................84 
8.1 
Adverse Event Definition ......................................................................... 84 
8.2 
Serious Adverse Event Definition ............................................................ 84 
8.3 
Eliciting Adverse Event Information ........................................................ 84 
8.4 
Adverse Event Reporting .......................................................................... 85 
8.5 
Adverse Event Reporting Period .............................................................. 85 
8.6 
Assessment of Causality ........................................................................... 86 
8.7 
Assessment of Severity ............................................................................. 86 
8.8 
Action Taken for Adverse Event .............................................................. 87 
8.9 
Outcome of Adverse Event ....................................................................... 87 
8.10 
Coding of Adverse Events ........................................................................ 87 
8.11 
Serious Adverse Event Reporting ............................................................. 87 
8.12 
Pregnancy Reporting ................................................................................. 88 
9 
Statistical Methods ...............................................................................................90 
9.1 
Sample Size ............................................................................................... 90 


 
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9.2 
Statistical Methodology ............................................................................ 90 
9.2.1 Populations to be Analyzed .......................................................... 90 
9.2.2 Baseline Evaluations ..................................................................... 90 
9.2.3 Efficacy Analyses ......................................................................... 90 
9.2.4 Safety Analyses ............................................................................. 91 
9.2.5 Pharmacodynamics ....................................................................... 92 
9.2.6 Pharmacokinetics .......................................................................... 92 
9.2.7 Summary of Efficacy Assessments ............................................... 92 
9.2.8 Other Assessments ........................................................................ 93 
9.2.9 Interim Analysis ............................................................................ 93 
9.2.10 Missing Data ................................................................................. 93 
10 
Study Management ..............................................................................................94 
10.1 
Data Handling and Quality Assurance ...................................................... 94 
10.1.1 Case Report Forms ........................................................................ 94 
10.1.2 Monitoring .................................................................................... 94 
10.1.3 Inspections .................................................................................... 94 
10.2 
Regulatory Guidelines .............................................................................. 94 
10.2.1 Institutional Review Board/Independent Ethics Committee......... 95 
10.2.2 Regulatory Authorities .................................................................. 95 
10.2.3 Modification of the Protocol ......................................................... 95 
10.2.4 Informed Consent Form ................................................................ 95 
10.2.5 Study Reporting Requirements ..................................................... 96 
10.2.6 Financial Disclosure Reporting Obligations ................................. 96 
10.3 
Study Committees ..................................................................................... 96 
10.3.1 Data Monitoring Committee ......................................................... 96 
10.3.2 Clinical Adjudication Committee ................................................. 96 
10.3.3 Interim Analysis Committee ......................................................... 96 
10.4 
Ancillary Research .................................................................................... 97 
10.5 
Study Record Retention ............................................................................ 97 
10.6 
Discontinuation of the Study by Alnylam ................................................ 97 
10.7 
Study Documentation................................................................................ 97 
10.8 
Confidentiality .......................................................................................... 98 
10.9 
Publications/Reports ................................................................................. 99 
11 
References ...........................................................................................................100 
12 
Appendices ..........................................................................................................104 
 
 
 


 
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List of Tables 
Table 1-1: 
Schedule of Assessments; Screening to 9-Month Efficacy Assessment .. 17 
Table 1-2: 
Schedule of Assessments; Week 39 to Week 86 (Follow-up) / Early 
Withdrawal 
................................................................................................................... 21 
Table 1-3: 
Modified Schedule of Assessments for Patients who Discontinue Study 
Drug for Rapid Disease Progression; Week 39 to End of Study ...................................... 26 
 
 
List of Figures 
Figure 1: 
Study Schematic........................................................................................ 43 
 
 
List of Appendices 
Appendix 1: 
Karnofsky Scale ...................................................................................... 104 
Appendix 2: 
New York Heart Association Classification of Heart Failure ................ 105 
Appendix 3: 
Categorization of Infusion-Related Reactions ........................................ 106 
Appendix 4: 
Neuropathy Scores and Their Components ............................................ 107 
Appendix 5: 
Polyneuropathy Disability Score ............................................................ 108 
Appendix 6: 
Familial Amyloidotic Polyneuropathy Stage .......................................... 109 
 


 
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PROTOCOL SYNOPSIS 
Protocol Title 
APOLLO:  A Phase 3 Multicenter, Multinational, Randomized, 
Double-blind, Placebo-controlled Study to Evaluate the Efficacy 
and Safety of Patisiran (ALN-TTR02) in Transthyretin (TTR)-
Mediated Polyneuropathy (Familial Amyloidotic 
Polyneuropathy-FAP) 
Indication 
Treatment of transthyretin-mediated amyloidosis (ATTR) in 
patients with symptomatic polyneuropathy 
Protocol Number 
ALN-TTR02-004 
Phase of 
Development 
3 
Design 
This is a multicenter, multinational, randomized, double-blind 
study comparing patisiran (ALN-TTR02) to placebo in ATTR 
patients with symptomatic Familial Amyloidotic Polyneuropathy 
(FAP). 
Consented eligible patients will be randomized to receive either 
0.3 mg/kg patisiran or placebo in a 2:1 ratio (patisiran to placebo) 
in a blinded manner.  Treatment arms will be balanced at entry 
for Neuropathy Impairment Score (NIS; 5-49 vs 50-130), early 
onset V30M (<50 years of age at onset) vs. all other mutations 
(including late onset V30M), and previous tetramer stabilizer use 
(tafamidis or diflunisal) vs no previous tetramer stabilizer use.  
Patients will receive patisiran or placebo once every 21 days for 
78 weeks. 
Patients will have baseline efficacy assessments and efficacy 
assessments at 9 and 18 months.  The study personnel performing 
these assessments will be blinded to the results of any previous 
assessments (e.g., Screening/Baseline, Baseline, or 9-month 
assessments). 
At the 9-month time point, if the clinical adjudication committee 
determines that a patient is exhibiting rapid disease progression 
(defined as ≥24 point increase in modified NIS+7 (mNIS+7) 
from baseline [based on an average of 2 measurements] and FAP 
stage progression relative to baseline), the patient’s treating 
physician will provide the patient with the option of 
discontinuing study drug and receiving local standard of care 
treatment for FAP.  Patients who discontinue study drug will 
remain on study, following a modified schedule of visits, through 
completion of the 18-month efficacy assessments (blinding will 
be maintained throughout). 


 
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Patients who complete the 18-month efficacy assessments can 
elect to participate in an extension study in which patients would 
receive open-label administration of 0.3 mg/kg patisiran once 
every 21 days. 
A Data Monitoring Committee (DMC) will be implemented for 
the study and will operate under a prespecified charter.  
Study Sites 
This study will be conducted at multiple sites worldwide. 
Investigational 
Drug 
Patisiran (comprising a small interfering ribonucleic acid 
[siRNA] targeting mutant and wild-type TTR mRNA, in a lipid 
nanoparticle formulation for intravenous [IV] administration) 
Dosage, Route of 
Administration 
and Duration of 
Treatment of 
Investigational 
Drug 
Patients randomized to the active treatment group will receive 
0.3 mg/kg patisiran once every 21 (±3) days administered as an 
IV infusion over 70 minutes (approximately 1 mL/minute for the 
first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device.  
Prior to each dose of study drug, patients will receive the 
following premedications at least 60 minutes prior to the 
infusion: 
• Intravenous dexamethasone (10 mg) or equivalent; 
• Oral paracetamol/acetaminophen (500 mg) or equivalent; 
• Intravenous H2 blocker (e.g., ranitidine 50 mg, famotidine 
20 mg, or equivalent other H2 blocker dose); and 
• Intravenous H1 blocker: diphenhydramine 50 mg (or 
equivalent other IV H1 blocker available at the study site).  
Hydroxyzine or fexofenadine 25 mg per oral suspension 
(PO, orally) or cetirizine 10 mg PO may be substituted for 
any patient who does not tolerate intravenous 
diphenhydramine or other intravenous H1 blocker. 
Control Drug 
Placebo (normal saline 0.9% for IV administration) 
Dosage, Route of 
Administration 
and Duration of 
Treatment of 
Control Drug 
Patients randomized to placebo will receive IV normal saline 
(0.9%) using the same dosing schedule and infusion rate as the 
active treatment group.   
Placebo patients will also receive the same premedication 
regimen as the active treatment group. 
Time on Study 
The duration of patient participation in this study is 
approximately 21 months (inclusive of a 42-day screening 
window and up to a 56-day post last dose study visit). 
Primary 
Objective 
The primary objective of the study is to determine the efficacy of 
patisiran by evaluating the difference between the patisiran and 
placebo groups in the change from baseline of mNIS+7 score at 
18 months. 


 
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Secondary 
Objectives 
The secondary objectives of the study are to determine the effect 
of patisiran on various clinical parameters by assessing the 
difference between patisiran and placebo in the change from 
baseline in the following measurements at 18 months: 
• Norfolk Quality of Life-Diabetic Neuropathy 
(Norfolk QOL-DN) questionnaire; 
• NIS-weakness (NIS-W) score; 
• Modified body mass index (mBMI); 
• Timed 10-meter walk test; 
• Autonomic symptoms questionnaire (Composite Autonomic 
Symptom Score [COMPASS-31]). 
Exploratory 
Objectives: 
The exploratory objectives of the study are: 
• To determine the difference between the patisiran and 
placebo groups in the change from baseline in the following 
measurements at 18 months: 
• 
NIS+7 score; 
• 
Grip strength; 
• 
EuroQOL (EQ-5D) questionnaire; 
• 
Level of disability (Rasch-built Overall Disability Scale 
[R-ODS]); 
• 
Large vs small nerve fiber function including nerve 
conduction studies (NCS) 5 attributes (Σ5), quantitative 
sensory testing by body surface area including touch 
pressure and heat pain (QST), vibration detection 
threshold (VDT), heart rate response to deep breathing 
(HRdb), postural blood pressure; 
• 
Pathologic evaluation of sensory and autonomic 
innervation through voluntary skin punch biopsies and 
analysis of intraepidermal nerve fiber density (IENFD) 
and sweat gland nerve fiber density (SGNFD); 
• 
Assessment of ambulation through FAP stage and 
Polyneuropathy Disability (PND) score; 
• 
Cardiac assessment through echocardiogram, troponin I, 
and N-terminal prohormone of B-type natriuretic 
peptide (NT-proBNP) levels; 
• 
Pharmacodynamic (PD) biomarkers (TTR, retinol 
binding protein [RBP], vitamin A); 
• 
To compare the proportion of patients in the patisiran and 
placebo groups who meet the pre-defined criterion for rapid 
disease progression (defined as ≥24 point increase in 
mNIS+7 from baseline [based on an average of 


 
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2 measurements] and FAP stage progression relative to 
baseline) at 9 months. 
Sample Size: 
Approximately 200 patients will be enrolled in this study.  Of 
those 200 patients, no more than 40 patients will have a NIS 
range of 101 to 130.  An mNIS+7 progression rate (primary 
endpoint) in the placebo group of 24 ± 16 points in 18 months 
was estimated using natural history data from FAP patients.  A 
sample of 154 patients provides 90% power for a 2-sided test 
with an 8.95 point (37.5%) mean difference between treatment 
groups in the primary endpoint at 2-sided alpha = 0.05.  
Assuming a 25% random premature discontinuation rate (due to 
liver transplantation or other factors), the sample size for this 
study is approximately 200.  Additional patients may be enrolled 
based on a recommendation to increase the sample size in the 
interim analysis. 
Inclusion and 
Exclusion 
Criteria: 
To be enrolled in the study, each patient must meet the following 
criteria at the Screening visit, except where specified: 
1. 
Male or female of 18 to 85 years of age (inclusive); 
2. 
Have a diagnosis of FAP with documented TTR mutation;  
3. 
Have an NIS of 5 to 130 (inclusive) and a PND score of ≤3b 
(Note:  This criterion must be met at the Screening/Baseline 
visit); 
4. 
Have an NCS sum of the sural sensory nerve action potential 
(SNAP), tibial compound muscle action potential (CMAP), 
ulnar SNAP, ulnar CMAP, and peroneal CMAP of ≥2 
points; (Note:  This criterion must be met at the 
Screening/Baseline visit); 
5. 
Have a Karnofsky performance status of ≥60%; 
6. 
Have an absolute neutrophil count (ANC) ≥1500 cells/mm³, 
and a platelet count ≥50,000 cells/mm³; 
7. 
Have aspartate transaminase (AST) and alanine 
transaminase (ALT) levels ≤2.5 × the upper limit of normal 
(ULN), total bilirubin within normal limits, international 
normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed). Patients with 
total bilirubin ≤ 2 X ULN are eligible if the elevation is 
secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and 
the patient has ALT and AST levels within normal ranges; 
8. 
Have a serum creatinine ≤2 × ULN; 


 
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9. 
No active infection with hepatitis B or hepatitis C by 
serology; 
10. Women of child-bearing potential must have a negative 
pregnancy test, cannot be breastfeeding, and must be using 
2 highly effective methods of contraception prior to 
screening, throughout study participation, and for 75 days 
after the last dose of study drug.  Highly effective methods 
of birth control are defined in Section 4.7; 
11. Males with partners of child-bearing potential must agree to 
use 1 barrier method (e.g., condom) and 1 additional method 
(e.g., spermicide) of contraception throughout study 
participation and for 75 days after the last dose of study 
drug; males must also abstain from sperm donation after the 
first dose of study drug through study participation and for 
75 days after the last dose of study drug; 
12. Must be willing and able to comply with protocol-required 
visit schedule and visit requirements and provide written 
informed consent. 
 
A patient will be excluded if they meet any of the following 
criteria at the time of the Screening visit: 
1. 
Had a prior liver transplant or is planning to undergo liver 
transplant during the study period; 
2. 
Has other known causes of sensorimotor or autonomic 
neuropathy (e.g., autoimmune disease, monoclonal 
gammopathy); 
3. 
Has known primary amyloidosis or leptomeningeal 
amyloidosis; 
4. 
Has known type I diabetes; 
5. 
Has had type II diabetes mellitus for ≥5 years; 
6. 
Has vitamin B12 levels below the lower limit of normal 
(LLN); 
7. 
Has untreated hypo- or hyperthyroidism; 
8. 
Has had a major surgery within the past 3 months or has a 
major surgery planned during any point of the study period; 
9. 
Has known human immunodeficiency virus (HIV) infection; 
10. Has an active infection requiring systemic antiviral or 
antimicrobial therapy that will not be completed prior to the 
first dose of study drug administration; 


 
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11. Had a malignancy within 2 years, except for basal or 
squamous cell carcinoma of the skin or carcinoma in situ of 
the cervix that has been successfully treated; 
12. Has a New York Heart Association heart failure 
classification >2; 
13. Had acute coronary syndrome within the past 3 months; 
14. Has uncontrolled cardiac arrhythmia or unstable angina; 
15. Has a known history of alcohol abuse within the past 2 years 
or daily heavy alcohol consumption (females: more than 14 
units of alcohol per week; males: more than 21 units of 
alcohol per week [unit: 1 glass of wine [125 mL] = 1 
measure of spirits = ½ pint of beer]); 
16. Received an investigational agent or device within 30 days 
of anticipated study drug administration or 5 half-lives of the 
investigational drug, whichever is longer; 
17. Participated in a clinical trial with antisense oligonucleotide, 
must have completed a 3-month wash-out prior to start of 
the study drug administration in this study; 
18. Is currently taking tafamidis, doxycycline, or 
tauroursodeoxycholic acid; if previously on any of these 
agents, must have completed a 14-day wash-out prior to start 
of study drug administration in this study; 
19. Is currently taking diflunisal; if previously on this agent, 
must have at least a 3-day wash-out prior to start of study 
drug administration in this study; 
20. Had a prior severe reaction to a liposomal product or a 
known hypersensitivity to oligonucleotides or any 
component of patisiran; 
21. Is unable to take the required premedications; 
22. Anticipated survival is less than 2 years, in the opinion of 
the Investigator; 
23. Is considered unfit for the study by the Investigator; 
24. Is under legal protection (defined as “any person who 
becomes incapable of protecting his/her interests due to a 
medically diagnosed impairment of his/her mental faculties 
that may limit or prevent the expression of his/her will”). 
Efficacy 
Assessments 
Efficacy parameters will include the following (baseline evaluations 
will be conducted as well as evaluations at 9 and 18 months): 


 
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• 
Neurologic impairment will be assessed using the mNIS+7 
composite score.  The mNIS+7 includes the modified NIS 
(weakness and reflexes), NCS Σ5, QST, as well as 
autonomic assessment through postural blood pressure; 
• 
Patient-reported QOL will be evaluated using the Norfolk 
QOL-DN and the EQ-5D.  Disability will be reported by 
patients using the R-ODS; 
• 
Autonomic symptoms will be assessed using the 
COMPASS-31; 
• 
Motor function assessments to be evaluated include NIS-W, 
timed 10-meter walk test, and grip strength test; 
• 
PND score and FAP stage; 
• 
Nutritional status will be assessed using mBMI; 
• 
Pathologic evaluation of sensory and autonomic innervation 
will be evaluated by IENFD analysis and quantitation of 
dermal SGNFD via tandem 3 mm skin punch biopsies taken 
from the leg; 
• 
Neurologic impairment will also be assessed by NIS+7 
(including full NIS, NCS, VDT, and HRdb); 
• 
Cardiac structure and function will be assessed through 
echocardiograms as well as measurement of serum levels of 
NT-proBNP and troponin I. 
Pharmaco-
dynamic 
Assessments 
Pharmacodynamic markers assessed serially will include serum 
TTR, vitamin A, and RBP.  Additional blood samples will be 
collected for exploratory biomarkers related to FAP. 
Pharmacokinetic 
Assessments 
The plasma pharmacokinetic (PK) evaluation will include, 
whenever possible, plasma-concentration time profiles for siRNA 
and the novel lipid components in patisiran: DLin-MC3-DMA 
and polyethylene glycol (PEG)2000-C-DMG.  The siRNA, DLin-
MC3-DMA, and PEG2000-C-DMG concentrations will be 
determined for all patients at time points specified in Table 1-1, 
Table 1-2, and Table 1-3.  
Urine will be collected with void volume recorded for all patients 
at time points specified in Table 1-1, Table 1-2, and Table 1-3 
and to determine renal clearance (CLR) of siRNA and 
4-dimethylaminodibutyric acid (the metabolite of DLin-
MC3-DMA) after dosing with study drug. 


 
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Safety 
Assessments 
Safety will be assessed throughout the study by collecting 
adverse events (AEs; including serious adverse events [SAEs]); 
clinical laboratory tests, including hematology, clinical chemistry 
(including liver function tests), thyroid function parameters, and 
urinalysis; measurement of anti-drug antibodies; 
electrocardiograms; vital signs; physical examination findings; 
and ophthalmology examinations. 
Other 
Assessments 
Disease burden and healthcare utilization will be assessed using a 
patient-reported pharmacoeconomics questionnaire.  The 
investigator will periodically assess mental status as it relates to 
suicidal ideation and behavior by using the Columbia–Suicide 
Severity Rating Scale (C-SSRS) questionnaire.   
Follow-Up 
Patients who complete the 18-month efficacy assessments can 
elect to participate in an extension study in which patients would 
receive open-label administration of 0.3 mg/kg patisiran once 
every 21 days.  Eligible patients who elect to participate will 
return for a follow-up visit 21 days after last dose of study drug. 
If the patient decides not to participate in the extension study, the 
patient will complete 2 follow-up visits at 21 and 56 days after 
the last dose of study drug.  Each follow-up visit includes safety 
assessments and the 21-day follow-up also includes PD 
measurements. 
Statistical 
Methods 
A full statistical analysis plan (SAP) will be finalized prior to 
database lock. 
The primary analysis will compare patients administered 
patisiran versus those administered placebo in the modified 
intent-to-treat (mITT) population.  Specifically, patients who are 
randomized and receive at least 1 dose of study drug will be 
included in this analysis.  The primary analysis will compare 
change in mNIS+7 from baseline at 18 months between patisiran 
and placebo groups, adjusted for the stratification factors.  
Analysis of covariance (ANCOVA) will be used to analyze the 
primary endpoint.  Primary endpoint data that are missing will be 
inferred using multiple imputations.  Sensitivity analyses, 
including mixed model repeated measures (MMRM) analyses, 
will assess the robustness of the primary analysis for the mITT 
and per protocol (PP) populations.  
Type I error control for secondary endpoints will be achieved by 
a hierarchical ordering procedure.  Briefly, endpoints will be 
evaluated in order to control for multiplicity. 
An independent interim analysis committee (IAC) will conduct a 
blinded interim analysis when approximately 50% of patients 
have completed their 9-month mNIS+7 assessments.  This 


 
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interim analysis will estimate the overall variance in the mNIS+7 
score.  Based on the results of the interim analysis, the committee 
can recommend either increasing the study sample size or making 
no adjustment to the sample size. 
PK analyses will be conducted using non-compartmental and/or 
compartmental evaluation.  The PK parameters of siRNA, DLin-
MC3-DMA, and PEG2000-C-DMG in plasma will be evaluated. 
Population PK analyses will be performed whenever possible on 
available siRNA, DLin-MC3-DMA, and PEG2000-C-DMG from 
sparse samples collected at various time points during the 
duration of the study. 
Inferential statistics of PD and PK/PD parameters, correlation 
between siRNA, DLin-MC3-DMA or PEG2000C-DMG exposure 
versus TTR, RBP, or vitamin A, and between TTR versus RBP 
and vitamin A will be provided. 
 


 
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Table 1-1: 
Schedule of Assessments; Screening to 9-Month Efficacy Assessment 
Procedure 
Visit Type 
Screening (a) 
Screening/ 
Baseline (a) 
Baseline (a) 
Predosing 
Dosing 
9-Month 
Efficacy 
Assessment(y)
Study Day 
Day -42 to 0 
D0 
Predose 
D0 
D21 
D42 
D63 
D84 
D105 
D126 
D147 
D168 
D189 
D210 
D231 
D252 
D253-
D272 
Study Week 
NA 
0 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
Windows 
NA 
0 
0 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NA 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X (a) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X (b) 
X (b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Documentation of TTR Genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Status Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
New York Heart Classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology Testing (c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Paraprotein by IFE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
NIS (d) / NCS (d) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mNIS+7 (e) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
NIS + 7 (f) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
PND Score and FAP Stage 
 
X (g) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Skin Punch Biopsy (IENFD and SGNFD) (h) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
mBMI (i) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
10-meter Walk Test (j) 
 
X (z) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Grip Strength Test (k) 
 
X (z) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Norfolk QOL-DN; COMPASS 31 
Questionnaires 
 
X (z) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
EQ-5D; R-ODS Questionnaires 
 
X (z) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram 
 
X (z) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NT-proBNP and Troponin I 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic Assessments (l) 
TTR Protein, Vitamin A, and RBP 
 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Obtain Blood Sample for Long-term Storage 
 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 


 
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Table 1-1: Schedule of Assessments; Screening to 9-Month Efficacy Assessment (continued) 
Procedure 
Visit Type 
Screening (a) 
Screening/ 
Baseline (a) 
Baseline (a) 
Predosing 
Dosing 
9-Month 
Efficacy 
Assessment(y)
Study Day 
Day -42 to 0 
D0 
Predose 
D0 
D21 
D42 
D63 
D84 
D105 
D126 
D147 
D168 
D189 
D210 
D231 
D252 
D253-
D272 
Study Week 
NA 
0 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
Windows 
NA 
0 
0 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NA 
Safety Assessments (m) 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight (n) 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (o) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG (p) 
 
X (z) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Serum Chemistry 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Hematology, Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Thyroid Function Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation Studies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-drug Antibody Testing (q) 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Pregnancy Test (r) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology Exam (s) 
 
X 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
Adverse Events 
 
 
 
X 
Pharmacokinetic Assessments 
Plasma PK Sampling (t) 
 
 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urine PK Sampling (u) 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Other Assessments 
Pharmacoeconomic Questionnaire 
 
X (z) 
 
 
 
 
 
 
 
 
 
 
 
X 
C-SSRS Questionnaire 
 
X (z) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug Administration 
Randomization (v) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication Administration (w) 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Administration (x) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 


 
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Table 1-1 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; EQ-5D = EuroQOL-5 Dimensions; ECG = electrocardiogram; FAP = familial amyloidotic 
polyneuropathy; HIV = human immunodeficiency virus; IENFD = Intraepidermal nerve fiber density; IFE = immunofixation electrophoresis; mBMI = modified body mass 
index; mNIS = Modified Neuropathy Impairment Score; NCS = nerve conduction studies; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-
type natriuretic peptide; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; RBP = retinol binding protein; R-ODS = Rausch-built Overall 
Disability Scale; SGNFD = Sweat gland nerve fiber density; TTR = transthyretin. 
a. 
The Screening/Baseline and Baseline visits will be performed on separate days.  The Screening/Baseline visit must be performed within 21 days prior to the first dose of study 
drug (Day 0).  The Baseline visit must be conducted at least 24 hours (approximately), but not more than 7 days, after the Screening/Baseline visit.  In conjunction with the 
decision of the Medical Monitor(s), patients may be allowed to rescreen after a minimum of 5 days have elapsed from their last screening assessment.  Note:  Inclusion 
Criteria 3 (i.e., NIS of 5 to 130 [inclusive] and PND score ≤3b) and 4 (i.e., NCS sum of the sural sensory nerve action potential [SNAP], tibial compound muscle action 
potential [CMAP], ulnar SNAP, ulnar CMAP, and peroneal CMAP of ≥2 points) must be met at the Screening/Baseline visit.  All other entry criteria (inclusion and exclusion) 
will be assessed at the Screening visit only. 
b. 
An interval medical history will be collected at the Screening/Baseline and Baseline visit.  Only changes since the Screening visit will be collected. 
c. 
Serologies will include hepatitis B surface antibody (HbsAb), hepatitis B surface antigen (HbsAg), and anti–hepatitis C virus antibody (anti-HCV Ab). 
d. 
The NIS and NCS will be assessed for the likelihood of a patient meeting the NIS and NCS eligibility criteria at the Screening/Baseline visit. The documented results of 
previously performed NIS and NCS may be used to qualify a patient for this study if these tests were performed within 60 days prior to the date of informed consent. 
e. 
The mNIS+7 consists of the modified NIS tool (weakness and reflexes), NCS 5 attributes (Σ5), quantitative sensory testing (QST) by body surface area including touch 
pressure (TP) and heat pain (HP), and postural blood pressure.  At the 9-month efficacy assessment, 2 assessments of the mNIS+7 will be performed on separate days 
(1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each assessment (e.g., the weakness component should not 
be performed more than once on any given day). 
f. 
The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, vibration detection threshold (VDT), and heart rate response to deep breathing (HRdB).  At 
the 9-month efficacy assessment, 2 assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart.  Components that are shared between the mNIS+7 and NIS+7 (including 
NIS and NCS) will be performed once at each assessment (e.g., the weakness component should not be performed more than once on any given day). 
g. 
At the Screening/Baseline visit, only PND score is required. 
h. 
If the patient has provided separate informed consent for skin biopsies, 2 sets of tandem 3-mm skin punch biopsies are to be obtained (4 biopsies total).  One set of biopsies 
will be taken from the distal lower leg, when a patient’s clinical status allows, and one set from the distal thigh at each time point.  Skin biopsies will be performed at a central 
assessment site (CAS). 
i. 
The mBMI calculation will take place programmatically in the clinical database; the site will not perform the calculation. 
j. 
The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers are permitted.  
The time required for the patient to walk 10 meters will be recorded.  At the 9-month efficacy assessment, 2 assessments of the 10-meter walk test will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 
7 days apart.  
k. 
Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient throughout the 
duration of the study.  At the 9-month efficacy assessment, 2 assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second 
(repeat) assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
l. 
On dosing days, blood samples for PD assessments will be obtained prior to dosing and vitamin A supplementation. 


 
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Table 1-1 Footnotes (continued): 
m. On dosing days, all safety assessments are performed pre-dose. 
n. 
Weight from previous visit should be used for calculating dose.  Weight must be collected pre-dose. 
o. 
Vital signs to include: blood pressure, pulse rate, temperature, and respiratory rate.  Parameters are to be measured in the supine position using an automated instrument after 
the patient has rested comfortably for 10 minutes.  Vital signs must be collected pre-dose.  On Day 0, vital signs will also be collected post-dose. 
p. 
All ECGs are to be obtained in triplicate. 
q. 
Blood samples for anti-drug antibody testing will be collected prior to study drug dosing. 
r. 
A pregnancy test (urine- or serum-based) will be performed on all females of child-bearing potential. 
s. 
The baseline ophthalmology examination may be performed any time after the patient is deemed eligible for participation in the study through Day 21.  The 9-month 
ophthalmology examination will be performed between Days 231(±3) and 272 at a CAS. 
t. 
Plasma PK samples will be collected as follows:  Day 0:  pre-dose (within 1 hour of planned study drug dosing) and at the end of infusion (+5 minutes).  Day 21 and Day 252: 
pre-dose (within 1 hour of planned study drug dosing) and 30 minutes after the end of the infusion (+15 minutes).  Day 126: pre-dose (within 1 hour of planned study drug 
dosing) and at the end of infusion (+5 minutes). 
 
u. 
Urine PK samples will be collected pre-dose (within 1 hour of planned study drug dosing). 
v. 
Randomization procedures are described in Section 4.4.1. 
w. Prior to dosing, all patients will receive premedications administered at least 60 minutes prior to the start of infusion of study drug.  The regimen is described in Section 5.3.1.  
x. 
The patient’s infusion site should be assessed for signs of any localized reaction during the infusion and for 30 minutes after the end of the infusion.  The patient will remain 
at the study site for 1 hour following completion of dosing for observation and completion of assessments. 
y. 
Patients who discontinue study drug due to rapid disease progression based on the 9-month efficacy assessments will continue on to the Modified Visit Schedule (See Table 
1-3). 
z. 
Assessment must be completed at a single time point during one of the specified visits, at the discretion of the investigator. 


 
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Table 1-2: 
Schedule of Assessments; Week 39 to Week 86 (Follow-up) / Early Withdrawal 
Procedure 
Visit 
Type 
Dosing 
18-Month Efficacy 
Assessment 
End of Study(a) 
Follow-up(a) 
Early Withdrawal(b) 
Follow-up for 
Patients who 
Discontinue 
Treatment but 
Return at 9 
and/or 18 mo(c) 
Study Day 
D273 
D294 
D315 
D336 
D357 
D378 
D399 
D420 
D441 
D462 
D483 
D504 
D525 
D546 
D553-
D560 
D567 
D602 
NA 
D253-
D272 
D553-
D560 
Study Week 
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
86 
NA 
36-39 
79-80 
Windows 
+3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NA 
±7D 
±10D 
2D to 
7D 
±10D 
±10D 
Efficacy Assessments 
mNIS+7(d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
NIS+7(e) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
PND Score and FAP 
Stage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Skin Punch Biopsy 
(IENFD and SGNFD)(f) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
mBMI(g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
10-meterWalkTest(h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
Grip Strength Test(i) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
Norfolk QOL-DN; EQ-
5D; R-ODS Disability; 
COMPASS31 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X(j) 
X(j) 
Echocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
NT-pro BNP and 
Troponin I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Pharmacodynamic Assessments(k) 
TTR Protein, Vitamin A, 
and RBP 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
X 
Obtain Blood Sample 
for Long-term Storage 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
 


 
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Procedure 
Visit 
Type 
Dosing 
18-Month Efficacy 
Assessment 
End of Study(a) 
Follow-up(a) 
Early Withdrawal(b) 
Follow-up for 
Patients who 
Discontinue 
Treatment but 
Return at 9 
and/or 18 mo(c) 
Study Day 
D273 
D294 
D315 
D336 
D357 
D378 
D399 
D420 
D441 
D462 
D483 
D504 
D525 
D546 
D553-
D560 
D567 
D602 
NA 
D253-
D272 
D553-
D560 
Study Week 
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
86 
NA 
36-39 
79-80 
Windows 
+3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NA 
±7D 
±10D 
2D to 
7D 
±10D 
±10D 
Safety Assessment(l) 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Weight(m) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Vital Signs(n) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-Lead ECG(o) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Serum Chemistry 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
Coagulation(w) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Hematology, Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Thyroid Function Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Anti-drug Antibody 
Testing(p) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Pregnancy Test(q) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
Ophthalmology(r) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Concomitant 
Medications 
X 
Adverse Events 
X 
 
 
Pharmacokinetic Assessments 
Plasma Pharmacokinetic 
Sampling(s) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Urine Pharmacokinetic 
Sampling(t) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Other Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacoeconomic 
Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 


 
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Procedure 
Visit 
Type 
Dosing 
18-Month Efficacy 
Assessment 
End of Study(a) 
Follow-up(a) 
Early Withdrawal(b) 
Follow-up for 
Patients who 
Discontinue 
Treatment but 
Return at 9 
and/or 18 mo(c) 
Study Day 
D273 
D294 
D315 
D336 
D357 
D378 
D399 
D420 
D441 
D462 
D483 
D504 
D525 
D546 
D553-
D560 
D567 
D602 
NA 
D253-
D272 
D553-
D560 
Study Week 
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
86 
NA 
36-39 
79-80 
Windows 
+3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3
D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NA 
±7D 
±10D 
2D to 
7D 
±10D 
±10D 
C-SSRS Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Drug Administration 
Premedication 
Administration(u) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Study Drug 
Administration(v) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Karnosky performance 
status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
NYHA class 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


 
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Table 1-2 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; C-SSRS = Columbia–Suicide Severity Rating Scale; EQ-5D = EuroQOL; ECG = electrocardiogram; 
FAP = familial amyloidotic polyneuropathy; IENFD = Intraepidermal nerve fiber density; mBMI = modified body mass index; mNIS = Modified Neuropathy Impairment 
Score; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; PND = polyneuropathy disability; QOL-DN = Quality of 
Life-Diabetic Neuropathy; RBP = retinol binding protein; R-ODS = Rausch-built Overall Disability Scale; SGNFD = Sweat gland nerve fiber density; TTR = transthyretin. 
a.  
If a patient enrolls in the extension study, the patient will only have to complete the 21-day follow-up assessments (EOS; Day 567) and not the 56-day follow-up assessments 
(Day 602).  Patients who do not enroll in the extension study will need to complete both follow-up visits (Days 567 and 602). 
b.  The Early Withdrawal visit will take place over 2 days to allow for the repeat assessment of the mNIS+7, NIS+7, timed 10-meter walk, and grip strength test. 
c. 
Patients who discontinue treatment may return for follow-up visits at 9 and/or 18 months. 
d.  The mNIS+7 consists of the modified NIS tool (weakness and reflexes), NCS Σ5, QST by body surface area including TP and HP, and postural blood pressure.  Two 
assessments will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) after the 
first assessment, but not more than 7 days apart.  Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment (e.g., the weakness component should not be performed more than once on any given day).   
e.  
The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, VDT, and heart rate response to deep breathing.  Two assessments will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 
7 days apart.  Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each assessment (e.g., the weakness 
component should not be performed more than once on any given day).   
f.  
If the patient has provided separate informed consent for skin biopsies, 2 sets of tandem 3-mm skin punch biopsies are to be obtained (4 biopsies total).  One set of biopsies 
will be taken from the distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh at each time point. 
g.  The mBMI calculation will take place programmatically in the clinical database; the site will not perform the calculation.  
h.  The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers are permitted.  
The time required for the patient to walk 10 meters will be recorded.  Two assessments will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart.   
i.  
Grip strength will be measured using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient throughout the duration of the 
study.  Two assessments will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) 
after the first assessment, but not more than 7 days apart.   
j. 
Only the Norfolk and EQ-5D are to be performed for patients who discontinue treatment and return for the 9 and 18 month visits. 
k. 
On dosing days, blood samples for PD assessments will be obtained prior to dosing and vitamin A supplementation. 
l.  
On dosing day, all safety assessments are performed pre-dose. 
m.  Weight from previous visit should be used for calculating dose.  Weight must be collected pre-dose. 
n.  Vital signs to include: blood pressure, pulse rate, temperature, and respiratory rate.  Parameters are to be measured in the supine position using an automated instrument after 
the patient has rested comfortably for 10 minutes.  Vital signs must be collected pre-dose. 
o. 
All ECGs are to be obtained in triplicate. 
p.  On study drug dosing days, blood samples for anti-drug antibody testing will be collected pre-dose. 
q.  A pregnancy test (urine- or serum-based) will be performed on all females of child-bearing potential. 
r. 
The 18-month ophthalmology examination will be performed between Days 546(±3) and 560 at a CAS. 


 
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Table 1-2 Footnotes (continued): 
s. 
Plasma PK samples will be collected as follows:  Day 399: pre-dose (within 1 hour of planned study drug dosing) and at the end of infusion (+5 minutes).  Day 546: pre-dose 
(within 1 hour of planned study drug dosing) and 30 minutes after the end of the infusion (+15 minutes).  Early Withdrawal:  any time within the visit window. 
t. 
Urine PK samples will be collected as follows:  Day 399 and Day 546:  pre-dose (within 1 hour of planned study drug dosing).  Early Withdrawal:  any time within the visit 
window. 
u. 
Prior to dosing, all patients will receive premedications administered at least 60 minutes prior to the start of infusion of study drug.  The regimen is described in Section 5.3.1. 
v.  The patient’s infusion site should be assessed for signs of any localized reaction during the infusion and for 30 minutes after the end of the infusion.  The patient will remain 
at the study site for 1 hour following completion of dosing for observation and completion of assessments. 
w. INR assessment only, which is to be used for qualification for Study TTR02-006. 


