Conditions: Transthyretin (TTR) Mediated Familial Amyloidotic Cardiomyopathy (FAC) Amyloidosis, Hereditary Amyloid Neuropathies, Familial Amyloid Neuropathies Amyloidosis, Hereditary, Transthyretin-Related Familial Transthyretin Cardiac Amyloidosis
Keywords: Cardiomyopathy Heart Failure FAC Amyloid Transthyretin TTR RNAi therapeutic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 206
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the safety and efficacy of revusiran (ALN-TTRSC) in patients with transthyretin (TTR) mediated Familial Amyloidotic Cardiomyopathy. Dosing has been discontinued; patients are being followed-up for safety.

Detailed description:

Arms:
arm 1: administered by subcutaneous (SC) injection arm 2: administered by subcutaneous (SC) injection

Interventions: intervention 1: Revusiran (ALN-TTRSC) intervention 2: Sterile Normal Saline (0.9% NaCl)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
ALN-TTRSC-004 
ALN-TTRSC 
ALN-TTRSC-004 
19 February 2016 
A Phase 3 Multicenter, Multinational, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
ALN-TTRSC in Patients with Transthyretin (TTR) Mediated Familial 
Amyloidotic Cardiomyopathy (FAC) 
Original Protocol: 
Amendment 0.1 (Sweden): 
Amendment 0.2 (Germany): 
Amendment 0.3 (Belgium): 
Amendment 1: 
EudraCT Number 
IND Number: 
Sponsor: 
Sponsor Contact: 
Sponsor 
Signature: 
Name 
(print): 
03 October 2014 
05 January 2015 
11February2015 
05 March 2015 
19 February 2016 
2014-003835-20 
119040 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
 
Senior Vice President, Clinical Development 
Date: 
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 express 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. 
Version 2.0 
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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 
 
Date  
Name (print)  
 
 
 
 
 
 
 


 
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STUDY SYNOPSIS 
Protocol Title 
A Phase 3 Multicenter, Multinational, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety of ALN-TTRSC 
in Patients With Transthyretin (TTR) Mediated Familial Amyloidotic 
Cardiomyopathy (FAC) 
Indication 
Treatment of patients with TTR mediated FAC 
Protocol Number 
ALN-TTRSC-004 
Phase of Development 
3 
Design 
This is a multicenter, multinational, randomized, double-blind study comparing 
the efficacy and safety of ALN-TTRSC (International Nonproprietary Name:   
revusiran) to placebo in patients with TTR mediated FAC. 
Consented eligible patients will be randomized to receive either 500 mg 
ALN-TTRSC or placebo in a 2:1 ratio (ALN-TTRSC:placebo) in a blinded 
manner.  Treatment groups will be balanced at entry for New York Heart 
Association (NYHA) classification (I and II vs III), TTR mutation (V122I 
versus other FAC mutations), and Screening/Baseline 6-minute walk distance 
(6-MWD [≤325 meters vs >325 meters]).  Patients will receive ALN-TTRSC or 
placebo for 5 daily doses during the first week and then once every week for 
approximately 18 months.  Patients will return to clinic for a follow-up visit 
approximately 4 weeks after their last dose of study drug. 
Patients will undergo efficacy and safety assessments at Screening/Baseline, 
each month for first 3 months and then at 3-6 month intervals.  In addition, 
pharmacokinetics (PK) of ALN-TTRSC and its effect on quality of life and 
pharmacoeconomics will be characterized at selected time points. 
Eligible patients who complete study dosing and the 18 month efficacy 
assessments may be eligible to participate in a ALN-TTRSC open-label 
extension study. 
An independent Data Monitoring Committee (DMC) will be implemented for 
the study and will operate under a prespecified charter. 
An independent Clinical Adjudication Committee (CAC) will adjudicate the 
secondary endpoints of mortality and hospitalization. 
Study Sites 
This study is to be conducted at approximately 60 study sites worldwide. 
Investigational Drug 
ALN-TTRSC is comprised of a small interfering ribonucleic acid (siRNA) 
targeting mutant and wild-type (WT) TTR messenger RNA (mRNA) with a 
covalently attached N-acetylgalactosamine (GalNAc) ligand formulated in 
water for injection. 
Dosage, Route of 
Administration and 
Duration of Treatment 
of Investigational Drug 
Patients randomized to ALN-TTRSC will receive 5 daily subcutaneous (SC) 
injections of 500 mg of ALN-TTRSC (Day 0 through Day 4).  The same dose 
will be administered at Day 7 and then once weekly through 18 months. 
Control Drug 
Placebo (normal saline 0.9% for SC administration).  Placebo will be packaged 
and administered identically to ALN-TTRSC. 
Dosage, Route of 
Administration and 
Patients randomized to placebo will receive SC normal saline (0.9%) using the 


 
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Duration of Treatment 
of Control Drug 
same dosing schedule as the active treatment group. 
Time on Study 
The duration of patient participation in this study is approximately 20 months 
(inclusive of up to a 45 day Screening/Baseline window and up to 35 days of 
follow-up after the last dose). 
Primary Objective 
The primary objective of the study is to determine the efficacy of ALN-TTRSC 
in patients with FAC. 
This will be assessed as the difference between treatment and placebo groups at 
18 months using a co-primary endpoint of: (1) change in meters in 6-MWD 
compared to baseline distance; and (2) percent reduction in serum TTR levels 
compared to baseline levels. 
Sample Size 
Approximately 200 patients will be randomized in this study.  For the 6-MWD 
primary endpoint, a sample size of 180 with a 2:1 treatment allocation (N=120 
on ALN-TTRSC and N=60 on placebo) has 90% power to detect a treatment 
difference of 0.55 standard deviations using a Finkelstein and Schoenfeld 
analysis with a significance level of 0.05.  This assumes 20% of placebo 
patients and 13% of ALN-TTRSC patients die before the 18 month assessment 
(ie, hazard ratio [HR] = 0.6).  Assuming a standard deviation of 70 meters in 
change from baseline, this would correspond to 90% power to detect a treatment 
effect of 39 meters in the 6-MWT. Assuming a 10% patient dropout rate, 
approximately 200 patients will be enrolled in the study.  Note that power for 
the comparison of percent reduction in serum TTR between treatment groups is 
expected to be >90% for a significance level of 0.05.  For this reason, overall 
power to establish efficacy is expected to be approximately 90% under the 
assumptions described above. 
Inclusion Criteria 
1. Are male or female of 18 to 90 years of age (inclusive). 
2. Have a documented TTR mutation. 
3. Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo 
Red (or equivalent) staining or technetium scintigraphy (
99mTc -3,3-
diphosphono-1,2-propanodicarboxylic acid [DPD-Tc] or 99mTc-
pyrophosphate [PYP-Tc]) with Grade 2 or 3 cardiac uptake, centrally 
confirmed.  
4. If patient has monoclonal gammopathy, TTR amyloidosis needs to be 
confirmed through TTR protein identification by 
immunohistochemistry or mass spectrometry. 
5. Have a medical history of heart failure (HF) with at least 1 prior 
hospitalization for HF, which may include hospitalization for 
arrhythmia or pacemaker placement, OR clinical evidence of HF (as 
evidenced by one or more of the following:  elevated jugular venous 
pressure, peripheral edema, shortness of breath or signs of pulmonary 
congestion on x-ray or auscultation) that either requires/required 
treatment with diuretics or is/was associated with an N-terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) >400 ng/L or 
B-type natriuretic peptide (BNP) >100 ng/L. 
6. Have evidence of cardiac involvement by Screening/Baseline 
echocardiogram including an end-diastolic interventricular septum 
thickness of ≥12 mm.  For patients with an end-diastolic 
interventricular septum thickness of <12 mm, an endomyocardial 
biopsy showing amyloid deposition is required. 


 
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7. Can walk ≥150 meters on a 6-minute walk test (6-MWT). 
8. Have a Karnofsky performance status of ≥50%. 
9. Symptoms of HF optimally managed with no CV hospitalizations 
within 4 weeks prior to consent or during Screening/Baseline. 
10. Have adequate liver function, demonstrated by an aspartate 
transaminase (AST) and alanine transaminase (ALT) ≤2.0× upper limit 
of normal (ULN), albumin >3 g/dL (>4.35 μmol/L), and total bilirubin 
<2.0 mg/dL (34.2 μmol/L), unless elevation in total bilirubin is due to 
Gilbert’s Syndrome. 
11. No active infection with hepatitis B (HBV) or hepatitis C (HCV) by 
serology.  
12. Women of child-bearing potential must have a negative pregnancy test, 
cannot be breastfeeding, and use 1 highly effective method of 
contraception in combination with a barrier method throughout study 
participation, and for 28 days after last dose of study drug.  
13. Males with partners of child-bearing potential, must agree to use a 
condom, accompanied with spermicidal foam, gel, film, cream, or 
suppository, except in countries where spermicide is not available for 
use in combination with condom, throughout study participation and 
for 28 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 28 days after the last dose of study drug. 
14. Must be willing and able to comply with protocol-required visit 
schedule and visit requirements and provide informed consent or have 
a legal guardian who can provide informed consent. 
Exclusion Criteria 
1. Has estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m
2 
(using the Modification of Diet in Renal Disease [MDRD] formula). 
2. Has known primary amyloidosis (AL), leptomeningeal amyloidosis, 
non-FAC hereditary cardiomyopathy, hypertensive cardiomyopathy, or 
cardiomyopathy due to valvular heart disease. 
3. Has non-amyloid diseases affecting exercise testing (e.g., severe 
chronic obstructive lung disease, severe arthritis, peripheral vascular 
disease affecting ambulation). 
4. Has uncontrolled hypertension. 
5. Has uncontrolled ischemic heart disease. 
6. Has uncontrolled clinically significant cardiac arrhythmia. 
7. Had acute coronary syndrome within the past 3 months. 
8. Has a Polyneuropathy Disability score >2. 
9. Has untreated hypo- or hyperthyroidism. 
10. Has a New York Heart Association (NYHA) classification of IV. 
11. Has known or suspected systemic bacterial, viral, parasitic, or fungal 
infection. 
12. Has known human immunodeficiency virus (HIV) infection. 
13. Current, heavy alcohol use, defined as regular consumption of greater 
than 2 to 3 units/day for women and 3 to 4 units/day for men (a unit of 
alcohol equals 1 glass of wine [125 mL], 1 measure of spirits, or ½ pint 
of beer), or a known history of alcohol abuse within the past 2 years. 
14. Has received an investigational agent or device within 30 days of 


 
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anticipated study drug administration or 5 half-lives of the 
investigational drug, whichever is longer. 
15. 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. 
16. Had metastatic cancer within the past 5 years. 
17. History of allergic reaction to an oligonucleotide or 
N-acetylgalactosamine (GalNAc). 
18. Has a history of intolerance to SC injection. 
19. Has other medical conditions or comorbidities which, in the opinion of 
the Investigator, would interfere with study compliance or data 
interpretation. 
20. Has had a heart or liver transplant, or is being considered for a 
transplant during the study period. 
21. Known history of clinically significant chronic liver disease in the 
opinion of the Investigator. 


 
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Efficacy Endpoints 
 
 
Primary endpoints: 
The co-primary endpoints of the study are to evaluate the difference between the 
ALN-TTRSC and placebo groups for: 
1. Change in 6-MWD at 18 months compared to baseline  
2. Percent reduction in serum TTR burden over 18 months 
Secondary endpoints: 
The secondary endpoints of the study are to determine the effect of 
ALN-TTRSC on various clinical parameters by assessing the difference 
between the ALN-TTRSC and placebo groups at18 months for: 
• Composite CV mortality and CV hospitalization   
• Change in New York Heart Association (NYHA) class (Appendix 
1) compared to baseline 
• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) 
compared to baseline 
• Cardiovascular (CV) mortality 
• CV hospitalization 
• All-cause mortality 
Exploratory endpoints: 
The exploratory endpoints of the study are to determine the difference between 
the ALN-TTRSC and placebo groups in the change from baseline at 18 months 
in the following measurements: 
• EuroQOL (EQ-5D) questionnaire 
• Echocardiogram parameters 
• Karnofsky performance status (Appendix 2) 
• Troponin T and I, and N-terminal prohormone of B-type natriuretic 
peptide (NT proBNP) levels 
• Cardiac magnetic resonance imaging (CMR) parameters (only at 
selected sites) 
• 99mTechnetium scintigraphy parameters (only at selected sites) 
• Amyloid in abdominal wall fat pad aspirates  
• Polyneuropathy Disability (PND) Score (Appendix 3) 
• Modified body mass index (mBMI) 
• Estimated glomerular filtration rate (eGFR) 
•  HF hospitalization 
Safety Assessments 
The safety of ALN-TTRSC will be evaluated by: 
• Assessment of adverse events (AEs), including serious adverse events 
(SAEs) 


 
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• Clinical laboratory safety tests (hematology, serum chemistry 
including liver function tests (LFTs), thyroid function, coagulation, 
vitamin A and urinalysis) 
• Measurement of anti-drug antibodies 
• Vital sign measurements (blood pressure, pulse rate, oral body 
temperature, and respiratory rate) 
• 12-Lead electrocardiogram (ECG) 
• Physical examinations 
• Ophthalmology examinations 
Pharmacokinetic 
Assessments 
Samples will be taken for the assessment of plasma levels of ALN-TTRSC. 
Exploratory analyses may also be conducted on plasma samples to evaluate 
metabolites of ALN-TTRSC. 
Other Assessments 
Disease burden and healthcare utilization will be assessed using a patient 
reported pharmacoeconomics questionnaire 
Statistical Methods 
The following patient populations (ie, analysis sets) will be evaluated and used 
for presentation of the data: 
• Modified intent to treat (mITT) population:  all patients who were 
randomized and received at least 1 dose of ALN-TTRSC or placebo. 
• Per protocol (PP) population:  all patients who did not have any major 
protocol violations; and completed the 18-month 6-MWD assessment 
or died on-study. 
• Safety population:  All patients who received at least 1 dose of ALN-
TTRSC or placebo (analyzed as treated, not as randomized). 
The primary population for efficacy analyses will be the mITT population; key 
efficacy results will also be analyzed 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. 
There are two co-primary endpoints.  The first co-primary endpoint is change 
from baseline (in meters) for 6-MWD conducted 18 months after 
randomization.  The primary efficacy analysis for the comparison of 6-MWD 
between treatment groups will be conducted using Wilcoxon Mann Whitney-
based test statistics that will take into account informative missingness due to 
death and the loss of ability to perform the test (stratified Finkelstein and 
Schoenfeld Joint Rank Test 1999).  Briefly, in this stratified non-parametric 
rank sum analysis, all pairs of patients within a stratum are compared.  A pair of 
patients is compared first on time to death (if death occurs before 18 months); 
second on time until the inability to perform the test (if it cannot be determined 
as to which patient in a pair lived longer); and third on the change from baseline 
in 6-MWD at the time of the last assessment shared by both patients (if it cannot 
be determined as to which patient in a pair lived longer and which retained the 
ability to perform the 6-MWD longer).  The analysis will be stratified based on 
the stratification parameters that are used for randomization. 


 
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The second co-primary endpoint is percent reduction from baseline in serum 
TTR using enzyme-linked immunosorbent assay.  The area under the effect 
curve (eAUC) for percent reduction from baseline in serum TTR over time, 
where the y-axis is percent reduction and the x-axis is time since randomization, 
will be compared across groups using Analysis of Covariance (ANCOVA), in 
which the stratification variables and baseline serum TTR level will be included 
in the model as covariates.  The eAUC will be computed using the trapezoidal 
method, where assessments missing due to death or discontinuation will be 
imputed using the baseline level, i.e., the percent reduction will be assumed to 
be 0%.  
The study will have demonstrated efficacy if the p-value for each co-primary 
endpoints is ≤0.05 (2-sided). 
Sensitivity analyses for each of the co-primary endpoints, including different 
methods for handling of the missing data, will assess the robustness of the 
primary analysis for the mITT population. 
Secondary endpoints will be tested hierarchically in the order presented above 
in Efficacy Endpoints.  The secondary composite of CV mortality and CV 
hospitalization, as well as change in NYHA class and change in KCCQ will all 
be compared across treatment groups using stratified Finkelstein and Schoenfeld 
Joint Rank Tests.  CV mortality and all-cause mortality will be compared across 
treatment groups using stratified log-rank tests.  CV hospitalizations will be 
compared using stratified Anderson-Gill model for recurrent events.  Analyses 
will be stratified using the stratification parameters that are used for 
randomization. 
Plasma pharmacokinetics (PK) will be summarized and descriptive statistics 
conducted for each time point. 
Inferential statistics of efficacy and PK/pharmacodynamic (PD) relationships 
will be conducted where possible. 
Adverse events will be summarized by Medical Dictionary for Regulatory 
Activities (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. 
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. 
An unblinded interim analysis for futility may be conducted once approximately 
half the patients have completed the study.  Further details will be included in 
the Statistical Analysis Plan (SAP). 