 
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Table 1-3: 
Modified Schedule of Assessments for Patients who Discontinue Study Drug for Rapid Disease Progression; 
Week 39 to End of Study 
Procedure 
Visit Type  
Dosing 
18-Month Efficacy 
Assessment 
End of Study 
Early Withdrawal (a)  
Study Day 
D273 (b) 
D294 
D378 
D462 
D546 
D553-
D560 
D567 
NA 
Study Week 
39 
42 
54 
66 
78 
79-80 
81 
NA 
Windows 
+3D 
±3D 
±3D 
±3D 
±3D 
NA 
±7D 
2D to 7D 
Consultation on treatment options (c) 
X 
 
 
 
 
 
 
 
  
Efficacy Assessments 
   mNIS+7  (d) 
 
 
 
 
 
X 
X 
 
X 
X 
   NIS + 7 (e) 
 
 
 
 
 
X 
X 
 
X 
X 
   PND Score and FAP Stage 
 
 
 
 
 
X 
 
X 
   Skin Punch Biopsy (IENFD and SGNFD) (f) 
 
 
 
 
 
X 
 
X 
   mBMI (g) 
 
 
 
 
 
X 
 
X 
   10-meter Walk Test (h) 
 
 
 
 
 
X 
X 
 
X 
X 
   Grip Strength Test (i) 
 
 
 
 
 
X 
X 
 
X 
X 
   Norfolk QOL-DN; EQ-5D; R-ODS Disability; COMPASS 31 
Questionnaires 
 
 
 
 
 
X 
 
X 
    Echocardiogram 
 
 
 
 
 
X 
 
X 
    NT-proBNP and Troponin I 
 
 
 
 
 
X 
 
X 
PD Assessments 
    TTR Protein, Vitamin A, and RBP 
 
X 
 
 
X 
 
X 
X 
    Obtain Blood Sample for Long-term Storage 
 
X 
 
 
X 
 
X 
X 
 


 
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Table 1-3: 
Modified Schedule of Assessments for Patients who Discontinue Study Drug for Rapid Disease Progression; 
Week 39 to End of Study (continued) 
Procedure 
Visit Type  
Dosing 
18-Month Efficacy 
Assessment 
End of Study 
Early Withdrawal (a)  
Study Day 
D273 (b) 
D294 
D378 
D462 
D546 
D553-
D560 
D567 
NA 
Study Week 
39 
42 
54 
66 
78 
79-80 
81 
NA 
Windows 
+3D 
±3D 
±3D 
±3D 
±3D 
NA 
±7D 
2D to 7D 
Safety Assessments 
    Physical Examination 
 
X 
 
 
X 
 
X 
X 
    Weight 
 
 
 
 
X 
X 
X 
X 
X 
X 
    Vital Signs (j) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 12-Lead ECG (k) 
 
 
 
 
 
X 
 
X 
    Serum Chemistry 
 
X 
 
 
X 
 
 
X 
   Coagulation (r) 
 
 
 
 
X 
 
 
 
    Hematology, Urinalysis  
 
 
 
 
X 
 
 
 
    Thyroid Function Tests 
 
 
 
 
X 
 
 
X 
    Anti-drug Antibody Testing 
 
 
 
 
X 
 
 
X 
    Pregnancy Test (l) 
 
X 
 
 
X 
 
 
X 
    Concomitant Medications (m) 
X 
 
 
 
 
 
 
    Adverse Events (n) 
X 
 
 
 
 
 
 
    Study-procedure-related Adverse Events (o) 
 
 
X 
PK Assessments 
    Plasma PK Sampling 
 
X 
 
 
X 
 
 
 
    Urine PK Sampling 
 
X 
 
 
X 
 
 
 
Other Assessments 
    Pharmacoeconomic Questionnaire 
 
 
 
 
X 
 
 
X 
    C-SSRS Questionnaire 
 
 
 
 
 
X 
 
X 
   Collect Data on Subsequent FAP Treatment Regimens 
 
X 
X(p) 
X(p) 
X 
 
X 
X 
Phone Contact to Obtain Health Status Update (q) 
 
 
X 
X 
 
 
 
 


 
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Table 1-3 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; C-SSRS = Columbia–Suicide Severity Rating Scale; EQ-5D = EuroQOL; ECG = electrocardiogram; 
FAP = familial amyloidotic polyneuropathy; IENFD = Intraepidermal nerve fiber density; mNIS = Modified Neuropathy Impairment Score; NIS = Neuropathy Impairment 
Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; RBP = retinol 
binding protein; R-ODS = Rausch-built Overall Disability Scale; SGNFD = Sweat gland nerve fiber density; TTR = transthyretin. 
a. 
The Early Withdrawal visit will be conducted for any patient who discontinues from the study after the Day 273 visit (e.g., from  Day 274 onward).  This visit will take place 
over 2 days (at least 24 hours [approximately], but not more than 7 days apart) to allow for the repeat assessment of the mNIS+7, NIS+7, timed 10-meter walk, and grip 
strength test. 
b. 
Patients who discontinue study drug and also decide to discontinue from the study at the time of this visit will not have any additional visits after the Day 273 assessments are 
completed. 
c.  
The patient will consult with the Investigator on a subsequent plan of care, which may include receiving therapy for FAP as per the local standard of care. 
d 
The mNIS+7 consists of the modified NIS tool (weakness and reflexes), NCS Σ5, QST by body surface area including TP and HP, and postural blood pressure.  Two 
assessments will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) after the 
first assessment, but not more than 7 days apart.  Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment (e.g., the weakness component should not be performed more than once on any given day). 
e. 
The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, VDT, and heart rate response to deep breathing.  Two assessments will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 
7 days apart. Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each assessment (e.g., the weakness 
component should not be performed more than once on any given day). 
f. 
If the patient has provided separate informed consent for skin biopsies, 2 sets of tandem 3-mm skin punch biopsies are to be obtained (4 biopsies total).  One set of biopsies 
will be taken from the distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh at each time point. 
g. 
The mBMI calculation will take place programmatically in the clinical database; the site will not perform the calculation. 
h. 
The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers are permitted.  
The time required for the patient to walk 10 meters will be recorded.  Two assessments will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart.   
i. 
Grip strength will be measured using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient throughout the duration of the 
study.  Two assessments will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) 
after the first assessment, but not more than 7 days apart.   
j. 
Vital signs to include: blood pressure, pulse rate, temperature, and respiratory rate.  Parameters are to be measured in the supine position using an automated instrument after 
the patient has rested comfortably for 10 minutes. 
k. 
All ECGs are to be obtained in triplicate. 
l. 
A pregnancy test (urine- or serum-based) will be performed on all females of child-bearing potential. 
m. Concomitant medications/treatments will be collected through Day 294 (Week 42) only.  Data on subsequent FAP treatment regimens will be collected separately.  
n. 
Adverse events will be collected through Day 294 (Week 42) only.  See Section 8.5 for SAE reporting periods. 
o.  Following the Day 294 (Week 42) visit, only adverse events that are considered related to the study procedures will be collected (e.g., skin biopsies, venipunctures). 
p. 
At these time points, data will be collected through phone contact. 
q. 
Study personnel will contact patients by phone to query for general health status and information on subsequent FAP treatment regimens. 
r. 
INR assessment only, which is to be used for qualification visit for Study TTR02-006. 


 
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ABBREVIATIONS 
Abbreviation 
Definition 
Σ5 
5 attributes 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
ATTR 
Transthyretin-mediated amyloidosis 
BUN 
Blood urea nitrogen 
CAS 
Central Assessment Site 
CC 
Complete case 
CFR 
Code of Federal Regulations 
CLR 
Renal clearance 
CMAP 
Compound muscle action potential 
COMPASS-31 
Composite Autonomic Symptom Score 
CRF 
Case Report Form 
CRO 
Contract research organization 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
DEHP 
di(2-ethylhexyl)phthalate 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EQ-5D 
EuroQOL 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ELISA 
Enzyme linked immunosorbent assay 
ERG 
Electroretinography 
EU 
European Union 
FAC 
Familial amyloidotic cardiomyopathy 
FAP 
Familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
H1/H2 blocker 
Histamine H1/H2 receptor antagonist 


 
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Abbreviation 
Definition 
HIPAA 
Health Insurance Portability and Accountability Act of 
1996 
HIV 
Human immunodeficiency virus 
HP 
Heat pain 
HPLC 
High performance liquid chromatography 
HRdb 
Heart rate response to deep breathing 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
Intraepidermal nerve fiber density 
IFE 
Immunofixation electrophoresis 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IRS 
Interactive response system 
IV 
Intravenous(ly) 
LLN 
Lower limit of normal 
LOCF 
Last observation carried forward 
LNP 
Lipid nanoparticles 
mBMI 
Modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
MMRM 
Mixed model repeated measures 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
Messenger ribonucleic acid 
NIS 
Neuropathy Impairment Score 
NCS 
Nerve conduction studies 
NOAEL 
No observed adverse effect limit 
Norfolk QOL-DN 
Norfolk Quality of Life-Diabetic Neuropathy 
NSAID 
Nonsteroidal anti-inflammatory 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
OTC 
Over-the-counter 
PCS 
Patient Care Site 
PD 
Pharmacodynamic 
PEG2000-C-DMG 
3-N-[(ω-methoxy poly(ethylene glycol)2000) carbamoyl]-
1,2-dimyristyloxy-propylamine 


 
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Abbreviation 
Definition 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PND 
Polyneuropathy disability  
PO 
Per os (orally) 
PP 
Per protocol 
PVC 
Polyvinyl chloride 
PT 
Prothrombin time 
QST 
Quantitative sensory testing 
QTc 
QT interval corrected for heart rate 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RNAi 
RNA interference 
R-ODS 
Rausch-built Overall Disability Scale 
SAE 
Serious adverse event 
SGNFD 
Sweat gland nerve fiber density 
siRNA 
Small interfering ribonucleic acid 
SNAP 
Sensory nerve action potential 
SUSAR 
Suspected unexpected serious adverse reaction 
T3 
Triiodothyronine 
T4 
Thyroxine 
TP 
Touch pressure 
TSH 
Thyroid stimulating hormone 
TTR 
Transthyretin 
TUDCA 
Tauroursodeoxycholic acid 
ULN 
Upper limit of normal 
US/USA 
United States 
USP/EP 
United States Pharmacopeia/European Pharmacopoeia 
V30M 
Val30Met 
VDT 
Vibration detection threshold 
WBC 
White blood cell 
WHO 
World Health Organization 
WT 
Wild type 


 
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1 
INTRODUCTION 
1.1 
Background and Rationale 
1.1.1 Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is an inherited, autosomal dominant, 
systemic disease caused by a mutation in the transthyretin (TTR) gene.1  Transthyretin is 
a tetrameric 127 amino acid protein that is secreted predominantly (>95%) by 
hepatocytes, with a smaller fraction produced by the choroid plexus and retina.2  
Physiologically, TTR is a major serum carrier for retinol binding protein (RBP) and a 
minor carrier of thyroxine (T4).  Mutations in the TTR protein lead to destabilization of 
the tetrameric form and dissociation into dimers and monomers; misfolding of mutated 
monomers from the α-helical to the β-pleated sheet structure results in tissue deposition 
of amyloid fibrils.3  Amyloid deposits typically contain both mutant and wild-type (WT) 
TTR.  The particular TTR mutation and site of amyloid deposition determines the clinical 
manifestations of the disease, which include sensory and motor neuropathy, autonomic 
neuropathy, and/or cardiomyopathy.  ATTR is a progressive disease associated with 
severe morbidity, with a life expectancy limited to 5 to 15 years from symptom onset.4  
There are over 100 reported TTR mutations which are associated with 2 clinical 
syndromes: familial amyloidotic polyneuropathy (FAP) and familial amyloidotic 
cardiomyopathy (FAC).5,6,7   
“Patisiran” (the International Nonproprietary Name [INN] name for the drug product 
previously referred to as ALN-TTR02) is being developed for the treatment of ATTR 
patients with symptomatic FAP. 
The estimated worldwide prevalence of FAP is 5,000 to 10,000, with the majority of 
cases in Portugal, Sweden, France, Japan, Brazil, and the United States.8,9  The most 
common causative mutation of FAP is TTR Val30Met (V30M), with the onset of 
symptoms typically occurring between 30 and 55 years of age.10  Amyloid deposition 
occurs largely in the peripheral nerves, starting as a nerve length-dependent sensory 
polyneuropathy in the feet causing numbness and pain and progressing to painful 
dysesthesias.  Disabling motor neuropathy follows, characterized by leg weakness and 
eventual inability to walk.  Autonomic neuropathy is another common feature of the 
disease, resulting in severe gastrointestinal pathology (including diarrhea or constipation 
and malabsorption, leading to severe malnutrition), orthostatic hypotension, and bladder 
dysfunction with recurring urinary tract infections.11,12,13,14  For several mutations, 
cardiac pathology also occurs due to amyloid infiltration of the sinus node, 
atrioventricular conduction system, and infiltration of the myocardium.15,16  Involvement 
of the conduction system can lead to sudden death due to dysrhythmias, and myocardial 
infiltration can lead to diastolic dysfunction and right-sided heart failure.17  The 
cardiomyopathy proceeds inexorably, leading to death typically within 10 years.18 
There are multiple lines of evidence demonstrating that reduction of circulating TTR 
improves outcomes in patients with ATTR.  Because the liver is the primary source of 
WT and mutant TTR, orthotopic liver transplantation has been used since 1990 in an 
attempt to treat FAP,19 and is the current standard of care in patients who are eligible for 
transplant (patients with minimal neuropathy symptoms and no cardiac involvement).  


 
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When liver transplantation is performed early in the course of the disease, it can stabilize 
and slow the course of neuropathic disease in patients with FAP due to V30M, but is less 
effective in patients with other TTR mutations.20  However, it is less effective in patients 
with more advanced disease, especially those with heart involvement, due to the 
continued production and deposition of WT TTR in tissues with pre-existing 
amyloid.21,22,23 
It is estimated that approximately two-thirds of FAP patients are not transplant-eligible.  
Furthermore, liver transplant poses risks from the surgical procedure and from life-
threatening complications due to graft rejection or infections.  The 1-year mortality rate 
post-transplant is 10%.24 
Nonsurgical options that are used for the treatment of FAP (depending on geographic 
location) include tafamidis (Vyndaqel®) and diflunisal.  Tafamidis is a small molecule 
TTR stabilizer that binds to the thyroxine binding sites of the TTR tetramer, thus 
preventing its dissociation to monomers and potentially preventing fibril formation.  
While tafamidis is approved in the European Union (EU) for the treatment of ATTR in 
adult patients with Stage 1 symptomatic polyneuropathy to delay peripheral neurologic 
impairment, it is not considered the standard of care throughout the EU and it has not 
been approved for use outside the EU.25 
Diflunisal is a generic, nonsteroidal anti-inflammatory drug (NSAID) that is also a 
tetramer stabilizer and binds to TTR in a similar manner as tafamidis.  A multinational, 
placebo-controlled Phase 3 study in patients with all stages of FAP was recently 
completed; however, the results have not been released.  Due to the restricted use of liver 
transplantation and tafamidis in patients with early stage of disease, and the non-standard 
use of diflunisal among practitioners, there remains an unmet medical need for a potent 
and effective therapy for FAP that will have an impact on patients across a broad range of 
neurologic impairment, regardless of their mutation (V30M or non-V30M). 
1.1.2 RNA Interference 
Ribonucleic acid interference (RNAi) is a naturally occurring cellular mechanism for 
regulating gene expression that is mediated by “small interfering ribonucleic acids” 
(siRNAs).26  Typically, synthetic siRNAs are 19 to 23 base pair double-stranded 
oligonucleotides in a staggered duplex with a 2-nucleotide overhang at one or both of the 
3' ends.  Such siRNAs can be designed to target an endogenous or virally-expressed gene.  
When introduced into cells, the net effect of an RNAi-based pharmacological approach is 
the binding of the siRNA to its complementary messenger ribonucleic acid (mRNA) 
sequence, cleavage of this target mRNA, and suppression of the target protein.27  The 
ability to selectively and potently degrade the mRNA encoding the TTR protein using an 
siRNA offers a potent and specific approach for the treatment of ATTR. 
Unformulated siRNAs, and those without chemical modification, are rapidly degraded 
and eliminated upon systemic administration, and thus do not achieve significant tissue 
distribution.28  As a result, various formulations are used to target siRNA distribution to 
tissues, and to facilitate their uptake into the relevant cell type.  One approach that has 
been used successfully in vivo, including in rodents, non-human primates, and humans, 
employs IV delivery of siRNAs in lipid nanoparticles (LNPs).29,30,31,32  These LNPs, with 


 
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their small size (<100 nm) and low surface charge, can pass through the fenestrated 
vascular endothelium of the liver.  Endocytosis of the intact LNPs, followed by fusion 
with the endosomal membrane and release of the siRNA into the cytoplasm, results in the 
siRNA engaging the endogenous RNAi machinery described above leading to targeted 
degradation of the mRNA, and a consequent reduction in target protein levels. 33,34 
1.1.3 PATISIRAN 
Patisiran comprises a small interfering ribonucleic acid (siRNA) which is specific for 
TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) for intravenous (IV) 
administration.35  This TTR siRNA has a target region within the 3’UTR region of TTR 
gene to ensure and confirm homology with WT TTR as well as all reported TTR 
mutations.  Following LNP-mediated delivery to the liver, patisiran targets TTR mRNA 
for degradation, resulting in the potent and sustained reduction of mutant and WT TTR 
protein via the RNAi mechanism.   
Since circulating TTR is almost exclusively synthesized in the liver, the IV 
administration of patisiran is postulated to reduce the level of precursors that lead to 
amyloid fibril deposition, resulting in clinical benefit to patients with FAP.   
1.1.4 Therapeutic Hypothesis 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and 
life-threatening orphan disease. The therapeutic hypothesis that systemic amyloidoses can 
be managed by reduction in circulating levels of amyloidogenic protein has been 
validated in other acquired (e.g., immunoglobulin light chain systemic [AL], or amyloid 
A [AA]) and hereditary (e.g. Fibrinogen A α-chain, ApoA1) amyloidosis.  The 
experience from these systemic amyloidotic disorders,36,37,38,39 as well as the liver 
transplant data in FAP, suggest that lowering of the circulating amyloidogenic protein by 
at least 50% is required to impact the clinical course of the disease, with reductions in 
protein beyond 50% providing further incremental improvements in outcomes.  It is 
therefore postulated that the >80% suppression in both WT and mutant TTR observed 
upon administration of 0.3 mg/kg patisiran once every 21 days will result in clinical 
benefit in FAP patients with mild to moderate polyneuropathy.  This hypothesis is further 
supported by evidence from tafamidis suggesting that reduction in free TTR monomer 
can slow neuropathy progression in early-stage V30M patients with FAP.10   
1.2 
Summary of Patisiran Nonclinical Data  
 
 
 
 
 
 
 
 
 


 
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Further information can be found in the patisiran (ALN-TTR02) IB. 
1.3 
Summary of Clinical Data with Patisiran 
A Phase 1 multicenter, randomized, placebo-controlled, single-blind, single-ascending 
dose clinical study of patisiran in healthy volunteers was completed in the UK.  Patisiran 
was administered as a single 60-minute IV infusion to healthy volunteers at doses of 0.01 
to 0.05 mg/kg.  Patients were premedicated with dexamethasone, H1 and H2 blockers, 
and paracetamol/acetaminophen prior to dosing to minimize the risk of infusion-related 
reactions (IRRs).  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  Transthyretin 
levels showed evidence of recovery beginning at around Day 21 to 28, returning to 
baseline by Day 70. 
An open-label, Phase 2, multiple-ascending dose study of patisiran in ATTR patients with 
FAP (Study ALN-TTR02-002) to determine the safety and tolerability, pharmacokinetics 
(PK), and pharmacodynamics (PD) of a 60-70 minute IV infusion of patisiran 
administered once every 3 or 4 weeks for 2 doses has completed enrollment (N=29).  
Preliminary data show >80% TTR knockdown with 0.3 mg/kg after the first and second 
doses (p<0.001), with better sustained suppression of >80% observed throughout the 
dosing interval with the once every 3 week dosing schedule compared with once every 4 
weeks.  In V30M patients, both mutant and wild-type TTR were suppressed to the same 
extent.  Multiple doses of patisiran have been generally safe and well-tolerated, including 
0.3 mg/kg administered once every 3 or 4 weeks with either a 60-minute infusion and 
original premedication regimen (total of 28 mg dexamethasone or equivalent, 
administered the night before and morning of infusion) or a 70-minute step-wise infusion 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 
3 mL/minutes for the remainder of the infusion) and a simplified premedication regimen 
(total of 10 mg dexamethasone or equivalent, administered at least 60 minutes prior to 
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Patients completing Study ALN-TTR02-002 are eligible to enroll into a Phase 2, 
open-label, extension study (ALN-TTR02-003) designed to evaluate the safety and 
tolerability of long-term patisiran dosing administered to patients with FAP; additional 
information will be evaluated including PK, PD, and clinical activity.  Patients will 
receive 0.3 mg/kg patisiran once every 21 days for approximately 2 years.  Data from this 
study of March 13, 2015 demonstrate a sustained mean serum TTR knockdown of 
approximately 80%, with mean nadir up to 88% between doses, for approximately 16 months 
in patients receiving patisiran 0.3 mg/kg once every 3 weeks (n=20). Neuropathy impairment 
scores were stable through 12 months with mean change in mNIS+7 and NIS of -2.5 and +0.4 
points, respectively. 
Further details on these clinical studies can be found in the patisiran (ALN-TTR02) IB. 
1.4 
Study Design Rationale 
This is a Phase 3 randomized, double-blind, placebo-controlled, multicenter, 
multinational study of patisiran in FAP patients.  The patients proposed for this study are 
reflective of the FAP population encountered by clinicians in various different countries 
worldwide, including patients with a range of neuropathy severity and broad spectrum of 
TTR mutations.  Disease progression will be assessed by neurological measures and 
functional tests; therefore, the range of baseline neuropathy severity (NIS of 5-130) is 
selected such that the lower end is advanced enough to show significant progression in 
the placebo group, while the upper end is not so advanced as to preclude detection of 
change as a result of a ceiling effect of neuropathy measures or to be confounded by other 
comorbidities. 
The inclusion of placebo as a control allows for a rigorous analysis of the treatment effect 
of patisiran.  However, given the 18-month duration of the study, those patients who have 
evidence of rapid disease progression at 9 months (defined as ≥24 point increase in 
mNIS+7 from baseline [based on an average of 2 measurements] and FAP stage 
progression relative to baseline) will be given the option of discontinuing study drug and 
receiving local standard of care treatment for their FAP.  Such patients will be asked to 
follow a modified study visit schedule and return for their 18-month efficacy assessment 
(blinding will be maintained throughout).  It is expected that fewer than 5% of patients 
involved in the ALN-TTR02-004 study will meet the definition of rapid disease 
progression at 9 months. 
Given the orphan nature of the disease and the significant, progressive morbidities 
associated with FAP, randomization to patisiran or placebo will be performed in a 
2:1 ratio (patisiran:placebo) to increase the probability that patients will receive active 
drug.  Treatment groups will be balanced at entry for NIS (5-49 vs 50-130), early onset 
V30M (<50 years of age at onset) vs all other mutations (including late onset V30M), and 
previous tetramer stabilizer use (tafamidis or diflunisal) vs no previous tetramer stabilizer 
use. 
The primary endpoint for this study is the change from baseline at 18 months in a 
composite measure of neurologic impairment termed modified NIS+7 (mNIS+7), which 
includes a clinical exam-based assessment of neurologic impairment (NIS) combined 
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and measurement of autonomic function (postural blood pressure).  The utility of various 
neuropathy endpoints in demonstrating a treatment effect in randomized, controlled 
clinical trials in patients with FAP has been established through Phase 3 studies using the 
small molecule TTR tetramer stabilizers tafamidis and diflunisal.  For these studies, the 
primary efficacy endpoint utilized variations of NIS (NIS-Lower Limbs in the case of 
tafamidis and NIS+7 for diflunisal).  Composite endpoints, such as NIS+7, have been 
found to be more sensitive in detecting abnormalities in patients with generalized 
peripheral neuropathy, such as diabetic polyneuropathy and chronic idiopathic 
demyelinating polyneuropathy, and the reproducibility of composite scores has been 
shown to be greater than for individual tests.  The use of mNIS+7 in this study is 
expected to increase the sensitivity and reproducibility of the measurement of neuropathy 
progression in a heterogeneous group of FAP patients presenting with a broad spectrum 
of disease severity and TTR mutations. 
The 18-month endpoint was selected based on the expected rate of neuropathy 
progression in patients with FAP, derived from a global natural history dataset of 
283 patients from Alnylam collaborators in the USA, Portugal, France, and Italy.  From 
these data, it is estimated that a patient’s mNIS+7 score will have increased by 
approximately 24 points in the placebo group after 18 months, thereby providing 
adequate disease progression for the detection of a treatment effect in the patisiran group. 
1.5 
Dose Selection and Dosing Schedule Rationale 
Given the fundamental role of TTR in the pathogenesis of the disease and the data from 
liver transplantation in FAP, it is postulated that the optimal dose and schedule for 
patisiran is one that will result in the greatest level of sustained TTR suppression with an 
acceptable safety profile.  Based on the data to date from the nonclinical and clinical 
studies with patisiran, >80% maintained suppression of circulating TTR is consistently 
achieved at the 0.3 mg/kg dose administered once every 3 weeks, and this dose was 
generally well tolerated.  Patisiran will be administered every 21 days as a 70-minute IV 
infusion (approximately 1 mL/minute for the first 15 minutes followed by approximately 
3 mL/minute for the remainder of the infusion) with a premedication regimen consisting 
of IV dexamethasone and H1/H2 blockers along with oral paracetamol/acetaminophen 
given at least 60 minutes prior to each infusion.   
The chronic toxicology studies in rodents (6-month duration) and monkeys (9-month 
duration), in which animals safely tolerated 14 doses of patisiran at ≥0.3 mg/kg once 
every 2 or 3 weeks (rats or monkeys, respectively), also supports long-term dosing in 
FAP patients at 0.3 mg/kg once every 21 days. 
1.6 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that 
systemic amyloidoses can be managed by reducing circulating levels of amyloidogenic 
protein has been established in other acquired and hereditary amyloidoses.  The experience 
from these systemic amyloidotic disorders, as well as the liver transplant data in FAP, 
suggest that lowering of the circulating amyloidogenic protein could impact the clinical 
course of the disease.  Based on nonclinical and clinical data that showed suppression in 


 
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levels of WT and mutant TTR upon administration of 0.3 mg/kg patisiran once every 21 
days, it is possible that long term treatment with patisiran may have a clinical benefit in FAP 
patients with mild to moderate polyneuropathy and that further study is warranted. 
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and 
ALN-TTR02-003), single and multiple doses of patisiran have been generally well 
tolerated.  Potential risks of patisiran include the following: 
• Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain 
biological agents such as liposomes or monoclonal antibodies.  In order to reduce the 
potential for an IRR with patisiran, all patients in this study will be premedicated 
prior to dosing with patisiran or placebo.  The step-wise infusion regimen over 
approximately 70 minutes (starting with a slower infusion rate of approximately 
1 mL/minute for the first 15 minutes before increasing to 3 mL/minute for the 
remainder of the infusion), may further reduce the risk of an IRR. 
• Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and 
histopathology in the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 
mg/kg in monkeys.  In general, all of the findings were not observed or were 
observed at lower severity at the end of the 60-90 day dose free period, indicating that 
the toxicities were reversible.  In clinical studies to date, there have been no clinically 
significant changes in liver function tests in either the single-dose or multiple-dose 
studies. Patients in the study are monitored for liver function via serial laboratory 
assessments. 
• Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering 
of circulating vitamin A levels.  Preclinical and clinical data have shown that the 
lowering of circulating vitamin A associated with suppression of RBP does not result 
in severe vitamin A deficiency.  Furthermore, there are individuals with RBP/TTR 
mutations who have life-long low levels of circulating vitamin A and are essentially 
in good health, suggesting that there are compensatory transport mechanisms for 
vitamin A that are yet undescribed.40  This has also been confirmed in TTR knockout 
mice, which do not exhibit any manifestations of vitamin A deficiency, with vitamin 
A uptake by most tissues continuing in the absence of RBP.41  Provided there is 
adequate vitamin A in the diet, tissue stores of vitamin A should not be affected by 
the lowering of TTR and RBP.  However, as the vitamin A content of the diet may 
vary between different countries and different individuals within a country, all 
patients on the study will be asked to take a daily supplement containing the 
recommended daily allowance of vitamin A.  Patients should have started vitamin A 
supplementation by the time they start his/her first dose of patisiran or placebo. 
• Osteoporosis 
Patients with FAP may be at risk for osteoporosis.42 In addition, as part of the 
premedication regimen administered prior to patisiran dosing every three weeks, FAP 


 
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patients participating in this study are given glucocorticoids, a drug known to have 
the potential to reduce bone mineralization.  If there are no medical contraindications, 
and per investigator judgment and local standard of care, study participants should, if 
appropriate, receive therapy for the prevention and early treatment of osteoporosis 
such as: calcium and vitamin D supplementation, bisphosphonates, calcitonin, 
parathyroid hormone, estrogen agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the IB. 
 


 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to determine the efficacy of patisiran (ALN-TTR02) 
by evaluating the difference between the patisiran and placebo groups in the change from 
baseline of mNIS+7 score at 18 months.   
2.2 
Secondary Objectives 
The secondary objectives of the study are to determine the effect of patisiran on various 
clinical parameters by assessing the difference between patisiran and placebo in the 
change from baseline in the following measurements at 18 months: 
• Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire; 
• NIS-weakness (NIS-W) score; 
• Modified body mass index (mBMI); 
• Timed 10-meter walk test; 
• Autonomic symptoms questionnaire (Composite Autonomic Symptom Score 
[COMPASS-31]). 
2.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To determine the difference between the patisiran and placebo groups in the change 
from baseline in the following measurements at 18 months: 
• NIS+7 score; 
• Grip strength; 
• EuroQOL (EQ-5D) questionnaire; 
• Level of disability (Rasch-built Overall Disability Scale [R-ODS]); 
• Large vs small nerve fiber function including nerve conduction studies (NCS) 
5 attributes (Σ5), quantitative sensory testing (QST) by body surface area 
including touch pressure (TP) and heat pain (HP), vibration detection threshold 
(VDT), heart rate response to deep breathing (HRdb), postural blood pressure; 
• Pathologic evaluation of sensory and autonomic innervation through voluntary 
skin punch biopsies and analysis of intraepidermal nerve fiber density (IENFD) 
and sweat gland nerve fiber density (SGNFD); 
• Assessment of ambulation through FAP stage and Polyneuropathy Disability 
(PND) score; 
• Cardiac assessment through echocardiogram, troponin I, and N terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) levels; 
• Pharmacodynamic (PD) biomarkers (TTR, RBP, vitamin A); 


 
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• To compare the proportion of patients in the patisiran and placebo groups who meet 
the pre-defined criterion for rapid disease progression (defined as ≥24 point increase 
in mNIS+7 from baseline [based on an average of 2 measurements] and FAP stage 
progression relative to baseline) at 9 months. 


 
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3 
STUDY PLAN 
3.1 
Overall Design 
This is a multicenter, multinational, randomized, double-blind, placebo-controlled, 
Phase 3 study designed to demonstrate the clinical efficacy of patisiran (ALN-TTR02) 
and to establish the safety of chronic dosing in adult patients with FAP.  A schematic of 
the study design is presented in Figure 1. 
The duration of patient participation in this study is approximately 21 months.  Patients 
will be screened within 42 days prior to administration of study drug.  Consented eligible 
patients will be randomized to receive either patisiran or placebo (2:1 ratio, patisiran to 
placebo) once every 21 days for 78 weeks.  Treatment groups will be balanced at entry 
for NIS (5-49 vs 50-130), early onset V30M (<50 years of age at onset) vs all other 
mutations (including late onset V30M), and previous tetramer stabilizer use (tafamidis or 
diflunisal) vs no previous tetramer stabilizer use.  
Prior to dosing, patients will receive premedications in order to reduce the risk of 
experiencing an IRR.  The premedications will be administered at least 60 minutes prior 
to the start of infusion of study drug.  Blinded study drug will be administered as a 70-
minute IV infusion (approximately 1 mL/minute for the first 15-minutes followed by 
approximately 3 mL/minute for the remainder of the infusion).  In addition to returning to 
the site for dosing of study drug once every 21 days, patients will also return for out-
patient visits at 9 and 18 months for efficacy assessments (see Section 6 for details).  The 
study personnel performing these assessments will be blinded to the results of any 
previous assessments (e.g., Screening/Baseline, Baseline, or 9-month assessments). 
At the 9-month time point, if the clinical adjudication committee determines that a patient 
is exhibiting rapid disease progression (defined as ≥24 point increase in mNIS+7 from 
baseline [based on an average of 2 measurements] and FAP stage progression relative to 
baseline, see Section 4.6), the patient’s treating physician will provide the patient with the 
option of discontinuing study drug and receiving local standard of care treatment for 
FAP.  Patients who discontinue study drug will remain on study through completion of 
the 18-month efficacy assessments, following a modified visit schedule as shown in 
Table 1-3 and described in Section 6.4.  Blinding will be maintained throughout. Patients 
who complete the 18-month efficacy assessments can elect to participate in an extension 
study in which patients will receive open-label administration of 0.3 mg/kg patisiran once 
every 21 days. 
A Data Monitoring Committee (DMC) will be implemented for the study and will 
operate under a prespecified charter. 


 
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Figure 1: 
Study Schematic 
 
 
 
 
 
Screening and 
Baseline 
(Day -42 
to Day 0) 
Screening (Preliminary Eligibility) 
Screening (Eligibility Confirmation) / Baseline 1 
*Screening tests for confirmation of eligibility include NIS and NCS.  
Baseline 2 
First Dose  
(Day 0) 
Randomize (2:1; Patisiran  or placebo) 
and 
Administer the first double-blind dose of study drug 
Treatment 
Period 
 
(Day 1 
 To 
 Day 560) 
End of Study and 
Follow-up 
 
(Day 561  
To 
 Day 602) 
Day 21 to 252: Continue the double-blind dosing – every 3 weeks 
9-Month Efficacy Assessments – Day 253 to Day 272 
Rapid Disease Progression? 
(defined as ≥24 point increase in mNIS+7 from baseline [based on an average of 2 
measurements] and FAP stage progression relative to baseline, based on clinical 
adjudication committee review; blinding will be maintained) 
No 
Yes 
Patient will 
continue to receive 
study drug 
Decision to continue 
study drug 
Decision to discontinue 
study drug (and many 
receive additional therapy 
as per the local standard of 
care) 
Day 273 to 546: Continue the double-blind dosing – every 3 weeks 
Continue on study 
(modified visit schedule) 
18-Month Efficacy Assessments – Day 553 to Day 560 
Day 567 : End of Study Visit  
Participate in the open-label extension? 
No 
Yes 
Day 602: Follow-up Visits (not required for those who 
had Rapid Disease Progression and discontinued study 
drug at Month 9) 
Provide informed consent and enter the open-label 
extension study 


 
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3.2 
Efficacy Assessments 
Efficacy parameters will include the following (baseline evaluations will be conducted as 
well as evaluations at 9 and 18 months): 
• Neurologic impairment will be assessed using the mNIS+7 composite score.  The 
mNIS+7 includes the modified NIS (weakness and reflexes), NCS Σ5, QST, as well 
as autonomic assessment through postural blood pressure; 
• Patient-reported QOL will be evaluated using the Norfolk QOL-DN and the EQ-5D.  
Disability will be reported by patients using the R-ODS; 
• Autonomic symptoms will be assessed using the COMPASS-31; 
• Motor function assessments to be evaluated include NIS-W, timed 10-meter walk 
test, and grip strength test; 
• PND score and FAP stage; 
• Nutritional status will be assessed using mBMI; 
• Pathologic evaluation of sensory and autonomic innervation will be evaluated by 
IENFD analysis and quantitation of SGNFD via tandem 3 mm skin punch biopsies 
taken from the leg; 
• Neurologic impairment will also be assessed by NIS+7 (including full NIS, NCS, 
VDT, and HRdb); 
• Cardiac structure and function will be assessed through echocardiograms as well as 
measurement of serum levels of NT-proBNP and troponin I. 
3.3 
Safety Assessments 
Safety will be assessed throughout the study by collecting adverse events (AEs; including 
serious adverse events [SAEs]); clinical laboratory tests, including hematology, clinical 
chemistry (including liver function tests), thyroid function parameters, and urinalysis; 
measurement of anti-drug antibodies; electrocardiograms; vital signs; physical 
examination findings; and ophthalmology examinations.   
3.4 
Pharmacodynamic Assessments 
Pharmacodynamic markers assessed serially will include serum TTR, vitamin A, and 
RBP.  Additional blood samples will be collected for exploratory biomarkers related to 
FAP. 
3.5 
Pharmacokinetic Assessments 
The plasma PK evaluation will include, whenever possible, plasma-concentration time 
profiles for siRNA and the novel lipid components in patisiran: DLin-MC3-DMA and 
polyethylene glycol (PEG)2000-C-DMG.  The siRNA, DLin-MC3-DMA, and PEG2000-C-
DMG concentration will be determined for all patients at time points specified in Table 
1-1, Table 1-2, and Table 1-3.  
Urine will be collected with void volume recorded for all patients at time points specified 
in Table 1-1, Table 1-2, and Table 1-3 and to determine renal clearance (CLR) of siRNA 


 
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and 4-dimethylaminodibutyric acid (the metabolite of DLin-MC3-DMA) after dosing 
with study drug. 
3.6 
Other Assessments 
Disease burden and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  The investigator will periodically assess mental 
status as it relates to suicidal ideation and behavior by using the Columbia–Suicide 
Severity Rating Scale (C-SSRS) questionnaire.   