 
 
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Table 1-1: Schedule of Assessments for Site Visits 
Procedurea 
 
 
Screeningb/ 
Baseline 
Pre-dose 
Daily Dosing 
Weekly Dosing 
End  
of Study 
Early Terminationc 
Month 
 
 
 M1  M2  
M3 
 
M6 
 
M9 
 M12  M15  M18 M19y 
Days/Weeks 
D-45 
to -1 
D0 
D0 
D1 
D2 
D3 
D4 
D7/W1 
W2 
W3 
W4 
W5-8 
W9 
W10-12 
W13 
W14-25 
W26 
W27-38 
W39 
W40-51 
W52 
W53-64 
W65 
W66-77 
W78 
W82 
Visit Window 
(Days)
d 
 
± 
1D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
7D 
Informed Consent 
X 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Administratione 
 
 X X X X X X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Inc/Exc Criteriaf 
X X       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyg 
X X       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X       
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Body Weight 
X 
X       
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Height 
X 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology 
Examb 
X 
       
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Xbb 
X 
X 
12-Lead ECGh 
X 
       
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Vital Signs
i 
X X X X X X X  
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X X 
Serum Chemistry 
(including LFTs)
a 
X 
X     X  
 
 
X 
 
X 
 
X 
Xz 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Hematology and 
Urinalysisa  
X 
X       
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Pregnancy Testa, j 
X X       
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Xbb 
X X 
Coagulation 
Studies
a,k 
X 
X       
 
 
X 
 
X 
 
X 
Xz 
X 
 
 
 
X 
 
 
 
Xbb 
X 
X 
Thyroid Stimulating 
Hormonea  
X 
       
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Xbb 
X 
X 
Serologyl 
X 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Procedurea 
 
 
Screeningb/ 
Baseline 
Pre-dose 
Daily Dosing 
Weekly Dosing 
End  
of Study 
Early Terminationc 
Month 
 
 
 M1  M2  
M3 
 
M6 
 
M9 
 M12  M15  M18 M19y 
Days/Weeks 
D-45 
to -1 
D0 
D0 
D1 
D2 
D3 
D4 
D7/W1 
W2 
W3 
W4 
W5-8 
W9 
W10-12 
W13 
W14-25 
W26 
W27-38 
W39 
W40-51 
W52 
W53-64 
W65 
W66-77 
W78 
W82 
Visit Window 
(Days)
d 
 
± 
1D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
7D 
eGFR
a,m 
X X       
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
NT-proBNP, BNP, 
Troponin T and Ia,n 
X 
X    
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TTR Proteina,o 
 X     
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vitamin Aa 
X 
       
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Anti-drug 
Antibodiesa,p 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Exploratory 
Biomarkersa,q 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Serum SPEP with 
IFE, Urine SPEP 
with IFE and Serum 
FLCaa 
X 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Voluntary DNA 
Sampleb,r 
 
X       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
Samplings 
 
X X   
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
6-MWTa,t 
X X    
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
NYHA 
Classification 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Karnofsky 
Performance Status 
X 
       
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
KCCQ 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
PND score 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
mBMI 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
EQ-5D QoL 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Pharmacoeconomics 
Questionnaire 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 


 
 
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Procedurea 
 
 
Screeningb/ 
Baseline 
Pre-dose 
Daily Dosing 
Weekly Dosing 
End  
of Study 
Early Terminationc 
Month 
 
 
 M1  M2  
M3 
 
M6 
 
M9 
 M12  M15  M18 M19y 
Days/Weeks 
D-45 
to -1 
D0 
D0 
D1 
D2 
D3 
D4 
D7/W1 
W2 
W3 
W4 
W5-8 
W9 
W10-12 
W13 
W14-25 
W26 
W27-38 
W39 
W40-51 
W52 
W53-64 
W65 
W66-77 
W78 
W82 
Visit Window 
(Days)
d 
 
± 
1D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
2D 
±2/ 
±14Dd 
± 
7D 
Echocardiography 
by Doppleru 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
CMRb,v 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
99mTc Scintigraphy 
by 3D SPECTb,w 
X 
    
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Voluntary Fat Pad 
Biopsyx 
X 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
Review/Record 
Concomitant 
Medications and 
AEs 
X 
ONGOING THROUGHOUT THE DURATION OF THE STUDY 
White boxes are site visits whereas the grey boxes are for dosing procedures that may be conducted at home. 
Abbreviations:  6-MWT = Six-minute Walk Test, 99mTc = 99mTechnetium; AE = Adverse event, CMR = cardiac MRI, D = Day, ECG = Electrocardiogram, eGFR 
= estimated glomerular filtration rate, FLC = Free light chain, KCCQ = Kansas City Cardiomyopathy Questionnaire, LFT = Liver function test, MRI = magnetic 
resonance imaging, NT-proBNP = N-terminal prohormone of B-type natriuretic peptide, NYHA = New York Heart Association, PD = Pharmacodynamic, PK = 
Pharmacokinetic, PND Score = polyneuropathy disability score, QoL = Quality of life; SPECT = single-photon emission computed tomography, SPEP with IFE = 
serum protein electrophoresis with Immunofixation Electrophoresis, TSH = thyroid stimulating hormone, TTR = Transthyretin.
 
a On dosing days, procedure to be perform prior to dosing. 
b Screening assessments are to be performed within 45 days of first dose, with the exception of LFTs and 6-MWT, which must be performed within 28 days of 
the first dose.  Screening/Baseline assessments may be performed during several site visits.  Patients are not required to repeat CMR and 
99mTc scintigraphy 
or the ophthalmology examination if assessments were performed, respectively, within 6 months and 90 days of randomization.  The voluntary DNA sample 
and the voluntary fat pad biopsy should only be obtained once during Screening.  Screening laboratory tests can be repeated once if results are expected to be 
transient and reversible.  Additional repeats require discussion with the Medical Monitor. 
c The withdrawn patient will be asked to consent to either be contacted by telephone or to allow non-patient contact follow-up (e.g., medical record check) 
18 months after enrolling onto the study to document their overall health status. 
d Dosing on Days 1, 2, 3, and 4 must be performed approximately 24±4 hours after the preceding dose of study drug.  After Day 7, doses will be administered 
weekly (±2 days).  Doses may be administered at the clinical site or at home by a health care professional trained in the protocol.  An additional window 
(±14 days) is only allowed for study assessments. 


 
 
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e SC injection of ALN-TTRSC into the abdomen on Day 0 and then on subsequent days into other quadrants of the abdomen.  The upper arm or thigh may 
also be used. 
f The results from the laboratory samples collected on Day 0 are not needed prior to dosing. 
g On Day 0 pre-dose, only interval medical history will be collected.  Changes in medical history during the dosing period will be captured as 
treatment-emergent adverse events (TEAEs) or concomitant medication(s) as appropriate. 
h For the 12-lead ECG, each lead shall be recorded for at least 3 beats at a speed of 25 mm/s.  Triplicate recordings will be obtained.  The electrophysiological 
parameters assessed will be rhythm, ventricular rate, PR interval, QRS duration, QT interval, ST and T waves, Fredericia-corrected QT interval (QTcF), and 
Bazett-corrected QT (QTcB). 
i Vital signs include blood pressure, pulse rate, oral body temperature, and respiratory rate.  Vital signs will be measured in the supine position after the 
patient has rested comfortably for 10 minutes.  Vital signs should be collected at each site visit. 
j The pregnancy test will be performed for women of child-bearing potential (WOCBP) only.  A serum pregnancy test will be performed at 
Screening/Baseline and urine pregnancy tests at all designated visits thereafter and anytime pregnancy is suspected.  Urine pregnancy test may also be 
performed more frequently (monthly) based on local country requirements.  The results of the pregnancy test at Screening/Baseline and the Day 0 pre-dose 
visit must be known prior to administration of study drug. 
k Coagulation studies include PT, aPTT, and INR. 
l Serology tests include HBsAb, HBsAg, and anti-HCV Ab. 
m eGFR will be calculated by the central lab and reported with the lab results. 
n BNP is only collected during Screening/Baseline.  NT-proBNP, Troponin T and I are collected at each timepoint. 
o All samples should be taken within 1 hour pre-dose. 
p Blood samples for anti-drug antibody testing will be collected prior to study drug dosing.  A sample will be collected at the Early Termination visit, if 
applicable. 
q Where allowed per local regulations and IRB/EC approval, serum and plasma samples for exploratory biomarker testing will be collected. 
r Where allowed per local regulations, IRB/EC approval and patient consent, DNA sample will be collected. 
s PK will be assessed within 1 hour predose and 2.5±1 hour postdose. 
t The 6-MWT will be conducted twice during the Screening/Baseline visit (practice and actual test to be performed at least 1 hour apart) and both tests must 
be completed within 28 days of Day 0.  The assessments will include pre- and post-walk assessment of O2 saturation, blood pressure, heart rate, and the Borg 
scale ratings for fatigue and dyspnea.  The higher of the 2 values at Screening/Baseline will be used for eligibility purposes.  The 6-MWT will be conducted 
only once, prior to dosing, at all subsequent time points. 
u An ECHO done at Screening/Baseline and for all subsequent time points will be evaluated by a central laboratory.  
v Cardiac MRI with late gadolinium enhancement (LGE) is only to be obtained in patients without contraindications (i.e., pacemakers, defibrillators, 
inadequate renal function or allergy to gadolinium) at selected sites on a subset of patients (up to 60).  All time points will be evaluated by a central lab. 
w 
99mTc scintigraphy by 3D SPECT during the study is an exploratory assessment and is not intended for diagnostic purposes or to fulfill eligibility criteria for 
the study.  Either 
99mTc pyrophosphate (99mTc-PYP) or 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) can be used as a tracer. The tracer 
should not be changed for the patient during the study.  This assessment will only be performed at selected sites on a subset of patients (up to 60).  All time 
points will be evaluated by a central lab. 
x This assessment is voluntary and will only be performed at selected sites.  Additional time points may not be collected depending on the status of the 
Screening/Baseline biopsy sample.  Repeat Screening/Baseline biopsy samples may be collected if the initial sample is not of sufficient quality. 
y Patients enrolling in the open-label extension study (ALN-TTRSC-006) will not need to complete the Month 19 visit.  For these patients, Month 18 
assessments will constitute the End of Study assessments. 
z Serum chemistry (including LFTs) and coagulation tests are to be performed at Week 17 and Week 21. 


 
 
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aa Serum SPEP with IFE, urine SPEP with IFE and serum FLC is to be performed at Screening/Baseline.  If available, documented local results obtained within 
1 year of Screening/Baseline may be used to fulfill this requirement. 
bb These assessment will only be performed for patients enrolling in the ALN-TTRSC-006 study. 
 
 


 
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TABLE OF CONTENTS 
STUDY SYNOPSIS 
................................
................................
........................................................3 
TABLE OF CONTENTS 
.............................................................................................................15 
LIST OF TABLES 
.......................................................................................................................20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
................................................21
 
1. 
INTRODUCTION 
................................
................................
......................................25 
1.1. 
Background and Rationale 
.........................................................................................25 
1.1.1. 
Transthyretin Biology 
...............................................................................................25 
1.1.2. 
Disease Overview 
................................
................................
.......................................25 
1.1.2.1. 
Transthyretin-mediated amyloidosis definition and familial amyloidotic 
cardiomyopathy 
................................
................................
..........................................25 
1.1.2.2. 
Pathogenesis and Outcome 
................................
.........................................................26 
1.1.2.3. 
Current Management and Unmet Medical Need 
........................................................26
 
1.1.3. 
RNA Interference 
......................................................................................................26 
1.1.4. 
Investigational Drug ALN-TTRSC Overview 
............................................................27
 
1.1.5. 
Therapeutic Hypothesis 
................................
..............................................................27 
1.2. 
Summary of ALN-TTRSC Nonclinical Data 
.............................................................28
 
1.3. 
Summary of Clinical Data with ALN-TTRSC 
...........................................................29
 
1.4. 
Study Design Rationale 
................................
..............................................................30 
1.5. 
Dose Selection and Rationale 
................................
.....................................................31 
1.6. 
Risk-Benefit Assessment 
................................
............................................................32 
1.6.1. 
Injection Site Reactions 
................................
..............................................................32 
1.6.2. 
Abnormal Liver Function Tests 
.................................................................................32 
1.6.3. 
Vitamin A Lowering 
.................................................................................................32 
2. 
STUDY OBJECTIVES ..............................................................................................34 
2.1. 
Primary Objective 
.....................................................................................................34 
3. 
INVESTIGATIONAL PLAN 
....................................................................................35 
3.1. 
Overall Study Design 
................................................................................................35 
3.2. 
Number of Patients 
................................
................................
.....................................35 
3.3. 
Efficacy Endpoints 
....................................................................................................35 
3.3.1. 
Primary endpoints: 
....................................................................................................35 


 
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3.3.2. 
Secondary endpoints: 
................................................................................................35 
3.3.3. 
Exploratory endpoints: 
..............................................................................................36 
3.4. 
Safety Assessments 
...................................................................................................36 
3.5. 
Pharmacokinetic Assessments 
................................
....................................................36 
3.6. 
Other Assessments 
....................................................................................................36 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
..............................................37
 
4.1. 
Patient Inclusion Criteria 
................................
............................................................37 
4.2. 
Patient Exclusion Criteria 
................................
...........................................................38 
4.3. 
Study Drug Discontinuation 
................................
.......................................................39 
4.4. 
Patient Withdrawal 
................................
................................
.....................................39 
5. 
TREATMENT OF PATIENTS 
................................
..................................................40 
5.1. 
Concomitant Medications 
..........................................................................................40 
5.2. 
Contraceptive Requirements 
......................................................................................40 
5.2.1. 
Requirements for Women of Child-bearing Potential 
................................................40
 
5.2.2. 
Requirements for Male Patients 
.................................................................................41 
5.3. 
Treatment Compliance 
..............................................................................................41 
5.4. 
Randomization and Blinding 
................................
......................................................42 
5.5. 
Patient Numbering 
................................
................................
......................................42 
5.6. 
Blinding 
................................
................................
......................................................42 
5.7. 
Breaking the Blind 
....................................................................................................42 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
...........................................43
 
6.1. 
Presentation of Study Drug 
........................................................................................43 
6.2. 
Study Drug Packaging and Labeling 
................................
..........................................43 
6.3. 
Study Drug Storage 
...................................................................................................43 
6.4. 
Study Drug Preparation 
................................
..............................................................43 
6.5. 
Administration 
................................
................................
............................................44 
6.6. 
Dosing Modification Criteria 
.....................................................................................44 
6.7. 
Study Drug Accountability 
................................
.........................................................45 
6.8. 
Study Drug Handling and Disposal 
................................
............................................45 
7. 
STUDY ASSESSMENTS 
................................
..........................................................46 
7.1. 
Informed Consent 
................................
................................
.......................................46 
7.2. 
Demographics and Medical History 
................................
...........................................46 


 
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7.3. 
Efficacy Assessments 
................................
................................
.................................46 
7.3.1. 
Six-Minute Walk Test 
...............................................................................................46 
7.3.2. 
Transthyretin 
.............................................................................................................46 
7.3.3. 
Modified Body Mass Index 
................................
........................................................47 
7.3.4. 
Estimated Glomerular Filtration Rate 
........................................................................47 
7.3.5. 
Fat Pad Biopsy 
..........................................................................................................47 
7.3.6. 
Karnofsky Performance Status 
................................
...................................................47 
7.3.7. 
Polyneuropathy Disability Score 
................................
................................................47 
7.3.8. 
NYHA Classification 
................................................................................................47 
7.3.9. 
Imaging 
................................
................................
.......................................................47 
7.3.9.1. 
Echocardiography 
................................
................................
.......................................47 
7.3.9.2. 
Cardiac Magnetic Resonance Imaging 
................................
.......................................48 
7.3.9.3. 
Technetium Imaging 
.................................................................................................48 
7.3.10. 
Questionnaires 
................................
................................
............................................48 
7.3.10.1. Kansas City Cardiomyopathy Questionnaire 
..............................................................48 
7.3.10.2. EQ-5D Quality of Life 
..............................................................................................48 
7.3.11. 
NT-proBNP, BNP, Troponin T, and Troponin I ........................................................48 
7.3.12. 
Mortality and Hospitalization 
................................
.....................................................49 
7.4. 
Pharmacokinetic Assessment 
.....................................................................................49 
7.5. 
Safety Assessments 
...................................................................................................49 
7.5.1. 
Physical Examination 
................................
................................
.................................49 
7.5.2. 
Vital Signs ..................................................................................................................49 
7.5.3. 
Weight and Height 
....................................................................................................49  
7.5.4. 
Electrocardiogram (ECG) 
................................
...........................................................49 
7.5.5. 
Laboratory Assessments 
................................
.............................................................50 
7.5.5.1. 
Anti-drug Antibodies 
................................
................................
..................................52 
7.5.5.2. 
Pregnancy Screen 
......................................................................................................52 
7.5.6. 
Ophthalmologic Examination 
....................................................................................52 
7.5.7. 
Concomitant Medications 
..........................................................................................52 
7.5.8. 
Adverse Events 
................................
................................
...........................................52 
7.6. 
Other Assessments 
....................................................................................................53 
7.6.1. 
Exploratory Biomarkers 
.............................................................................................53 


 
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7.6.2. 
DNA Sample 
.............................................................................................................53 
7.6.3. 
Pharmacoeconomics Questionnaire 
...........................................................................53 
8. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
...................................................54
 
8.1. 
Adverse Events Definition 
.........................................................................................54 
8.1.1. 
Adverse Events of Clinical Interest 
................................
............................................54 
8.2. 
Serious Adverse Event (SAE) Definition 
................................
...................................54 
8.3. 
Eliciting Adverse Event Information 
.........................................................................54 
8.4. 
Adverse Event Reporting 
...........................................................................................55 
8.5. 
Adverse Event Reporting Period 
................................
................................................55 
8.6. 
Assessment of Causality 
................................
.............................................................56 
8.7. 
Assessment of Severity 
..............................................................................................56 
8.8. 
Coding of Adverse Events 
................................
..........................................................57 
8.9. 
Serious Adverse Event Reporting 
..............................................................................57 
8.9.1. 
Notifying the IRB/IEC 
..............................................................................................57 
8.9.2. 
Sponsor Reporting: Notifying Regulatory Authorities 
...............................................58 
8.9.3. 
Sponsor Reporting: Notifying Participating Investigators .........................................58
 