 
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4 
PATIENT POPULATION 
4.1 
Eligibility of Patients 
Approximately 200 patients are expected to be enrolled at multiple centers worldwide.  
All centers will be selected on the basis of their experience in the treatment of patients 
with FAP. 
4.2 
Inclusion Criteria 
To be enrolled in the study, each patient must meet the following criteria at the Screening 
visit, except where specified: 
1. 
Male or female of 18 to 85 years of age (inclusive); 
2. 
Have a diagnosis of FAP with documented TTR mutation;  
3. 
Have an NIS of 5 to 130 (inclusive) and a PND score of ≤3b (Note:  This criterion 
must be met at the Screening/Baseline visit); 
4. 
Have an NCS sum of the sural sensory nerve action potential (SNAP), tibial 
compound muscle action potential (CMAP), ulnar SNAP, ulnar CMAP, and 
peroneal CMAP of ≥2 points (Note:  This criterion must be met at the 
Screening/Baseline visit); 
5. 
Have a Karnofsky performance status of ≥60%; 
6. 
Have an absolute neutrophil count (ANC) ≥1500 cells/mm³, and a platelet count 
≥50,000 cells/mm³; 
7. 
Have aspartate transaminase (AST) and alanine transaminase (ALT) levels 
≤2.5 × the upper limit of normal (ULN), total bilirubin within normal limits, 
international normalized ratio (INR) ≤2.0 (patients on anticoagulant therapy with 
an INR of ≤3.5 will be allowed). Patients with total bilirubin ≤ 2 × ULN are 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation 
of unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT 
and AST levels within normal ranges; 
8. 
Have a serum creatinine ≤2 × ULN; 
9. 
No active infection with hepatitis B or hepatitis C by serology; 
10. 
Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception 
prior to screening, throughout study participation, and for 75 days after the last 
dose of study drug.  Highly effective methods of birth control are defined in 
Section 4.7; 
11. 
Males with partners of child-bearing potential, must agree to use 1 barrier method 
(e.g., condom) and 1 additional method (e.g., spermicide) of contraception 
throughout study participation and for 75 days after the last dose of study drug; 
males must also abstain from sperm donation after the first dose of study drug 
through study participation and for 75 days after the last dose of study drug; 


 
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12. 
Must be willing and able to comply with protocol-required visit schedule and visit 
requirements and provide written informed consent. 
4.3 
Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria at the time of 
Screening visit: 
1. 
Had a prior liver transplant or is planning to undergo liver transplant during the 
study period; 
2. 
Has other known causes of sensorimotor or autonomic neuropathy 
(e.g., autoimmune disease, monoclonal gammopathy, etc.); 
3. 
Has known primary amyloidosis or leptomeningeal amyloidosis; 
4. 
Has known type I diabetes; 
5. 
Has had type II diabetes mellitus for ≥5 years; 
6. 
Has vitamin B12 levels below the lower limit of normal (LLN);  
7. 
Has untreated hypo- or hyperthyroidism;   
8. 
Has had a major surgery within the past 3 months or has a major surgery planned 
during any point of the study period; 
9. 
Has known human immunodeficiency virus (HIV) infection; 
10. 
Has an active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to the first dose of study drug administration; 
11. 
Had a malignancy within 2 years, except for basal or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix that has been successfully treated; 
12. 
Has a New York Heart Association heart failure classification >2; 
13. 
Had acute coronary syndrome within the past 3 months; 
14. 
Has uncontrolled cardiac arrhythmia or unstable angina; 
15 
Has a known history of alcohol abuse within the past 2 years or daily heavy 
alcohol consumption (females: more than 14 units of alcohol per week; males: 
more than 21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 
measure of spirits = ½ pint of beer]); 
16. 
Received an investigational agent or device within 30 days of anticipated study 
drug administration or 5 half-lives of the investigational drug, whichever is 
longer;  
17. 
Participated in a clinical trial with antisense oligonucleotide, must have completed 
a 3-month wash-out prior to start of the study drug administration in this study; 
18. 
Is currently taking tafamidis, doxycycline, or tauroursodeoxycholic acid 
(TUDCA); if previously on any of these agents, must have completed a 14-day 
wash-out prior to start of study drug administration in this study; 


 
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19. 
Is currently taking diflunisal; if previously on this agent, must have at least a 
3-day wash-out prior to start of study drug administration in this study; 
20. 
Had a prior severe reaction to a liposomal product or a known hypersensitivity to 
oligonucleotides or any component of patisiran (ALN-TTR02); 
21. 
Is unable to take the required premedications; 
22. 
Anticipated survival is less than 2 years, in the opinion of the Investigator; 
23. 
Is considered unfit for the study by the Investigator. 
24. 
Is under legal protection (defined as “any person who becomes incapable of 
protecting his/her interests due to a medically diagnosed impairment of his/her 
mental faculties that may limit or prevent the expression of his/her will”). 
4.4 
Assignment to Treatment Group/Patient Number 
4.4.1 Randomization Procedures 
Patients will be randomly assigned in a 2:1 ratio to receive either 0.3 mg/kg patisiran or 
placebo (normal saline 0.9%). 
Patients will be randomized via an interactive response system (IRS).  Either designated 
unblinded site personnel or the pharmacist may request randomization for the patient, but 
only the pharmacist or unblinded personnel will be allowed to receive the treatment code.  
The treatment code will be delivered to the unblinded personnel and the pharmacist will 
use the necessary number of vials for that patient based on their weight. 
Treatment arms will be balanced at entry for NIS (5-49 vs 50-130), early onset V30M 
(<50 years of age at onset) vs all other mutations (including late onset V30M), and 
previous tetramer stabilizer use (tafamidis or diflunisal) vs no previous tetramer stabilizer 
use. 
4.4.2 Patient Numbering 
At enrollment, each patient will be uniquely identified in the study by a combination of 
his/her center number and screening number.  The center number will be assigned by the 
Sponsor.  Upon signing the informed consent form, the patient will be assigned a 
screening number by the IRS.  The Investigator or his/her delegate will contact the IRS 
(via phone or web) after confirming that the patient fulfills all the inclusion criteria and 
none of the exclusion criteria.  The patient will be randomized via the IRS, assigned a 
patient number and a study treatment.  A combination of the center number, screening 
number, enrollment number, and patient initials will create the unique patient identifier.  
In countries with regulations prohibiting the use of patient initials, a strategy consistent 
with local regulations will be used to generate replacement values for the patient initials. 
4.4.3 Blinding Procedure 
Only the pharmacist and designated site personnel who dispense or administer study drug 
will be unblinded to the study treatment.  All other site personnel will be blinded to the 
treatment.  Study personnel performing assessments related to the efficacy endpoints will 
be different from the Investigator and other personnel managing the patient, and all of 
these study personnel will be blinded to any clinical laboratory results that could 


 
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potentially unblind them (e.g., TTR levels, vitamin A levels, thyroid function tests).  In 
addition, the study personnel performing assessments related to the efficacy endpoints 
will also be blinded to the results of any previous assessments (e.g., Screening/Baseline, 
Baseline, or 9-month assessments). 
All patients will be blinded to treatment and will receive an IV infusion once every 
21 days using identical volumes for placebo and patisiran.  The tubing and the lines will 
be covered so that it will not be possible to detect a difference in active versus placebo 
drug.   
Furthermore, unblinded source documentation containing all descriptions of pharmacy 
preparations and infusions or distribution of study drug or randomization data will be 
stored separate from all other study data/records and from other pharmacy staff not 
participating on the study. 
Unblinding is only to occur in the case of patient emergencies or when necessary from a 
regulatory reporting perspective (e.g., Suspected Unexpected Serious Adverse Reactions 
[SUSAR] occurring in the EU), and at the conclusion of the study. 
Patients who discontinue study drug at 9 months due to rapid disease progression will 
remain blinded throughout the study. 
4.4.4 Breaking the Blind 
In the event that the Investigator requests to know a patient’s study treatment assignment, 
the Investigator will first contact the CRO Medical Monitor to discuss the need for 
unblinding.  In case of an emergency, the treatment allocation for each patient will be 
available from the unblinded site personnel, pharmacist, or the IRS system. 
If a patient becomes pregnant or seriously ill during the study, the blind should be broken 
only if knowledge of the treatment administered will affect treatment options available to 
the patient.  Before breaking the blind, the PI or Sub-investigator should attempt to 
contact the CRO Medical Monitor.  If the Medical Monitor is immediately unreachable, 
the PI or Sub-investigator should break the blind as necessary using the code breaking 
information provided and contact the Medical Monitor as soon as possible.  A record 
should be kept of when the blind was broken, who broke it, and why. 
4.5 
Early Patient Discontinuation or Withdrawal 
Patients are free to discontinue treatment or withdraw from the study at any time and for 
any reason, without penalty to their continuing medical care. 
There are 3 ways for a patient to discontinue treatment and/or withdraw from the study: 
1) The patient or investigator decides to discontinue study treatment, but the patient 
agrees to remain in the study and undergo follow-up assessments (as described in 
Section 6.3). 
2) The patient experiences protocol-defined rapid disease progression at Month 9 
and elects to discontinue study treatment but remain in the study and return for 
protocol-specified visits, including follow-up assessment at Month 18 (as 
described in Section 4.6).  
3) The patient decides to no longer participate in the study and withdraws consent. 


 
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A patient will be considered to have completed the study if the patient does not withdraw 
consent from the study and completes protocol-specified procedures up through the 18-
month efficacy assessment visit. 
4.5.1 Reasons for Treatment Discontinuation or Withdrawal 
The Investigator may discontinue treatment or withdraw a patient from the study if the 
patient: 
• Is in violation of the protocol; 
• Experiences a serious or intolerable AE; 
• Becomes pregnant; 
• Requires a prohibited medication (see Section 5.8); 
• Requests to discontinue treatment or be withdrawn from the study; 
• Is found to be considerably noncompliant with the protocol-required patisiran dosing 
visits. 
A patient may discontinue treatment or be withdrawn from the study if, in the 
Investigator’s opinion, they are unable to continue.  The Investigator will also withdraw 
the patient from the study upon the request of Alnylam, including if Alnylam terminates 
the study.  Upon occurrence of a serious or intolerable AE, the Investigator will confer 
with Alnylam before discontinuing treatment.   
In general, patients who discontinue treatment will be encouraged to remain on the study 
to complete study assessments, particularly the Month 9 and Month 18 assessments, so 
that their experience is captured in the final analyses.  However, a patient may withdraw 
consent to participate in the study at any time. 
Missing an occasional dose of study drug will not necessarily result in the patient being 
withdrawn from the study.  However, if a patient misses 2 consecutive doses of study 
drug, the Investigator at the site and the Medical Monitor will determine whether 
treatment should be discontinued.   
4.5.2 Handling of Withdrawals or Patients who Discontinue from Treatment 
In the event a patient discontinues treatment, withdraws, or is withdrawn from the study, 
the CRO Medical Monitor must be informed immediately.  If there is a medical reason 
for withdrawal, the patient will remain under the supervision of the Investigator for 
protocol-specified safety follow-up procedures.   
If a patient discontinues treatment, withdraws, or is withdrawn from the study, the 
primary reason for discontinuation must be recorded in the appropriate section of the 
CRF and all efforts will be made to complete and report the observations as thoroughly as 
possible.   
If a patient withdraws or is withdrawn from the study, the site staff is to encourage the 
patient to complete the Early Withdrawal visit.  Patients who withdraw or are withdrawn 
from the study, or patients who remain on the study and permanently discontinue study 
treatment for reasons other than rapid disease progression at Month 9 (see Section 4.6), 


 
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will not be eligible to participate in the planned extension study in which patients will 
receive open-label administration of 0.3 mg/kg patisiran once every 21 days. 
4.5.3 Replacements 
No replacements will be allowed for patients who withdraw early from the study. 
4.6 
Discontinuation Due to Rapid Disease Progression 
At the 9-month time point, if the clinical adjudication committee determines that a patient 
is exhibiting rapid disease progression (defined as ≥24 point increase in mNIS+7 from 
baseline [based on an average of 2 measurements] and FAP stage progression relative to 
baseline), the patient’s treating physician will provide the patient with the option of 
discontinuing study drug and receiving local standard of care treatment for FAP.  
Patients who discontinue due to rapid disease progression will remain on study through 
completion of the 18-month efficacy assessments (blinding will be maintained 
throughout), following a modified visit schedule as shown in Table 1-3.  Patients who 
complete the 18-month efficacy assessments can elect to participate in an extension study 
in which patients will receive open-label administration of 0.3 mg/kg patisiran once every 
21 days.  Patients who discontinue study drug due to rapid disease progression and also 
decide to withdraw from the study will not have any additional visits after the Day 273 
assessments are completed and will not be eligible to participate in the planned extension 
study. 
4.7 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements 
Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
screening, throughout study participation, and for 75 days after the last dose of study 
drug.  Highly effective methods of birth control result in a low failure rate (i.e., less than 
1% per year)43.  Acceptable forms of effective contraception are defined as follows: 
• Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception; 
• Placement of an intrauterine device (IUD); 
• Placement of an intrauterine system (IUS); 
• Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository); 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception. Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled. 
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient); 


 
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• Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use two different forms of effective contraception from 
the list above.  Examples of two forms of highly effective contraception are as follows:  
• Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide; 
• IUD in conjunction with condom or diaphragm and spermicide; 
• Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide. 
Males (including men who have had vasectomies) with partners of child-bearing 
potential, must agree to use 1 barrier method (e.g., condom) and 1 additional method 
(e.g., spermicidal foam, gel, film, cream, or suppository) of contraception throughout 
study participation and for 75 days (i.e., a whole spermatogenic cycle) after the last dose 
of study drug.  Males must also abstain from sperm donation after the first dose of study 
drug through study participation and for 75 days after last dose of study drug. 
Pregnancy reporting guidelines are provided in Section 8.12. 


 
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5 
STUDY MEDICATION 
5.1 
Presentation of Study Drug 
Patisiran (ALN-TTR02) Solution for Injection is an RNAi therapeutic consisting of an 
siRNA targeting TTR mRNA formulated in a LNP.  The patisiran drug product is a 
sterile formulation of TTR siRNA with lipid excipients (DLin-MC3-DMA, DSPC, 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of TTR siRNA drug substance. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  
The container closure system consists of a United States Pharmacopeia/European 
Pharmacopoeia (USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber 
stopper, and an aluminium flip-off cap. 
The control drug for this study will be a placebo (normal saline 0.9% for IV 
administration).  Control drug will be provided by a central supplier. 
5.2 
Preparation of Study Drug 
Each investigational site will be responsible for IV preparation and labeling, according to 
separate handling instructions, and allocating treatments to the patients. 
The pharmacist or unblinded study personnel will prepare the study drug under aseptic 
conditions.  The total amount to be infused into each patient at each dosing visit will be 
200 mL.  To maintain the blind, all IV infusion bags and lines will have amber-colored 
covers added prior to leaving the pharmacy.  
Additional study drug preparation details are provided in the patisiran (ALN-TTR02) 
Pharmacy Manual. 
5.2.1 Preparation of Patisiran 
The amount (in mg) of patisiran to be administered will be determined based on the 
patient’s body weight (kg).  For each dose administered, the weight obtained during the 
previous visit will be used to calculate the dose of study drug.  In the event that the 
weight obtained on the previous dosing day is not available, the weight obtained predose 
on the dosing day can be used for dose calculation.  Patients who weigh 105 kg or more 
will receive patisiran dosing based on an assumption of a body weight of 104 kg. 
Sterile normal saline (0.9% NaCl) will be added to a sterile infusion bag, and the 
calculated volume of patisiran will be withdrawn from the vials and injected into the 
infusion bag. 
5.2.2 Preparation of Placebo 
Normal saline (0.9% NaCl), provided by a central supplier, will be infused into patients 
randomized into the control group.  Depending on the availability, saline may need to be 
withdrawn from a larger bag or additional saline may need to be added to a sterile 
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5.3 
Drug Administration 
5.3.1 Premedication 
Prior to each dose of study drug, in order to reduce the risk of experiencing an IRR, 
patients will receive the following premedications at least 60 minutes prior to the 
infusion: 
• Intravenous dexamethasone (10 mg) or equivalent; 
• Oral paracetamol/acetaminophen (500 mg) or equivalent; 
• Intravenous H2 blocker (e.g., ranitidine 50 mg, famotidine 20 mg, or equivalent other 
H2 blocker dose); 
• Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) 
or cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Patients will be started on the above premedication regimen.  However, modifications 
may be made to the premedication regimen after consultation with the medical monitor 
either due to a patient’s inability to tolerate one or more of the premedications or to the 
occurrence of IRRs unresponsive to slowing of the infusion rate. 
• If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 
patient develops uncontrolled hyperglycemia, altered mental status, or other 
complication), then lowering of the steroid premedication may be allowed for that 
patient after consultation with the medical monitor.  
• If after consultation with the medical monitor, it is agreed that an individual patient’s  
steroid premedication will be lowered, then the following steps must be followed: 
1) If the current steroid dosage is 10 mg intravenous dexamethasone or equivalent, 
then the patient may be lowered in increments no greater than 2.5 mg 
intravenous dexamethasone or equivalent. 
2) After each incremental lowering below 10 mg intravenous dexamethasone or 
equivalent, the patient must receive three consecutive intravenous doses of 
patisiran without IRR and continued signs or symptoms of steroid intolerance 
before further reductions in steroid premedications.   
3) The premedication steroid dosage should not be reduced below 5 mg intravenous 
dexamethasone or equivalent. 
Alternatively, if a patient experiences an IRR when 10 mg or less of intravenous 
dexamethasone or equivalent is used as the steroid premedication, then proceed to 
Section 5.9. 
Further details (including a table of equivalent premedications) can be found in the 
patisiran (ALN-TTR02) Pharmacy Manual. 


 
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5.3.2 Study Drug Administration 
Patients who are randomized into the active treatment group will receive 0.3 mg/kg 
patisiran once every 21 days (± 3 days).  Patients who are randomized into the control 
group will receive placebo (normal saline 0.9%) once every 21 days (± 3 days). 
The body weight that was obtained during the previous visit must be used to calculate the 
dose of study drug.  In the event that the body weight obtained on the previous dosing 
day is not available, the body weight obtained pre-dose on the dosing day can be used for 
the dose calculation.  Patients who weigh 105 kg or more will receive patisiran dosing 
based on an assumption of a body weight of 104 kg. 
Study drug (either patisiran or placebo) will be administered under the supervision of the 
unblinded site personnel, as a 70-minute IV infusion (approximately 1 mL/minute for the 
first 15 minutes followed by approximately 3 mL/minute for the remainder of the 
infusion).  The study drug will be administered via a controlled infusion device with an 
extension set containing a 1.2 micron filter supplied by Alnylam or designee.  Infusion 
products must not contain polyvinyl chloride, di(2-ethylhexyl)phthalate (PVC, DEHP).  
As described in Section 4.4.3, the tubing and the lines will be covered so that it will not 
be possible to detect a difference in active versus placebo drug. 
• If the patient experiences an IRR the infusion time may be extended up to 3 hours in 
the event of a mild or moderate IRR. 
1) If the patient experiences a mild or moderate IRR that resolves by slowing the 
infusion rate then no further premedication changes are recommended. 
2) If the patient experiences a severe IRR, then study drug administration will not 
be resumed until the case is discussed with the medical monitor (see Section 
5.9).   
• If the infusion time for a patient was extended due to an IRR, that modified infusion 
duration should be continued throughout the duration of the study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a 
discussion with the medical monitor. 
• For the first 3 infusions of study drug on this study, the patient’s infusion site should 
be assessed for signs of any localized reaction during the infusion and for 30 minutes 
after the end of the infusion, and the patient will remain at the clinical site for 1 hour 
following completion of dosing. 
If a patient does not receive a dose of study drug within the dosing window (±3 days), the 
dose will be considered missed and not administered. 
Additional details can be found in the patisiran (ALN-TTR02) Pharmacy Manual. 
In addition, patients will receive an oral daily supplemental dose of the recommended 
daily allowance of vitamin A. 
5.4 
Storage of Study Drug 
All study drug must be stored in a secure, temperature controlled location and may be 
dispensed only by a staff member specifically authorized by the Investigator or by a 


 
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pharmacist, as appropriate.  All study drug will be stored upright and refrigerated at 
approximately 5 ± 3oC.  Any deviation from the recommended storage conditions must 
be reported to the CRO and/or Alnylam and use of the study drug halted until 
authorization for its continued use has been given by Alnylam or designee. 
No special procedures for the safe handling of patisiran are required.  An unblinded 
Alnylam Monitor or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
No study product(s) may be administered to any person not enrolled in the study. 
Additional preparation details are provided in the patisiran (ALN-TTR02) Pharmacy 
Manual. 
5.5 
Labeling and Packaging of Study Drug 
All packaging and labeling as well as the preparation of patisiran and placebo will be in 
compliance with Good Manufacturing Practice (GMP) specifications, as described in the 
Manufacture of Investigational Medicinal Products Volume 4 Annex 13, and any other or 
local applicable regulations. 
Study drug labels will include all appropriate local labeling requirements on the vial and 
external label.  Sample labels will be submitted to health authorities, per local country 
submission requirements.  
5.6 
Measurement of Patient Compliance 
Treatment compliance with study drug administration is dependent on the proper 
preparation and administration of IV infusions by unblinded study site personnel as well 
as attendance by the patient to the clinic.  Treatment compliance with study drug 
administration will be verified by unblinded study staff observation.  A dose will be 
considered completed if 80% or more of the total volume of the IV solution has been 
administered to the patient.  Patients will be permitted to miss an occasional dose of study 
drug.  However, if a patient misses 2 consecutive doses, the PI, in consultation with the 
Medical Monitor, will discuss whether the patient will be able to continue on the study. 
Patients failing to complete the 18-month efficacy assessment visit will not be eligible to 
receive patisiran on the open-label extension study. 
5.7 
Study Drug Accountability 
The Investigator will maintain accurate records of receipt and the condition of all study 
drugs including dates of receipt.  In addition, accurate records will be kept of the weight 
used to calculate each dispensed patisiran dose, and when and how much study drug is 
dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by unblinded 
Alnylam Monitor or designee that will not have a role in any other aspect of managing 
the study.  Remaining study drug (all used, partially used, and unused vials) will be 
returned to Alnylam or its specified designee/depot or destroyed at the site according to 
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Study drug must not be used for any purpose other than the present study.  Study drug 
which has been dispensed for a patient and returned unused must not be redispensed. 
Further instructions about study drug accountability are detailed in the patisiran (ALN-
TTR02) Pharmacy Manual. 
5.8 
Concomitant Medication / Treatment 
Use of the following medications/treatments is prohibited during study participation (with 
the exclusion of patients who have rapid disease progression and discontinue study drug 
after the 9-month efficacy assessments): 
• Any investigational agent other than patisiran; 
• Tafamidis (use prior to screening permitted); 
• Diflunisal (use prior to screening permitted); 
• Doxycycline/TUDCA (use prior to screening permitted); 
• Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (e.g., asthma, rheumatoid 
arthritis, etc.), systemically administered steroids may be permitted provided that: 1) 
the dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Medications and treatments other than those specified above, including palliative and 
supportive care approved by the investigator for disease-related symptoms, are permitted 
during the study. 
Investigator should review over-the-counter (OTC) and or herbal preparations to ensure 
that these are not potentially disease modifying. 
Use of all concomitant medications and treatments will be recorded on the patient’s CRF 
through the time points shown in Table 1-1, Table 1-2, and Table 1-3.  This will include 
all prescription drugs, herbal preparations, OTC medications, vitamins, and minerals.  
Any changes in medications during the study will also be recorded on the CRF. 
Any concomitant medication or treatment that is required for the patient’s welfare may be 
given by the Investigator.  However, it is the responsibility of the Investigator to ensure 
that details regarding the medication or treatment are recorded on the CRF, and coded 
using an internationally recognized and accepted coding dictionary. 
5.9 
Suggested Guidelines for Management of Infusion-related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
• In the event of an IRR, the infusion of study drug may be stopped and the patient 
closely monitored until resolution of the reaction.  Drugs that may be used to 
facilitate resolution and permit resumption of study drug administration include, but 
are not limited to: paracetamol/acetaminophen (or equivalent), additional histamine 
H1/H2 receptor antagonists (eg, ranitidine), NSAIDs, adrenaline, supplemental 
oxygen, IV fluids, and/or corticosteroids. 


 
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• Following resolution of a mild or moderate IRR that required interruption of the study 
drug infusion, resumption of administration may occur at the Investigator’s discretion 
at a slower infusion rate (but not to exceed 3 hours) for that dose and for all 
subsequent doses of study drug.  If the infusion is delayed, the administration of the 
infusion should be completed no more than 6 hours from the initial start of the 
infusion.   
•  Study drug administration will not be resumed for any patient following a severe IRR 
until the case is discussed with the Medical Monitor. 
• If after consultation with the medical monitor it is agreed that an individual patient’s  
steroid premedication will be increased then the following steps are recommended: 
1) 
If the IRR occurred while the patient received 10 mg intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and did not 
resolve with slowing of the infusion rate, then the patient should be increased by 
multiples of 5 mg intravenous dexamethasone or equivalent at least 60 minutes 
before the infusion and/or 5 mg oral dexamethasone or equivalent the night 
before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 
20 mg intravenous dexamethasone or equivalent on the day of infusion and 8 mg 
oral dexamethasone or equivalent taken the night before the infusion.  
3) If the IRR occurred while the patient received less than 10 mg intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous dexamethasone or equivalent that did not result in an IRR. 
The patient’s infusion site should be assessed for signs of any localized reaction during 
the infusion and for 30 minutes after the end of the infusion.  The patient will remain at 
the study site for 1 hour following completion of dosing for observation and completion 
of assessments.  Patients will be instructed to call the Investigator if they experience 
symptoms such as fever, chills, myalgia, or nausea/vomiting after discharge from the site. 


 
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6 
STUDY VISITS 
The duration of a patient’s participation in this study is approximately 21 months 
(inclusive of a 42-day screening period and up to a 56-day post last dose study visit).   
Screening evaluations are to be performed within 42 days before receiving the first dose 
of study drug, as indicated in Table 1-1.  Patients determined to be eligible based on 
Screening assessments will receive blinded study drug IV infusion of either patisiran 
(ALN-TTR02) or placebo once every 21 days.  Patients will remain at the study site for 
1 hour following completion of dosing for observation and completion of assessments. 
In order to decrease the variability in the efficacy assessment testing, there will be a 
limited number of sites within any one territory that conduct efficacy assessments at 
Screening/Baseline, Baseline, 9-month, and 18-month visits (referred to as “Central 
Assessment Sites [CAS]”); these sites can also screen, dose, and manage patients.  There 
will also be sites that screen, dose, and manage the patients (“Patient Care Sites [PCS])”, 
while sending the patients to the nearest CAS for their Screening/Baseline, Baseline, 
9- and 18-month efficacy assessments. 
Prior to starting the study and screening patients in the protocol, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is 
responsible for which tests and safety parameters to ensure adherence to the protocol.  
This document will become part of the study site specific documentation. 
All patients who discontinue from the study early will return to the study site for their 
Early Withdrawal assessments. 
6.1 
Screening, Screening/Baseline, and Baseline Visits (Days –42 to Day 0) 
Screening evaluations will be conducted over 3 or more visits (Screening, 
Screening/Baseline, and Baseline).  All screening visits must occur within 42 days of the 
first dose of study drug (Day 0).  Table 1-1 provides an overview of the schedule of 
events required at each screening visit. 
Prior to screening activities, the patient will sign and date an informed consent form 
(ICF) and receive a copy of the signed ICF.  No study procedures should be performed 
prior to informed consent being obtained.  The Investigator or another person authorized 
by the Investigator will also sign and date the informed consent prior to giving a copy to 
the patient.  The ICF will be filed in the patient’s medical record. 
In conjunction with the decision of the Medical Monitor(s), patients may be allowed to 
rescreen after a minimum of 5 days have elapsed from their last screening assessment. 
6.1.1 Screening 
The following activities must be performed during the Screening visit as part of the initial 
review of patient eligibility: 
• Assess study eligibility using the inclusion and exclusion criteria; 
• Obtain medical history information, including inquiry into HIV status; 
• Obtain demographic information; 


 
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• Determine Karnofsky Performance Status (see Appendix 1); 
• Determine New York Heart Association classification of heart failure (see Appendix 
2); 
• Collect and review documentation for TTR genotype; 
• Perform a physical examination; 
• Measure weight; 
• Measure height; 
• Measure vital signs; 
• Collect blood samples for clinical laboratory tests, including: 
• Paraprotein (assessed by immunofixation electrophoresis [IFE]); 
• Vitamin B12; 
• Serology; 
• Hematology; 
• Serum chemistries; 
• Coagulation studies; 
• Thyroid function tests. 
• Collect urine sample for urinalysis; 
• Perform a pregnancy test (for females of child-bearing potential only); 
• Obtain information on concomitant medications; 
• Perform NIS and NCS.  Note:  The documented results of previously performed NIS 
and NCS may be used to qualify a patient for this study if these tests were performed 
within 60 days prior to the date of informed consent.  These studies may be 
completed as per local protocol. 
6.1.2 Screening/Baseline Visit 
Patients who meet all of the Screening criteria (including NIS and NCS assessments) will 
complete the screening process during 2 subsequent visits (which will be conducted at 
CAS for patients screened at PCS): a Screening/Baseline visit and a Baseline visit. 
The Screening/Baseline visit must be performed within 21 days prior to the first dose of 
study drug (Day 0). 
The following assessments must be performed during the Screening/Baseline visit: 
• Perform the following efficacy assessments: 
• mNIS+7*; 
• NIS+7*; 
*Note:  Components that are shared between the mNIS+7 and NIS+7 (including 
NIS and NCS) will be performed only once. 


 
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• PND score; 
• Collect blood sample for long-term frozen storage of serum to permit testing of 
additional proteins related to FAP; 
• Measure vital signs; 
• Measure weight; 
• Obtain information on concomitant medications; 
• Obtain an interval medical history; 
• Confirm that NIS, PND, and NCS results meet study eligibility requirements.  
Inclusion Criteria 3 (i.e., NIS of 5 to 130 [inclusive] and PND score of ≤3b) and 4 
(i.e., NCS sum of the sural SNAP, tibial CMAP, ulnar SNAP, ulnar CMAP, and 
peroneal CMAP of ≥2 points).  
Note:  The following assessments may be performed at a single time point during either 
the Screening/Baseline visit or as noted below, at the discretion of the investigator. 
At the Screening/Baseline or Baseline visit: 
• Perform a 12-lead ECG; 
• Complete the Norfolk QOL-DN, and COMPASS-31 questionnaires; 
• Complete the C-SSRS questionnaire; 
At any time after the patient is deemed eligible for participation in the study, but before 
the first administration of study drug: 
• Perform a timed 10-meter walk test. 
At any time after the patient is deemed eligible for participation in the study through the 
Day 0 visit: 
• Perform a grip strength test; 
• Perform an echocardiogram; 
• Complete the EQ-5D and R-ODS questionnaires; 
At any time after the patient is deemed eligible for participation in the study through the 
Day 21 visit: 
• Perform an ophthalmology exam; 
• Complete the pharmacoeconomics questionnaire. 
6.1.3 Baseline Visit 
The Baseline visit will occur at least 24 hours (approximately), but no greater than 
7 days, from the Screening/Baseline visit.  The following activities should be performed 
during the Baseline visit: 
• Perform a 12-lead ECG (if not completed at the Screening/Baseline visit); 
• Measure vital signs; 


 
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• Measure weight; 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.  Additionally, 
aliquots of serum samples will be taken for long-term frozen storage, to permit testing 
of additional proteins related to FAP; 
• Obtain information on concomitant medications; 
• Perform the following efficacy assessments: 
• mNIS+7*; 
• NIS+7*; 
*Note:  Components that are shared between the mNIS+7 and NIS+7 
(including NIS and NCS) will be performed only once. 
• PND score (see Appendix 5); 
• FAP stage (see Appendix 6); 
• If the patient has provided separate informed consent for the skin biopsies, 
obtain 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total; 1 set from 
the distal lower leg, when a patient’s clinical status allows, and 1 set from the 
distal thigh). Skin biopsies will be performed at a CAS; 
• mBMI (Note:  The site will only measure the patient’s weight.  Using this 
weight, mBMI will be calculated programmatically in the clinical database; 
the site will not perform the calculation.); 
• Collect blood samples for NT-proBNP and troponin I; 
• Norfolk QOL-DN (if not completed at the Screening/Baseline visit); 
• COMPASS-31 (if not completed at the Screening/Baseline visit). 
• Complete the C-SSRS questionnaire (if not completed at the Screening/Baseline 
visit); 
• Obtain an interval medical history. 
The following activities may also be completed at the Baseline visit if not completed at 
the Screening/Baseline visit, as described in Section 6.1.2: 
• Timed 10-meter walk test; 
• Grip strength test; 
• Echocardiogram; 
• EQ-5D and R-ODS questionnaires; 
• Ophthalmology examination at a CAS; 
• Pharmacoeconomics questionnaire. 


 
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6.2 
Treatment Visits 
Patients who are determined to be eligible for the study will be enrolled on Day 0. 
On all study visit days, patients should take their vitamin A supplement after completing 
the blood draws.  
Prior to dosing, all patients will receive premedications in order to reduce the risk of 
experiencing an IRR as described in Section 5.3.1. 
6.2.1 Day 0 
6.2.1.1 Pre-dose on Day 0 
On Day 0, patients will undergo the following procedures prior to study drug 
administration: 
• Measure weight; 
• Measure vital signs; 
• Timed 10-meter walk test (if not completed at the Screening/Baseline or Baseline 
visits); 
• Collect blood samples for clinical laboratory tests, including: 
• Serum chemistries; 
• Anti-drug antibody testing. 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.  Additionally, 
aliquots of serum samples will be taken for long-term frozen storage, to permit testing 
of additional proteins related to FAP; 
• Collect blood sample for plasma PK assessment within 1 hour of planned study drug 
dosing start; 
• Collect urine sample for PK assessment within 1 hour of planned study drug dosing 
start; 
• Obtain information on concomitant medications; 
• Randomize the patient (See Section 4.4.1); 
• Administer premedications at least 60-minutes prior to the start of administration of 
study drug (see Section 5.3.1); 
• Document any AEs. 
The following activities are to be completed on Day 0 pre- or post-dosing if not 
completed at the Screening/Baseline or Baseline visits, as described in Section 6.1.2: 
• Grip strength test; 
• Echocardiogram; 
• EQ-5D and R-ODS questionnaires. 


 
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6.2.1.2 Administration of Study Drug on Day 0 
As described in Section 5.3.2, after completion of all pre-dose evaluations and 
procedures, study drug will be administered by a controlled infusion device as a 
70-minute IV infusion (approximately 1 mL/minute for the first 15 minutes followed by 
approximately 3 mL/minute for the remainder of the infusion) or at a more prolonged 
infusion rate (up to 3 hours) if required due to prior IRR.  The patient’s infusion site 
should be assessed for signs of any localized reaction during the infusion and for 
30 minutes after the end of the infusion. 
The infusion time may be extended up to 3 hours in the event of a mild or moderate IRR.  
Study drug administration will not be resumed for any patient following a severe infusion 
reaction until the case is discussed with the Medical Monitor.   
Suggested guidelines for management of IRRs are provided in Section 5.9.   
6.2.1.3 Post-dose on Day 0 
The patient’s infusion site should be assessed for signs of any localized reaction during 
the infusion and for 30 minutes after the end of the infusion.  The patient will remain at 
the study site for 1 hour following completion of dosing for observation and completion 
of assessments:  
• Measure vital signs; 
• Collect a PK sample at the end of infusion (+5 minutes); 
• Obtain information on concomitant medications; 
• Document any AEs. 
The following activities may also be completed on Day 0 if not completed at the 
Screening/Baseline or Baseline visits, as described in Section 6.1.2: 
• Ophthalmology examination at a CAS; 
• Pharmacoeconomics questionnaire. 
6.2.2 Routine Study Visits 
The procedures described below are to be performed for all routine study visits (from 
Day 21 through Day 546), with the exception of the 9-month and 18-month efficacy 
assessments (occurring on Days 253-272 and Days 553-560, respectively).  All visits 
have a window of “±3 days” except for the Day 273 visit which has a window of 
“+3 days” to allow adequate time for the assessment of the patient’s 9-month mNIS+7 
and FAP stage testing, which will determine if the patient met the criteria for Rapid 
Disease Progression. 
Patients will undergo the following procedures before study drug dosing: 
• At all dosing visits, administer premedications at least 60 minutes prior to the start of 
administration of study drug (see Section 5.3.1); 
• At all dosing visits, measure weight; 
• At all dosing visits, measure vital signs; 


 
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• On Days 252 and 546, perform a physical examination; 
• On Days 126 and 399, perform a 12-lead ECG; 
• On Days 21, 126, 252, 273, 399, and 546, collect blood sample for serum TTR 
protein, RBP, and vitamin A.  Additionally, aliquots of serum samples will be taken 
for long-term frozen storage, to permit testing of additional proteins related to FAP; 
• On Days 84, 189, 357, 462, and 546, collect blood samples for serum chemistry tests; 
• On Day 546, collect blood sample for INR; 
• On Days 21, 126, 252, 399, and 546, collect a blood sample for anti-drug antibody 
assessment; 
• On Days 252 and 546, collect blood samples for clinical laboratory tests, including: 
• Hematology; 
• Thyroid function tests.  
• On Days 252 and 546, collect urine sample for urinalysis; 
• On Days 21, 126, 252, 399, and 546, collect a plasma PK sample pre-dose (within 
1 hour of planned study drug dosing); 
• On Days 21, 126, 252, 399, and 546, collect a urine PK sample pre-dose (within 
1 hour of planned dosing start); 
• Perform ophthalmology examinations on Day 21 (if baseline examination was not 
completed prior to the Day 21 visit), once between Days 231(±3) and 272 at a CAS, 
and once between Days 546(±3) and 560 at a CAS; 
• Complete the pharmacoeconomics questionnaire on Day 21, if not completed prior to 
the Day 21 visit; 
• At all dosing visits, obtain information on concomitant medications; 
• At all dosing visits, document any AEs. 
Following the completion of all required pre-dose activities and assessments, administer 
the study drug at all dosing visits, as described in Section 6.2.1.2. 
Following dosing, collect plasma PK samples as follows: 
• On Days 126 and 399, collect a plasma PK sample at the end of the infusion 
(+5 minutes); 
• On Days 21, 252, and 546, collect a plasma PK sample 30 minutes after the end of the 
infusion (+15 minutes). 
6.2.3 Efficacy Assessment Visits (9 Months and 18 Months) 
Efficacy assessment will be performed on all patients at approximately 9 and 18 months 
(Days 253-272 and 553-560, respectively).  Patients will not receive any study drug on 
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As described in Section 4.6, in consultation with the Investigator on Day 273 (+3 days), 
patients who meet the criteria for Rapid Disease Progression based on the 9-month 
efficacy assessments may continue study drug dosing or discontinue study drug dosing.  
Patients who discontinue study drug dosing may receive additional therapy for FAP, as 
per the local standard of care.  These patients will remain on the study and follow the 
modified schedule of assessments shown in Table 1-3 and described in Section 6.4.  
Blinding will be maintained throughout.  
The 9- and 18-month efficacy assessment visits will take place over 2 days. 
• Perform the following efficacy assessments: 
• mNIS+7*; 
• NIS+7*;  
• Timed 10-meter walk test*; 
• Grip strength test*; 
*Note:  For the mNIS+7, NIS+7, timed 10-meter walk test, and grip strength test, 
an independent assessment will be performed on each day.  Each site will make 
every effort to have these assessments performed by the same Investigator.  
Assessments are to be performed at least 24 hours (approximately) apart from 
each other but no greater than 7 days apart.  For the mNIS+7 and NIS+7, 
components that are shared (including NIS and NCS) will be performed only once 
on each assessment day. 
• PND score (see Appendix 5); 
• FAP stage (see Appendix 6); 
• If the patient has provided separate informed consent for the skin biopsies, 
obtain 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total); 1 set 
from the distal lower leg when a patient’s clinical status allows, and 1 set from 
the distal thigh. Skin biopsies will be performed at a CAS; 
• mBMI (Note:  The site will only measure the patient’s weight.  Using this 
weight, mBMI will be calculated programmatically in the clinical database; 
the site will not perform the calculation.);  
• Echocardiogram; 
• Collect blood samples for NT-proBNP and troponin I; 
• Norfolk QOL-DN; 
• EQ-5D; 
• R-ODS; 
• COMPASS-31. 
• Measure weight on both efficacy assessment days; 
• Measure vital signs on both efficacy assessment days; 


 
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• Complete the C-SSRS questionnaire; 
• Complete the pharmacoeconomics questionnaire; 
• Perform a 12-lead ECG; 
• Collect blood samples for: 
• TTR protein, RBP, and vitamin A; 
• Additional aliquots of serum for long-term frozen storage, to permit testing of 
additional proteins related to FAP. 
• Perform an ophthalmology examination (2 exams with 1 being completed between 
Days 231(±3) and 272 at a CAS, and 1 completed between Days 546(±3) and 560 at a 
CAS); 
• Obtain information on concomitant medications; 
• Document any AEs. 
6.2.4 Follow-Up Visits 
Patients will return to the study site for 2 follow-up visits, 21 days and 56 days after 
receiving their last dose of study drug.  If a patient enrolls in the extension study, they 
will only have to complete the 21-day follow-up assessments (End of Study [EOS]; 
Day 567) and not the 56-day follow-up assessments (Day 602).  Patients who do not 
enroll in the extension study will need to complete both follow-up visits (EOS [Day 567] 
and Day 602). 
6.2.4.1 Twenty-One-Day Follow-up Visit (End of Study) 
The following procedures will be performed at the 21-Day Follow-up visit (EOS; 
Day 567). 
• Perform a physical examination; 
• Measure weight; 
• Measure vital signs; 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.  Additionally, 
aliquots of serum samples will be taken for long-term frozen storage, to permit testing 
of additional proteins related to FAP; 
• Perform a pregnancy test (for females of child-bearing potential only); 
• Obtain information on concomitant medications; 
• Document any AEs. 
6.2.4.2 Fifty-Six-Day Follow-up Visit 
This visit will only be conducted for patients who do not enroll in the extension study. 
The following procedures will be performed at the 56-Day Follow-up visit (Day 602): 
• Perform a physical examination; 


 
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• Measure vital signs; 
• Collect blood sample for serum chemistry testing; 
• Perform a pregnancy test (only for females of child-bearing potential); 
• Obtain concomitant medications information; 
• Document any AEs. 
6.3 
Early Withdrawal Visit and Follow-up Visits for Patients who Permanently 
Discontinue Study Treatment  
6.3.1 Early Withdrawal Visit 
For patients who withdraw early from the study, every effort will be made to have them 
return to the study site to have the following procedures performed.  These visits will take 
place over 2 days. 
• Perform the following efficacy assessments: 
• mNIS+7*; 
• NIS+7*; 
• Timed 10-meter walk test*; 
• Grip strength test*. 
*Note:  For the mNIS+7, NIS+7, timed 10-meter walk test, and grip strength test, 
an independent assessment will be performed on each day.  Each site will make 
every effort to have these assessments performed by the same Investigator.  
Assessments are to be performed at least 24 hours (approximately) apart from 
each other but no greater than 7 days apart.  For the mNIS+7 and NIS+7, 
components that are shared (including NIS and NCS) will be performed only once 
on each assessment day. 
• PND score (see Appendix 5); 
• FAP stage (see Appendix 6); 
• If the patient has provided separate informed consent for the skin biopsies, 
obtain 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total); 1 set 
from the distal lower leg when a patient’s clinical status allows, and 1 set from 
the distal thigh; 
• mBMI (Note:  The site will only measure the patient’s weight.  Using this 
weight, mBMI will be calculated programmatically in the clinical database; 
the site will not perform the calculation.); 
• Echocardiogram; 
• Collect blood samples for NT-proBNP and troponin I; 
• Norfolk QOL-DN; 
• EQ-5D; 


 
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• R-ODS; 
• COMPASS-31. 
• Complete the pharmacoeconomics and C-SSRS questionnaires. 
• Measure weight on both efficacy assessment days. 
• Measure vital signs on both efficacy assessment days. 
• Perform a physical examination. 
• Collect a 12-lead ECG. 
• Collect blood samples for clinical laboratory tests, including: 
• Hematology; 
• Serum chemistries; 
• Thyroid function tests; 
• Anti-drug antibody testing. 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.  Additionally, 
aliquots of serum samples will be taken for long-term frozen storage, to permit testing 
of additional proteins related to FAP. 
• Collect urine sample for urinalysis. 
• Perform a pregnancy test (only for females of child-bearing potential). 
• Collect a blood sample for plasma PK assessment; 
• Collect a urine sample for PK assessment; 
• Obtain information on concomitant medications; 
• Document any AEs. 
6.3.2 Follow-up Visits for Patients who Permanently Discontinue Study Treatment  
Patients who permanently discontinue study treatment  at any time after their first dose of 
study drug (due to decision made by treating physician or by the patient) may consent to 
return for follow-up visits at Months 9 and/or 18.  If the patient discontinues study 
treatment  >24 weeks prior to the Month 9 evaluation visit, the patient will complete 
follow-up visits at 9 and 18 months;  if the patient discontinues study treatment after the 
Month 9 evaluation visit and >24 weeks before the Month 18 evaluation visit, the patient 
will complete a follow-up visit at 18 months.   
These visits will take place over 2 days (at least 24 hours [approximately], but not more 
than 7 days apart).  The following procedures will be performed:  
• Perform the following efficacy assessments: 
• mNIS+7*; 
• NIS+7*; 


 
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*Note:  For the mNIS+7 and NIS+7, an independent assessment will be 
performed on each day.  Each site will make every effort to have these 
assessments performed by the same Investigator.  Assessments are to be 
performed at least 24 hours (approximately) apart from each other but no greater 
than 7 days apart.  For the mNIS+7 and NIS+7, components that are shared 
(including NIS and NCS) will be performed only once on each assessment day. 
• PND score (see Appendix 5); 
• FAP stage (see Appendix 6); 
• mBMI (Note:  The site will only measure the patient’s weight.  Using this 
weight, mBMI will be calculated programmatically in the clinical database; 
the site will not perform the calculation.); 
• Norfolk QOL-DN; 
• EQ-5D 
• Perform a physical examination; 
• Measure weight on both efficacy assessment days; 
• Measure vital signs on both efficacy assessment days; 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.   
• Determine Karnofsky Performance Status (see Appendix 1); 
• Determine New York Heart Association classification of heart failure (see Appendix 
2); 
• Collect a blood sample for plasma PK assessment; 
• Collect data on subsequent FAP treatment regimens. 
 
6.4 
Modified Visit Schedule for Patients who Discontinue Study Drug for 
Rapid Disease Progression at Month 9 
As described in Section 4.6, in consultation with the Investigator, patients who meet the 
criteria for Rapid Disease Progression based on the 9-month efficacy assessments may 
continue study drug dosing or discontinue study drug dosing.  Patients who discontinue 
study drug dosing may receive additional therapy for FAP, as per the local standard of 
care.  These patients will remain on the study and follow a modified visit schedule as 
shown in Table 1-3 and described in detail below.  Blinding will be maintained 
throughout. 
6.4.1 Modified Day 273 
The following procedures will be performed on Day 273 (+3 days): 
• Consult with the patient on a subsequent plan of care, which may include receiving 
therapy for FAP as per the local standard of care; 
• Measure vital signs; 


 
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• Collect information on concomitant medications; 
• Document any AEs. 
Patients who discontinue treatment and also decide to discontinue from the study at the 
time of this visit will not have any additional visits after the Day 273 assessments are 
completed. 
6.4.2 Modified Day 294 
The following procedures will be performed: 
• Perform a physical examination; 
• Measure vital signs; 
• Collect blood sample for serum chemistry testing; 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.  Additionally, 
aliquots of serum samples will be taken for long-term frozen storage, to permit testing 
of additional proteins related to FAP; 
• Collect a blood sample for plasma PK assessment; 
• Collect a urine sample for PK assessment; 
• Perform a pregnancy test (only for females of child-bearing potential); 
• Obtain concomitant medications information (this will be the final collection of 
concomitant medications); 
• Document any AEs (following this visit, only AEs that are considered related to study 
procedures will be collected); 
• Collect data on subsequent FAP treatment regimens. 
6.4.3 Modified Day 378 and Day 462 
Study personnel will contact the patient by phone to query for general health status and 
data on subsequent FAP treatment regimens. 
6.4.4 Modified Day 546 
The following procedures will be performed: 
• Perform a physical examination; 
• Measure weight; 
• Measure vital signs; 
• Collect blood samples for clinical laboratory tests, including: 
• Hematology; 
• Serum chemistries and INR; 
• Thyroid function tests; 
• Anti-drug antibody testing. 


 
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• Collect urine sample for urinalysis; 
• Perform a pregnancy test (only for females of child-bearing potential); 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.  Additionally, 
aliquots of serum samples will be taken for long-term frozen storage, to permit testing 
of additional proteins related to FAP; 
• Collect a blood sample for plasma PK assessment; 
• Collect a urine sample for PK assessment; 
• Complete the pharmacoeconomics questionnaire; 
• Document any study-procedure-related AEs; 
• Collect data on subsequent FAP treatment regimens. 
6.4.5 Modified 18-Month Efficacy Assessment Visit 
This visit will take place over 2 days.  The following procedures will be performed: 
• Perform the following efficacy assessments: 
• mNIS+7*; 
• NIS+7*; 
• Timed 10-meter walk test*; 
• Grip strength test*; 
*Note:  For the mNIS+7, NIS+7, timed 10-meter walk test, and grip strength test, 
an independent assessment will be performed on each day.  Each site will make 
every effort to have these assessments performed by the same Investigator.  
Assessments are to be performed at least 24 hours (approximately) apart from 
each other but no greater than 7 days apart.  For the mNIS+7 and NIS+7, 
components that are shared (including NIS and NCS) will be performed only once 
on each assessment day. 
• PND score (see Appendix 5); 
• FAP stage (see Appendix 6); 
• If the patient has provided separate informed consent for the skin biopsies, 
obtain 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total); 1 set 
from the distal lower leg when a patient’s clinical status allows, and 1 set from 
the distal thigh; 
• mBMI (Note:  The site will only measure the patient’s weight.  Using this 
weight, mBMI will be calculated programmatically in the clinical database; 
the site will not perform the calculation.); 
• Echocardiogram; 
• Collect blood samples for NT-proBNP and troponin I; 
• Norfolk QOL-DN; 


 
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• EQ-5D; 
• R-ODS; 
• COMPASS-31. 
• Measure weight on both efficacy assessment days; 
• Measure vital signs on both efficacy assessment days; 
• Collect a 12-lead ECG; 
• Complete the C-SSRS questionnaire; 
• Document any study-procedure-related AEs. 
6.4.6 Modified Twenty-One-Day Follow-up Visit (End of Study) 
The following procedures will be performed: 
• Perform a physical examination; 
• Measure weight; 
• Measure vital signs; 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.  Additionally, 
aliquots of serum samples will be taken for long-term frozen storage, to permit testing 
of additional proteins related to FAP; 
• Document any study-procedure-related AEs; 
• Collect data on subsequent FAP treatment regimens. 
6.4.7 Modified Early Withdrawal Visit 
If the patient on the modified visit schedule discontinues from the study any time after 
the Day 273 assessments are completed (i.e., Day 274 onward), every effort will be made 
to have the patient return to the study site for the Modified Early Withdrawal visit.  This 
visit will take place over 2 days (at least 24 hours [approximately], but not more than 
7 days apart).  The following procedures will be performed: 
• Perform the following efficacy assessments: 
• mNIS+7*; 
• NIS+7*; 
• Timed 10-meter walk test*; 
• Grip strength test*; 
*Note:  For the mNIS+7, NIS+7, timed 10-meter walk test, and grip strength test, 
an independent assessment will be performed on each day.  Each site will make 
every effort to have these assessments performed by the same Investigator.  
Assessments are to be performed at least 24 hours (approximately) apart from 
each other but no greater than 7 days apart.  For the mNIS+7 and NIS+7, 
components that are shared (including NIS and NCS) will be performed only once 
on each assessment day. 


 
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• PND score (see Appendix 5); 
• FAP stage (see Appendix 6); 
• If the patient has provided separate informed consent for the skin biopsies, 
obtain 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total); 1 set 
from the distal lower leg when a patient’s clinical status allows, and 1 set from 
the distal thigh; 
• mBMI (Note:  The site will only measure the patient’s weight.  Using this 
weight, mBMI will be calculated programmatically in the clinical database; 
the site will not perform the calculation.); 
• Echocardiogram; 
• Collect blood samples for NT-proBNP and troponin I; 
• Norfolk QOL-DN; 
• EQ-5D; 
• R-ODS; 
• COMPASS-31. 
• Complete the pharmacoeconomics and C-SSRS questionnaires; 
• Perform a physical examination; 
• Measure weight on both efficacy assessment days; 
• Measure vital signs on both efficacy assessment days; 
• Collect a 12-lead ECG; 
• Collect blood sample for serum TTR protein, RBP, and vitamin A.  Additionally, 
aliquots of serum samples will be taken for long-term frozen storage, to permit testing 
of additional proteins related to FAP; 
• Collect blood samples for clinical laboratory tests, including: 
• Serum chemistries; 
• Thyroid function tests; 
• Anti-drug antibody testing. 
• Perform a pregnancy test (only for females of child-bearing potential); 
• Document any study-procedure-related AEs; 
• Collect data on subsequent FAP treatment regimens. 
6.5 
Unscheduled Visits 
Unscheduled visits for study assessments may occur if deemed necessary by the study 
personnel. 


 
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7 
STUDY ASSESSMENTS 
7.1 
Demographic Data and Medical History 
At the Screening visit, patient demographic data and a complete medical history will be 
obtained, including review of documentation of TTR genotype.  At the 
Screening/Baseline visit and Baseline visit, an interval medical history will be obtained, 
capturing only changes since the Screening visit. 
At the Screening visit, HIV status will be obtained.  The Investigator will assess the 
patient according to the Karnofsky Scale (see Appendix 1) and the New York Heart 
Association Classification of Heart Failure (see Appendix 2). 
7.2 
Efficacy Assessments 
Efficacy assessments will occur at Screening/Baseline, Baseline, 9 months, 18 months, 
and Early Withdrawal (if applicable).  A central neurologic testing core facility will 
review the data derived from the various neuropathy measures at each participating site to 
ensure compliance with testing procedures and quality of the data.  A central 
echocardiography core lab will analyze the echocardiogram data. A core lab will also be 
responsible for processing and analyzing skin punch biopsy samples. 
The study personnel performing assessments related to the efficacy endpoints will be 
blinded to the results of any previous assessments (e.g., Screening/Baseline, Baseline, or 
9-month assessments). 
Further details on performing these assessments will be provided in the Study Reference 
Manual. 
7.2.1 Modified Neurological Impairment Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which 
includes the following measures: 
• Clinical exam-based neurologic impairment score (NIS-weakness and reflexes); 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
• NCS Σ5; 
• QST by body surface area including TP and HP. 
• Autonomic function (postural blood pressure). 
A summary of the scoring of the components of the mNIS+7 is provided in Appendix 4. 
At each time point, 2 independent assessments will be performed.  Each site will make 
every effort to have these assessments performed by the same blinded study personnel, 
who will be different from the Investigator and other personnel managing the patient.  
Assessments are to be performed at least 24 hours (approximately) apart from each other 
but no greater than 7 days apart.  In order to limit potential intra-operator bias, results of 
any of the prior assessments will not be available to the examiner when performing the 
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Every effort will be made to use the same devices for NCS and QST for a patient 
throughout the duration of the study.   
7.2.2 Neurological Impairment Score +7 
The NIS+7 consists of the following measures: 
• Full NIS (including weakness, sensation, and reflexes); 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
• NCS Σ5; 
• VDT. 
• HRdb. 
A summary of the scoring of the components of the NIS+7 is provided in Appendix 4. 
At each time point, 2 independent assessments will be performed in the same manner as 
described above for mNIS+7.  Every effort will be made to use the same devices for NCS 
and VDT for a patient throughout the duration of the study.   
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) 
will be performed once at each assessment. 
7.2.3 Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the PND score and FAP stage (see 
Appendix 5 and Appendix 6, respectively).44,45 
7.2.4 Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via IENFD and SGNFD.  Patients 
who have provided additional voluntary consent for skin biopsy will undergo tandem 
3mm skin punch biopsies for IENFD and SGNFD assessment.  At each time point, 1 set 
of biopsies will be taken from the distal lower leg, when a patient’s clinical status allows, 
and 1 set from the distal thigh (4 biopsies total).   
A repeat baseline biopsy may be performed if the initial sample is not of sufficient 
quality. 
Details on sample collection, processing, and storage will be provided in the Study 
Laboratory Manual. 
7.2.5 Modified Body Mass Index 
Sites will measure body weight at the time points specified in Table 1-1, Table 1-2, and 
Table 1-3.  Using that data, the mBMI will be calculated (BMI × albumin).  This 
calculation will take place programmatically in the clinical database; the sites will not 
perform the calculation. 
7.2.6 Timed Ten-meter Walk Test 
To perform the timed 10-meter walk, the patient will be asked to walk 10 meters.  The 
walk must be completed without assistance from another person; ambulatory aids such as 


 
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canes and walkers are permitted.  The time required for the patient to walk 10 meters will 
be recorded.  At the 9-month, 18-month, and Early Withdrawal visits, the assessments 
will be conducted on 2 days, at least 24 hours (approximately), but not more than 7 days 
apart. 
7.2.7 Grip Strength Test 
Hand grip strength will be measured by dynamometer.  Sites will be trained on 
dynamometer and testing for the study.  When performing the test, patients will stand, 
holding the dynamometer in their dominant hand, with their arm parallel to the body 
without squeezing the arm against the body.  Tests will be performed in triplicate on the 
same day for each time point.   
Every effort will be made to use the same dynamometer for a patient throughout the 
duration of the study. 
At the 9-month, 18-month, and Early Withdrawal visits, the assessments will be 
conducted on 2 days, at least 24 hours (approximately), but not more than 7 days apart.  
7.2.8 Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the COMPASS-31 
questionnaire.  The questionnaire consists of 31 clinically selected questions evaluating 
6 autonomic domains (orthostatic intolerance, secretomotor, gastrointestinal, bladder, and 
pupillomotor).46 
7.2.9 Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk QOL-DN questionnaire, a 
standardized 47-item patient-reported outcomes measure that is sensitive to the different 
features of diabetic neuropathy (DN)-small fiber, large fiber, and autonomic nerve 
function.47 
7.2.10 EuroQoL Quality of Life Questionnaire 
Quality of life will be assessed through the use of the EQ-5D, a standardized 5-question 
instrument for use as a measure of health outcomes.48 
7.2.11 Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the 
R-ODS.49  The R-ODS is comprised of a 24-item linearly weighted scale that specifically 
captures activity and social participation limitations in patients. 
7.2.12 Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms as well as 
measurement of serum levels of the cardiac biomarkers NT-proBNP and troponin I.   
Echocardiograms will be performed at the time points specified in Table 1-1, Table 1-2, 
and Table 1-3 and interpreted at a central echocardiography core lab.  Image acquisition, 
storage, and transfer guidelines will be provided in a Study Manual. 


 
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Blood samples will be drawn to measure levels of NT-proBNP and troponin I at the time 
points specified in Table 1-1, Table 1-2, and Table 1-3.  Details on sample collection, 
processing, and storage will be provided in a Study Laboratory Manual. 
7.3 
Pharmacodynamic Assessments 
Pharmacodynamic sample collection, processing, and storage guidelines will be provided 
in a Study Laboratory Manual. 
7.3.1 Transthyretin 
Blood for serum TTR levels will be collected at the Baseline visit and prior to the 
administration of study drug at the time points specified in Table 1-1, Table 1-2, and 
Table 1-3.   
Serum TTR will be assessed using both ELISA (enzyme linked immunosorbent assay) 
and turbidimetric assays. 
7.3.2 Retinol Binding Protein 
Blood for serum RBP levels will be collected at the Baseline visit and prior to the 
administration of study drug at the time points specified in Table 1-1, Table 1-2, and 
Table 1-3.  
Serum RBP will be quantified using nephelometry. 
7.3.3 Vitamin A 
Blood for serum vitamin A levels will be collected at the Baseline visit and prior to the 
administration of study drug at the time points specified in Table 1-1, Table 1-2, and 
Table 1-3.  Supplemental vitamin A will be taken at the time points specified in Table 
1-1, Table 1-2, and Table 1-3. 
7.3.4 Exploratory Biomarkers 
To explore the expression of hepatocyte derived proteins to further characterize the 
biological effects of siRNA and/ or to explore possible metabolite profiling of patisiran 
(ALN-TTR02), serum and plasma samples will be collected at the time points specified 
in Table 1-1, Table 1-2, and Table 1-3. 
Details on biomarker sample collection, processing, and storage will be provided in a 
Laboratory Manual. 
Biological samples for biomarker research and possible metabolic profiling can be 
retained on behalf of Alnylam for a maximum of 15 years following the last patient’s last 
visit in the study. 
7.4 
Pharmacokinetic Evaluations 
Details on PK sample collection, processing, and storage will be provided in a Laboratory 
Manual.  Plasma and urine samples will be evaluated using a validated ATTO-Probe-
HPLC (high performance liquid chromatography) assay to determine siRNA 
concentration and by LC/MS/MS for DLin-MC3-DMA and PEG2000-C-DMG 
concentrations. 


 
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7.4.1 Plasma Pharmacokinetics 
Plasma samples will be collected at the time points shown in Table 1-1, Table 1-2, and 
Table 1-3 for assessment of siRNA, DLin-MC3-DMA and PEG2000-C-DMG.  PK 
parameters, including population PK will be analyzed, whenever possible as outlined in 
Section 9.2.6. 
7.4.2 Urine Pharmacokinetics 
Urine samples and urine volume void will be obtained at specified time points as 
specified in Table 1-1, Table 1-2, and Table 1-3.  Renal clearance (CLR) will be 
determined whenever possible for siRNA and 4-dimethylaminobuttyric acid, metabolite 
of DLin-MC3-DMA, excreted in the urine.  PK parameters will be analyzed, whenever 
possible, as outlined in Section 9.2.6. 
7.5 
Safety Assessments 
All safety assessment measures will be recorded in the patient’s medical record and CRF. 
7.5.1 Physical Examination 
A complete physical examination (including general appearance; head, ears, eyes, nose, 
and throat [HEENT]; cardiovascular; dermatologic; abdominal; genito-urinary; lymph 
nodes; hepatic; musculoskeletal; respiratory; and neurological) is to be at the study visits 
listed in Table 1-1, Table 1-2, and Table 1-3.   
7.5.2 Body Weight and Height 
Body weight will be measured at the study visits listed in Table 1-1, Table 1-2, and Table 
1-3.  The rules for using body weight to calculate dose are described in Section 5.3.2.  
Height will only be measured at Screening. 
7.5.3 Vital Signs 
Vital signs will be measured at the time points specified in Table 1-1, Table 1-2, and 
Table 1-3.  Vital signs include systolic/diastolic blood pressure, pulse rate, respiratory 
rate, and temperature, and will be measured in the supine position using an automated 
instrument after the patient has rested comfortably for 10 minutes.  Each patient’s blood 
pressure should be taken using the same arm.  Temperature will be recorded in Celsius or 
Fahrenheit.  Heart rate will be counted for a full minute and recorded in beats per minute.  
Respirations will be counted for a full minute and recorded in breaths per minute. 
For the safety of the patient, additional vital signs may be added at the discretion of the 
Investigator. 
7.5.4 Electrocardiogram 
Computerized 12-lead ECG recordings will be obtained in triplicate at each time point 
listed in Table 1-1, Table 1-2, and Table 1-3 and read locally by a cardiologist or 
qualified physician.  Each lead shall be recorded for at least 3 beats at a speed of 25 
mm/s. 
The following electrophysiologic parameters will be assessed: rhythm, ventricular rate, 
PR interval, QRS duration, and QT interval.  If the ECG machine does not calculate the 


 
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heart rate corrected QT interval (QTc), either Bazett’s and/or Fridericia’s formula will be 
used to calculate the QTc. 
For any clinically significant abnormal results, the Investigator must contact the CRO 
Medical Monitor to discuss continued participation of the patient in the study (e.g., 
ischemic ECG changes, wave/interval changes, or arrhythmia).  
7.5.5 Clinical Laboratory Tests 
Blood samples for clinical laboratory testing will be collected prior to study drug dosing 
at the time points listed in Table 1-1, Table 1-2, and Table 1-3.  Samples will be sent to a 
central laboratory for analysis.  Details on sample collection, processing, and shipping 
will be provided in a Laboratory Manual. 
In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
study drug administration, the test should be repeated and followed up at the discretion of 
the Investigator until it has returned to the normal range or stabilized, and/or a diagnosis 
is made to adequately explain the abnormality. 
The following clinical laboratory parameters are to be determined:  
Hematology 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
Serum Chemistries 
 
• Aspartate transaminase (AST) 
• 
Alkaline phosphatase 
• Alanine transaminase (ALT) 
• 
Bilirubin (total and direct) 
• Sodium 
• 
Glucose 
• Potassium 
• 
Phosphate 
• Blood urea nitrogen (BUN) 
• 
Albumin 
• Creatinine 
• 
Calcium 


 
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Coagulation Studies 
 
• Prothrombin time (PT) 
• International Normalized Ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
 
Thyroid Function Tests 
 
• Thyroid stimulating hormone (TSH) 
• Triiodothyronine (Free T3) 
• Thyroxine (Free T4)  
 
Anti-drug Antibodies 
 
• Anti-PEG antibodies 
 
Urinalysis 
 
• Visual inspection for color and appearance 
• Leukocytes 
• pH 
• Bilirubin 
• Specific gravity 
• Nitrite 
• Ketones 
• Urobilinogen 
• Protein 
• Microscopic inspection of sediment 
• Glucose 
 
Serology 
 
• Hepatitis B surface antibody (HbsAb) 
• Anti–hepatitis C virus antibody (anti-HCVAb) 
• Hepatitis B surface antigen (HbsAg) 
 
Cardiac Biomarkers 
• N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) 
• Troponin I 
Other 
• 
β-human chorionic gonadotropin (women of child-bearing potential only; may be a urine- or 
serum-based test) 
• 
Vitamin B12 
• 
Paraprotein by IFE 
7.5.5.1 Pregnancy Test 
The pregnancy test may be urine- or serum-based, at the discretion of the Investigator.  
The test will only be performed for women of child-bearing potential.  The timing of the 
tests is specified in Table 1-1, Table 1-2, and Table 1-3; additional testing may be done 
any time pregnancy is suspected.  The results must be known prior to administration of 


 
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study drug.  Patients who are pregnant are not eligible for study participation.  Patients 
who become pregnant while on study will be followed until the pregnancy outcome is 
known (see Section 8.12). 
7.5.6 Ophthalmology Examination 
The timing of the ophthalmology examinations is specified in Section 6.2.2 and in Table 
1-1 and Table 1-2.  These examinations will be performed at a CAS and will include 
assessment of visual acuity, slit-lamp evaluation, intraocular pressure, dilated indirect 
ophthalmoscopy, color fundus photography, visual field, and electroretinography (ERG).  
Visual acuity should be evaluated at the beginning of each specified visit in the study 
(i.e., prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit prior to visual acuity testing and will be used to obtain a correction for 
visual acuity evaluations.  Visual acuity testing should be done with best (most recent) 
correction. ERG evaluations will be centrally read.  
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
7.5.7 Adverse Events and Study-Procedure-Related Adverse Events 
Adverse events will be assessed and recorded at the time points specified in Table 1-1, 
Table 1-2, and Table 1-3.   
As shown in Table 1-3, only study-procedure-related AEs (e.g., skin-biopsy-related AE, 
venipuncture-related AE) will be collected after Day 294 for patients who meet the 
criteria for Rapid Disease Progression at Month 9 and receive their last dose of study 
drug on Day 252 but remain on the study.  
Section 8 provides assessment and reporting guidelines. 
7.5.8 Concomitant Medications and Treatments 
Use of all concomitant medications and treatments will be recorded on the patient’s CRF 
through the time points shown in Table 1-1, Table 1-2, and Table 1-3.  This will include 
all prescription drugs, herbal preparations, OTC medications, vitamins, and minerals.  
Any changes in medications during the study will also be recorded on the CRF.  
Section 5.8 provides guidelines on concomitant medications and treatments. 
7.6 
Other Assessments 
7.6.1 Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported, 
21-question pharmacoeconomics questionnaire.  This assessment will be performed at a 
CAS. 
7.6.2 Suicidality Questionnaire 
The Columbia–Suicide Severity Rating Scale (C-SSRS) will be used to assess patient’s 
mental status as it relates to suicidal ideation and behavior.50  This questionnaire will be 
administered to the patient by trained study personnel. 


 
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7.6.3 Phone Contact for Health Status Update and FAP Treatment 
Patients following the Modified Schedule of Assessments will be called on the telephone 
by study personnel at the time points specified in Table 1-3.  Patients will be asked about 
their general health status and any treatments they may have received for FAP. 


 
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8 
REPORTING ADVERSE EVENTS 
8.1 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be 
considered an AE. 
All IRRs will be recorded as AEs. 
For patients who meet the criteria for rapid disease progression at Month 9 and receive 
their last dose of study drug on Day 252 but remain on the study, AEs will be followed 
through Day 294.  Following Day 294, only study-procedure-related AEs will be 
collected (e.g., skin-biopsy-related AE, venipuncture-related AE).   
8.2 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly or birth defect; 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (e.g., such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse). 
8.3 
Eliciting Adverse Event Information 
The patient should be asked about medically relevant changes in his/her health since the 
last visit.  The patient should also be asked if he/she has been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication routines (both 
prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, ECG changes, or other findings. 


 
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8.4 
Adverse Event Reporting 
The Investigator is responsible for reporting all AEs that are observed or reported after 
the first dose of study drug regardless of their relationship to study drug through until the 
end of the reporting periods defined in Section 8.5.  For patients who meet the criteria for 
Rapid Disease Progression at Month 9 and receive their last dose of study drug on 
Day 252 but remain on the study, AEs will be followed through Day 294.  Following 
Day 294, only study-procedure-related AEs will be collected (e.g., skin-biopsy-related 
AE, venipuncture-related AE).   
Any medical condition that is present when a patient is screened and does not deteriorate 
should not be reported as an AE.  However, if it does deteriorate at any time during the 
study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, 
whether or not they are considered to be drug-related.  Each AE should be described in 
detail: onset time and date, description of event, severity, relationship to investigational 
product, action taken, and outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through until the end of the reporting periods defined 
in Section 8.5 or until recovery to the normal state has been achieved, whichever occurs 
first.  In the event of a patient not returning to the clinical unit, the outcome of this event 
will be recorded as lost at follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until 
resolution or 28 days from last dose, whichever occurs first. 
8.5 
Adverse Event Reporting Period 
AEs and SAEs will be reported according to the following timeframes: 
• For patients who complete the study, AEs will be assessed through the End of Study 
visit on Day 567 or the Follow-up visit on Day 602 (depending whether or not the 
patient plans to roll over to the open-label extension study).  All AEs that occur after 
the start of study drug administration on Day 0 must be reported in detail on the 
appropriate CRF page and followed to satisfactory resolution, or through the end of 
study visit on Day 567 or Day 602 (depending whether or not the patient plans to roll 
over to the open label extension study) after the last dose of study drug 
administration.  SAEs will be followed through the end of study visit on Day 567 or 
Day 602 (depending whether or not the patient plans to roll over to the open label 
extension study), or until satisfactory resolution, or until the SAE is considered by the 
Investigator to be chronic or the patient is stable, whichever occurs first. 
• For patients who meet the criteria for Rapid Disease Progression at Month 9 and 
receive their last dose of study drug on Day 252 but remain on the study, AEs will be 
followed through Day 294.  Following Day 294, only study-procedure-related AEs 
will be collected (e.g., skin-biopsy-related AE, venipuncture-related AE).  SAEs will 
be followed by the Investigator until satisfactory resolution or the Investigator deems 
the SAE to be chronic or stable. 


 
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• For patients who withdraw from the study early, ongoing AEs will be followed until 
resolution or 28 days from last dose, whichever occurs first.  SAEs will be followed 
by the Investigator until satisfactory resolution or the Investigator deems the SAE to 
be chronic or stable. 
8.6 
Assessment of Causality 
Causal relationship assessment to drug treatments is required for purposes of reporting 
AEs.  To promote consistency, the following guidelines should be taken into 
consideration along with good clinical and scientific judgment when determining the 
relationship of drug treatments to an AE: 
Definitely Related: A clinical event, including laboratory test abnormality, occurring 
in a plausible time relationship to the medication administration, 
and which cannot be explained by concurrent disease or other 
drugs or chemicals.  The response to withdrawal of the drug 
should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to the medication administration, but 
which could also be explained by concurrent disease or other 
drugs or chemicals.  Information on the drug withdrawal may be 
lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little 
or no temporal relationship to medication administration, and 
which other drugs, chemicals, or underlying disease provide 
plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely 
alternative etiology. 
8.7 
Assessment of Severity 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no 
disruption of normal daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to 
interfere with daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual 
activity. 
Changes in severity should be documented in the medical record to allow assessment of 
the duration of the event at each level of severity.  Adverse events characterized as 
intermittent require documentation of the start and stop of each incidence.  When changes 


 
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in the severity of an AE occur more frequently than once a day, the maximum severity 
for the experience that day should be noted.  If the severity category changes over a 
number of days, then those changes should be recorded separately (with distinct onset 
dates). 
8.8 
Action Taken for Adverse Event 
Action taken in regards to study drug will be defined as: 
• None; 
• Infusion interrupted and restarted at a later time; 
• Infusion stopped and was not restarted at a later time; 
• Infusion cycle delayed. 
8.9 
Outcome of Adverse Event 
Outcome will be defined as: 
• Resolved (with or without sequelae); 
• Ongoing; 
• Lost to follow-up. 
8.10 
Coding of Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code AEs. 
8.11 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE 
and laboratory abnormality that meets the above seriousness criteria (Section 8.2) must 
be reported immediately to the CRO, always within 24 hours from the time that site 
personnel first learn of the event.  All SAEs must be reported regardless of the 
relationship to study drug. 
The initial report should include at least the following information: 
• Patient’s study number; 
• Description and date of onset of the event; 
• Criterion for serious; 
• Preliminary assignment of causality to study drug. 
SAE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the electronic data capture 
(EDC) system for the study.  When the form is completed, 
Safety personnel 
will be notified electronically and will retrieve the form.  If the event meets serious 
criteria and it is not possible to access the EDC system, send an email to 
 
 
 
 or call the 
 SAE hotline (phone 
number will be provided in the Study Manual), and fax the completed back-up paper 
SAE form to 
(fax number will be provided in the Study Manual) within 


 
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24 hours of awareness.  When the EDC system becomes available, the SAE information 
must be entered into the EDC system within 24 hours of the system becoming available.  
 Safety personnel will be available for SAE reporting on a 24-hour basis.  
Incoming reports will be reviewed during normal business hours. 
 