8.10. 
Pregnancy Reporting ..................................................................................................58 
9. 
STATISTICS 
................................
................................
..............................................60 
9.1. 
Sample Size ................................................................................................................60 
9.2. 
Statistical Methodology 
................................
..............................................................60 
9.2.1. 
Populations to be Analyzed 
................................
........................................................60 
9.2.2. 
Baseline Evaluations 
.................................................................................................60 
9.2.3. 
Efficacy Analyses 
................................
................................
.......................................61 
9.2.3.1. 
Primary Efficacy Endpoint 
................................
.........................................................61 
9.2.3.2. 
Secondary Efficacy Endpoints 
...................................................................................61 
9.2.4. 
Safety Analyses ..........................................................................................................62 
9.2.5. 
Pharmacokinetic Analyses 
.........................................................................................62 
9.2.6. 
Interim Analysis 
........................................................................................................62 
10. 
STUDY MANAGEMENT 
................................
.........................................................63 
10.1. 
Data Handling and Quality Assurance .......................................................................63 
10.1.1. 
Electronic Case Report Forms 
................................
....................................................63 
10.1.2. 
Monitoring 
................................
................................
..................................................63 


 
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10.1.3. 
Inspections 
................................
................................
..................................................63 
10.2. 
Regulatory Guidelines 
................................
................................
................................64 
10.2.1. 
Institutional Review Board/Independent Ethics Committee 
......................................64
 
10.2.2. 
Regulatory Authorities 
..............................................................................................64 
10.2.3. 
Modification of the Protocol 
......................................................................................64 
10.2.4. 
Informed Consent Form 
.............................................................................................64 
10.2.5. 
Study Reporting Requirements 
..................................................................................65 
10.2.6. 
Financial Disclosure Reporting Obligations 
...............................................................65 
10.3. 
Study Committees 
.....................................................................................................65 
10.3.1. 
Data Monitoring Committee 
......................................................................................65 
10.3.2. 
Independent Clinical Adjudication Committee 
..........................................................65
 
10.4. 
Ancillary Research 
....................................................................................................66 
10.5. 
Study Record Retention 
.............................................................................................66 
10.6. 
Discontinuation of the Study by the Sponsor 
.............................................................66 
10.7. 
Confidentiality 
................................
................................
............................................66 
10.8. 
Publications/Reports 
................................
................................
...................................67 
11. 
LIST OF REFERENCES 
...........................................................................................68 
12. 
APPENDICES 
................................
................................
............................................71 
APPENDIX 1. NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
HEART FAILURE 
................................
................................
.....................................71 
APPENDIX 2. KARNOFSKY SCALE 
................................
......................................................72 
APPENDIX 3. POLYNEUROPATHY DISABILITY SCORE 
.................................................73
 
 


 
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LIST OF TABLES 
Table 1-1: Schedule of Assessments for Site Visits ..................................................................10 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term Explanation 
6-MWD 
Six-minute walk distance 
6-MWT 
Six-minute Walk Test 
99mTc 
99mTechnetium 
AA 
Amyloid A 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AL 
Amyloid light-chain 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of Covariance 
aPTT 
Activated partial thromboplastin time 
ASGPR 
Asialoglycoprotein receptor 
AST 
Aspartate transaminase 
ATTR 
Transthyretin-mediated amyloidosis 
BNP 
B-type natriuretic peptide 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CAC 
Clinical Adjudication Committee 
CFR 
Code of Federal Regulations 
CMR 
Cardiac magnetic resonance imaging (Cardiac MRI) 
CRF 
Case Report Form 
CRO 
Clinical research organization 
CV 
Cardiovascular (related) 
CYP 
Cytochrome P450 
DMC 
Data monitoring committee 
DPD-Tc 
99mTc -3,3-diphosphono-1,2-propanodicarboxylic acid 
eAUC 
Area under the effect curve 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data capture 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme linked immunosorbent assay 
ET 
Early termination 


 
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Abbreviation or Specialist Term Explanation 
FAC 
Familial amyloidotic cardiomyopathy 
FAP 
Familial amyloidotic polyneuropathy 
FNAFP 
Fine-needle aspirate of the abdominal fat pad 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HbsAb 
Hepatitis B surface antibody 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus 
HF 
Heart failure 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRS 
Interactive response system 
IUD 
Intrauterine device  
IUS 
Intrauterine system 
IV 
Intravenous(ly) 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
MAD 
Multiple ascending dose 
mBMI 
Modified body mass index 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent to treat 
mRNA 
Messenger ribonucleic acid 
NHP 
Non-human primate 
NOAEL 
No-observed-adverse-effect-level 


 
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Abbreviation or Specialist Term Explanation 
NOEL 
No-observed-effect-level 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
Over-the-counter 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PND 
Polyneuropathy Disability 
PP 
Per protocol 
PT 
Prothrombin time 
PV & DSS 
Pharmacovigilance and Drug Safety Services 
PYP-Tc 
99m-Tc-Pyrophosphate 
QoL 
Quality of life 
QTcB 
Bazett-corrected QT interval 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RNAi 
RNA interference 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous(ly) 
siRNA 
Small interfering ribonucleic acid 
SOA 
Schedule of assessments 
SSA 
Senile systemic amyloidosis 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
T4 
Thyroxine 
T60A 
Threonine to alanine substitution at position 60 
TEAE 
Treatment-emergent adverse events 
TSH 
Thyroid stimulating hormone 
TTR 
Transthyretin 
TRACS 
TTR amyloidosis cardiac study 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US/USA 
United States 
USP/EP 
United States Pharmacopeia/European Pharmacopoeia 
WBC 
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Abbreviation or Specialist Term Explanation 
WHO 
World Health Organization 
WOCBP 
Women of child-bearing potential 
WT 
Wild-type 


 
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1. 
INTRODUCTION 
1.1. 
Background and Rationale 
1.1.1. 
Transthyretin Biology 
Transthyretin (TTR), also known as prealbumin, is a tetrameric protein produced predominantly 
by hepatocytes (>95% of TTR is liver-derived), with small fractions produced in the choroid 
plexus and retina.1  The primary physiological role of TTR is to serve as a carrier of retinol (also 
known as vitamin A) through its interaction with retinol binding protein (RBP); it also plays a 
minor role as a carrier for thyroxine (T4).  In humans, approximately 15% of T4 circulating in 
the plasma is bound to TTR; the remainder is predominantly bound to thyroxine-binding 
globulin. 
Mutations in the TTR protein lead to destabilization of the tetrameric form and dissociation into 
dimers and monomers.  The misfolding of mutated monomers results in tissue deposition of 
oligomers and amyloid fibrils.  Amyloid deposits typically contain both mutant and wild-type 
(WT) TTR in addition to serum amyloid P protein and glycosaminoglycans, and over time these 
deposits lead to significant tissue injury. 
1.1.2. 
Disease Overview 
1.1.2.1. Transthyretin-mediated amyloidosis definition and familial amyloidotic 
cardiomyopathy 
Transthyretin-mediated amyloidosis (ATTR) is caused by deposition of TTR amyloid fibrils in 
various tissues.  The hereditary form of ATTR is caused by an autosomal dominant mutation in 
the TTR gene that leads to destabilization of the TTR tetramer and aggregation of misfolded 
monomers; this, in turn, results in cardiac and neuronal extracellular deposition of TTR amyloid 
fibrils culminating in life-threatening cardiomyopathy and/or debilitating neuropathy.  There are 
over 100 reported TTR genetic mutations2 that phenotypically result in at least 2 distinct clinical 
syndromes of ATTR: familial amyloidotic cardiomyopathy (FAC) and familial amyloidotic 
polyneuropathy (FAP), both of which are characterized by amyloid deposits of mutant and 
WT-type TTR.
3  Senile systemic amyloidosis (SSA) is a sporadic form of ATTR occurring in the 
elderly (predominantly males) and characterized by deposition of WT TTR in the heart tissue.4 
FAC is a serious, life-threatening orphan disease. The estimated worldwide prevalence of FAC is 
40,000 to 50,000.  However, the number of identified FAC patients is substantially smaller due 
to limited disease awareness resulting in underdiagnoses or misdiagnosis.  FAC is primarily 
identified and diagnosed at a few amyloidosis centers in the United States (US), and Europe.  
The TTR mutations most commonly associated with cardiac-predominant disease include valine 
to isoleucine substitution at position 122 (V122I; seen in the US and UK), threonine to alanine 
substitution at position 60 (T60A; seen in US, UK, and Northern Ireland), leucine to methionine 
substitution at position 111 (L111M; seen in Denmark), and isoleucine to leucine substitution at 
position 68 (I68L; seen in Italy). 


 
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The V122I mutation is the most common and estimated to be present in up to 4% of African 
Americans and in over 5% of West African populations.5  Disease develops predominantly in 
males with the mean age at diagnosis of approximately 70 years, and symptom onset typically 
occurring after the age of 60.  In the US there are estimated to be approximately 
100,000-150,000 African American males over age 65 who are heterozygous carriers of the 
V122I allele.
6  However, the extent of disease penetrance is currently unknown.  
The T60A mutation found in 1% of the population in County Donegal in North-West Ireland, is 
the next most common FAC mutation worldwide, and the commonest TTR variant in the British 
population.  The median age of onset of cardiac symptoms in this population is approximately 
60 years.  It should be noted that while T60A is categorized as FAP rather than FAC, it is 
nonetheless predominantly a disease of the heart and autonomic nerves, with <25% of patients 
developing peripheral sensorimotor neuropathy.7  
1.1.2.2. Pathogenesis and Outcome 
Cardiomyopathy in FAC occurs when insoluble TTR amyloid fibrils deposit in cardiac tissue 
causing heart wall thickening with diastolic and systolic dysfunction, conduction defects, and 
arrhythmias, leading to congestive heart failure and death.  Neuropathy is uncommon in FAC.  
While there is a paucity of longitudinal clinical data on FAC, a few published reports have 
shown that FAC patients have a significantly worse prognosis compared to other causes of heart 
failure, with rapid deterioration of functional capacity, including their ability to walk as 
measured by the 6-MWD, and quality of life (QOL) resulting in early mortality. 
The median survival of V122I patients from time of diagnosis in two retrospective studies was 
278 to 41 months
8,9 and in the prospective Transthyretin Amyloidosis Cardiac Study (TRACS) 
study median survival was 26 months.10 
1.1.2.3. Current Management and Unmet Medical Need 
There are currently no approved treatment options for patients with FAC. Patients are largely 
managed with supportive care aimed at alleviation of heart failure symptoms, including 
restriction of salt intake, diuretics, pacemakers, and arrhythmia management.  Heart 
transplantation has been used rarely, as many patients are too old to undergo the procedure.  
There is a high unmet need for novel therapeutics to treat FAC. 
ALN-TTRSC (International Nonproprietary Name: revusiran) is currently being developed as an 
RNA interference (RNAi) therapeutic for patients with FAC. 
1.1.3. 
RNA Interference 
RNAi is a naturally occurring cellular mechanism for regulating gene expression that is mediated 
by small interfering ribonucleic acids (siRNAs).11  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 endogenous or exogenous 
(infectious organisms) disease causing genes.  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 


 
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of the target protein.12  The ability to selectively and potently degrade the mRNA encoding the 
TTR protein using a 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.
13  
As a result, various formulations and/or chemical modifications of the siRNAs are used to 
increase distribution to tissues, and to facilitate their uptake into the relevant cell type. 
One approach that has been used successfully in humans for delivery of siRNAs to the liver 
employs intravenous (IV) administration of siRNAs formulated in lipid nanoparticles.
13,14,15  
Another approach for liver-specific gene silencing has been to use subcutaneously (SC) 
administered siRNA conjugated to an N-acetylgalactosamine (GalNAc) ligand.  It has been 
shown that conjugation of a triantennary GalNAc ligand to the 3’ end of the sense strand of 
siRNA results in high affinity (ie, nM) binding to the hepatic expressed asialoglycoprotein 
receptor (ASGPR) and subsequent receptor-mediated uptake into hepatocytes.  Single and 
multiple doses of SC administered siRNA-GalNAc conjugates have achieved sustained 
suppression of multiple different hepatocyte-expressed targets in rodents and non-human 
primates (NHPs), including TTR (see the ALN-TTRSC Investigator’s Brochure [IB] for further 
details).  Importantly, this approach for delivering siRNA to hepatocytes has also shown 
translation in humans with ALN-TTRSC. 
1.1.4. 
Investigational Drug ALN-TTRSC Overview 
ALN-TTRSC is comprised of a siRNA targeting mutant and WT TTR mRNA with a 
covalently-attached triantennary GalNAc ligand formulated in water for injection.  The siRNA 
consists of a 21-mer duplex oligonucleotide targeting the 3’UTR of the TTR mRNA, thereby 
conferring homology to WT TTR and all reported TTR mutations.  Once delivered to 
hepatocytes, ALN-TTRSC targets TTR mRNA for degradation, resulting in reduction of mutant 
and WT TTR protein via the RNAi mechanism.  Since TTR is almost exclusively synthesized in 
the liver, ALN-TTRSC is postulated to reduce levels of mutant and WT monomers and prevent 
amyloid fibril deposition, resulting in clinical benefit to patients with FAC. 
1.1.5. 
Therapeutic Hypothesis 
ALN-TTRSC is a novel investigational therapeutic for the treatment of FAC, a serious life 
threatening orphan disease.  The therapeutic hypothesis for treatment with ALN-TTRSC in 
patients with FAC is that potent and sustained lowering of serum TTR protein through inhibition 
of hepatic production will result in clinical benefit.  Support for this approach comes from 
evidence that lowering of the amyloidogenic protein by ≥50% improves clinical outcomes in 
other amyloidotic disorders, including both primary amyloid light-chain (AL) amyloidosis and 
secondary Amyloid A (AA) amyloidosis.  The AL amyloidosis example is particularly relevant, 
since cardiac involvement is the main cause of morbidity and mortality, and the lowering of 
serum free light chains through chemotherapy and stem cell transplantation has been shown to 
improve cardiac function and overall survival.  In TTR-mediated FAP, the elimination of mutant 
TTR by transplantation of the liver has been shown to slow neuropathy progression and improve 
survival in early-stage V30M patients.  Similarly, studies in FAP patients with tafamidis have 
shown that reducing circulating TTR monomers via stabilization of the TTR tetramer results in 


 
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improved clinical outcomes.  These precedents suggest that potent lowering of circulating TTR 
with ALN-TTRSC could potentially confer clinical benefit in patients with FAC. 
1.2. 
Summary of ALN-TTRSC Nonclinical Data 
The safety pharmacology and toxicology of ALN-TTRSC was evaluated in a series of in vitro 
and in vivo nonclinical studies. 
• 
 
 
  
 
 
 
 
• A safety pharmacology study conducted with revusrian in cynomolgus monkeys 
demonstrated that the no-observed-effect-level (NOEL) for the cardiovascular 
(electrocardiogram [ECG], QT interval changes, and hemodynamics) and respiratory 
systems was 100 mg/kg revusrian (the highest dose tested). 
• The toxicity profile of SC administered ALN-TTRSC was initially evaluated in 
6-week (10-dose) toxicology studies in rats and cynomolgus monkeys.  ALN-TTRSC 
is pharmacologically active in monkeys but not in rats.  Repeated SC administration 
of ALN-TTRSC was clinically well tolerated by rats and monkeys.  In rats, the no 
observed adverse effect level (NOAEL) was 30mg/kg based on minimal to moderate 
hepatocellular vacuolation with correlating transient mild (<50%) changes in liver 
function tests noted at ≥100 mg/kg.  The NOAEL in monkeys was greater than the 
highest dose tested (≥300 mg/kg). 
• 
 
 
 
 
 
 
 
 
 
 
. 
• 
 
. 
Further nonclinical information can be found in the ALN-TTRSC IB. 