Within 24 hours of receipt of follow-up information, the investigator must update the 
SAE form electronically in the EDC system for the study and submit any supporting 
documentation (e.g., patient discharge summary or autopsy reports) to 
 Safety 
personnel via fax or e-mail.  If it is not possible to access the EDC system, refer to the 
procedures outlined above for initial reporting of SAEs.  
Appropriate remedial measures should be taken by the Investigator using his/her best 
medical judgment to treat the SAE.  These measures and the patient’s response to these 
measures should be recorded.  All SAEs, regardless of relationship to study drug, will be 
followed by the Investigator until satisfactory resolution or the Investigator deems the 
SAE to be chronic or stable.  Clinical, laboratory, and diagnostic measures should be 
employed by the Investigator as needed to adequately determine the etiology of the event.   
The Investigator will be responsible for reporting all SAEs to the local independent ethics 
committee (IEC) or Institutional Review Board (IRB) when required by national 
regulations. 
Alnylam or its representative will be responsible for the reporting of all relevant events to 
the concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and 
the Ethics Committees in the concerned Member States will be notified of fatal and life-
threatening Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as 
possible but no later than 7 calendar days after Alnylam or its representative has first 
knowledge of the minimum criteria for expedited reporting.  Non-fatal and non-life-
threatening SUSARs should be reported no later than 15 calendar days after Alnylam or 
its representative has first knowledge of them. 
The Investigator may be informed by Alnylam or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These 
SAEs should also be reported promptly to the IEC/IRB that approved the study.  All SAE 
reports should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a 
copy of that transmittal should be maintained in the Investigator’s files and forwarded to 
Alnylam as part of the TMF on study completion. 
8.12 
Pregnancy Reporting 
A female patient with a positive pregnancy test at Screening is ineligible for this study.  If 
a female patient is found to be pregnant during the course of the study or during the 
first month after receiving the last dose of study drug, the Investigator should report the 
pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  The patient should receive 
any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus.   


 
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The pregnancy should be followed by the Investigator until completion. At the 
completion of the pregnancy, the Investigator will document the outcome of the 
pregnancy.  If the outcome of the pregnancy meets the criteria for an SAE 
(i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), then the Investigator should follow the procedures for reporting an 
SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be 
reported to the Investigator, who will then report this to the CRO and follow to outcome 
as described above. 


 
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9 
STATISTICAL METHODS 
9.1 
Sample Size 
Approximately 200 patients will be enrolled in this study.  Of those 200 patients, no more 
than 40 patients will have a NIS range of 101 to 130.  An mNIS+7progression rate 
(primary endpoint) in the placebo group of 24 ± 16 points in 18 months was estimated 
using natural history data from FAP patients.  A sample of 154 patients provides 90% 
power for a 2-sided test with an 8.95 point (37.5%) mean difference between treatment 
groups in the primary endpoint at 2-sided alpha = 0.05.  Assuming a 25% random 
premature discontinuation rate (due to liver transplantation or other factors), the sample 
size for this study is approximately 200.  Additional patients may be enrolled based on a 
recommendation to increase the sample size in the interim analysis. 
9.2 
Statistical Methodology 
A full statistical analysis plan will be finalized prior to database lock. 
9.2.1 Populations to be Analyzed 
The following patient populations (i.e., analysis sets) may be evaluated and used for 
presentation of the data: 
• Modified ITT (mITT) population:  All patients who were randomized and received at 
least 1 dose of study drug; 
• Per protocol (PP) population:  All patients who completed the 18-month efficacy 
assessment visit and did not have any major protocol violations; 
• Safety population:  All patients who received at least 1 dose of study drug (analyzed 
as treated, not as randomized). 
The primary population for efficacy analyses will be the mITT population; key efficacy 
results will also be analyzed secondarily for the PP population.  For efficacy analyses, 
patients will be grouped according to the treatment to which they were randomized.  The 
primary population for safety analysis will be the safety population.  Patients will be 
grouped according to treatment received for summaries of safety. 
9.2.2 Baseline Evaluations 
Demographic and baseline disease characteristic data will be summarized.  Data to be 
tabulated will include sex, age, and race, as well as disease-specific information. 
9.2.3 Efficacy Analyses 
9.2.3.1 Primary Efficacy Endpoint 
The primary analysis will compare change in mNIS+7 from baseline between treatment 
groups of the mITT population.  An analysis of covariance (ANCOVA) model, with 
baseline mNIS+7 value and age as continuous covariates and genotype (V30M vs Non-
V30M), prior tetramer stabilizer (tafamidis or diflunisal) use (Yes vs No), and treatment 
group (patisiran [ALN-TTR02] vs Placebo) as factors will be employed to analyze the 
primary mNIS+7 endpoint.  The mNIS+7 change from baseline will be assessed at 
78 weeks.  Primary endpoint data that are missing will be inferred using multiple 


 
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imputation (MI) (see Section 9.2.10).  Analyses will be conducted using PROC MI and 
PROC MIANALYZE in SAS 9.2 (or later).  The efficacy of patisiran will have been 
established if the estimate of the parameter associated with treatment variable 
demonstrates that patisiran improves mNIS+7 relative to placebo with a p-value (2-sided) 
less than or equal to 0.05, based on the MI methodology. 
Sensitivity analyses will assess the robustness of the primary analysis in the mITT and PP 
populations for different methods of handling missing data, including mixed model 
repeated measures (MMRM), complete cases (CC), and last observation carried forward 
(LOCF). 
9.2.3.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed using methods similar to those employed 
for the primary analysis, e.g. ANCOVA with multiple imputations, as appropriate.  
Type I error control for secondary endpoints will be achieved by a hierarchical ordering 
procedure.  Endpoints will be tested in the following prespecified hierarchy: 
• Norfolk QOL-DN questionnaire; 
• NIS-W score; 
• mBMI; 
• Timed 10-meter walk test; 
• COMPASS-31. 
If and only if a comparison is significant at p<0.05, the next endpoint in the hierarchy 
may be tested.  
9.2.3.3 Exploratory Efficacy Endpoints 
Continuous exploratory efficacy variables, including those closely related to the mNIS+7 
primary endpoint, may be compared using methods similar to those employed for the 
primary analysis, e.g. ANCOVA with multiple imputations, as appropriate.  Binary 
secondary endpoints will be assessed by the Cochran-Mantel-Haenszel test, stratified by 
the randomization stratification factors.   
9.2.4 Safety Analyses 
A summary of study drug exposure, including the durations of the infusions and doses, 
and the proportions of patients with modifications in the durations of infusions will be 
produced. 
Adverse events will be summarized by MedDRA system organ class and preferred term.  
Separate tabulations will be produced for all treatment emergent AEs, treatment-related 
AEs (those considered by the Investigator as at least possibly drug related), SAEs, and 
discontinuations due to AEs.  By-patient listings will be provided for deaths, SAEs, and 
events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, 
presented as both actual values and changes from baseline relative to each on-study 
evaluation and to the last evaluation on study. 


 
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Descriptive statistics will be provided for ECG interval data and presented as both actual 
values and changes from baseline relative to each on-study evaluation and to the last 
evaluation on study. Details of any abnormalities will be included in patient listings. 
9.2.5 Pharmacodynamics 
Summary tables and graphical displays of observed values and changes from baseline in 
serum TTR will be used to assess the durability of suppression over the course of the 
study.  Similar analyses will be performed for the secondary PD biomarkers (RBP and 
vitamin A). 
9.2.6 Pharmacokinetics 
Pharmacokinetic analyses will be conducted using non-compartmental and/or 
compartmental evaluation.  Whenever possible, the PK parameters of siRNA, 
DLin-MC3-DMA, and PEG2000-DMG (lipid) in sparse plasma samples collected from all 
patients.  PK parameters will be calculated using a validated version of WinNonlin® 
Enterprise (Version 5.2 or higher) with NCA Model 200.  
Population PK analyses, will be performed whenever possible, on available siRNA, 
DLin-MC3-DMA, and PEG2000-C-DMG from sparse plasma samples obtained from all 
patients during the duration of the study using Phoenix NLME (Version 1.1 or later).  
Summary tables and figures and inferential statistics will be generated with Phoenix 
NLME (Version 1.1 or later) or similar software.  
Pharmacokinetic/PD analysis will be conducted whenever possible, of sparse plasma 
samples collected during the study period.  The analysis will include, but not limited to, 
the determination of the relationship between exposure to siRNA, DLin-MC3-DMA, and 
PEG2000-C-DMG and the extent of suppression of TTR, RBP, and vitamin A and their 
correlation will be evaluated.  Correlation between TTR versus RBP and vitamin A will 
also be performed.  The strength of the relationship will be assessed using statistical 
estimators.  As part of the PK/PD analysis, additional PD baseline analysis on serum 
TTR, RBP, and vitamin A may be conducted to include the PD data obtained post-PD 
recovery period.  The PD and PK/PD analysis will be performed with WinNonLin or 
Phoenix NLME (Version 1.1 or later) or similar software.  The PD and PK/PD 
parameters summary tables and figures and inferential statistics will be generated and 
will not be limited to descriptive statistics.  
9.2.7 Summary of Efficacy Assessments 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS+7 composite score. Summaries will also be provided for the components of the 
composite score (e.g., the NIS weakness and reflex scores, the NCS Σ5, and QST values). 
The NIS+7 score, including its components (e.g. full NIS, HRdb, VDT) will also be 
summarized. 
Patient reported quality of life and disability will be assessed by summary statistics for 
the Norfolk QOL-DN, EQ-5D, and R-ODS. Summary statistics will be provided for 
observed values and changes from baseline.  Patient reported autonomic neuropathy 
symptoms will be assessed by descriptive statistics for the COMPASS-31. 


 
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Descriptive statistics will also be provided for observed values and changes from baseline 
in motor function (10-meter walk test and test of grip strength), nutritional status 
(mBMI), sensory and autonomic innervation (IENFD and SGNFD), and ambulation 
(FAP stage and PND score).  Descriptive statistics will also be provided for proportions 
of patients in each group that meet the rapid progression definition at 9 months and those 
that meet the responder criterion at 18 months. 
9.2.8 Other Assessments 
The observed values and changes from baseline in burden of disease and healthcare 
utilization will be evaluated and summarized using descriptive statistics. Data on 
suicidality will be summarized by treatment group using descriptive statistics. 
9.2.9 Interim Analysis 
Because the sample size estimates are based on limited data for variance and disease 
progression, it is intended that an interim analysis will be conducted by an independent 
committee when approximately 50% of patients have completed their 9-month mNIS+7 
assessment.  This interim analysis will be blinded and will only estimate the overall 
variance observed in the primary endpoint.  Since the interim analysis examines only the 
pooled variance of all patients in a blinded fashion, it does not require an adjustment to 
the overall alpha level for the test of the primary endpoint.  Based on the results of the 
interim analysis, the committee can recommend either increasing the study size or 
making no adjustment to the sample size.  Details regarding the Interim Analysis 
Committee are provided in Section 10.3.3. 
9.2.10 Missing Data 
Patients who discontinue due to rapid disease progression will have their 78-week 
mNIS+7 change from baseline value imputed using a stepwise regression approach for 
identification of explanatory variables (e.g., demographics, stratifying variables, and 
baseline/9-month mNIS+7 data when available); treatment assignment will not be 
included in the imputation.  Imputed datasets will then be analyzed as complete cases via 
the ANCOVA model specified for the primary analysis, and then combined to produce 
inferential results. Further details on imputations and sensitivity analyses will be included 
in the SAP that will be finalized before database lock. 


 
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10 
STUDY MANAGEMENT 
The Investigator is accountable for the conduct of the study.  If any responsibilities are 
delegated, the Investigator should maintain a list of appropriately qualified staff to whom 
he/she has delegated specified significant trial related duties. 
10.1 
Data Handling and Quality Assurance 
10.1.1 Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source 
documentation as part of these case histories.  Source documents are the originals of any 
documents used by the Investigator or hospital/institution that allow verification of the 
existence of the patient and substantiate the integrity of the data collected during the trial. 
Alnylam will supply CRFs for each patient.  Case report forms must be completed only 
by persons designated by the Investigator.  Corrections must be made so as not to 
obliterate original data and must be identified and dated by the person who made the 
correction.  All data entered into the CRF must also be available in the source documents.  
The Investigator will allow designated Alnylam representatives and regulatory bodies to 
have direct access to the source documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a 
timely manner.  The completed CRF will be the records maintained by Alnylam.  A copy 
of the CRF will remain in the Investigator’s files. 
10.1.2 Monitoring 
The clinical monitor, as a representative of Alnylam, has an obligation to follow the study 
closely.  In doing so, the monitor will visit the Investigators and sites periodically as well 
as maintain frequent telephone and written contact.  The monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation and discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by Alnylam or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice 
(GCP) and current standard operating procedures. 
10.1.3 Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB 
and/or Regulatory Authorities, providing direct access to source data/documents.  The 
study may be subject to audit by Alnylam or its representatives or by regulatory 
authorities.  If such an audit occurs, the Investigator must agree to allow access to the 
required patient records.  In the event of an audit, the Investigator agrees to allow 
Alnylam, representatives from Alnylam, or regulatory agencies access to all study 
records. 
10.2 
Regulatory Guidelines 
This study will be performed in accordance with the clinical trial agreement, the protocol, 
all applicable government laws, regulations, and guidances where the study is being 
conducted including policies with foundations in the World Health Organization (WHO) 


 
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Declaration of Helsinki, the International Conference on Harmonization (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human Use, the Health 
Insurance Portability and Accountability Act of 1996 (“HIPAA”), and all other applicable 
medical privacy laws and regulations. 
10.2.1 Institutional Review Board/Independent Ethics Committee 
National regulations and ICH require that approval be obtained from an IRB or an IEC 
prior to participation of patients in research studies.  Prior to the study onset, the protocol, 
any protocol amendments, ICFs, advertisements to be used for patient recruitment, and 
any other written information regarding this study to be provided to a patient or patient’s 
legal guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (e.g., name and address), the clinical 
protocol by title and/or protocol number, and the date of approval or favorable opinion 
was granted for the clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization 
has been received by Alnylam or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at 
least annually or more often if specified by the IRB or IEC.  The Investigator must supply 
Alnylam with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and 
operates in accordance with Federal and ICH GCP and any local regulations. 
10.2.2 Regulatory Authorities 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
10.2.3 Modification of the Protocol 
Major changes in this research activity, except those to remove an apparent immediate 
hazard to the patient, must be reviewed and approved by Alnylam and the IRB or IEC 
that approved the study.  Amendments to the protocol must be submitted in writing to the 
Investigator’s IRB or IEC and the Regulatory Authority for approval prior to patients 
being enrolled under the amended protocol. 
10.2.4 Informed Consent Form 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 
and ICH will be obtained from each patient prior to undergoing any protocol-specific 
tests or procedures that are not part of routine care.   
Alnylam or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or 
IEC, the site-specific ICF must be reviewed and approved by Alnylam or designee.  Any 
changes requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC 
approved ICF must be provided to Alnylam.  Revisions to the ICF required during the 
study must be agreed upon, and a copy of the revised ICF provided to Alnylam. 


 
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At the time of recruitment, each prospective patient (or legal guardian) will be given a 
full explanation of the study and be allowed to read the ICF.  Once the Investigator is 
assured that the patient/legal guardian understands the commitments of participating in 
the study, the patient/legal guardian will be asked to sign and date the ICF.  A copy of the 
fully signed and dated ICF will be given to the patient.  The original will be maintained in 
the patient’s medical record at the site.  All active patients will sign an updated ICF if 
revisions are made to the ICF during the course of the study. 
10.2.5 Study Reporting Requirements 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local 
reporting requirements, or at least annually and at the conclusion of the study.  The 
reports will be made available to Alnylam or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the 
CRO within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that 
impact this protocol or the qualifications of study personnel should be promptly reported 
to the CRO. 
10.2.6 Financial Disclosure Reporting Obligations 
Each Investigator (including principal and any sub-investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure 
information according to all applicable legal requirements.  In addition, Investigators 
must commit to promptly updating this information if any relevant changes occur during 
the study and for a period of one year after the completion of the study. 
10.3 
Study Committees 
10.3.1 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be involved in the conduct of this study.  The 
DMC has the responsibility for monitoring the progress of the clinical study and the 
safety of the study participants.  The DMC will perform periodic reviews of data and 
study conduct during the course of the clinical trial, as defined in the DMC Charter for 
this clinical trial.  The membership of the DMC and reporting structure are defined in the 
DMC Charter. 
10.3.2 Clinical Adjudication Committee 
An independent clinical adjudication committee will perform a blinded adjudication of 
the results of those patients who have clinical evidence of rapid disease progression 
(defined as ≥24 point increase in mNIS+7 from baseline [based on an average of 
2 measurements] and FAP stage progression relative to baseline) at 9 months.  Each 
review will follow procedures detailed in the committee’s charter. 
10.3.3 Interim Analysis Committee 
An Interim Analysis Committee (IAC), comprised of 2 statisticians (1 blinded and 
1 unblinded) independent of the conduct of the study, will be responsible for the 


 
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implementation of the interim analysis and for the calculations and recommendations 
surrounding whether an adjustment to the sample size is warranted, and if so, the 
appropriate adjustment, based on the study’s primary endpoint data from the interim 
analysis.  The Sponsor, the CROs, and all other parties conducting the study will remain 
blinded to all interim analyses until study completion.  The IAC will follow the procedure 
outlined in the committee’s charter. 
10.4 
Ancillary Research 
Research ancillary to this main protocol may not be performed by individual study sites 
without prior discussion and approval by Alnylam. 
10.5 
Study Record Retention 
Essential documents should be retained for the period of time required by applicable local 
law.  The essential documents include the signed and dated final protocol, signed and 
dated amendments(s), if applicable, signed and dated Curriculum Vitae (CVs) of the 
Investigators, copies of the completed CRFs, signed ICFs, IEC/IRB approval and all 
related correspondence, financial agreements, regulatory approval, drug accountability, 
study correspondence, and patient identification codes.  Records will not be destroyed 
without informing Alnylam in writing and giving Alnylam the opportunity to store the 
records for a longer period of time at Alnylam’s expense. 
The International Conference on Harmonization requires that patient identification codes 
be retained for at least 15 years after the completion or discontinuation of the study. 
10.6 
Discontinuation of the Study by Alnylam 
Alnylam reserves the right to discontinue the study for clinical or administrative reasons 
at any time.  If the site does not recruit at a reasonable rate, the study may be 
discontinued at that site.  Should the study be terminated and/or the site closed for 
whatever reason, all documentation and study drug pertaining to the study must be 
returned to Alnylam or its representative, and the Investigators, IEC/IRB and Regulatory 
Authorities will be promptly informed of the termination and the reason for the decision.  
The Investigator should promptly inform the patients and assure appropriate therapy and 
follow-up. 
10.7 
Study Documentation 
Prior to beginning the study, the Investigator will be asked to comply with ICH E6 and 
21 CFR by providing at least the following essential documents: 
• An original signed Investigator agreement page of the protocol and any amendments; 
• An IEC/IRB and Alnylam approved ICF; 
• IEC/IRB approval of the protocol, and any amendments; 
• Completed and signed FDA form 1572; 
• Curriculum vitae for the Investigator signed and dated by the Investigator indicating 
that it is current; 
• Financial disclosure information (if applicable); 


 
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• Other documents which the Investigator should provide before study start include: 
• Curriculum vitae for all Sub-investigators; these should be signed and dated 
by the Sub-investigators indicating that they are current; 
• Financial disclosure information for all Sub-investigators (if applicable); 
• Advertisements for patient recruitment and any other written information to be 
given to patients, family members or legal guardians and IEC/IRB approval of 
any advertisements and any other written information; 
• IEC/IRB composition:  If the Investigator or any of the Sub-investigators is a 
member of the IEC/IRB, assurance that he/she refrained from voting should 
be provided; 
• Laboratory accreditation and reference ranges for any laboratory values for 
local laboratories. 
10.8 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the 
CRFs or other documents submitted to Alnylam or designees, patients should not be 
identified by their names, but by the assigned patient number and initials.  If patient 
names are included on copies of documents submitted to Alnylam or designees, the 
names (except for initials) will be obliterated and the assigned patient number added to 
the document.  Documents not for submission to Alnylam (e.g. signed ICFs) should be 
maintained by the Investigator in strict confidence. 
Following the principles of the Good Clinical Practice, if local regulations specify a 
patient’s number and initials will be used to identify the patient on their study records.  
Laboratory samples may be labeled with an independent numbering code, and the label 
will not contain any other personal identification information.  The numbering code 
associated with these labels will be held by the study CRO and Alnylam, thereby 
allowing no unwarranted access to the information.  When reporting results for interim 
safety assessment, the interim analysis, and at the end of the study, the code will be 
shared per standard operating procedures with the responsible member of the 
Biostatistical and Data Management Departments of the CRO.  The numbering code will 
also be held for samples in storage until marketing approval of patisiran (ALN-TTR02) in 
the countries where this study was conducted, or until clinical development of patisiran is 
halted.  Throughout sample collection, storage (limited, staff only access area containing 
locked sample storage, and limited access sample tracking) and processing, the samples 
will only be handled by appropriate personnel per the laboratory’s standard operating 
procedures. 
The Investigator must treat all of the information related to the study and the compiled 
data as confidential, whose use is for the purpose of conducting the study.  Alnylam must 
approve any transfer of information not directly involved in the study. 


 
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10.9 
Publications/Reports 
Following completion of the study, the data may be considered for publication in a 
scientific journal or for reporting at a scientific meeting.  A copy of the manuscript must 
be provided and confirmed received at Alnylam at least 30 days prior to its submission. 
No submission of a manuscript may be made until the results from all of the study sites 
have been received and analyzed by Alnylam, or the study has been terminated at all 
centers.  A separate, individual publication of the results of the study will be delayed until 
initial publication of the results of the multicenter study, or a decision not to publish is 
made.  If an initial draft is not produced within 18 months of completion of the study at 
all centers, or the timeframe for publication is not satisfactory, the Investigator may 
disclose the results after providing a copy and Alnylam confirms receipt of the 
manuscript 30 days prior to submission. 


 
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11 
REFERENCES 


 
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Benson MD and Kincaid JC. The molecular biology and clinical features of amyloid 
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Eriksson P and Olofsson BO. Pacemaker treatment in familial amyloidosis with 
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Shah KB, Inoue Y, et al. Amyloidosis and the heart: a comprehensive review. Arch Intern 
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19  
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial 
amyloid polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
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Bergethon PR, Sabin TD, et al. Improvement in the polyneuropathy associated with 
familial amyloid polyneuropathy after liver transplantation. Neurology. 1996;47(4):944-
951. 
21  
Garzuly, F., R. Vidal, et al. Familial meningocerebrovascular amyloidosis, Hungarian 
type, with mutant transthyretin (TTR Asp18Gly). Neurology. 1996; 47(6): 1562-1567. 
22  
Sekijima, Y., R. L. Wiseman, et al. The biological and chemical basis for tissue-selective 
amyloid disease. Cell.2005;121(1): 73-85. 
23  
Sekijima, Y., P. Hammarstrom, et al. Energetic characteristics of the new transthyretin 
variant A25T may explain its atypical central nervous system pathology. Lab Invest 
2003;83(3): 409-417. 
24  
Bispo M, Marcelino P, et al. High incidence of thrombotic complications early after liver 
transplantation for familial amyloidotic polyneuropathy. Transpl Int. 2009;22(2):165-171. 
25  
Statement from Advisory Group for National Specialised Services (AGNSS) regarding 
Eculizumab and Tafamidis.   Dated 23 January 2013.  
http://www.specialisedservices.nhs.uk/news/view/132, last accessed on 7 August 2013.  
26  
Vaishnaw AK, Gollob J, Gamba-Vitalo C, et al. A status report on RNAi therapeutics. 
Silence. 2010;1(1):14. 
27  
Elbashir SM, Lendeckel W, Tuschi T. RNA interference is mediated by 21- and 22-
nucleotide RNAs. Genes Dev. 2001;15:188-200. 
28  
Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by 
systemic administration of modified siRNAs. Nature. 2004;432:173-178. 
29  
Geisbert TW, Hensley LE, Kagan E, et al. Postexposure protection of guinea pigs against 
a lethal ebola virus challenge is conferred by RNA interference. J Infect Dis. 
2006;193:1650-1657. 
30  
Judge AD, Bola G, Lee AC, MacLachlan I. Design of noninflammatory synthetic siRNA 
mediating potent gene silencing in vivo. Mol Ther. 2006;13:494-505. 
31  
Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-HBV 
activity of chemically modified siRNAs. Nat Biotechnol. 2005;23:1002-1007. 
32  
Zimmermann TS, Lee AC, Akinc A, et al. RNAi-mediated gene silencing in non-human 
primates. Nature. 2006;441(7089):111-4.  
33  
Maurer N, Mori A, Palmer L, et al. Lipid-based systems for the intracellular delivery of 
genetic drugs. Mol Membr Biol. 1999;16:129-140. 
34  
Akinc A, Querbes W, De S, Qin J, et al. Targeted delivery of RNAi therapeutics with 
endogenous and exogenous ligand-based mechanisms. Mol Ther. 2010;18(7):1357-1364. 
35  
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery 
of RNAi therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
36  
Lachmann HJ, et al. Outcome in systemic AL amyloidosis in relation to changes in 
concentration of circulating free immunoglobulin light chains following chemotherapy. 
Br J Haematol, 2003;122:78-84. 
 


 
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37  
Lachmann HJ, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J 
Med. 2007;356:2361-71. 
38  
Gillmore JD, et al. Organ transplantation in hereditary apolipoprotein AI amyloidosis. 
Am J Transplant. 2006;6:2342-7. 
39  
Stangou AJ, Banner NR, Hendry BM, et al. Hereditary fibrinogen A alpha-chain 
amyloidosis: phenotypic characterization of a systemic disease and the role of liver 
transplantation. Blood. 2010;115:2998-3007. 
40  
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from 
mutations in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
41  
Episkopou, V., et al., Disruption of the transthyretin gene results in mice with depressed 
levels of plasma retinol and thyroid hormone. Proc Natl Acad Sci U S A, 1993. 90: p. 
2375-2379. 
42  
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid 
polyneuropathy and in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
43  
MHRA Clarification of contraceptive wording in clinical trials conducted in the UK. 
http://www.mhra.gov.uk/home/groups/l-
unit1/documents/websiteresources/con2033037.pdf Version 2 Amended 21 May 2010. 
Accessed 30 July 2013. 
44  
Yamamoto S, Wilczek HE, Nowak G, et al.  Liver transplantation for familial 
amyloidotic polyneuropathy (FAP): a single-center experience over 16 years. Am J 
Transplant. 2007;7:2597-604. 
45  
Coutinho P, DeSilva AM, Lima JL, Barbosa AR. Forty years of experience with type I 
amyloid neuropathy: review of 483 cases. In: Glenner GG, Pinho P, Costa E, Falcao de 
Freitas A, Eds. Amyloid and Amyloidosis. Amsterdam: Excerpta Medica; 1980:88-98. 
46  
Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS-31: a refined and 
abbreviated composite autonomic symptom score. Mayo Clin Proc. 2012;87:1196-1201. 
47  
Vinik EJ, Hayes RP, Oglesby A, et al.  The development and validation of the Norfolk 
QOL-DN, a new measure of patients' perception of the effects of diabetes and diabetic 
neuropathy.  Diabetes Technol Ther. 2005 Jun;7(3):497-508. 
48  
The EuroQol Group.  EuroQol-a new facility for the measurement of health-related 
quality of life. Health Policy.1990;16(3):199-208. 
49  
van Nes SI, Vanhoutte EK, van Doorn PA, et al. Rasch-built Overall Disability Scale (R-
ODS) for immune-mediated peripheral neuropathies. Neurology. 2011;76:337-45.  
50  
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry. 2011 Dec;168:1266-77. 


 
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12 
APPENDICES 
Appendix 1: Karnofsky Scale 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 


 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one 
to two blocks on the level and climbing more than one flight of 
stairs in normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity 
without fatigue or dyspnea. 
 
 
 


 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (IRR) usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  Signs/symptoms may include: allergic reaction/hypersensitivity 
(including drug fever), arthralgia (joint pain), bronchospasm, cough, dizziness, dyspnea 
(shortness of breath), fatigue (asthenia, lethargy, malaise), headache, hypertension, 
hypotension, myalgia (muscle pain), nausea, pruritus/itching, rash/desquamation, 
rigors/chills, sweating (diaphoresis), tachycardia, urticaria (hives, welts, wheals), 
vomiting. 
Categorization of IRRs is as follows: 
 
Categorization 
Description 
Mild 
Mild reaction:  infusion may be continued; if intervention is 
indicated it is minimal and additional treatment (other than 
paracetamol for delayed reactions) is not required. 
Moderate 
Moderate reaction:  requires treatment including more intensive 
therapy (e.g., IV fluids, nonsteroidal anti-inflammatory [NSAIDs]) 
in addition to infusion interruption but responds promptly to 
medication.  Treatment is indicated for ≤24 hours. 
Severe 
More than moderate reaction:  not rapidly responsive to medication 
or to interruption of infusion; and/ or prolonged (treatment is 
indicated for >24 hours); recurrence of severe symptoms following 
initial improvement. 
 
 
 


 
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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
• 
Weakness (192) 
• 
Sensation (32) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (18.6)a 
• 
Sural SNAP, tibial motor n. distal latency, peroneal 
SNAP/motor n. conduction velocity/motor n. distal 
latency 
• 
Vibration detection threshold (3.7) 
• 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
• 
Weakness (192) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (10)a 
• 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
• 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
• 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at 
each assessment. 
 
 


 
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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 


 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 


 
APOLLO Global Protocol Amendment Summary 
Version 4.0 – 30 Jan 2018 
1 
ALN-TTR02-004 
APOLLO Global Protocol Amendment Summary 
Version 4.0 – 30 January 2017 
 
Protocol 
Version 
No. 
Date 
Summary of Changes 
1.0 
(Original) 
15 August 
2013 
N/A 
2.0  
18 October 
2013 
• 
Secondary endpoints reordered and methods of analysis were modified 
o 
EuroQOL questionnaire was made an exploratory endpoint 
o 
Removal of the analysis by families 
• 
Clarification that study personnel performing the efficacy assessments will remain blinded to the 
results of any previous assessment until the study has been completed 
• 
Change of the schedule of assessments in tables 1-1,1-2, and 1-3 and Sections 6.1.1, 6.1.2, and 6.1.3  
• 
Inclusion criteria modified to allow an INR of ≤3 only for patients on warfarin 
• 
Definition of “highly effective birth control” was clarified in Section 4.7 
• 
Premedication regimen was modified to reflect those used in earlier trials of ALN-TTR02 
• 
Addition that either Bazett’s or Friderica’s correction may be used in the case that an ECG machine 
does not calculate QTc 
• 
Description of the pharmacoeconomics questionnaire was corrected to reflect the inclusion of 21, 
rather than 16, questions 
3.0  
21 March 
2014 
• 
Additional clarification that entry criteria, besides Inclusion Criteria #3 [Have a NIS of 10 to 100 
(inclusive)] and #4 [
 
], will be assessed at the Screening Visit only  
• 
Inclusion Criterion #1 [Male or female of 18 to 80 years of age (inclusive)] modified to allow for 
enrollment of subjects up to 85 years of age (inclusive) 
• 
Lower limit of the Neuropathy Impairment Score (NIS) from 10 to 5 in Inclusion Criterion #3 [Have a NIS 
of 10 to 100 (inclusive)] 
• 
Inclusion Criterion #4 
 
 
 
• 
Inclusion Criterion #6 [Have an absolute neutrophil count (ANC) ≥1500 cells/mm³, a platelet count 
≥100,000 cells/mm³, and hemoglobin ≥10 g/dL (or ≥100 g/L)] modified from a platelet count of ≥ 
100,000 cells/mm3 to ≥50000 cells/mm3 
• 
Inclusion Criterion #7 [Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × 
the upper limit of normal (ULN), total bilirubin within normal limits, albumin >3 g/dL (or >30 g/L), 
international normalized ratio (INR) ≤1.2 (patients on warfarin with an INR of ≤3 will be allowed)] 
modified to increase INR value from ≤3 to ≤3.5 
• 
Exclusion Criterion #1 [Has vitamin A levels below the lower limit of normal (LLN)] was clarified to 
exclude patients with vitamin A levels consistent with vitamin A deficiency (ie, <20µg/dL) 
• 
Exclusion Criterion #18 was removed ([Participated in a clinical trial with an antisense oligonucleotide 
for more than 3 months; if in a clinical trial with antisense oligonucleotide for ≤3 months, must have 
completed a 3‑month wash-out prior to start of study drug administration in this study] 
• 
Diflusinal was removed from Exclusion Criterion #19 [Is currently taking diflunisal, tafamidis, 
doxycycline, or tauroursodeoxycholic acid; if previously on any of these agents, must have completed a 
14-day wash-out prior to start of study drug administration in this study] and added as new Exclusion 
Criterion #20 [Is currently taking diflunisal; if previously on this agent, must have at least a 3-day wash-
out prior to start of study drug administration in this study] to clarify that a 3-day washout period prior  
to start of study drug for this particular agent is sufficient for that agent 
 
 
 


 
APOLLO Global Protocol Amendment Summary 
Version 4.0 – 30 Jan 2018 
2 
Protocol 
Version 
No. 
Date 
Summary of Changes 
4.0  
24 April 
2014 
• 
The screening window was expanded from 28 days to 42 days to make it less restrictive for traveling 
patients. 
• 
Corrected typographical errors identified in the SOA in version 3.0 
5.0  
04 August 
2014 
• 
Inclusion Criterion #3 [Have an NIS of 5 to 100 (inclusive) (Note:  This criterion must be met at the 
Screening/Baseline Visit)] changed to the upper limit NIS from 100 to 130 and added requirement for a 
Polyneuropathy Disability (PND) score of ≤3b. 
• 
Inclusion Criterion #7 [Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × 
the upper limit of normal (ULN), total bilirubin within normal limits, albumin >3 g/dL (or >30 g/L), 
international normalized ratio (INR) ≤1.2 (patients on anticoagulant therapy with an INR of ≤3.5 will be 
allowed)] modified to remove albumin criterion and to increase INR criterion from ≤1.2 to ≤2.0  
• 
Inclusion Criterion #8 [Have a serum creatinine ≤1.5 × ULN] modified from serum creatinine ≤1.5 to ≤2 
× ULN 
• 
Inclusion Criterion #9 [Have negative serology for hepatitis B virus (HBV) and hepatitis C virus (HCV] 
clarified to exclude only patients with an active hepatitis B or hepatitis C infection 
• 
Inclusion Criterion #10 [Women of child-bearing potential must have a negative pregnancy test, cannot 
be breastfeeding, and must be using 2 highly effective methods of contraception prior to screening, 
throughout study participation, and for 1 month after last dose of study drug.  Highly effective methods 
of birth control are defined in Section 4.7] modified to extend the period from 1 month to 75 days after 
last dose of study drug for WOCBP 
• 
Inclusion Criterion #11 [Males with partners of child-bearing potential, must agree to use 1 barrier 
method (e.g., condom) and 1 additional method (e.g., spermicide) of contraception  throughout study 
participation and for 1 month after the last dose of study drug; males must also abstain from sperm 
donation after the first dose of study drug through study participation and for 1 month after last dose 
of study drug] modified to extend the period that males with partners of child-bearing potential must 
use 1 barrier method and 1 additional method of contraception from 1 month to 75 days after the last 
dose of study drug 
• 
Exclusion Criterion #1 [Has vitamin A levels consistent with vitamin A deficiency (<20 µg/dL)] removed 
• 
Exclusion Criterion #16 [Has a known history of alcohol abuse or daily heavy alcohol consumption 
(females: more than 14 units of alcohol per week; males: more than 21 units of alcohol per week [unit: 
1 glass of wine [125 mL] = 1 measure of spirits = ½ pint of beer])] clarified to patients with a history of 
alcohol abuse within the past 2 years or daily heavy alcohol consumption 
• 
Exclusion Criterion #17 [Participated in a clinical trial with antisense oligonucleotide, must have 
completed a 3-month wash-out prior to start of the study drug administration in this study] added to 
exclude patients who participated in a clinical trial with antisense oligonucleotide unless there is a 3 
month wash-out period 
• 
Exclusion Criterion #24 [Is under legal protection] modified to define “under legal protection” 
• 
The protocol has been modified to permit select changes to the premedication regimen for an 
individual having difficulty tolerating the premedication regimen only after consultation with the study 
medical monitors. 
• 
The sample size was modified to limit the number of patients with a Neuropathy Impairment Score 
(NIS) in the range of 101 to 130 to no more than 40 of the 200 planned patients to prevent 
overenrolling patients with more severe impairment.  