 
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1.3. 
Summary of Clinical Data with ALN-TTRSC 
Study ALN-TTRSC-001 was a Phase 1 randomized, double -blind, placebo-controlled study of 
ALN-TTRSC administration in healthy subjects.  Subjects received single ascending doses or 
multiple ascending doses of up to 10 mg/kg or fixed doses of up to 600 mg of ALN-TTRSC, or 
placebo.  In the multiple dose cohorts, subjects received a total of 10 doses over a 35 day period 
administered as 5 daily SC doses followed by 5 weekly doses.  
In this study, ALN-TTRSC was generally well-tolerated.  The majority of treatment-emergent 
adverse events (AEs) were mild or moderate in severity and considered unrelated to study 
treatment.  There were no serious adverse events (SAEs).  Injection site reactions (ISRs) were 
the most common AEs related to study treatment.  All ISRs were mild or moderate in severity 
and resolved without sequelae.  Overall, the incidence of alanine transaminase (ALT) and 
aspartate transaminase (AST) elevation >1× upper limit of normal (ULN) was similar in placebo 
and ALN-TTRSC-treated subjects.  One subject who received 600 mg ALN-TTRSC developed 
an asymptomatic elevation of ALT (4.3×ULN) and AST (1.9×ULN), which was defined in the 
protocol as a dose limiting toxicity and resulted in study discontinuation.  There were no other 
AEs leading to dose interruption or dose reduction.  No elevations in cytokines, C-reactive 
protein, or other abnormal clinical findings were noted.  The pharmacodynamic (PD) effect of 
ALN-TTRSC was dose-dependent and resulted in >85% reduction of TTR at ≥5 mg/kg of 
ALN-TTRSC and was accompanied by reduction of RBP and vitamin A.  Fixed doses of 500 mg 
and 600 mg ALN-TTRSC also demonstrated similar safety and PD effect over a wide range of 
body weights compared to that observed in cohorts with weight-based dosing.  
ALN-TTRSC-002 was an open-label, multiple-dose Phase 2 study of ALN-TTRSC administered 
to patients with ATTR cardiac amyloidosis.  Patients received ALN-TTRSC 5 mg/kg or 
7.5 mg/kg for 10 doses over a 35 day period administered as 5 daily SC doses followed by 5 
weekly doses.  Multiple doses of ALN-TTRSC were generally well-tolerated.  The majority of 
AEs were mild or moderate in severity, not related to study drug and expected for the population 
under study.  Three patients experienced 1 SAE each, 2 of which were unrelated to study drug 
(non-cardiac chest pain and implantable defibrillator insertion).  The third SAE was 
asymptomatic elevation of ALT (4.2×ULN) and AST (3.2×ULN) after administration of 6 doses 
of 5 mg/kg ALN-TTRSC and was considered mild in severity and possibly related to study drug.  
Study drug was interrupted for 1 dose and then resumed with subsequent normalization of ALT 
and AST during the remaining period of dosing.  The most common AEs related to study 
treatment were ISRs which were localized, mild in severity, self-limiting and did not result in 
interruption or discontinuation of treatment.  There were no other AEs leading to dose 
interruption or dose reduction.  A PD effect of >85% TTR reduction with 5 mg/kg or 7.5 mg/kg 
ALN-TTRSC dosing was observed. 
ALN-TTRSC-003 is an ongoing, Phase 2 open-label extension study to evaluate long-term 
treatment with ALN-TTRSC for patients who completed the ALN-TTRSC-002 study.  Patients 
receive ALN-TTRSC 500 mg administered as 5 daily SC doses, followed by weekly SC doses 
for approximately 2 years.  As of 05 January 2016, 25 patients have been treated with 
ALN-TTRSC for approximately 8 months (range 1-13 months).  Multiple doses of ALN-TTRSC 
have been generally well-tolerated.  The majority of AEs were mild or moderate in severity.  The 
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erythema, pruritus, pain, or swelling at or around the injection site.  Occasionally, these reactions 
have been recurrent, of longer duration and increased intensity.  In some cases, ISRs have led to 
interruption or discontinuation of study drug.  Elevations of ALT and AST have been observed, 
the majority of which have been mild, transient, <3×ULN and not associated with any changes in 
total bilirubin or clinical symptoms.  In several subjects, the elevations may have led to 
interruption and/or dose reduction of study treatment.  There were no serious hepatic AEs. 
ALN-TTRSC-004 is an ongoing, Phase 3 randomized, double-blind, placebo-controlled study of 
ALN-TTRSC in patients with FAC.  Patients receive ALN-TTRSC 500 mg or placebo 
administered as 5 daily SC doses, followed by weekly SC doses for 18 months.  As of 
14 January 2016, 83 patients have been treated with blinded study drug for approximately 
3 months (range 0-13 months).  The majority of AEs were mild or moderate in severity.  The 
most common AEs considered related to blinded study treatment have been ISRs.  One patient 
developed symptoms of anorexia, weight loss, and a cholestatic liver enzyme profile.  The 
patient was hospitalized and an evaluation was consistent with drug-induced acute hepatitis and 
cholestasis.  The event was considered possibly related to study treatment and a contributory role 
could not be excluded.  The subject also had a number of other potential contributory factors.   
Further details on these clinical studies can be found in the ALN-TTRSC IB. 
1.4. 
Study Design Rationale 
This is a Phase 3 randomized, double-blind, placebo-controlled, multicenter, multinational study 
to evaluate the efficacy and safety of ALN-TTRSC in FAC patients.  The patients proposed for 
this study are reflective of the FAC population encountered by clinicians in various different 
countries worldwide, including patients with a range of disease severity and spectrum of TTR 
mutations. 
The target population for this study is FAC patients with clinical evidence of mild-to-moderate 
heart failure.  The study is being restricted to FAC in order to minimize the phenotypic 
heterogeneity and focus on a genetically-defined population where the disease pathogenesis is 
more clearly defined and where there is the greatest unmet need.  Patients with FAC appear to 
have more rapid disease progression compared to patients with SSA, thereby providing a greater 
opportunity to demonstrate a disease-modifying effect with ALN-TTRSC treatment.  Heart 
failure severity will be limited to New York Heart Association (NYHA) class I, II and III, and 
patients must have a Karnofsky performance status of ≥ 50%.  Since a 6-minute walk distance 
(6-MWD) of <150 meters is associated with early poor outcomes,16,17 and since disease in such 
patients may be too advanced to be impacted by ALN-TTRSC, eligible patients must minimally 
have a 6-MWD of ≥150 meters.  Analysis of the UK natural history dataset (National 
Amyloidosis Center, unpublished results) that includes information on both 6-MWD and NYHA 
class suggests that a 6-MWD cut-off of 150 meters will enrich for NYHA class I-II and early 
class III patients.  
The inclusion of placebo as a control allows for unbiased analysis of the treatment effect of 
ALN-TTRSC on TTR-mediated FAC.  Saline will be used as placebo.  FAC is currently 
managed by treatment of symptoms, mostly with the use of diuretics and antiarrhythmic drugs, 
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Given the orphan nature of the disease and the significant, progressive morbidities associated 
with FAC, randomization to ALN-TTRSC or placebo will be performed in a 2:1 ratio (ALN-
TTRSC:placebo) to increase the probability that patients will receive active drug.  Since NYHA 
class and 6-MWD are predictive of outcomes in heart failure,
18,19 treatment groups will be 
balanced at entry for NYHA classification (I and II vs III), and Screening 6-MWD (≤325 meters 
vs >325 meters).  Patients will also be stratified for V122I versus all other mutations, in order to 
balance for phenotypic heterogeneity among the different FAC mutations with the prognosis 
being worse for V122I (the most common FAC mutation worldwide) compared to T60A,7,9 and 
outcomes less well described for other FAC mutations is considered prudent.  
The co-primary endpoint for this study is the change from baseline in meters walked during the 
6-minute walk test (6-MWT) at 18 months and percent reduction from baseline in serum TTR 
levels over 18 months compared between treatment groups.  Serum TTR levels are expected to 
reach nadir within approximately 3 weeks following the onset of dosing.  The 18-month endpoint 
was selected based on the rapid rate of 6-MWD decline with V122I FAC patients, derived from a 
natural history dataset from the UK (National Amyloidosis Center, unpublished results) and the 
prospective TRACS study.  From these data it is estimated that FAC patients decline in 6-MWD 
by 74 to 118 meters in 18 months, thereby providing adequate disease progression for the 
detection of a treatment effect in ALN-TTRSC treated patients.  The clinical relevance of TTR 
lowering is supported by improved survival of patients with FAP after liver transplantation
20,21,22 
and improved survival in AL and AA patients after treatment that effectively reduces the amount 
of circulating amyloidogenic protein.23,24  It is anticipated that a marked, sustained reduction in 
serum TTR levels over 18 months by ALN-TTRSC will result in stabilization or improvement in 
cardiac amyloid deposition, with a corresponding beneficial effect on cardiac function and 
clinical outcomes, including the 6-MWD. 
1.5. 
Dose Selection and Rationale 
Dose selection for proposed Phase 3 trial is based on the therapeutic hypothesis that maximal 
TTR suppression is required to fully realize clinical benefit with ALN-TTRSC.  Clinical data 
demonstrate that administration of multiple doses of ALN-TTRSC in healthy volunteers resulted 
in >85% mean TTR reduction at nadir with doses of 5.0 to 10.0 mg/kg or with fixed doses of 
500 and 600 mg; these doses were well tolerated.  The fixed dose of 500 mg had a wide PD and 
safety window across both heavy and light subjects, with a TTR lowering effect that matched 5.0 
and 10.0 mg/kg. In the ongoing Phase 2 study in patients with FAC and SSA, doses of 5.0 and 
7.5 mg/kg have resulted in similar degrees of TTR reduction as were seen in healthy volunteers.  
Based on these consistent PD data in both healthy volunteers and FAC/SSA patients showing 
maximization of TTR lowering with either fixed or mg/kg dosing at a total dose of ≥500 mg, 
along with the favorable safety profile observed with the 500 mg fixed dose, 500 mg is the 
planned dose for the Phase 3 study.  The dose selection is also supported by the absence of new 
findings in the ongoing long term toxicology studies in rats and monkeys.  ALN-TTRSC will be 
administered via SC injections once daily for the first 5 days, followed by dosing on Day 7, and 
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1.6. 
Risk-Benefit Assessment 
FAC is a rare disease, that leads to significant morbidity and mortality. There are no approved 
therapies and patients are currently managed with supportive care aimed at alleviation of heart 
failure symptoms.  Clinical experience with ALN-TTRSC indicates that ALN-TTRSC is 
well-tolerated at fixed doses of 500 mg and results in a reduction in serum levels of TTR of 
>85%.  The hypothesis is that a reduction of mutant and WT TTR amyloid deposition in the 
heart will lead to clinical benefit in these patients. 
1.6.1. 
Injection Site Reactions 
ISRs have been observed in subjects receiving ALN-TTRSC in clinical studies.  The majority 
have been mild or moderate in severity.  Typically, the reactions consist of localized erythema, 
pain, swelling, pruritus, or rash at or around the injection site, and are transient in nature.  
Occasionally, these reactions have been of longer duration, more severe in nature and/or 
recurrent.  In some subjects, this resulted in discontinuation of ALN-TTRSC.  If such reactions 
occur, rotation of the injection site (e.g., to the extremities) is recommended as a potential 
mitigation strategy (see Section 6.5). Dose reduction may be considered in some cases after 
consultation with the Medical Monitor (see Section 6.6). 
1.6.2. 
Abnormal Liver Function Tests 
Elevations of ALT and/or AST have been seen in subjects receiving ALN-TTRSC in completed 
and ongoing clinical studies.  The majority of abnormalities have been mild and transient 
elevations of ALT and/or AST <3×ULN, and are not associated with changes in total bilirubin or 
clinical symptoms.  In some subjects, higher ALT and/or AST elevations have been observed 
and led to interruption or discontinuation of study treatment.  Serious hepatic adverse events 
have also been reported, including a case of  possible drug-induced hepatitis and cholestasis; in 
this case a contributory role of study drug could not be excluded. 
The risk of liver toxicity is lowered by requiring patients to have adequate liver function at study 
entry, as well as regular monitoring of LFTs during the study.  If a patient develops clinical signs 
or symptoms such as unexplained anorexia, fatigue, jaundice, or dark urine, the Investigator 
should consider liver injury as a potential etiology. 
Dose reduction may be considered in some cases after consultation with the Medical Monitor 
(see Section 6.6). 
1.6.3. 
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.  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.  Provided 
there is adequate vitamin A in the diet, tissue stores of vitamin A should not be affected by the 