 
APOLLO Global Protocol Amendment Summary 
Version 4.0 – 30 Jan 2018 
3 
Protocol 
Version 
No. 
Date 
Summary of Changes 
6.0  
08 
September 
2015 
• 
Implemented a reduced dose of dexamethasone for the protocol-specified premedication regimen 
• 
Included that specified patients who are intolerant of 10 mg IV dexamethasone or equivalent on the 
day of infusion may be considered for further step-wise reduction in dexamethasone or equivalent 
after consultation with the medical monitor 
• 
The risk benefit assessment has been updated to reflect liver function test abnormalities and risk for 
osteoporosis 
• 
Because patients may be at risk for osteoporosis, it has been added that, if appropriate, study 
participants should receive therapy for the prevention and early treatment of osteoporosis   
• 
Inclusion #4 
 
Note:  This criterion must be met at 
the Screening/Baseline visit)] added ulnar SNAP and ulnar CAP measurements to the qualifying NCS 
• 
Inclusion #7 [Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), total bilirubin within normal limits, international normalized ratio (INR) ≤2.0 
(patients on anticoagulant therapy with an INR of ≤3.5 will be allowed)] changed to permit patients 
with a total bilirubin level elevation to ≤ 2 x upper limit of normal to enroll 
• 
Exclusion #14 [Has uncontrolled clinically significant cardiac arrhythmia or unstable angina] changed to 
include clarification that patients with any uncontrolled cardiac arrhythmia or unstable angina are not 
permitted to enroll in the study 
• 
Included the option for patients to permanently discontinue study treatment and remain on-study 
• 
Provided clarification about local personnel responsible for reading ECGs to include that ECGs will be 
read locally by a cardiologist or qualified physician 
 

SAP_001.pdf: 
 
 
Official Title:    
APOLLO: A Phase 3 Multicenter, Multinational, Randomized, Doubleblind, 
Placebo‐controlled Study to Evaluate the Efficacy and Safety of 
ALN‐TTR02 in Transthyretin (TTR)‐Mediated Polyneuropathy 
(Familial Amyloidotic Polyneuropathy‐FAP) 
 
NCT Number:    
NCT01960348 
Document Date:   
Statistical Analysis Plan Version 2.1, 23 August 2017 




Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-004 
Final Version 2.1 
CONFIDENTIAL 
3 
TABLE OF CONTENTS 
Section 
Page 
1. 
Information from the Study Protocol ............................................................................ 8 
1.1. 
Introduction and Objectives ................................................................................... 8 
1.1.1. 
Introduction ............................................................................................. 8 
1.1.2. 
Document and Study Objectives........................................................... 10 
1.2. 
Study Design ........................................................................................................ 11 
1.2.1. 
Synopsis of Study Design ..................................................................... 11 
1.2.2. 
Randomization Methodology ............................................................... 12 
1.2.3. 
Rapid Disease Progression.................................................................... 12 
1.2.4. 
Withdrawals, Dropouts, Loss to Follow-up .......................................... 12 
1.2.5. 
Unblinding ............................................................................................ 13 
1.2.6. 
Study Procedures .................................................................................. 13 
1.2.7. 
Efficacy, Pharmacokinetic, Pharmacodynamic, and Safety Parameters
 .............................................................................................................. 13 
2. 
Patient Population .......................................................................................................... 15 
2.1. 
Population Definitions ......................................................................................... 15 
2.2. 
Protocol Deviations .............................................................................................. 15 
3. 
General Statistical Methods .......................................................................................... 17 
3.1. 
Sample Size Justification ..................................................................................... 17 
3.2. 
General Methods .................................................................................................. 17 
3.3. 
Computing Environment ...................................................................................... 17 
3.4. 
Baseline Definitions ............................................................................................. 18 
3.5. 
Randomization Stratification Factors .................................................................. 18 
3.6. 
Multiple Comparisons/Multiplicity ..................................................................... 18 
3.7. 
Initiation of Alternative Treatment for FAP ........................................................ 18 
3.8. 
Missing Data with Efficacy Endpoints ................................................................ 19 
3.8.1. 
Missing Subcomponents within Primary and Secondary Efficacy 
Endpoints .............................................................................................. 19 
3.8.2. 
Summary of Missing Data .................................................................... 19 
3.8.3. 
Handling of Missing Data ..................................................................... 19 
3.9. 
Visit Windows ..................................................................................................... 20 
3.10. 
Interim Analyses .................................................................................................. 20 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-004 
Final Version 2.1 
CONFIDENTIAL 
4 
Section 
Page 
3.11. 
Final Analyses ...................................................................................................... 20 
4. 
Study Analyses ............................................................................................................... 21 
4.1. 
Patient Disposition ............................................................................................... 21 
4.2. 
Demographics and Baseline Characteristics ........................................................ 21 
4.3. 
Efficacy Evaluation .............................................................................................. 22 
4.3.1. 
Primary Efficacy Evaluations ............................................................... 22 
4.3.2. 
Secondary Efficacy Evaluations ........................................................... 25 
4.3.3. 
Exploratory Efficacy Evaluations ......................................................... 26 
4.3.4. 
Subgroup Analyses ............................................................................... 27 
4.3.5. 
Component Analyses ............................................................................ 27 
4.4. 
Pharmacodynamic Analyses ................................................................................ 27 
4.5. 
Pharmacokinetic Analyses ................................................................................... 28 
4.5.1. 
Study Variables ..................................................................................... 28 
4.5.2. 
Statistical Methods ................................................................................ 28 
4.6. 
Safety Analyses .................................................................................................... 29 
4.6.1. 
Study Drug Exposure ............................................................................ 29 
4.6.2. 
Adverse Events ..................................................................................... 29 
4.6.3. 
Laboratory Data .................................................................................... 30 
4.6.4. 
Vital Signs and Physical Examination .................................................. 31 
4.6.5. 
Electrocardiogram ................................................................................. 31 
4.6.6. 
Premedication ....................................................................................... 32 
4.6.7. 
Prior and Concomitant Medications ..................................................... 33 
4.6.8. 
Ophthalmology Examinations .............................................................. 33 
4.6.9. 
Suicidality Questionnaire ...................................................................... 33 
4.7. 
Anti-Drug Antibody ............................................................................................. 34 
5. 
Changes to Planned Analyses ....................................................................................... 35 
5.1. 
Primary Analysis Method for Efficacy Endpoints ............................................... 35 
5.2. 
Multiple Imputation/ANCOVA Method.............................................................. 35 
5.3. 
Hierarchical Testing Order of Secondary Endpoints ........................................... 36 
5.4. 
Adjustment for Covariates in Statistical Models ................................................. 36 
5.5. 
Binary Analysis of mNIS+7................................................................................. 37 
5.6. 
Censoring Data Post Alternative FAP Treatment ................................................ 37 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-004 
Final Version 2.1 
CONFIDENTIAL 
5 
Section 
Page 
5.7. 
Other Changes ...................................................................................................... 38 
6. 
References ....................................................................................................................... 40 
7. 
Appendices ...................................................................................................................... 41 
7.1. 
Detailed Statistical Methodology for Pattern Mixture Model ............................. 41 
7.2. 
Questionnaire/Scoring.......................................................................................... 43 
7.2.1. 
Modified Neuropathy Impairment Score (mNIS+7) and Original 
Neuropathy Impairment Score + 7 Nerve Tests (NIS+7) ..................... 43 
7.2.2. 
Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) ................... 51 
7.2.3. 
EuroQOL-5-Dimension 5-Level (EQ-5D-5L) ...................................... 52 
7.2.4. 
Rasch-Built Overall Disability Scale (R-ODS) .................................... 53 
7.2.5. 
Composite Autonomic Symptom Score (COMPASS-31) .................... 53 
 
 
 
 
 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-004 
Final Version 2.1 
CONFIDENTIAL 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
Σ5 
5 Attributes 
AA 
Amyloid A 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomic Therapeutic Class 
BMI 
Body mass index 
CMAP 
Compound Muscle Action Potential 
Cmax 
Post-Infusion Peak Concentration 
Cmax_ss 
Post-Infusion Peak Concentration at Steady State 
COMPASS-31 
Autonomic Symptoms Questionnaire (Composite Autonomic Symptom 
Score) 
Cp(30min) 
30 Minutes Post-Infusion Concentration 
Cp_ss(30min) 
30 Minutes Post-Infusion Concentration at Steady State 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
Ctrough 
Pre-Infusion Trough Concentration 
Ctrough_ss 
Pre-Infusion Trough Concentration at Steady State 
CV 
Coefficient of Variation 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EQ-5D 
Euro Quality of Life- 5 Dimensions 
EU 
European Union 
FAC 
Familial Amyloidotic cardiomyopathy 
FAP 
Familial Amyloidotic Polyneuropathy 
hATTR 
Hereditary Transthyretin-Mediated Amyloidosis 
HP 
Heat pain 
HRdb 
Heart Rate Response to Deep Breathing 
ICH 
International Conference on Harmonisation 
IENFD 
Intraepidermal Nerve Fiber Density 
INN 
International Nonproprietary Name 
IRS 
Interactive response system 
IV 
Intravenous 
LNP 
Lipid Nanoparticle 
LS 
Least Squares 
mBMI 
Modified Body Mass Index 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Definition 
MI 
Multiple Imputation 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed-Effects Model Repeated Measures 
mNIS 
Modified Neuropathy Impairment Score 
NCS 
Nerve Conduction Studies 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score-Weakness Score 
Norfolk QOL-DN 
Norfolk Quality of Life-Diabetic Neuropathy Questionnaire 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NT-proBNP 
N Terminal Prohormone of B-Type Natriuretic Peptide 
PD 
Pharmacodynamic 
PEG 
Polyethylene glycol 
PK 
Pharmacokinetic 
PMM 
Pattern Mixture Model 
PND 
Polyneuropathy Disability 
PP 
Per-Protocol 
QST 
Quantitative Sensory Testing 
RBP 
Retinol Binding Protein 
RNAi 
RNA interference 
R-ODS 
Rasch-Built Overall Disability Scale 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
SGNFD 
Sweat Gland Nerve Fiber Density 
siRNA 
Small Interfering Ribonucleic Acid 
SNAP 
Sensory Nerve Action Potential 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T4 
Thyroxine 
TP 
Touch pressure 
TTR 
Transthyretin 
V30M 
Val30Met Genotype 
VAS 
Visual Analog Scale 
VDT 
Vibration Detection Threshold 
WHO 
World Health Organization Drug Dictionary 
WT 
Wild-Type 


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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, autosomal dominant, 
systemic disease caused by mutations in the transthyretin (TTR) gene [1]. Transthyretin is a 
tetrameric 127 amino acid protein that is secreted predominantly (> 95%) by hepatocytes, with a 
smaller fraction produced by the choroid plexus and retina [1]. Physiologically, TTR is a major 
serum carrier for retinol binding protein (RBP) and a minor carrier of thyroxine (T4). Mutations 
in the TTR protein lead to destabilization of the tetrameric form and dissociation into dimers 
and monomers. Misfolding of mutated monomers from the α-helical to the β-pleated sheet 
structure, results in tissue deposition of amyloid fibrils [2]. Amyloid deposits typically contain 
both mutant and wild-type (WT) TTR. The particular TTR mutation and site of amyloid 
deposition determines the clinical manifestations of the disease, which include sensory and 
motor neuropathy, autonomic neuropathy, and/or cardiomyopathy. hATTR is a progressive 
disease associated with severe morbidity, with a life expectancy limited to 5 to 15 years from 
symptom onset [2]. There are over 100 reported TTR mutations which are associated with 
2 clinical syndromes: familial amyloidotic polyneuropathy (FAP) and familial amyloidotic 
cardiomyopathy (FAC) [2, 3, 4]. 
‘Patisiran’ (the International Nonproprietary Name [INN] name for ALN-TTR02) is being 
developed for the treatment of hATTR patients with symptomatic polyneuropathy. 
The estimated worldwide prevalence of FAP is 5,000 to 10,000, with the majority of cases in 
Portugal, Sweden, France, Japan, Brazil, and the United States [2, 3]. The most common 
causative mutation of FAP is TTR Val30Met (V30M), with the onset of symptoms typically 
occurring between 30 and 55 years of age [4]. Amyloid deposition occurs largely in the 
peripheral nerves, starting as a nerve length-dependent sensory polyneuropathy in the feet 
causing numbness and pain and progressing to painful dysesthesias. Disabling motor neuropathy 
follows, characterized by leg weakness and eventually the inability to walk. Autonomic 
neuropathy is another common feature of the disease, resulting in severe gastrointestinal 
pathology (including diarrhea or constipation and malabsorption, leading to severe 
malnutrition), orthostatic hypotension, and bladder dysfunction with recurring urinary tract 
infections [4, 5, 6, 7]. For several mutations, cardiac pathology also occurs due to amyloid 
infiltration of the sinus node, atrioventricular conduction system, and infiltration of the 
myocardium [4, 5]. Involvement of the conduction system can lead to sudden death due to 
dysrhythmias, and myocardial infiltration can lead to diastolic dysfunction and right-sided heart 
failure [4]. Cardiomyopathy then proceeds inexorably, leading to death typically within 
10 years [4]. 
Because the liver is the primary source of WT and mutant TTR, orthotopic liver transplantation 
has been used since 1990 in an attempt to treat FAP [2], and is the current standard of care in 
patients who are eligible for transplant (patients with minimal neuropathy symptoms and no 
cardiac involvement). When liver transplantation is performed early in the course of the disease, 
it can stabilize and slow the course of neuropathic disease in patients with FAP due to V30M, 
but is less effective in patients with other TTR mutations [2]. However, it is less effective in 
patients with more advanced disease, especially those with heart involvement, due to the 
continued production and deposition of WT TTR in tissues with pre-existing amyloid [2, 3, 4]. 


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It is estimated that approximately two-thirds of FAP patients are not transplant-eligible. 
Furthermore, liver transplant poses risks from the surgical procedure and from life-threatening 
complications due to graft rejection or infections. The 1-year mortality rate post-transplant is 
10% [2]. 
Nonsurgical options that are used for the treatment of FAP (depending on geographic location) 
include tafamidis (Vyndaqel®) and diflunisal. Tafamidis is a small molecule TTR stabilizer that 
binds to the thyroxine binding sites of the TTR tetramer, thus preventing its dissociation to 
monomers and potentially preventing fibril formation. While tafamidis is approved in the 
European Union (EU) for the treatment of hATTR in adult patients with Stage 1 symptomatic 
polyneuropathy to delay peripheral neurologic impairment, the pivotal trial data were primarily 
from FAP patients with the V30M mutation; furthermore, tafamidis is not considered the 
standard of care throughout the EU and it has not been approved for use in the US [2]. 
Diflunisal is a generic, nonsteroidal anti-inflammatory drug (NSAID) that is also a tetramer 
stabilizer and binds to TTR in a similar manner as tafamidis. An NIH- sponsored multicenter, 
placebo-controlled Phase 3 study in FAP patients was completed in 2012; data suggest an effect 
of diflunisal on neuropathic score NIS+7, the primary endpoint of the study [2]. Due to the 
restricted use of liver transplantation and tafamidis in patients with early stage of disease, and 
the non-standard use of diflunisal among practitioners, there remains an unmet medical need for 
a potent and effective therapy for FAP that will have an impact on patients across a broad range 
of neurologic impairment, regardless of their mutation (V30M or non-V30M). 
Patisiran comprises a small interfering ribonucleic acid (siRNA) which is specific for TTR, and 
is formulated in a hepatotropic lipid nanoparticle (LNP) for intravenous (IV) administration [2]. 
This TTR siRNA has a target region within the 3’UTR region of the TTR gene to ensure and 
confirm homology with WT TTR as well as all reported TTR mutations. Following LNP-
mediated delivery to the liver, the siRNA targets TTR mRNA for degradation, resulting in the 
potent and sustained reduction of mutant and WT TTR protein via the RNA interference (RNAi) 
mechanism. 
Since circulating TTR is almost exclusively synthesized in the liver, the IV administration of 
patisiran is postulated to reduce the level of precursors that lead to amyloid fibril deposition, 
resulting in clinical benefit to patients with FAP. 
The therapeutic hypothesis that systemic amyloidoses can be managed by reduction in 
circulating levels of amyloidogenic protein has been validated in other acquired 
(e.g., immunoglobulin light chain systemic [AL], or amyloid A [AA]) and hereditary (e.g., 
Fibrinogen A α-chain, ApoA1) amyloidosis. The experience from these systemic amyloidotic 
disorders [2, 3, 4, 5], as well as the liver transplant data in FAP, suggest that lowering of the 
circulating amyloidogenic protein by at least 50% impacts the clinical course of the disease, 
with reductions in protein beyond 50% providing further incremental improvements in 
outcomes. It is therefore postulated that the > 80% suppression in both WT and mutant TTR 
observed upon administration of 0.3 mg/kg patisiran once every 21 days will result in clinical 
benefit in hATTR patients with polyneuropathy. This hypothesis is further supported by 
evidence from tafamidis suggesting that reduction in free TTR monomer can slow neuropathy 
progression in early-stage V30M patients with FAP [8]. 
Importantly, data from a Phase 2 open-label extension study with patisiran (ALN-TTR02-003) 
in 27 FAP patients showed a mean sustained TTR reduction of ~80% accompanied with 
stabilization of neuropathic impairment scores at 6 months, which compared favorably to the 
anticipated increase in scores based on natural history and other datasets [2]. 


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Patisiran is currently being investigated in APOLLO, a Phase 3 pivotal study (ALN-TTR02-
004) evaluating the efficacy and safety of patisiran in hATTR patients with polyneuropathy. 
This protocol was discussed with the Agency at the end-of-Phase 2 meeting on 23 September 
2013 (FDA ref ID # 3394206 for meeting minutes). 
The original statistical analysis plan (SAP) Version 1.0 was submitted to the Agency on 
07 April 2015 (FDA IND 117395 Serial No. 0019). The response to the Agency’s review 
comment on multiple imputation (MI) was submitted on 31 August 2015 (FDA serial No. 
0028). The SAP amendment Version 2.0 was submitted to the Agency on 01 June 2017. This 
SAP Version 2.1 incorporates a few minor updates for analysis of data from this study. 
1.1.2. 
Document and Study Objectives 
This SAP is designed to outline the methods to be used in the analysis of study data in order to 
address the study objectives of Study ALN-TTR02-004. Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP will also outline differences, if any, in the currently planned analytical objectives 
relative to those planned in the study protocol and/or in the original SAP V1.0. 
The study objectives from protocol are listed below. 
1.1.2.1. 
Primary Objective 
The primary objective of the study is to determine the efficacy of patisiran by evaluating the 
difference between the patisiran and placebo groups in the change from baseline of Modified 
Neuropathy Impairment Score (mNIS+7) score at 18 months. 
1.1.2.2. 
Secondary Objectives 
The secondary objectives of the study are to determine the effect of patisiran on various clinical 
parameters by assessing the difference between patisiran and placebo in the change from 
baseline in the following measurements at 18 months: 
• Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Total QoL Score. 
• Neuropathy Impairment Score-weakness (NIS-W) score. 
• Modified body mass index (mBMI), calculated by multiplying the BMI (kg/m2) by 
serum albumin level (g/L). 
• Timed 10-meter walk test speed (meter/second), calculated as 10 meters divided by the 
walking time (second). 
• Autonomic symptoms questionnaire (Composite Autonomic Symptom Score 
[COMPASS-31]). 
1.1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To determine the difference between the patisiran and placebo groups in the change from 
baseline in the following measurements at 18 months: 
o NIS+7 score; 


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o Grip strength; 
o EuroQOL (EQ-5D) questionnaire; 
o Level of disability (Rasch-built Overall Disability Scale [R-ODS]); 
o Large vs. small nerve fiber function including nerve conduction studies (NCS) 5 
attributes (Σ5), quantitative sensory testing by body surface area including touch 
pressure and heat pain (QST), vibration detection threshold (VDT), heart rate 
response to deep breathing (HRdb), postural blood pressure; 
o Pathologic evaluation of sensory and autonomic innervation through voluntary 
skin punch biopsies and analysis of intraepidermal nerve fiber density (IENFD) 
and sweat gland nerve fiber density (SGNFD) ) 
o Assessment of ambulation through FAP stage and Polyneuropathy Disability 
(PND) score; 
o Cardiac assessment through echocardiogram, troponin I, and N-terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) levels; 
o Pharmacodynamic (PD) biomarkers (TTR, RBP, vitamin A); 
• To compare the proportion of patients in the patisiran and placebo groups who meet the 
pre-defined criterion for rapid disease progression (defined as ≥24-point increase in 
mNIS+7 from baseline [based on an average of 2 measurements] and FAP stage 
progression relative to baseline) at 9 months; 
• To serially evaluate lower limb nerve injury via voluntary magnetic resonance (MR) 
neurography approximately every 6 months in a subset of patients receiving either 
patisiran or placebo who consent to perform this assessment. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This is a multicenter, multinational, randomized, double-blind study comparing patisiran to 
placebo in hATTR patients with symptomatic polyneuropathy. 
Consented eligible patients will be randomized to receive either 0.3 mg/kg patisiran or placebo 
in a 2:1 ratio (patisiran to placebo) in a blinded manner. Randomization will be stratified by 
Neuropathy Impairment Score (NIS; < 50 vs. ≥ 50), early onset V30M (< 50 years of age at 
onset) vs. all other mutations (including late onset V30M), and previous tetramer stabilizer use 
(tafamidis or diflunisal) vs. no previous tetramer stabilizer use. Patients will receive patisiran or 
placebo once every 21 days for 78 weeks (18 months). 
Patients will have efficacy assessments at Screening/Baseline, 9 months, and 18 months. Study 
personnel performing assessments related to the efficacy endpoints will be different from the 
Investigator and other personnel managing the patient, and all of these study personnel will be 
blinded to any clinical laboratory results that could potentially unblind them (e.g., TTR levels, 
vitamin A levels, thyroid function tests). In addition, the study personnel performing 
assessments related to the efficacy endpoints will also be blinded to the results of any previous 
assessments (e.g., Screening/Baseline, Baseline, or 9-month assessments). Whenever possible, 
the same site personnel (individual) will conduct efficacy assessments for a given patient across 
time points. 


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At the 9-month time point, if the clinical adjudication committee determines that a patient is 
exhibiting rapid disease progression (defined as ≥24-point increase in mNIS+7 from baseline 
[based on an average of 2 measurements] and FAP stage progression relative to baseline), the 
patient’s treating physician will provide the patient with the option of discontinuing study drug 
and receiving local standard of care treatment for FAP. Patients who discontinue study drug will 
remain on study, following a modified schedule of visits, through completion of the 18-month 
efficacy assessments and blinding will be maintained throughout. 
Patients who complete the 18-month efficacy assessments can elect to participate in an 
extension study in which patients would receive open-label administration of 0.3 mg/kg 
patisiran once every 21 days. 
A Data Monitoring Committee (DMC) will be implemented for the study and will operate under 
a pre-specified charter. 
1.2.2. 
Randomization Methodology 
Patients will be randomly assigned in a 2:1 ratio to receive either 0.3 mg/kg patisiran or placebo 
(normal saline 0.9%). 
Patients will be randomized via an interactive response system (IRS). Either designated site 
personnel or the pharmacist may request randomization for the patient, but only the pharmacist 
or pre-identified unblinded personnel will be allowed to receive the randomized treatment code. 
The treatment code will be delivered to the unblinded personnel or the pharmacist to prepare the 
necessary number of vials for that patient based on their weight. 
As described above in Section 1.2.1, the stratification factors for randomization include NIS 
(< 50 vs. ≥ 50), early onset V30M (< 50 years of age at onset) vs. all other mutations (including 
late onset V30M), and previous tetramer stabilizer use (tafamidis or diflunisal) vs. no previous 
tetramer stabilizer use. 
1.2.3. 
Rapid Disease Progression 
Patients who have evidence of rapid disease progression at 9 months (defined as ≥24-point 
increase in mNIS+7 from baseline [based on an average of 2 measurements] and FAP stage 
progression relative to baseline) will be given the option of discontinuing study drug and 
receiving local standard of care treatment for their FAP. Those who elect this option will be 
asked to follow a modified study visit schedule and return for their 18-month efficacy 
assessment (blinding will be maintained throughout). 
1.2.4. 
Withdrawals, Dropouts, Loss to Follow-up 
Patients are free to discontinue treatment or withdraw from the study at any time and for any 
reason, without penalty to their continuing medical care. 
There are 3 ways for a patient to discontinue treatment and/or withdraw from the study: 
1) The patient or investigator decides to discontinue study treatment, but the patient agrees 
to remain in the study and undergo follow-up assessments; 
2) The patient experiences protocol-defined rapid disease progression at Month 9 and elects 
to discontinue study treatment but remain in the study and return for protocol-specified 
visits, including follow-up assessment at Month 18; 
3) The patient decides to no longer participate in the study and withdraws consent. 


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A patient will be considered to have completed the study if the patient does not withdraw 
consent from the study and completes protocol-specified procedures up through the 18-month 
efficacy assessment visit. 
1.2.5. 
Unblinding 
Unblinding is only to occur in the case of patient emergencies or when necessary from a 
regulatory reporting perspective (e.g., Suspected Unexpected Serious Adverse Reaction 
[SUSAR] occurring in the EU), and at the conclusion of the study. 
Patients who discontinue study drug at 9 months due to rapid disease progression will remain 
blinded throughout the remainder of the study. 
In the event that the Investigator requests to know a patient’s study treatment assignment, the 
Investigator is instructed to contact the Contract Research Organization (CRO) Medical Monitor 
to discuss the need for unblinding. In case of an emergency, the treatment allocation for each 
patient will be available from the unblinded site personnel, pharmacist, or the IRS system. 
If a patient becomes pregnant or seriously ill during the study, the blind should be broken only if 
knowledge of the treatment administered will affect treatment options available to the patient. 
Before breaking the blind, the Principal or Sub-investigator should attempt to contact the CRO 
Medical Monitor. If the Medical Monitor is immediately unreachable, the Principal or Sub-
investigator should break the blind as necessary using the code breaking information provided 
and contact the CRO Medical Monitor as soon as possible. A record will be kept of when the 
blind was broken, who broke it, and why. 
1.2.6. 
Study Procedures 
The schedule of assessments is described in the study protocol (Table 1-1, Table 1-2, and 
Table 1-3). 
1.2.7. 
Efficacy, Pharmacokinetic, Pharmacodynamic, and Safety Parameters 
1.2.7.1. 
Efficacy Parameters 
Efficacy parameters will include the following. All evaluations will be conducted at baseline 
and at 9 and 18 months (except for mBMI as described below). 
Primary Endpoint 
• Neurologic impairment will be assessed using the mNIS+7 composite score (range: 0 to 
304 points). The mNIS+7 include the modified NIS (weakness and reflexes), Σ5 NCS, 
QST, as well as autonomic assessment through postural blood pressure. Two 
assessments will be performed at each visit; each component contributing to the 
composite score is the average of the 2 assessments. A scoring algorithm, including 
methods for handling missing components of the mNIS+7, is included in 
Appendix 7.2.1. 
Secondary Endpoints 
• Patient reported QOL will be evaluated using the Norfolk QOL-DN total score (range: -4 
to 136 points). A scoring algorithm for this instrument is included in Appendix 7.2.2. 
• Motor strength will be evaluated using NIS-W, calculated as the average of the 2 
assessments performed at each visit (range: 0 to 192 points). 


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• Level of disability will be assessed using the Rasch-built Overall Disability Scale 
(R-ODS; range: 0 to 48). A scoring algorithm for the R-ODS is included in Appendix 
7.2.4. 
• Functional status will additionally be assessed by 10-meter walk gait speed. 
• Nutritional status will be assessed using mBMI, calculated by multiplying the BMI 
(kg/m2) by serum albumin level (g/L). mBMI will be assessed at baseline, Day 84, 
Day 189, Day 357, Day 462 and Day 546.  
• Autonomic symptoms will be assessed using the COMPASS-31 total score (range: 0 to 
100 points). A scoring algorithm for the COMPASS-31 total score and domain scores is 
included in Appendix 7.2.5. 
Exploratory Endpoints 
Exploratory endpoints are detailed in Section 1.1.2.3. 
In addition, the evaluation of dermal amyloid content (% Congo Red staining) using same skin 
punch biopsy specimens analyzed for nerve fiber density (SGNFD and IENFD) will also be 
assessed as an exploratory endpoint. 
1.2.7.2. 
Pharmacokinetic Parameters 
Blood samples for determination of patisiran pharmacokinetics (PK) will be collected as 
outlined in the schedule of assessments. Plasma siRNA, DLin-MC3-DMA, and PEG2000-C-
DMG concentrations will be determined in all patients in order to estimate individual PK 
parameters such as peak and trough concentrations. 
Urine will be collected with void volume recorded for all patients at time points specified in the 
schedule of assessments to determine concentration of siRNA and 4-dimethylaminodibutyric 
acid (the metabolite of DLin-MC3-DMA) after dosing with study drug. 
Pharmacokinetic parameters will be estimated by the Clinical Pharmacology and 
Pharmacometrics Department at Alnylam Pharmaceuticals. 
1.2.7.3. 
Pharmacodynamic and Pharmacology Parameters 
Pharmacodynamic markers assessed serially will include serum TTR, vitamin A, and RBP. 
Additional blood samples will be collected for exploratory biomarkers related to FAP. Anti-drug 
antibodies (ADA) data will also be collected. 
1.2.7.4. 
Safety Parameters 
Safety evaluations to be performed during the study include monitoring of adverse events (AEs) 
and concomitant medications, physical examinations, measurement of vital signs, 12-lead 
ECGs, clinical laboratory evaluations including hematology, clinical chemistry (including liver 
function tests), thyroid function parameters, urinalysis, and ophthalmology examinations. 
Suicidal ideation and behavior will be assessed using the Columbia–Suicide Severity Rating 
Scale (C-SSRS) questionnaire. 


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2. 
PATIENT POPULATION 
2.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
• Modified Intent-to-Treat (mITT) population: All patients who were randomized and 
received at least 1 dose of patisiran or placebo. Patients will be analyzed according to the 
treatment to which they were randomized. 
• Per-protocol (PP) population: All randomized patients who received at least 1 dose of 
patisiran or placebo, completed baseline and either 9-month or 18-month mNIS+7 and 
Norfolk QOL assessments, and did not experience any major protocol deviations that 
may impact the efficacy results (Section 2.2). Patients will be analyzed according to 
treatment received. 
• Safety population: All patients who received at least 1 dose of patisiran or placebo. 
Patients will be analyzed according to the treatment received. 
• PK population: All patients in the Safety Population who provided at least 1 PK 
concentration measurement. 
The primary population for efficacy analysis will be the mITT population; the primary endpoint 
and the first secondary endpoint (Norfolk QOL) will also be analyzed using the PP population. 
The remaining secondary and exploratory efficacy endpoints will be analyzed using the mITT 
population only. Safety analysis will be conducted in the safety population. PK analysis will be 
conducted in the PK population. 
2.2. 
Protocol Deviations 
A deviation is considered any departure from the procedures set forth in the protocol. Protocol 
deviations will be classified into major and minor by medical review and recorded prior to 
database lock. A major deviation is a deviation that may impact patient safety or efficacy 
interpretation (for example, failure to meet key inclusion and exclusion criteria). Deviations not 
designated as major will be considered minor. 
The Sponsor or designee will be responsible for producing the final protocol deviation file 
(formatted as a Microsoft Excel file). This file will include a description of each protocol 
deviation and whether or not this deviation is classified as a major deviation. In addition, each 
major deviation will be clearly identified as to whether or not it warrants exclusion from the Per 
Protocol population, based on the potential impact on the efficacy results according to the 
judgment of the sponsor. This file will be finalized prior to database lock and unblinding of 
treatment assignments for all patients. 
The following are some examples of key inclusion/exclusion criteria. Failure to meet such 
criteria may warrant the exclusion from the Per Protocol population: 
 
Inclusion: 
1. Have a diagnosis of FAP with documented TTR mutation;  
2. Have an NIS of 5 to 130 (inclusive) and a PND score of ≤3b; 
3. Have a Karnofsky performance status of ≥60%. 


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Exclusion: 
1. Had a prior liver transplant or is planning to undergo liver transplant during the 
study period; 
2. Has known primary amyloidosis or leptomeningeal amyloidosis; 
3. Has known type I diabetes; 
4. Has had type II diabetes mellitus for ≥5 years; 
5. Received an investigational agent or device within 30 days of anticipated study 
drug administration or 5 half-lives of the investigational drug, whichever is 
longer; 
6. Participated in a clinical trial with antisense oligonucleotide, must have 
completed a 3-month wash-out prior to start of the study drug administration in 
this study. 
All protocol deviations and major protocol deviations will be presented in data listings. 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
For the estimation of sample size, a mean (±SD) mNIS+7 progression rate (primary endpoint) in 
the placebo group of 24 ± 16 points over 18 months was estimated using natural history data [1] 
from FAP patients. A sample of 154 patients provides 90% power for a 2-sided t-test with an 
8.95-point (37.5%) mean difference between treatment arms in the primary endpoint at 2-sided 
alpha = 0.05. Assuming a 25% random premature discontinuation rate (due to liver 
transplantation or other factors), the required sample size for this study is approximately 200. 
3.2. 
General Methods 
All data listings that contain an evaluation date will contain a study day relative to the day of the 
first dose of study drug, which is designated as Day 1. On-treatment study days will be 
calculated as evaluation date – first dose date +1 and pre-treatment days will be calculated as 
evaluation date – first dose date. For example, the day prior to study drug administration will be 
Day -1, the first dose day of study drug will be Day 1 and the day after the first dose of study 
drug will be Day 2, etc. 
All output will be incorporated into Microsoft Word files, sorted and labeled according to the 
International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) of the parameter will be presented. For 
continuous variables, the number of patients, mean, median, standard deviation (SD), minimum, 
and maximum values will be presented. 
Laboratory data (including vitamin A and RBP) collected and recorded as below the limit of 
detection will be set equal to the lower limit of detection for the calculation of summary 
statistics. 
For assessments that are repeated multiple times on the study day (e.g., 10-meter walk tests, 
IENFD, SGNFD, etc.), the average will be calculated unless otherwise noted. 
Formal statistical hypothesis testing will be performed on the primary and secondary efficacy 
endpoints with all tests conducted at the nominal 2-sided 0.05 level of significance. Secondary 
endpoints will be tested in a prespecified hierarchy (Section 3.6). Summary statistics will be 
presented, as well as 2-sided 95% confidence intervals on selected parameters, as described in 
the sections below. 
All summaries will be presented by treatment arm. All data recorded on the CRF will be 
included in data listings. 
3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.3 
(or later), unless otherwise noted. Medical history and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 18.0 (or later). Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary 
Version March 2015 (or later). 


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3.4. 
Baseline Definitions 
For the mNIS+7/NIS+7 individual components, total scores and related endpoints, the 
Screening/Baseline and Baseline visits were performed on separate days. Baseline will be 
calculated as the average of 2 replicate measures each assessed at the Screening/Baseline and 
Baseline visits. For grip strength and 10m walk test, if replicate measures are obtained at the 
Screening/Baseline and Baseline visits, baseline will also be calculated as the average of the 
2 replicates. 
For PD parameters (TTR, RBP, Vitamin A), baseline will be defined as the average of all 
records, including those from any unscheduled visits, prior to the date and time of first dose. 
For all other parameters, unless noted otherwise, baseline will be defined as the last non-missing 
measurement on or prior to the first dose of study treatment. 
3.5. 
Randomization Stratification Factors 
Stratification factors for randomization include Neuropathy Impairment Score (NIS; < 50 vs. 
≥ 50), early onset V30M (< 50 years of age at onset) vs. all other mutations (including late onset 
V30M), and previous tetramer stabilizer use (tafamidis or diflunisal) vs. no previous tetramer 
stabilizer use. 
Stratification factors are recorded in both the IVR and the clinical database. In statistical 
analyses that use randomization stratification factors as covariates, the stratum assignment will 
reflect the values as recorded in the clinical database. In the presence of stratification errors, the 
stratification used in analysis may not match that in the IVR. 
3.6. 
Multiple Comparisons/Multiplicity 
Type I error control for secondary endpoints will be achieved by a hierarchical ordering 
procedure. Endpoints will be tested in the following pre-specified hierarchy: 
1. Norfolk QOL-DN questionnaire [Total Score] 
2. NIS-W score  
3. R-ODS 
4. 10-meter walk test speed  
5. mBMI  
6. COMPASS-31 total score 
Only if a comparison is significant at a 2-sided 0.05 significance level, the next endpoint in the 
hierarchy may be formally tested; if a given comparison is not significant at a 2-sided 
0.05 significance level, the subsequent tests will be performed and the results summarized, but 
statistical significance will not be inferred. 
3.7. 
Initiation of Alternative Treatment for FAP 
Rapid progression patients have the option to discontinue study drug, receive alternative FAP 
treatment, and return for their 18-month efficacy assessment. Non-rapid progressors may also 
initiate alternative FAP treatment during study, although this would be a major protocol 
violation. Alternative FAP treatment may confound the efficacy outcome. For the primary 
analysis of mNIS+7, Norfolk QOL-DN and NIS-W, the assessments collected after alternative 
FAP treatment (liver transplant or use of tafamidis or diflunisal for more than 14 days) will be 


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treated as missing. The data post alternative FAP treatment will be included in efficacy listings 
with a footnote and will also be used in sensitivity analyses as specified. 
For all other efficacy endpoints, data collected post alternative FAP treatment will be included 
in analyses. 
A separate listing will be provided for patients who initiate alternative treatment for FAP while 
on study. 
3.8. 
Missing Data with Efficacy Endpoints 
All efficacy data collected during study, regardless of whether before or after treatment 
discontinuation, will be included for analyses, with the exception of mNIS+7, Norfolk QOL, 
and NIS-W assessments collected post alternative FAP treatment (discussed in Section 3.7). 
3.8.1. 
Missing Subcomponents within Primary and Secondary Efficacy Endpoints 
For each patient, missing subcomponents within the primary mNIS+7 endpoint and secondary 
efficacy endpoints will be imputed whenever possible according to the algorithm specified in 
Appendix 7.2.1 through Appendix 7.2.5. When this “partial imputation” is successful (i.e., 
complete mNIS+7 values are produced), these values will be used in all statistical analyses. 
When partial imputation is unsuccessful, the efficacy endpoint will be treated as completely 
missing. 
3.8.2. 
Summary of Missing Data 
For each of the primary and secondary efficacy endpoints, the number and percentage of 
missing data (completely missing) at each visit (baseline, 9-month, and 18-month) will be 
summarized by study arm. 
Time to treatment discontinuation will be estimated descriptively using Kaplan-Meier method 
by treatment arm. Patients completing study treatment will be censored at the last dose of study 
drug. 
Spaghetti plots will be presented to display the trajectories over time for individual patient’s 
change from baseline in mNIS+7 and Norfolk QOL-DN for patients who have missing 
18-month assessments. 
3.8.3. 
Handling of Missing Data 
For the primary and secondary efficacy endpoints, the primary analysis will be based on the 
mixed-effects model repeated measures (MMRM) method, which makes use of fully and 
partially observed data sequences from individual patients by estimating the covariance between 
data from different time points. The MMRM will be implemented using an unstructured 
approach to modeling both the treatment-by-time means and the (co)variances, leading to what 
is essentially a multivariate normal model wherein treatment arm means at the primary time 
point are adjusted to reflect both the actually observed data and the projected outcomes from the 
patients with missing data [11]. In this primary analysis, missing data will not be imputed and 
are assumed to be missing-at-random (MAR). 
For the primary endpoint mNIS+7 and the first secondary endpoint Norfolk QOL, sensitivity 
analyses will be conducted to assess the impact of missing data as discussed in Section 4.3. 


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3.9. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated and analyzed per the evaluation visit as recorded on the electronic case report form 
(eCRF) even if the assessment is outside of the visit window. 
For efficacy assessments, if the scheduled 9-month or 18-month visits are not performed, the 
unscheduled and/or discontinuation visits will be grouped with the 9-month or 18-month 
assessments if they are performed within 3 months of the scheduled assessment. The derived 
visits will be used for all analyses. 
Unless otherwise specified above, data collected at unscheduled visits will be included in by-
patient data listings and figures, but no assignment to a study visit will be made for the purpose 
of by-visit summary tabulations. However, unscheduled visits may be used in the calculation of 
baseline values (as discussed in Section 3.4) and for inclusion in any categorical shift summaries 
(e.g., shift from baseline to “worst” post-baseline value). 
3.10. 
Interim Analyses 
No interim analysis was conducted for this study. 
3.11. 
Final Analyses 
After the last patient completes the 18-month efficacy assessment or the 18-month efficacy visit 
window per protocol has elapsed, the sponsor will prepare for the final analysis. The study will 
then be unblinded and the final analysis will be conducted. If there is additional safety data 
collected after the final analysis, the data will be presented in listings only. 


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4. 
STUDY ANALYSES 
4.1. 
Patient Disposition 
Patient disposition will be tabulated and will include the following parameters: the number of 
patients in each analysis population, the number of patients randomized, the number of patients 
treated, the number of patients completing treatment, the number of patients completing study, 
the number of patients who discontinued treatment and primary reasons for treatment 
discontinuation, the number of patients who withdrew prior to completing the study and primary 
reasons for withdrawal, the number of patients meeting the protocol specified criteria for rapid 
disease progression, the number of patients who discontinued treatment but completed the 
study, and the number of patients who completed treatment but withdrew prior to completing 
the study. Patient disposition will be presented by randomized treatment arm (patisiran and 
placebo) and overall. 
The number and percent of patients enrolled by country and site will be summarized by 
randomized treatment arm and overall. The number and percent of patients in each 
randomization stratification factor recorded in IVR, and a comparison of the number and 
percent of patients in each randomization stratification factor in IVR versus the clinical database 
will be summarized by randomized treatment arm and overall. 
Data listings of treatment/study completion information including the reason for treatment 
discontinuation and/or study withdrawal will be presented. 
4.2. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics, baseline disease characteristics, baseline efficacy 
parameters, and medical history information will be summarized by treatment arm and overall. 
No formal statistical comparisons will be performed. 
Age, height, weight, and body mass index (BMI) will be summarized using descriptive statistics 
(number of patients, mean, SD, median, minimum, and maximum). Sex, race, ethnicity, and 
region will be summarized by presenting the numbers and percentages of patients in each 
category. 
The following baseline disease characteristics will be summarized by presenting the numbers 
and percentages of patients in each category: 
• Age at hATTR Symptom onset [< 50; ≥ 50] 
• Neuropathy Impairment Score (NIS) [< 50; ≥ 50 & < 100; ≥ 100] 
• Genotype [V30M; non-V30M] 
• Early onset V30M [< 50 years of age at onset] vs. all other mutations [including late 
onset V30M] 
• Previous tetramer stabilizer use [tafamidis or diflunisal] vs. no previous tetramer 
stabilizer use 
• Karnofsky Performance Status (KPS) [60; 70-80; 90-100] 
• Cardiac Subpopulation (defined below) 
• New York Heart Association (NYHA) Classification [I; II; III; IV] 


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The cardiac subpopulation will be comprised of patients with pre-existing cardiac amyloid 
involvement, defined as patients with baseline left ventricular (LV) wall thickness ≥ 1.3 cm and 
no aortic valve disease or hypertension in medical history. 
Time in years since diagnosis with hATTR will be summarized using descriptive statistics. For 
those who previously used tetramer stabilizers, the time from discontinuation of tetramer 
stabilizer to the start of study drug will be summarized using descriptive statistics. The number 
and percent of patients with each genotype will be summarized by country and treatment group. 
Continuous efficacy parameters will be summarized using descriptive summary statistics. The 
number and percent of patients in each category for PND score (I, II, IIIA, IIIB, IV) and FAP 
stage (I, II, III) will also be summarized. 
Medical history will be summarized by system organ class (SOC), high level term (HLT), and 
preferred term. A patient contributes only once to the count for a given condition (overall, by 
SOC, by HLT, by preferred term). 
All demographic and baseline data for each patient will be provided in data listings. Medical 
history data including prior neurological test scores, prior surgeries, and pregnancy test results 
will be presented in a data listing. Screening test results will also be presented in data listings. 
4.3. 
Efficacy Evaluation 
The primary efficacy analyses will be conducted using the mITT population. The primary 
endpoint mNIS+7 and the first secondary endpoint Norfolk QOL will also be evaluated for the 
PP population. 
4.3.1. 
Primary Efficacy Evaluations 
The primary efficacy endpoint is to compare change in mNIS+7 from baseline to Month 18 
between treatment arms for the mITT population. 
4.3.1.1. 
Primary Analysis using MMRM Method for the mITT Population 
The primary analysis will be performed using a restricted maximum likelihood (REML) based 
MMRM approach. The outcome variable is change from baseline in mNIS+7. The model 
includes baseline mNIS+7 score as a continuous covariate and fixed effect terms including 
treatment arm, visit (Month 9 or Month 18), treatment-by-visit interaction, genotype (V30M vs. 
non-V30M), age at hATTR Symptom onset (< 50; ≥ 50), region (North America, Western 
Europe, and Rest of World), and previous tetramer stabilizer use (yes vs. no). An unstructured 
covariance structure will be used to model the within-patient errors. The Satterthwaite 
approximation will be used to estimate the degrees of freedom. The primary comparison is the 
contrast (difference in least squares means [LS means]) between the patisiran and placebo 
groups at 18 months. Analysis will be implemented with SAS PROC MIXED. 
4.3.1.2. 
Analysis using MMRM Method for the PP Population 
The analysis of the primary endpoint using MMRM method will also be conducted for the Per 
Protocol (PP) population (defined in Section 2.1). 
4.3.1.3. 
Sensitivity Analyses 
Sensitivity analyses will be conducted using the following methods to assess the impact of 
missing data and the robustness of the primary analysis. 


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Multiple Imputation/ANCOVA Method 
Multiple Imputation is a broadly applicable technique for handling missing data. Missing data 
are imputed multiple times using a regression method. Each imputed data set is analyzed by 
analysis of covariance (ANCOVA) model, and the point estimates and standard errors are 
combined to provide inferences that reflect the uncertainty about the missing values. MI also 
makes assumption of missing at random (MAR) mechanism. 
Primary endpoint data that are missing will be multiply imputed separately for each treatment 
arm using a regression procedure, with baseline information including baseline score, genotype, 
age at ATTR onset, prior tetramer stabilizer use, region, KPS, FAP stage (I vs. II/III), cardiac 
subpopulation and gender, as well as 9-month efficacy assessment value (when available) as 
covariates. MI assumes monotone missingness. For non-monotone missing data, e.g., patients 
completely missing the 9-month assessment but for whom the 18-month assessment is available, 
the 9-month assessment will be imputed as the treatment group mean. The proportion of non-
monotone missing data is expected to be very small. 
After imputation, the complete dataset will be analyzed using the ANCOVA model. In the 
model, baseline mNIS+7 will be used as covariate and treatment arm (patisiran vs. placebo), 
genotype (V30M vs. non-V30M), age at ATTR onset (Before age 50 vs. After age 50), prior 
tetramer stabilizer use (Yes vs. No), and region (Western EU, North America, and Rest of 
World) as factors. 
One hundred imputed datasets (per treatment arm) will be generated from the MI regression 
procedure. Each of the imputed datasets will then be analyzed via the ANCOVA model and the 
resulting estimates (LS means and standard errors) combined using SAS PROC MIANALZYE 
to produce inferential results (difference in LS means, 95% CI for the difference, and the p-
value from the test that the difference is zero). Point estimates (LS means and differences) will 
be calculated as the average of the 100 complete-data estimates. A total variance estimate will 
be calculated as a weighted sum of within-imputation variance, which is the average of the 
complete-data variance estimates, and a between-imputation variance term. Complete details 
may be found in the SAS documentation for the MIANALYZE procedure (see Combining 
Inferences from Imputed Data Sets under Details). 
http://support.sas.com/documentation/onlinedoc/stat/131/mianalyze.pdf. 
Analyses will be conducted using PROC MI and PROC MIANALYZE in SAS 9.3 (or later). 
Pattern-Mixture Model (PMM) 
A sensitivity analysis using pattern mixture model (PMM) will be performed to assess the 
robustness of the primary MMRM results to the possible violation of the missing at random 
(MAR) missingness assumption. The PMM accommodates situations where the missingness 
mechanism is missing not at random (MNAR). The model will be based on the following 
assumptions: 
1. Patients who have missing data and are alive before Month 18: 
a. Placebo patients who have missing data (either Month 9 or 18): The missing data 
are considered MAR and will be imputed using MI estimated from placebo 
patients. The imputation is done regardless of whether a patient was on-treatment 
or discontinued treatment before the scheduled efficacy assessment.  
b. Patisiran patients who have missing data (either Month 9 or 18) while on 
treatment: Patients are expected to continue to show benefit from treatment 


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similar to that observed at the scheduled time point. Therefore, missing data 
during the on-treatment period (within 60 days of their last dose) are considered 
MAR and will be imputed using MI estimated from all non-missing data 
collected on treatment from the patisiran arm. 
c. Patisiran patients who have missing data (either Month 9 or 18) after stopping 
their study treatment: Patients will no longer benefit from treatment in the future 
and will have trajectory similar to placebo patients. Therefore, missing data after 
treatment discontinuation (more than 60 days after last dose of study drug) will 
be imputed using the data from placebo patients. 
2. Patients who die before Month 18 and have missing data: Assuming that deaths observed 
in the study will likely be related to worsening of disease, the missing data at Month 18 
will be imputed by taking random samples from the worst 10% mNIS+7 change scores 
in the entire population. The imputation will be done for patients from both patisiran and 
placebo arms. 
Missing values will be imputed 100 times to generate 100 complete datasets using procedures as 
described above. An ANCOVA model will be fit to each “complete” dataset for the change 
from baseline in mNIS+7 at Month 18. The ANCOVA model will include baseline mNIS+7 as a 
continuous covariate and treatment arm (patisiran vs. placebo), genotype (V30M vs. non-
V30M), age at ATTR onset (Before age 50 vs. After age 50), previous tetramer stabilizer use 
(Yes vs. No), and region (Western Europe, North America, and Rest of World) as factors. The 
resulting estimates from the 100 analyses will be combined using Rubin’s formulae, and the 
95% confidence interval will be constructed, similar to the procedure described in the 
MI/ANCOVA section. 
More details on the implementation of PMM are discussed in Appendix 7.1. 
Including Data Post Alternative Treatment for FAP 
The primary analysis will not include mNIS+7 assessments performed after the initiation of 
alternative treatment for FAP (Section 3.7). Sensitivity analysis including data post alternative 
treatment for FAP will be conducted using the MMRM model. In this sensitivity analysis, all 
assessments will be used in the analysis regardless of whether an assessment occurs before or 
after alternative treatment.     
Revised mNIS+7 Total Score Using a Different Algorithm to Handle Missing Components 
In the primary derivation of mNIS+7 total score, the “within treatment arm” imputation 
algorithm will be used for the imputation of missing component (Appendix 7.2.1). At each visit, 
if a patient has a missing component for mNIS+7, the value will be imputed using data from 
other patients who are on the same treatment arm and who had non-missing data for that 
component at that visit. In a sensitivity analysis, any such missing value will be imputed as the 
mean value for the component at the visit from all patients (combining placebo and patisiran 
arms). The analysis of this revised mNIS+7 derived scores will be conducted using the MMRM 
model. 
4.3.1.4. 
Binary Analyses 
The number and percentage of patients with < 10-point increase in mNIS+7 composite score 
from baseline to Month 18 will be calculated for each treatment arm and compared between 
2 arms using the Cochran-Mantel-Haenszel test, stratified by genotype (V30M vs. non-V30M). 
The percentage will be based on the mITT population. Patients with missing 18-month data will 
be counted in the denominators. 


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In addition, the number of percentage of patients with a decrease (change from baseline 
< 0-point) in mNIS+7 total score from baseline to Month 18 will also be calculated and 
analyzed similar as above. 
The planned analyses of the primary endpoint mNIS+7 are summarized in Table 1. 
Table 1 
Analysis of mNIS+7 
Statistical Method 
Analysis Population 
Primary analysis: MMRM 
mITT 
Sensitivity analysis: 
• 
MI/ANCOVA 
• 
PMM 
• 
MMRM - including Data Post Alternative Treatment for FAP 
• 
MMRM - revised mNIS+7 Total Score Using a Different 
Algorithm to Handle Missing Components 
mITT 
Other analysis: MMRM 
PP 
Other analysis: Binary analysis using stratified CMH 
mITT 
 
4.3.2. 
Secondary Efficacy Evaluations 
Secondary efficacy endpoints include Norfolk QOL-DN total score, NIS-W, R-ODS, 10-meter 
walk test speed, mBMI, and COMPASS-31. To control overall type I error, these endpoints will 
be tested in a hierarchical order as described in Section 3.6. 
All the secondary endpoints are assessed at baseline, Month 9, and Month 18 with the exception 
of mBMI. mBMI is assessed at baseline, Day 84, Day 189, Day 357, Day 462 and Day 546. 
Day 546 will be used as Month 18 assessment. 
For 10-meter walk test, the walk speed for patients unable to perform the walk will be imputed 
as 0. The change from baseline will then be calculated as 0 – baseline walk speed. 
Change from baseline at Month 18 in the secondary efficacy endpoints will be analyzed for the 
mITT population, using an MMRM model similar to the model described for the primary 
analysis of mNIS+7 while adjusting for baseline value of the endpoint being modeled. For these 
secondary endpoints (except NIS-W), MMRM model will also include baseline NIS (< 50 vs. 
≥ 50) as a factor. The MMRM model for NIS-W will not include baseline NIS since baseline 
NIS-W will be included as a covariate in the model. 
For the first secondary endpoint Norfolk QOL-DN Total Score, the MMRM method will also be 
conducted for the PP population. In addition, sensitivity analyses will be conducted using 
ANCOVA/MI and including data post alternative treatment for FAP similar as described for 
mNIS+7 (see Section 4.3.1.3). 
Month 18 change from baseline in mBMI will be estimated from the MMRM model using 
assessment results from all time points. 
The planned analyses of the secondary endpoints are summarized in Table 2. 


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Table 2 
Analysis of Secondary Endpoints 
Endpoint 
Statistical Method 
Analysis 
Population 
Special Notes 
Norfolk QOL-
DN total score 
Primary analysis: MMRM 
mITT 
 
Sensitivity analysis: 
• 
MI/ANCOVA 
• 
MMRM - including Data Post 
Alternative Treatment for FAP 
mITT 
 
Other analysis: MMRM 
PP 
 
NIS-W 
MMRM 
mITT 
Excludes data post 
alternative treatment 
for FAP 
R-ODS 
MMRM 
mITT 
 
10-meter walk 
test speed 
MMRM 
mITT 
For patients unable to 
perform the walk, 
walk speed imputed as 
0 
mBMI 
MMRM 
mITT 
Measured at baseline, 
Day 84, Day 189, 
Day 357, Day 462 and 
Day 546 
COMPASS-31 
MMRM 
mITT 
 
 
4.3.3. 
Exploratory Efficacy Evaluations 
The continuous exploratory endpoints including grip strength, SGNFD, IENFD, dermal amyloid 
content, EQ-5D-5L index, EQ VAS, original NIS+7 and small/large fiber function (defined in 
Appendix 7.2.1) will be analyzed using an MMRM model similar to those employed for the 
primary analysis. 
The categorical exploratory endpoints PND score and FAP stage will be descriptively 
summarized by presenting the number and percentage of patients in each category for each visit. 
The number of percentage of patients with improving, no change, and worsening in PND/FAP 
at each visit will also be summarized. 
For EQ-5D-5L, a categorical summary of the numbers and percentages of patients reporting 
each ordinal response within each EQ-5D domain will be presented. 
Cardiac structure and function will be assessed for all patients through echocardiograms. 
Cardiac stress and injury will be measured using serum levels of the cardiac biomarkers 
NT-proBNP and troponin I. Quantification of these biomarkers will be performed at a central 
laboratory. Descriptive statistics will be provided for actual values, changes, and percentage 
changes from baseline in echocardiogram parameters, serum levels of troponin I and 
NT-proBNP by treatment arm. 
For cardiac subpopulation (defined in Section 4.2), the change from baseline to Month 18 in LV 
wall thickness, LV mass, LVEF, LV longitudinal strain, NT-proBNP and troponin I will be 
compared between the 2 treatment arms using MMRM. The model will include baseline value 


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as covariate and fixed effect terms including treatment arm, visit, and treatment-by-visit 
interaction. 
All echocardiogram and cardiac function biomarkers data will be presented in data listings. 
MR neurography data will be presented in a data listing. 
4.3.4. 
Subgroup Analyses 
Subgroup analyses will be conducted to assess the consistency of treatment effect within various 
subgroups defined by the following baseline characteristics: 
• Age [≥65; <65 at randomization] 
• Sex [Male; Female] 
• Race [White; Non-White] 
• Region [North America; Western Europe; Rest of World] 
• NIS [< 50; ≥ 50] 
• Genotype Class [Early-onset V30M; Other] 
• Previous Tetramer Use [Yes; No] 
• Genotype [V30M; non-V30M] 
• FAP Stage [I; II & III] 
Subgroup analyses will be performed for the primary endpoint mNIS+7 and Norfolk QOL-DN 
using MMRM models with baseline mNIS+7 score as a continuous covariate and genotype 
(V30M vs. non-V30M) as a factor. A forest plot will be generated to illustrate the estimated 
treatment effect along with 95% CI within each subgroup. 
4.3.5. 
Component Analyses 
Component analyses will be conducted to assess the consistency of treatment effect on the 
change from baseline at Month 18 for each of the component of mNIS+7 including NIS-W, 
NIS-R, QST, ∑5 NCS, and postural blood pressure. The analyses will be performed using 
MMRM models similar to those employed for the primary analysis. A forest plot will be 
generated to illustrate the estimated treatment effect along with 95% CI for each component. 
4.4. 
Pharmacodynamic Analyses 
The PD parameters include serum TTR (ELISA), serum TTR (turbidimetric assay), RBP, and 
vitamin A. All summary tables and figures will be based on assessments within 21 days of last 
dose of study drug. Assessments more than 21 days after last dose will be presented in listings 
and individual patient plots only. 
Summary tables will be provided for observed values, changes and percentage changes from 
baseline for each scheduled time point by treatment arm. 
For serum TTR (ELISA), the maximum percentage reduction and mean percentage reduction 
over 18 months will be summarized using descriptive statistics. Subgroup analysis will be 
provided for age (≥ 65 vs. <65), sex (male vs. female), genotype (V30M vs. Non-V30M), and 
previous tetramer stabilizer use (yes vs. no). 


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For vitamin A and RBP, the mean percentage reduction over 18 months will be summarized 
using descriptive statistics. 
The correlation coefficient and p-value based on mixed model will be calculated to assess the 
correlation between the changes from baseline in ELISA TTR versus Turbidimetric TTR. A 
scatterplot will be provided to visualize the data. 
The therapeutic hypothesis for patisiran is that TTR reduction will result in clinical benefit in 
hATTR patients. The inter-patient variability in the degree of TTR reduction provides an 
opportunity to examine the relationship of TTR reduction to clinical endpoints. TTR reduction 
22 days after the first dose of Patisiran as the first TTR assessment timepoint and prior to the 
second dose, will be used for analysis of the correlation between TTR reduction and change in 
mNIS+7 because this time point reduces the impact of missed doses or missed TTR assessments 
over 18 months of dosing. Pearson correlation coefficients and 95% confidence intervals will be 
calculated for Day 22 TTR % reduction and mNIS+7 total score change from baseline at the 9- 
and 18-month time points, for patisiran arm and placebo arm separately. Scatterplots will be 
provided to visualize the data. 
All PD data will be displayed in data listings. 
4.5. 
Pharmacokinetic Analyses 
4.5.1. 
Study Variables 
4.5.1.1. 
Concentration Data 
Urinary concentrations of ALN-18328 (siRNA) and 4-dimethylaminobutyric acid, as well as 
plasma concentrations of ALN-18328, DLin-MC3-DMA and PEG2000-C-DMG will be obtained. 
Concentration values that are below the limit of quantification (LLOQ or BLQ) will be set to 
zero for analysis. 
4.5.1.2. 
Plasma ALN-TTR02 Pharmacokinetic Parameters 
Model independent PK parameters to be calculated by study visit include: 
• Observed post-infusion peak concentration (Cmax) 
• Observed 30 min post-infusion concentration (Cp (30 min)) 
• Observed pre-infusion trough concentration (Ctrough) 
In addition, steady-state Cmax (Cmax_ss), steady-state Ctrough (Ctrough_ss) and steady-state 
Cp(30 min) (Cp_ss(30min)) will be calculated. Ctrough_ss is the average Ctrough on Days 253, 
400 and 547. Cp_ss(30 min) is the average Cp(30 min) on Days 253 and 547. Cmax_ss is the 
Cmax on Day 400. 
4.5.2. 
Statistical Methods 
Descriptive statistics for plasma PK parameters will include the number of patients, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and geometric 
CV%. 
The plasma Cmax, Cp (30min) and Ctrough of ALN-18328 (siRNA), DLin-MC3-DMA and 
PEG2000-C-DMG will be summarized by nominal sampling day. Urinary amounts of ALN-
18328 and 4-dimethylaminobutyric acid recovered will be estimated as urine concentration 


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times the associated urine volume and will be summarized by nominal sampling day. Mean 
concentrations (+/- SD) will be plotted versus nominal sampling time. 
Steady-state PK parameters for ALN-18328 (siRNA), DLin-MC3-DMA and PEG2000-C-DMG 
will be summarized overall and by subgroup (gender, anti-drug antibody status).   
Plasma concentration data will be presented in by-patient listings. 
The PK-PD relationship between the plasma concentration of ALN-18328 and the percent 
change from baseline in TTR protein, vitamin A and RBP will be explored graphically. 
The PK exposure-response relationships for the primary endpoint (mNIS+7), TTR, and 
incidence of relevant AEs may also be explored. These may be summarized by ALN-18328, 
DLin-MC3-DMA and PEG2000-C-DMG PK exposure quartiles at 18-months (Day 546). 
Population PK and exposure-response modeling will be reported separately. 
4.6. 
Safety Analyses 
Safety analyses will be conducted using the Safety population. All safety summaries will be 
descriptive and will be presented by treatment arm. 
4.6.1. 
Study Drug Exposure 
Duration of drug exposure will be defined as (the last dose of study drug – the first dose of study 
drug + 21)/30.44 months. Duration of drug exposure, the total number of doses received, 
duration of infusion (per infusion) and amount of study drug received (per infusion and in total) 
will be summarized by descriptive statistics. Summaries of the numbers and percentages of 
patients with missing dose, and the number of missing doses per patient will also be provided. 
The total amount of drug received and the total volume infused will also be summarized. 
The number of patients who experienced interruptions of infusions for any reason will be 
tabulated, as well as the number of patients with infusion interruptions due to an acute infusion 
reaction. 
Dosing information for each patient will be presented in a data listing. 
4.6.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system (version 18.0 or later) and displayed 
in tables and data listings using SOC and preferred term. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE with onset during or after the administration of 
study drug through 28 days following the last dose of study drug. In addition, any event that was 
present at baseline but worsened in intensity or was subsequently considered drug-related by the 
Investigator through the end of the study will be considered treatment-emergent. Events with a 
fully or partially missing onset date will be assumed to be treatment emergent unless it can be 
unequivocally determined (from the partial onset date and/or a partial or complete stop date) 
that the event occurred prior to the first administration of study drug. 
Adverse events will be summarized by the numbers and percentages of patients reporting a 
given AE. A patient contributes only once to the count for a given AE (overall, by SOC, by 
preferred term). Overall event counts and frequencies may also be summarized. 


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An overall summary of AEs will include the number and percentage of patients with any AE, 
any AE assessed by the Investigator as related to treatment (definite or possible relationship), 
any severe AE, any severe AE related to treatment, any serious AE (SAE), any SAE related to 
treatment, any AE leading to treatment discontinuation, any study drug related AE leading to 
treatment discontinuation, any AE leading to study withdrawal, any study drug related AE 
leading to study withdrawal, and any deaths. 
Tabulations by SOC and preferred term will be produced for the following: all AEs; AEs related 
to treatment; severe AEs; AEs leading to infusion interruption; AEs leading to drug delay; AEs 
leading to treatment discontinuation; AEs leading to study withdrawal; and SAEs. Separate 
tables will be provided summarizing signs and symptoms of IRRs (overall and by premedication 
regimen) and AEs related to premedication (overall and by premedication regimen) by SOC and 
preferred term. The incidence and frequency of AEs and IRRs over time will also be 
summarized by SOC and preferred term. Adverse events and AEs related to treatment will also 
be tabulated by preferred term in decreasing order in frequency in the patisiran arm. Adverse 
events and SAEs will also be summarized by SOC and preferred term for the cardiac 
subpopulation. 
Separate tables will present AE incidence rates by maximum relationship to study drug and by 
maximum severity. Patients who report multiple occurrences of the same AE (preferred term) 
will be classified according to the most related or most severe occurrence, respectively. 
AEs mapping to the standardized MedDRA query (SMQ) Depression and Suicide/Self-injury 
will be summarized by preferred term. Adverse events mapping to the SMQ Drug Related 
Hepatic Disorder will be summarized by SOC and preferred term. Adverse events mapping to 
the SMQ Malignant or Unspecified Tumors will be summarized by high level term and 
preferred term. Other SMQs or AE groupings may be evaluated. 
All AEs will be presented in patient data listings. Separate listings will be provided for death, 
SAEs, AEs leading to treatment discontinuation, AEs leading to study withdrawal, IRRs, AEs 
related to premedications, AEs related to study procedures, and AEs mapping to the SMQ as 
described above. A listing of patients who underwent liver transplant will also be provided. 
4.6.3. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. 
Summary data for each laboratory parameter will be presented for each continuous clinical 
laboratory parameter (including hematology, serum chemistry, coagulation studies and thyroid 
and liver function tests). Descriptive statistics will be presented for the actual values, change 
from baseline, and percent change from baseline by visit. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges. Shift tables will be employed to summarize the baseline 
category versus the “worst” post-baseline category, where the “worst” post-baseline category 
will be based on the maximum difference (in absolute value) from the upper or lower limits of 
the normal range. 
A listing will be produced for all patients with abnormal liver function tests defined as an ALT 
> 3×ULN, AST > 3×ULN, and total bilirubin > 2×ULN at any time point. 
A table will be produced to summarize the number and percentage of patients in each of the 
below categories at any post-baseline time point. 


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• ALT > 1 & ≤ 3, > 3 & ≤ 5, > 5 & ≤ 10, > 10 & ≤ 20, > 20 ×ULN, 
• AST > 1 & ≤ 3, > 3 & ≤ 5, > 5 & ≤ 10, > 10 & ≤ 20, > 20 ×ULN, 
• ALT or AST > 1 & ≤ 3, > 3 & ≤ 5, > 5 & ≤ 10, > 10 & ≤ 20, > 20 ×ULN, 
• ALP > 1.5 ×ULN, 
• Total Bilirubin > 1.5 & ≤ 2, > 2 & ≤ 3, > 3 & ≤ 5 and > 5 ×ULN, 
• Total Bilirubin > 2 ×ULN concurrent with ALT or AST > 3 ×ULN. 
A shift table from baseline to worst post-baseline for ALT, AST, and total bilirubin will also be 
provided. In separate figures, the peak total bilirubin (at any time post-baseline) will be plotted 
against the peak AST, the peak ALT, and the peak AST or ALT levels at any time post-baseline. 
For hematology and blood chemistry, summary tables of potentially clinically significant 
abnormalities will be provided. The results may also be graded according to the NCI CTCAE 
Version 4.0 or above. A shift summary of baseline to maximum post-baseline CTCAE grade 
may be presented, as appropriate. 
The estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) will be categorized as below: 
≥ 90; 60-89; 30-59; 15-29 and < 15. A shift summary of baseline to worst post-baseline eGFR 
category will be presented. 
All laboratory data will be provided in data listings. Out-of-range laboratory results will be 
identified in the listings. 
4.6.4. 
Vital Signs and Physical Examination 
Descriptive statistics will be provided for vital signs, including blood pressure, pulse rate, oral 
body temperature and respiration rate. 
Vital sign measurements will be presented for each patient in a data listing. 
All physical examination findings will be presented in a by-patient data listing. Abnormal 
physical examination findings will be presented in a separate listing. 
4.6.5. 
Electrocardiogram 
Electrocardiogram (ECG) findings will include rhythm, ventricular rate, PR interval, QRS 
duration, QT interval, and QTc interval. For each time point, the results will be the average of 
measurements from the triplicate ECGs for each patient recorded at that time point. Descriptive 
statistics will be provided for each measure over time. Change from pre-dose to each post-dose 
assessment will also be summarized. The number and percentage of patients with normal, 
abnormal, and clinically significant abnormal results at baseline and each study visit will also be 
summarized. 
Corrected QT interval (QTc) will be calculated using both Fridericia’s and Bazett's correction 
formula. Categorical analyses of the QTcF/QTcB data will be conducted and summarized as 
follows: 
• The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB (< 30, 30 – 60, > 60 ms) 
• The number and percentage of patients with maximum post-baseline QTcF/QTcB 
(< 450, 450 – < 480, 480 – 500, > 500 ms) 


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All ECG data for each patient will be provided in a data listing. A separate listing will be 
provided for patients with any post-baseline value > 500ms or an increase from baseline 
> 60 ms. 
4.6.6. 
Premedication 
All patients received premedication in order to reduce the potential of an IRR. The original 
premedication regimen as outlined below was used at the start of the study. A subset of patients 
experienced AEs suspected to be related to steroids (e.g., flushing) and were transitioned to a 
modified premedication regimen, with a reduced dose of corticosteroid to mitigate these events, 
as sanctioned in the protocol. After observing that the subset of patients tolerated the lower 
corticosteroid dose with no increase in IRRs, the protocol was amended (Amendment 5.0) to 
transition the rest of the patients to the modified premedication regimen (see below).  
The following original premedication regimen was used prior to protocol amendment 5.0: 
• Dexamethasone 8 mg PO or equivalent administered the evening before dosing and 
20 mg PO at least 60 minutes prior to the start of the infusion of patisiran; 
• Paracetamol 500 mg PO or equivalent administered the evening before dosing and at 
least 60 minutes prior to the start of the infusion of patisiran; 
• H2 blocker PO (e.g., ranitidine 150 mg or famotidine 20 mg or equivalent other H2 
blocker dose) administered the evening before dosing and at least 60 minutes prior to 
start of the infusion of patisiran; and 
• H1 blocker PO, 10 mg cetirizine or equivalent (hydroxyzine 25 mg or fexofenadine 
could be substituted if patient did not tolerate cetirizine) administered the evening before 
dosing and at least 60 minutes prior to start of the infusion of patisiran. 
The following reduced premedication regimen was instituted for all patients with protocol 
amendment 5.0: 
• Dexamethasone 10 mg IV or equivalent, administered at least 60 minutes prior to the 
start of the infusion of patisiran; 
• Paracetamol 500 mg PO or equivalent at least 60 minutes prior to the start of the 
infusion of patisiran; 
• H2 blocker IV (e.g., ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 blocker 
dose) at least 60 minutes prior to the start of the infusion of patisiran; and 
• H1 blocker IV, diphenhydramine 50 mg (or equivalent other IV H1 blocker available at 
the study site) at least 60 minutes prior to the start of the infusion of patisiran. 
Hydroxyzine 25 mg PO or fexofenadine 30 or 60 mg PO or cetirizine 10 mg PO could 
be substituted for any patient who did not tolerate IV diphenhydramine or other IV H1 
blocker. 
A drug exposure table summarizing the treatment duration under “original” and “reduced” 
regimens will be provided. A patient who switches from “original” to “reduced” regimen during 
treatment will be counted in both categories. 
Premedications will be coded using the WHO Drug Dictionary (March 2015 or later). Results 
will be tabulated by anatomic therapeutic class (ATC) and preferred term. 


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Premedication data will be listed. In addition, a listing will be provided to present the durations 
of study drug exposure under original regimen and reduced regimen for each patient. 
4.6.7. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug Dictionary (March 2015 
or later). Results will be tabulated by ATC and preferred term. 
When there are partial or missing dates, imputed dates will be used to determine 1) if a 
medication is prior or concomitant, and 2) duration of exposure of alternative FAP treatment 
(tafamidis/diflunisal). Imputed dates will not be presented in the listings. 
For medications with partial start or stop dates: the first day/month will be imputed for start 
date, and the last day/month will be imputed for stop date. For medications with a completely 
missing start date, the medications will be considered as started prior to the first dose of study 
drug; medications will be classified as prior, concomitant or both depending on the medication 
stop dates. For medications with a completely missing stop date, the end of study date will be 
imputed. 
Prior and concomitant medications will be presented in data listings. 
4.6.8. 
Ophthalmology Examinations 
Ophthalmology examinations include Visual Acuity, Visual Field, Slit Lamp Biomicroscopy, 
Intraocular Pressure, Dilated Indirect Ophthalmoscopy, and Fundus Photography. 
Visual Acuity, Visual Field, and Intraocular Pressure Results: The actual value and change from 
baseline results will be summarized. 
Biomicroscopy (Slit Lamp) and Dilated Indirect Ophthalmoscopy Exam Results: For the 
baseline results, the number and percentage of patients falling into each category of the 
examination status (normal, abnormal/not clinically significant, abnormal/clinically significant) 
will be summarized for each eye structure. For post-baseline results, the number and percentage 
of patients falling into each category of the examination status (new findings/worsening of 
finding, no change, improvement of finding, etc.) will be summarized for each eye structure. 
Abnormal fundus findings at baseline will be recorded in the medical history log. Treatment-
emergent abnormal fundus findings that are considered clinically significant will be recorded in 
the AE log. 
Data for each of these assessments will be provided in a data listing. 
4.6.9. 
Suicidality Questionnaire 
The number and percentage of patients experiencing the suicidal ideation, suicidal behavior, or 
self-injurious behavior composite outcomes (and individual components) will be summarized by 
visit. A shift table will be employed to summarize the baseline C-SSRS category versus the 
worst post-baseline C-SSRS category; the categories are defined as 1) no suicidal ideation or 
behavior, 2) suicidal ideation, and 3) suicidal behavior. Patients experiencing both suicidal 
ideation and suicidal behavior are included in the suicidal behavior category. 
Data from the C-SSRS questionnaire will be provided in a data listing. 


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4.7. 
Anti-Drug Antibody 
The number and percentage of patients with confirmed positive ADA assay results at any time 
point during study as well as at each scheduled visit will be summarized. The titer results for 
patients with confirmed positive ADA results will also be summarized using descriptive 
statistics. 
For patients with confirmed positive ADA results, spaghetti plots for the serum TTR (ELISA) 
over time and the plasma concentration of ALN-18328, DLin-MC3-DMA and PEG2000-C-
DMG over time will be presented. Effect of positive ADAs on efficacy and safety (e.g., IRRs) 
may also be explored. 
Anti-drug antibody (ADA) data and patients with confirmed positive ADA results will be 
presented in data listings. 


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5. 
CHANGES TO PLANNED ANALYSES 
The SAP version 2.0 includes more details previously not discussed in the original SAP 
version 1.0. The following major changes will be implemented in the SAP version 2.0 that are 
different from the planned analysis specified in the SAP version 1.0 and/or the protocol 
version 6.0. 
This SAP Version 2.1 incorporates an additional change to censor data post alternative 
treatment for the analysis of NIS-W, which is documented in Section 5.6.  
5.1. 
Primary Analysis Method for Efficacy Endpoints 
In the study protocol and the original SAP V1.0, the primary analysis method specified for the 
primary and secondary efficacy endpoints was the MI/ANCOVA. The original SAP V1.0 was 
submitted for FDA review (IND Serial # 0019). Following FDA’s comment received on 
02July2015 and the sponsor’s responses on 31August2015, the primary analysis method for all 
efficacy endpoints will be changed to MMRM method. The history and rationales for the change 
of primary analysis method are described below. The change is aligned with the CHMP 
guideline on missing data in confirmatory clinical trials (EMA/CPMP/EWP/1776/99 Rev.1). 
Mixed-effects model repeated measures and MI are 2 common methods for handling missing 
data in analysis of continuous, longitudinal endpoints. For this study, ANCOVA/MI was 
originally selected as the primary analysis, with MMRM as a key sensitivity analysis. 
In the literature, MMRM and MI have been compared in several simulation studies. 
Collins et al. (2001) noted that the 2 methods yielded similar inference. However, 
Barnes et al. (2008) found a larger average standard error for MI relative to MMRM, suggesting 
that MI controls type I error conservatively and loses power to detect true treatment differences. 
Siddiqui (2011) compared MI/ ANCOVA and MMRM approaches using both simulated 
datasets and 25 New Drug Application (NDA) datasets of neuropsychiatric drug products, and 
concluded that MMRM appears to be a better choice in maintaining statistical properties relative 
to the MI approach when dealing with ignorable missing data. 
For the ALN-TTR02-004 trial setting, we compared the properties of these 2 methods via 
simulation. Our results demonstrated that, while both methods control type I error, MMRM 
appears to be more powerful in detecting true treatment effect compared with ANCOVA/MI. 
Moreover, White et al. (2012) argued that excessive focus on including all randomized patients 
with missing outcomes can lead to a choice of analysis that rests on implausible or unnecessarily 
complex imputation. The authors proposed that the main focus in choosing the primary analysis 
should be the plausibility of its assumptions, while inclusion of all randomized individuals is a 
requirement only for sensitivity analyses. The MI approach, which includes all randomized 
patients, is often designated as a sensitivity analysis. 
Given these findings – and consideration of the complexity inherent when using the multistep 
MI approach, the primary analysis method will be changed to MMRM for the primary and 
secondary efficacy endpoints. MI/ANCOVA will be performed as the key sensitivity analysis 
for the primary endpoint and for the first secondary endpoint (Norfolk QOL). 
5.2. 
Multiple Imputation/ANCOVA Method 
The MI/ANCOVA method, as described in this document and in SAP V1.0, differs from that 
described in the current clinical protocol (Version 6: September 2015) in the MI method and in 
the explanatory covariates included in the (complete data) ANCOVA (discussed in Section 5.4). 


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The MI (for completely missing mNIS+7 assessments) described in the SAP differs from that in 
the clinical protocol in that 1) stepwise variable selection has been replaced with a pre-specified 
set of covariates to be included; 2) imputation is done separately by treatment arm. The rationale 
for these changes is outlined below. 
• Stepwise variable selection was removed in order to simplify the analysis. 
• The SAP specifies that imputation is done separately by study arm; the current protocol 
specifies says that treatment assignment will not be included in the imputation. This 
change is motivated by simulations demonstrating a non-negligible loss in power when a 
single imputation model is employed and treatment is not included in the model; this 
loss in power is due to “cross-contamination” of imputation models between randomized 
arms [9]. 
In the protocol, the number of imputed datasets was specified as 100. In SAP V1.0, the number 
of imputed datasets was reduced to 10 following the conclusion that 3-5 imputations are often 
sufficient [10], however, in this SAP V2.0, the number of imputed datasets is increased to 100 
to have more precise estimates. 
5.3. 
Hierarchical Testing Order of Secondary Endpoints 
In the protocol and SAP version 1.0, it was specified that secondary endpoints would be tested 
in the following order for the control of overall type I error: Norfolk QOL, NIS-W score, 
mBMI, 10-meter walk test, and COMPASS-31. 
In this SAP amendment, R-ODS has been added as a secondary endpoint for controlled 
hypothesis testing, and 10-meter walk test has been moved up in the hierarchy. The revised list 
and order of secondary endpoints is the following: Norfolk QOL, NIS-W, R-ODS, 10-meter 
walk test, mBMI and COMPASS-31. 
These changes were based on the Sponsor’s re-assessment of the clinical importance of these 
endpoints in hATTR amyloidosis patients. 
5.4. 
Adjustment for Covariates in Statistical Models  
The table below summarizes the history of changes in baseline covariates used in the statistical 
models. 


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Baseline Covariates 
Protocol 
SAP V1.0 
SAP V2.0 
ANCOVA 
ANCOVA 
MMRM/ANCOVA 
Baseline mNIS+7 
X 
X 
X 
Genotype (V30M vs. Non-V30M) 
X 
 
X 
Genotype class (early onset V30M 
vs. Other) 
 
X 
 
Age at hATTR symptom onset 
(< 50 vs. ≥ 50) 
 
 
X 
Previous tetramer stabilizer use 
(Yes vs. No) 
X 
X 
X 
Region (Western EU, North 
America, Rest of World) 
 
 
X 
Age at study entry as continuous 
variable 
X 
 
 
Genotype class (early onset V30M vs. other) is one of the stratification factors at randomization. 
The early onset V30M subgroup includes patients who have the V30M genotype and were 
younger than 50 years old at hATTR amyloidosis symptom onset. At the time of this SAP 
amendment, the enrollment was complete and there were only 23 early onset V30M patients. 
Given the small sample size, the composite covariate “genotype class” is decomposed into 
2 separate covariates “genotype” and “age at hATTR amyloidosis symptom onset.” 
Region is added as a covariate because different rates of attrition and disease worsening were 
observed for different regions during blinded data monitoring. In addition, adding region may 
potentially address the influence of different non-V30M types observed across regions. 
5.5. 
Binary Analysis of mNIS+7 
In SAP V1.0, binary analysis of mNIS+7 included an analysis of patients with < 2-point 
increase in mNIS+7 change from baseline at Month 18. The 2-point threshold was originally 
used in the tafamidis Phase 3 trial in hATTR amyloidosis patients with polyneuropathy to define 
responders for the NIS-LL co-primary endpoint. That trial enrolled patients with very early 
stage neuropathy and mean baseline NIS-LL of approximately 8-11 points, in whom a 2-point 
worsening of NIS-LL was considered to be clinically meaningful. However, the patients 
enrolled onto this study have more advanced disease, with a mean baseline NIS of 
approximately 60 points, and the mNIS+7 primary endpoint is very different from NIS-LL, with 
a maximum score of 304 points compared to 88 points for NIS-LL. Therefore, a 2-point 
threshold was not deemed relevant for mNIS+7 change in this patient population. 
In this SAP V2.0, 2 thresholds, < 10-point increase and any decrease (< 0-point change from 
baseline) will be employed to conduct the binary analysis of mNIS+7. These thresholds of 
< 10-point and < 0-point were chosen based on the 18-month estimated mNIS+7 progression 
rate observed in a natural history study of hATTR amyloidosis patients and the observed effect 
of patisiran on mNIS+7 at 18 months in the Phase 2 OLE study, respectively. 
5.6. 
Censoring Data Post Alternative FAP Treatment 
In this SAP V2.0, for the primary analysis of mNIS+7 and Norfolk QoL, the data post 
alternative FAP treatment will be censored. This censoring rule was not previously specified in 
the protocol or SAP V1.0. The rationale of adding this censoring rule is to eliminate the 
potential confounding effect caused by alternative FAP treatment. Sensitivity analyses for 
mNIS+7 and Norfolk QoL will be conducted including data post alternative FAP treatment. 


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In SAP V2.1, an update was made to apply the censoring rule to NIS-W as well so that the 
results will be consistent with the component analysis of mNIS+7.  
For all other efficacy endpoints, the data will not be censored since no sensitivity analyses are 
planned. 
5.7. 
Other Changes 
Additional changes are listed in the table below. 
Change from Protocol  
and/or SAP V1.0 
Detailed Description/Rationale 
In the protocol and original SAP 
V1.0, the first day of drug 
administration was designated as 
Day 0. In this SAP amendment and 
the TLF outputs, the first dose day 
will be defined as Day 1. 
The change is made to follow CDISC convention. Each 
calculated study day after dosing is 1 day plus the reported study 
day following the protocol defined Schedule of Assessments. 
In the protocol and original SAP 
V1.0, it was intended that an 
interim analysis for sample size re-
estimation would be conducted; 
however, no interim analysis was 
conducted during the study. 
In 2013, Berk et al. published results of a randomized placebo-
controlled trial of diflunisal in FAP. This trial demonstrated that 
efficacy using a composite neurologic impairment score primary 
endpoint (NIS+7) could be established in a similar population 
with a similar study design and smaller study size (N=130). The 
sponsor believed that an interim analysis for sample size 
reassessment was therefore no longer necessary. 
In SAP V2.0, dermal amyloid 
content is added as an exploratory 
endpoint. 
In addition to IENFD and SGNFD, skin punch biopsies will also 
be assessed for dermal amyloid content, which has been added as 
an efficacy parameter in this SAP V2.0. 
In SAP V2.0, the walk speed for 
patients unable to perform the walk 
will be imputed as 0. 
The imputation algorithm is added to address the informative 
missing data for patients unable to perform the walk due to 
worsening of disease. 
Renal clearance for siRNA and 4-
dimethylaminobutyric acid 
(DMBA) will not be analyzed. 
As per protocol, renal clearance for siRNA and 4-
dimethylaminobutyric acid (DMBA) were to be determined 
whenever possible. Only sparse pre-dose urine collections (and 
volumes) were obtained in patients enrolled in this study on 
select days that patients returned to the clinic for dosing (Days 0, 
21, 126, 252, 399, 546 and at time of early withdrawal). In order 
to estimate renal clearance, detailed serial urine and 
corresponding plasma collections that describe a time course of 
exposures in both matrices over a dosing interval within 
individual subjects are required. As it is not possible to reliably 
estimate the renal clearance for either siRNA or DMBA in 
individual patients using standard pharmacokinetic methods 
based on the limited urine and plasma sampling implemented in 
this outpatient study, renal clearance estimation for either analyte 
were not performed and cannot be reported for this study. 


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Change from Protocol  
and/or SAP V1.0 
Detailed Description/Rationale 
In SAP V2.0, the definition for 
cardiac subpopulation was added. 
This subpopulation was not 
previously defined in the protocol 
or in SAP V1.0. 
In SAP V2.0, the cardiac subpopulation was defined in Section 
4.2 as the following: the cardiac subpopulation will be comprised 
of patients with pre-existing cardiac amyloid involvement, 
defined as patients with baseline left ventricular (LV) wall 
thickness ≥ 1.3 cm and no aortic valve disease or hypertension in 
medical history. 
 


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6. 
REFERENCES 
1 Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid 
polyneuropathy consists of abundant wild-type transthyretin. Biochem Biophys Res 
Commun. 2000; 274(3): 702-706. 
2 Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5): 615-620. 
3 Reixach NS. Deechongkit, et al. Tissue damage in the amyloidoses: Transthyretin 
monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc 
Natl Acad Sci U SA. 2004;101(9): 2817-2822. 
4 Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. 
Liver Transpl. 2000;6(3): 263-276. 
5 Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
6 Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
7 Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: 
Protein Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. 
New York, Springer US. 7: 259-283. 
8 Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM. 2013, accepted for publication. 
9 Rubin, DB (2006). http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-
4269b1_05_sponsor.pdf. 
10 Rubin, DB. Multiple Imputation after 18+ Years. Journal of the American Statistical Association, 
1996; 91:473–489. 
11 Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso JP. Recommendations for the 
primary analysis of continuous endpoints in longitudinal clinical trials. Drug Inf J. 
2008;7:303–319. 
12 Collins, L.M., Schafer, J.L., and Kam, C.M. (2001). A comparison of inclusive and 
restrictive missing-data strategies in modern missing-data procedures. Psychological 
Methods, 6, 330-351. 
13 Barnes, S. A., Kallin, C., David, S. R., Mallinckrodt, C. H (2008). The impact of missing 
data and how it is handled on the rate of false positive results in drug development. 
Pharmaceutical Statistics 7:215–225. 
14 Siddiqui, O. (2011). MMRM versus MI in Dealing with Missing Data – A Comparison 
Based on 25 NDA Data Sets, Journal of Biopharmaceutical Statistics, 21: 423–436, 2011. 
15 White I.R., Carpenter J, Horton N.J. (2012). Including all individuals is not enough: lessons 
for intention-to-treat analysis, Clinical Trials. 2012 Aug; 9 (4):396-407. 


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7. 
APPENDICES 
7.1. 
Detailed Statistical Methodology for Pattern Mixture Model 
In the PMM analysis, similar to the primary analysis, mNIS+7 assessments performed after the 
initiation of alternative treatment for FAP will be treated as missing. For non-monotone missing 
data, the 9-month assessment will be imputed as the treatment group mean. The non-monotone 
missing data is expected to be rare. 
As an initial step, an intermediate mNIS+7 dataset for all mITT patients will be prepared which 
will include the key variables listed in the table below. 
Key Variables 
Description 
Patient number 
Unique subject ID for each patient in mITT population 
Treatment arm 
Placebo or patisiran 
Baseline variables 
Including gender, genotype, age at ATTR onset, previous tetramer stabilizer 
use, region, KPS, FAP stage (I vs. II/III), and cardiac subpopulation. 
Baseline mNIS+7 score 
 
mNIS+7 total score change from 
baseline at Month 9 
Set as missing if a patient does not have 9-month data; 
If a patient has 18-month mNIS+7 but is missing 9-month (non-monotone 
missingness), the 9-month value will imputed as the treatment group mean. 
On-treatment flag for Month 9 
If 9-month assessment is non-missing:  
If assessment date – last dose date ≤ 60 days, then flag = “yes” 
otherwise flag = “no” 
If 9-month assessment is missing: 
If Day 254 (scheduled 9-month visit) – last dose date ≤ 60, then flag 
= “yes” otherwise flag = “no” 
mNIS+7 total score change from 
baseline at Month 18 
Set as missing if a patient does not have 18-month data 
On-treatment flag for Month 18 
If 18-month assessment is non-missing:  
If assessment date – last dose date ≤ 60 days, then flag = “yes” 
otherwise flag = “no” 
If 18-month assessment is missing: 
If Day 554 (scheduled 18-month visit) – last dose date ≤ 60, then 
flag = “yes” otherwise flag = “no” 
Death flag  
Flag = “yes” if a patient has missing 18-month mNIS+7 and death day ≤ 561; 
otherwise flag = “no” 
Step 1: For patients who have missing data and are alive before Month 18: imputation of 
missing data for the placebo arm and for the patisiran arm during the on-treatment period. 
In the first step, missing data for the placebo arm and missing data for the patisiran arm during 
the on-treatment period will be imputed under the MAR assumption. Multiple imputation will 
be conducted among patisran and placebo patients separately using a regression procedure, 
including the following covariates: baseline mNIS+7 score, genotype, age at ATTR onset, prior 
tetramer stabilizer use, region, KPS, FAP stage (I vs. II/III), cardiac subpopulation and gender. 
The input dataset DATAIN will include a subset of the above dataset with Death Flag = “no.” 
For patisiran patients, the mNIS+7 data collected after treatment discontinuation will be 
excluded (set as missing). If Treatment Arm = “patisiran”: 


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i) 
If On-Treatment Flag for Month 9 = “no” then mNIS+7 change at Month 9 will be 
set as missing. 
ii) 
If On-Treatment Flag for Month 18 = “no” then mNIS+7 change at Month 18 will be 
set as missing. 
Below is a sample SAS code: 
proc mi data=DATAIN out=DATA_STEP1 seed=234 nimpute=100; 
 
by treatment; 
 
monotone method=reg; 
var baseline_variables   mNIS_BASE   mNIS_chg_m9 mNIS_chg_m18; 
run; 
For patisiran arm, the imputed scores during the on-treatment period will be kept while the 
imputed scores after treatment discontinuation will be discarded and replaced by either observed 
non-missing values or imputed values described in the next step. In the output dataset 
DATA_STEP1, if Treatment Arm = “patisiran”: 
i) 
If On-Treatment Flag for Month 9 = “no” then mNIS+7 change at Month 9 will be 
replaced by the value in DATAIN. 
ii) 
If On-Treatment Flag for Month 18 = “no” then mNIS+7 change at Month 18 will be 
replaced by the value in DATAIN. 
Denote this updated dataset as DATA_STEP1_2. 
Step 2: For patients who have missing data and are alive before Month 18: imputation of 
missing data for the patisiran arm after treatment discontinuation. 
In the second step, missing data for the patisiran arm after treatment discontinuation will be 
imputed using the PMM approach by creating control-based pattern imputation. 
Below is a sample SAS code: 
proc mi data=DATA_STEP1_2 out=DATA_STEP2 nimpute=1 seed=xxx; 
 
by _imputation_; 
class treatment; 
monotone method=reg; 
mnar model (mNIS_chg_m9 mNIS_chg_m18/modelobs=(treatment=’placebo’)); 
var baseline_variables   mNIS_BASE  mNIS_chg_m9  mNIS_chg_m18; 
run; 
Step 3: Imputation of missing data for patients who died before Month 18, regardless of 
treatment arm. 
For patients with Death Flag = “yes,” missing 18-month mNIS+7 change from baseline scores 
will be imputed 100 times, using a random draw from the worst 10% 18-month mNIS+7 change 
scores among all non-missing values in the dataset DATAIN. Concatenate these records with 
DATA_STEP2, and sort by dataset number and patient number.  
After step 3, each of the complete dataset will be analyzed by an ANCOVA model. The 
resulting estimates (LS means and standard errors) will be combined using SAS PROC 
MIANALYZE. 


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7.2. 
Questionnaire/Scoring 
In questionnaires, if multiple responses are provided to a single-response question, the question 
is deemed as missing. 
7.2.1. 
Modified Neuropathy Impairment Score (mNIS+7) and Original Neuropathy 
Impairment Score + 7 Nerve Tests (NIS+7) 
Note: the mNIS+7 and NIS+7 measurements are conducted in duplicate per time point. The 
average of 2 complete duplicate values will be reported, except in cases of missing or partially 
missing data as described in the table below. 
Assessment Tool 
Total 
Points 
Components (maximum points) 
Modified NIS+7 
304 
• 
NIS-W: Weakness (192) 
• 
NIS-R: Reflexes (20) 
• 
Quantitative sensory testing by body surface area including touch 
pressure (TP) and heat as pain (HP): QST-BSATP+HP5 (80) 
• 
∑5 nerve conduction studies (10) 
• 
Ulnar compound muscle action potential (ulnar CMAP) 
• 
Ulnar sensory nerve action potential (ulnar SNAP) 
• 
Sural sensory nerve action potential (sural SNAP) 
• 
Tibial compound muscle action potential (tibial CMAP) 
• 
Peroneal compound muscle action potential (peroneal CMAP) 
• 
Postural blood pressure (BP) (2) 
NIS+7 
270 
• 
NIS-W: Weakness (192) 
• 
NIS-R: Reflexes (20) 
• 
NIS-S: Sensation (32) 
• 
∑7 Nerve tests 
• 
5 Nerve conduction studies ∑5 (18.6) 
• 
Peroneal compound muscle action potential (peroneal 
CMAP) 
• 
Peroneal motor nerve conduction velocity (peroneal MNCV) 
• 
Peroneal motor nerve distal latency (peroneal MNDL) 
• 
Tibial motor DL 
• 
Sural sensory nerve action potential (sural SNAP) 
• 
Vibration detection threshold (VDT) (3.72) 
• 
Heart rate response to deep breathing (HRdb) (3.72) 
 
7.2.1.1. 
Modified Neuropathy Impairment Score (mNIS+7) 
There are 5 components within mNIS+7 total score including NIS-W, NIS-R, QST, ∑5 NC, and 
postural BP, as described in details below. 
1. 
 
 
 


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• 
 
 
 
 
7.2.1.2. 
Original Neuropathy Impairment Score (NIS+7) 
The components of NIS+7 include the following: 
1. NIS-W as described in previous section. 
2. NIS-R as described in previous section. 
3. NIS-S is the sum of the finger and toe sensation components (touch pressure, pin-prick, 
vibration, joint position). Assessments are performed separately for the right- and left-hand 
side of the body. Scoring for the sensory assessment is 0 (normal), 1 (decreased) and 2 
(absent). The maximum total score for NIS-S is 32. 
4. ∑7 nerve tests normal deviates includes the following: 
• ∑5 nerve conductions: 
o For peroneal DL and tibial DL, using normal deviate 
o For peroneal CMAP, peroneal CV and sural SNAP, using (-1) × normal deviate 
• Vibration detection threshold (VDT): using normal deviate 
• Heart rate response to deep breathing (HRdb): using (-1) × normal deviate 
Each normal deviate ranges from -3.72 to +3.72. The total score is calculated as the mean 
normal deviates of the non-missing 7 nerve tests and multiply this value by 7. The total 
score ranges from -26 to +26. 
Missing values will be handled as follows: 
• Missing items within the 7 nerve tests are handled in step 5 above. 
• If a component of NIS+7 (NIS-W, NIS-R, NIS-S, and 7 nerve tests) is missing from 
replicate A, then impute the component from replicate B  recover 2 complete replicate 
NIS+7 measures A and B. 
• If both replicates A and B are incomplete at different components, insert A components 
into B and B components into A as necessary  recover 2 complete replicate NIS+7 
measures A and B. 
• If NIS-W component is missing from both replicates A & B, NIS+7 score is considered 
as missing. If 1 of the other NIS+7 components (NIS-R, NIS-S, and 7 nerve tests) is 
missing from both replicates A and B, impute this component as the average of the other 
patients at this time point who had non-missing data (within study arm). 
• If 1 entire NIS+7 replicate is missing, use the singular (other) replicate rather than the 
average of the 2 in subsequent calculations. 
• If no single complete NIS+7 measure can be found or recovered, NIS+7 score is 
considered as missing. 
7.2.1.3. 
NIS Total Score 
NIS total score is the sum of NIS-W, NIS-R, and NIS-S. The handling of missing data is similar 
as the steps described for mNIS+7. If NIS-W is missing from both replicates, NIS score is 
considered as missing. 


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7.2.1.4. 
Large Fiber Nerve Function 
The large fiber nerve function is the sum of the point scores of the following: 
• 
 
 
 
 
 
 
 
The maximum possible large fiber nerve function score is 52. 
The handling of missing data is similar as the steps described for mNIS+7. If QST-BSATP is 
missing from both replicates, the large fiber nerve function score is considered as missing. 
7.2.1.5. 
Small Fiber Nerve Function 
The small fiber nerve function score is the sum of the point score of the following: 
 
 
 
 
 
 
 
. The maximum possible small fiber nerve function score is 44. 
The handling of missing data is similar as the steps described for mNIS+7. If QST-BSAHP5 is 
missing from both replicates, the small fiber nerve function score is considered as missing. 
7.2.1.6. 
Algorithms for Setting Normal Deviates and Points 
For nerve conductions and HRdb tests, raw values are provided by the Mayo Clinic. Each raw 
value is first converted to a z-score which is then used to set either normal deviate or point 
score. 
 
 
 


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For a given parameter, the calculated z-score is then compared to 2 lookup tables (see below) 
using the following procedure to assign the normal deviate score: 
1. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6. 
 
 
 
 
 
 
 
 
 
 
The points for the parameters are calculated as follows: 
1. 
 
 
 
 
 
 
 
 
 


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Extended Percentiles Table 
Variable 
WLOWER 
WUPPER 
ZLOWER 
ZUPPER 
HRdb 
 
 
 
 
UMAE 
 
 
 
 
PMAK 
 
 
 
 
PMCVK 
 
 
 
 
PMLA 
 
 
 
 
TMAK 
 
 
 
 
TMLA 
 
 
 
 
USAW 
 
 
 
 
SSAB 
 
 
 
 
 
7.2.2. 
Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) 
QOL-DN is a tool for assessing patients’ perception of the effects of diabetes and diabetic 
neuropathy. There are 35 questions divided into 5 domains. The range of possible total scores 
is -4 to 136. 
Part I: Symptoms 
 
 


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Part II: Activities of Daily Life 
 
 
 
 
 
Subscales and Scoring Algorithm 
The Total QOL and 5 domains should be summed as follows:  
• 
Total QOL 
  
 
 
 
 
• 
Physical Functioning/Large Fiber 
 
 
• 
Activities of Daily Living (ADLs) 
 
 
• 
Symptoms 
 
 
 
 
 
 
• 
Small Fiber 
  
 
 
 
• 
Autonomic 
 
 
 
 
 
The total score and domain scores are calculated without weighting of any kind, and reported as 
the integer sum of the listed questionnaire items. 
Domain scores are calculated as the rounded integer value of the average scores of non-missing 
included items multiplied by the number of items if at least 50% of the items are non-missing. A 
domain score is missing if more than 50% of the included items are missing. 
If the scores for all 5 domains are non-missing, then Total QOL is the sum of scores of the 
5 domains; however, if at least 1 of the domains is missing and at least 50% of the items 
(18 items) are non-missing, then Total QOL is calculated as 35 times the mean of the non-
missing items, rounded to the nearest integer. Otherwise, Total QOL is deemed as missing. 
7.2.3. 
EuroQOL-5-Dimension 5-Level (EQ-5D-5L) 
Each of the 5 dimensions (Mobility, Self-Care, Usual Activities, Pain/Discomfort, 
Anxiety/Depression) is scored on a 5-point Likert scale from 1 (“I have no 
problems/pain/anxiety”) to 5 (“I am unable to…,” “I have extreme anxiety/depression”). 
The 5 scores are concatenated together (in the order of Mobility, Self-Care, Usual Activities, 
Pain/Discomfort, Anxiety/Depression) to create an EQ-5D-5L profile (e.g., 11111, 55555). The 
profile is then used to obtain an index value using the United States value set. The index values 
range from –0.109, associated with a profile of 55555, to 1.0, associated with a profile of 11111. 
Smaller index values indicate greater impairment. 
Missing values are handled as follows: 
• Missing items are coded as “9” in creating patient profiles. 
• The index value is deemed as missing when responses are missing for 1 or more of the 
5 dimensions. 
• 
If the entire instrument is missing, the EQ-5D-5L index value is considered as missing. 


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7.2.4. 
Rasch-Built Overall Disability Scale (R-ODS) 
The R-ODS consists of 24 items scored on a scale of 0 (unable to perform), 1 (able to perform, 
but with difficulty) or 2 (able to perform without difficulty). A total score will be calculated as 
the average of all non-missing items multiplied by 24 if at least 90% of the items are non-
missing. The total score will be deemed as missing if more than 10% of the items (3 or more 
items) are missing. 
7.2.5. 
Composite Autonomic Symptom Score (COMPASS-31) 
The COMPASS-31 questionnaire comprises 6 domains: Orthostatic intolerance, Vasomotor, 
Secretomotor, Gastrointestinal, Bladder, and Pupillomotor. Within each domain, individual 
questions are scored as follows: Simple yes or no questions are scored as 0 points for no and 
1 point for yes. Questions about a specific site of symptoms or symptoms under specific 
circumstances are scored as 0 if not present and as 1 if present for each site or circumstance. All 
questions regarding the frequency of symptoms are scored as 0 points for rarely or never, 
1 point for occasionally or sometimes, 2 points for frequently or “a lot of the time,” and 3 points 
for almost always or constantly. All questions regarding the severity of symptoms are scored as 
1 point for mild, 2 points for moderate, and 3 points for severe. Questions assessing the time 
course of a symptom are scored 0 points for responses such as “gotten somewhat better,” 
“gotten much better,” “completely gone,” and “I have not had any of these symptoms,” 1 point 
for “stayed about the same,” 2 points for “gotten somewhat worse,” and 3 points for “gotten 
much worse.” The scores for changes in bodily functions depend on the individual question 
asked. For example, “I get full a lot more quickly than I used to when eating a meal” is scored 
2 points and “I get full a lot less quickly than I used to” is scored 0 points, while the answer “I 
sweat much more than I used to” is given 1 point and “I sweat much less than I used to” is 
scored 2 points. 
The overall scoring proceeds as follows: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  


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The SAP version 2.0 includes more details previously not discussed in the original SAP 
version 1.0. The following major changes will be implemented in the SAP version 2.0 that are 
different from the planned analysis specified in the SAP version 1.0 and/or the protocol 
version 6.0. 
This SAP Version 2.1 incorporates an additional change to censor data post 
alternative treatment for the analysis of NIS-W, which is documented in Section 5.6.  
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In the study protocol and the original SAP V1.0, the primary analysis method specified for the 
primary and secondary efficacy endpoints was the MI/ANCOVA. The original SAP V1.0 was 
submitted for FDA review (IND Serial # 0019). Following FDA’s comment received on 
02July2015 and the sponsor’s responses on 31August2015, the primary analysis method for all 
efficacy endpoints will be changed to MMRM method. The history and rationales for the change 
of primary analysis method are described below. The change is aligned with the CHMP 
guideline on missing data in confirmatory clinical trials (EMA/CPMP/EWP/1776/99 Rev.1). 
Mixed-effects model repeated measures and MI are 2 common methods for handling missing 
data in analysis of continuous, longitudinal endpoints. For this study, ANCOVA/MI was 
originally selected as the primary analysis, with MMRM as a key sensitivity analysis. 
In the literature, MMRM and MI have been compared in several simulation studies. 
Collins et al. (2001) noted that the 2 methods yielded similar inference. However, 
Barnes et al. (2008) found a larger average standard error for MI relative to MMRM, suggesting 
that MI controls type I error conservatively and loses power to detect true treatment differences. 
Siddiqui (2011) compared MI/ ANCOVA and MMRM approaches using both simulated 
datasets and 25 New Drug Application (NDA) datasets of neuropsychiatric drug products, and 
concluded that MMRM appears to be a better choice in maintaining statistical properties relative 
to the MI approach when dealing with ignorable missing data. 
For the ALN-TTR02-004 trial setting, we compared the properties of these 2 methods via 
simulation. Our results demonstrated that, while both methods control type I error, MMRM 
appears to be more powerful in detecting true treatment effect compared with ANCOVA/MI. 
Moreover, White et al. (2012) argued that excessive focus on including all randomized patients 
with missing outcomes can lead to a choice of analysis that rests on implausible or unnecessarily 
complex imputation. The authors proposed that the main focus in choosing the primary analysis 
should be the plausibility of its assumptions, while inclusion of all randomized individuals is a 
requirement only for sensitivity analyses. The MI approach, which includes all randomized 
patients, is often designated as a sensitivity analysis. 
Given these findings – and consideration of the complexity inherent when using the multistep 
MI approach, the primary analysis method will be changed to MMRM for the primary and 
secondary efficacy endpoints. MI/ANCOVA will be performed as the key sensitivity analysis 
for the primary endpoint and for the first secondary endpoint (Norfolk QOL). 
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The MI/ANCOVA method, as described in this document and in SAP V1.0, differs from that 
described in the current clinical protocol (Version 6: September 2015) in the MI method and in 
the explanatory covariates included in the (complete data) ANCOVA (discussed in Section 5.4). 


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The MI (for completely missing mNIS+7 assessments) described in the SAP differs from that in 
the clinical protocol in that 1) stepwise variable selection has been replaced with a pre-specified 
set of covariates to be included; 2) imputation is done separately by treatment arm. The rationale 
for these changes is outlined below. 
x
Stepwise variable selection was removed in order to simplify the analysis. 
x
The SAP specifies that imputation is done separately by study arm; the current protocol 
specifies says that treatment assignment will not be included in the imputation. This 
change is motivated by simulations demonstrating a non-negligible loss in power when a 
single imputation model is employed and treatment is not included in the model; this 
loss in power is due to “cross-contamination” of imputation models between randomized 
arms [9]. 
In the protocol, the number of imputed datasets was specified as 100. In SAP V1.0, the number 
of imputed datasets was reduced to 10 following the conclusion that 3-5 imputations are often 
sufficient [10], however, in this SAP V2.0, the number of imputed datasets is increased to 100 
to have more precise estimates. 
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In the protocol and SAP version 1.0, it was specified that secondary endpoints would be tested 
in the following order for the control of overall type I error: Norfolk QOL, NIS-W score, 
mBMI, 10-meter walk test, and COMPASS-31. 
In this SAP amendment, R-ODS has been added as a secondary endpoint for controlled 
hypothesis testing, and 10-meter walk test has been moved up in the hierarchy. The revised list 
and order of secondary endpoints is the following: Norfolk QOL, NIS-W, R-ODS, 10-meter 
walk test, mBMI and COMPASS-31. 
These changes were based on the Sponsor’s re-assessment of the clinical importance of these 
endpoints in hATTR amyloidosis patients. 
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The table below summarizes the history of changes in baseline covariates used in the statistical 
models. 


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Baseline mNIS+7 
X 
X 
X 
Genotype (V30M vs. Non-V30M) 
X 
 
X 
Genotype class (early onset V30M 
vs. Other) 
 
X 
 
Age at hATTR symptom onset 
(< 50 vs. ≥ 50) 
 
 
X 
Previous tetramer stabilizer use 
(Yes vs. No) 
X 
X 
X 
Region (Western EU, North 
America, Rest of World) 
 
 
X 
Age at study entry as continuous 
variable 
X 
 
 
Genotype class (early onset V30M vs. other) is one of the stratification factors at randomization. 
The early onset V30M subgroup includes patients who have the V30M genotype and were 
younger than 50 years old at hATTR amyloidosis symptom onset. At the time of this SAP 
amendment, the enrollment was complete and there were only 23 early onset V30M patients. 
Given the small sample size, the composite covariate “genotype class” is decomposed into 
2 separate covariates “genotype” and “age at hATTR amyloidosis symptom onset.” 
Region is added as a covariate because different rates of attrition and disease worsening were 
observed for different regions during blinded data monitoring. In addition, adding region may 
potentially address the influence of different non-V30M types observed across regions. 
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In SAP V1.0, binary analysis of mNIS+7 included an analysis of patients with < 2-point 
increase in mNIS+7 change from baseline at Month 18. The 2-point threshold was originally 
used in the tafamidis Phase 3 trial in hATTR amyloidosis patients with polyneuropathy to define 
responders for the NIS-LL co-primary endpoint. That trial enrolled patients with very early 
stage neuropathy and mean baseline NIS-LL of approximately 8-11 points, in whom a 2-point 
worsening of NIS-LL was considered to be clinically meaningful. However, the patients 
enrolled onto this study have more advanced disease, with a mean baseline NIS of 
approximately 60 points, and the mNIS+7 primary endpoint is very different from NIS-LL, with 
a maximum score of 304 points compared to 88 points for NIS-LL. Therefore, a 2-point 
threshold was not deemed relevant for mNIS+7 change in this patient population. 
In this SAP V2.0, 2 thresholds, < 10-point increase and any decrease (< 0-point change from 
baseline) will be employed to conduct the binary analysis of mNIS+7. These thresholds of 
< 10-point and < 0-point were chosen based on the 18-month estimated mNIS+7 progression 
rate observed in a natural history study of hATTR amyloidosis patients and the observed effect 
of patisiran on mNIS+7 at 18 months in the Phase 2 OLE study, respectively. 
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In this SAP V2.0, for the primary analysis of mNIS+7 and Norfolk QoL, the data post 
alternative FAP treatment will be censored. This censoring rule was not previously specified in 
the protocol or SAP V1.0. The rationale of adding this censoring rule is to eliminate the 
potential confounding effect caused by alternative FAP treatment. Sensitivity analyses for 
mNIS+7 and Norfolk QoL will be conducted including data post alternative FAP treatment. 


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In SAP V2.1, an update was made to apply the censoring rule to NIS-W as well so that the 
results will be consistent with the component analysis of mNIS+7.  
For all other efficacy endpoints, the data will not be censored since no sensitivity analyses are 
planned. 
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Additional changes are listed in the table below. 
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In the protocol and original SAP 
V1.0, the first day of drug 
administration was designated as 
Day 0. In this SAP amendment and 
the TLF outputs, the first dose day 
will be defined as Day 1. 
The change is made to follow CDISC convention. Each 
calculated study day after dosing is 1 day plus the reported study 
day following the protocol defined Schedule of Assessments. 
In the protocol and original SAP 
V1.0, it was intended that an 
interim analysis for sample size re-
estimation would be conducted; 
however, no interim analysis was 
conducted during the study. 
In 2013, Berk et al. published results of a randomized placebo-
controlled trial of diflunisal in FAP. This trial demonstrated that 
efficacy using a composite neurologic impairment score primary 
endpoint (NIS+7) could be established in a similar population 
with a similar study design and smaller study size (N=130). The 
sponsor believed that an interim analysis for sample size 
reassessment was therefore no longer necessary. 
In SAP V2.0, dermal amyloid 
content is added as an exploratory 
endpoint. 
In addition to IENFD and SGNFD, skin punch biopsies will also 
be assessed for dermal amyloid content, which has been added as 
an efficacy parameter in this SAP V2.0. 
In SAP V2.0, the walk speed for 
patients unable to perform the walk 
will be imputed as 0. 
The imputation algorithm is added to address the informative 
missing data for patients unable to perform the walk due to 
worsening of disease. 
Renal clearance for siRNA and 4-
dimethylaminobutyric acid 
(DMBA) will not be analyzed. 
As per protocol, renal clearance for siRNA and 4-
dimethylaminobutyric acid (DMBA) were to be determined 
whenever possible. Only sparse pre-dose urine collections (and 
volumes) were obtained in patients enrolled in this study on 
select days that patients returned to the clinic for dosing (Days 0, 
21, 126, 252, 399, 546 and at time of early withdrawal). In order 
to estimate renal clearance, detailed serial urine and 
corresponding plasma collections that describe a time course of 
exposures in both matrices over a dosing interval within 
individual subjects are required. As it is not possible to reliably 
estimate the renal clearance for either siRNA or DMBA in 
individual patients using standard pharmacokinetic methods 
based on the limited urine and plasma sampling implemented in 
this outpatient study, renal clearance estimation for either analyte 
were not performed and cannot be reported for this study. 


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In SAP V2.0, the definition for 
cardiac subpopulation was added. 
This subpopulation was not 
previously defined in the protocol 
or in SAP V1.0. 
In SAP V2.0, the cardiac subpopulation was defined in Section 
4.2 as the following: the cardiac subpopulation will be comprised 
of patients with pre-existing cardiac amyloid involvement, 
defined as patients with baseline left ventricular (LV) wall 
thickness ≥ 1.3 cm and no aortic valve disease or hypertension in 
medical history.