 
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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 supplement containing the recommended daily allowance of vitamin A.  
Furthermore, the safety of lowering vitamin A through TTR suppression has been further 
confirmed by the absence of any vitamin A deficiency-related AEs in NHPs, healthy volunteers, 
and patients with FAP treated with patisiran (another RNAi therapeutic with an siRNA targeting 
TTR formulated in a lipid nanoparticle) who experienced >80% lowering of both TTR and 
vitamin A.  Periodic eye exams are planned for patients in this study to assess any potential 
impact of vitamin A lowering. 
Please see the ALN-TTRSC IB for expanded risk/benefit assessment. 


 
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to determine the efficacy of ALN-TTRSC in patients with 
FAC. 
This will be assessed as the difference between treatment and placebo groups at 18 months using 
a co-primary endpoint of: (1) change in meters in 6-MWD compared to baseline distance; and 
(2) percent reduction in serum TTR levels compared to baseline levels. 


 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, randomized, double-blind, placebo-controlled Phase 3 study 
designed to demonstrate the clinical efficacy and safety of ALN-TTRSC in patients with TTR 
mediated FAC. 
Approximately 200 consented eligible patients will be randomized to receive either 
ALN-TTRSC or placebo at a 2:1 ratio (ALN-TTRSC to placebo) in a blinded manner as a 
subcutaneous administration.  Treatment groups will be balanced at randomization for NYHA 
classification (I and II versus III), TTR mutation (V122I versus other FAC mutations), and 
6-MWD (≤325 meters versus >325 meters).  Patients will receive ALN-TTRSC or placebo daily 
for 5 days during the first week, a single dose on Day 7, and then once weekly for 18 months. 
Patients will undergo efficacy and safety assessments at Screening/Baseline,
 each month for first 
3 months, and then at 3-6 month intervals. 
The duration of patient participation in this study is approximately 20 months (inclusive of up to 
a 45 day Screening/Baseline window and up to 35 days of follow-up after the last dose). 
3.2. 
Number of Patients 
Approximately 200 patients will be enrolled in this study. 
3.3. 
Efficacy Endpoints 
3.3.1. 
Primary endpoints: 
The co-primary endpoints of the study are to evaluate the difference between the ALN-TTRSC 
and placebo groups for: 
1. Change in 6-MWD at 18 months compared to baseline  
2. Percent reduction in serum TTR burden over 18 months 
3.3.2. 
Secondary endpoints: 
The secondary endpoints of the study are to determine the effect of ALN-TTRSC on various 
clinical parameters by assessing the difference between the ALN-TTRSC and placebo groups 
at18 months for: 
• Composite CV mortality and CV hospitalization 
 
• Change in New York Heart Association (NYHA) class (Appendix 1) compared to 
baseline 
• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) compared to baseline 
• Cardiovascular (CV) mortality 
• CV hospitalization 


 
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• All-cause mortality 
3.3.3. 
Exploratory endpoints: 
The exploratory endpoints of the study are to determine the difference between the 
ALN-TTRSC and placebo groups in the change from baseline at 18 months in the following 
measurements: 
• 
EuroQOL (EQ-5D) questionnaire 
• 
Echocardiogram parameters 
• 
Karnofsky Performance Status (Appendix 2) 
• 
Troponin T and I, and N-terminal prohormone of B-type natriuretic peptide (NT proBNP) 
levels 
• 
Cardiac magnetic resonance imaging (CMR) parameters (only at selected sites) 
• 
99mTechnetium scintigraphy parameters (only at selected sites) 
• 
Amyloid in abdominal wall fat pad aspirates  
• Polyneuropathy Disability (PND) Score (Appendix 3)  
• 
Modified body mass index (mBMI) 
• 
Estimated glomerular filtration rate (eGFR) 
• 
HF hospitalization 
3.4. 
Safety Assessments 
Safety will be assessed throughout the study by collecting adverse events (AEs; including serious 
adverse events [SAEs]); clinical laboratory safety tests including, hematology, serum chemistry 
(including liver function tests), thyroid function, coagulation, vitamin A, and urinalysis; 
measurement of anti-drug antibodies; electrocardiograms; vital signs; physical examination 
findings; and ophthalmology examinations. 
3.5. 
Pharmacokinetic Assessments 
Pharmacokinetics will be assessed by collecting periodic  plasma samples for measure of 
ALN-TTRSC as well as metabolite concentrations. 
3.6. 
Other Assessments 
Disease burden and healthcare utilization will be assessed using a patient reported 
pharmacoeconomics questionnaire. 


 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, each patient must meet all of the following criteria during the 
Screening/Baseline visit(s): 
1. Are male or female of 18 to 90 years of age (inclusive). 
2. Have a documented TTR mutation. 
3. Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo Red (or 
equivalent) staining or technetium (
99mTc) scintigraphy (
99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 or 
3 cardiac uptake, centrally confirmed. 
4. If patient has monoclonal gammopathy, TTR amyloidosis needs to be confirmed through 
TTR protein identification by immunohistochemistry or mass spectrometry. 
5. Have a medical history of heart failure (HF) with at least 1 prior hospitalization for HF, 
which may include hospitalization for arrhythmia or pacemaker placement, OR clinical 
evidence of HF (as evidenced by one or more of the following: elevated jugular venous 
pressure, peripheral edema, shortness of breath or signs of pulmonary congestion on 
x-ray or auscultation) that either requires/required treatment with diuretics or is/was 
associated with an NT-proBNP > 400 ng/L or B-type natriuretic peptide (BNP) 
>100 ng/L. 
6. Have evidence of cardiac involvement by Screening/Baseline echocardiogram including 
an end-diastolic interventricular septum thickness of ≥12 mm.  For patients with an 
end-diastolic interventricular septum thickness of <12mm, an endomyocardial biopsy 
showing amyloid deposition is required. 
7. Can walk ≥150 meters on a 6-minute walk test (6-MWT). 
8. Have a Karnofsky performance status of ≥50%. 
9. Symptoms of HF optimally managed with no CV hospitalizations within 4 weeks prior to 
consent or during Screening/Baseline. 
10. Have adequate liver function, demonstrated by an AST and ALT ≤2.0×ULN, albumin 
>3 g/dL (>4.35 μmol/L), and total bilirubin <2.0 
mg/dL (34.2 μmol/L), unless elevation 
in total bilirubin is due to Gilbert
's Syndrome. 
11. No active infection with hepatitis B (HBV) or hepatitis C (HCV) by serology 
12. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and use 1 highly effective method of contraception in combination with a 
barrier method throughout study participation, and for 28 days after last dose of study 
drug (see Section 5.2.1) 
13. Males with partners of child-bearing potential, must agree to use a condom, accompanied 
with spermicidal foam, gel, film, cream, or suppository, except in countries where 


 
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spermicide is not available for use in combination with condom, throughout study 
participation and for 28 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 
28 days after the last dose of study drug. 
14. Must be willing and able to comply with protocol-required visit schedule and visit 
requirements and provide informed consent or have a legal guardian who can provide 
informed consent. 
4.2. 
Patient Exclusion Criteria 
Patients will be excluded from enrollment in the study if they meet any of the following criteria 
during the Screening/Baseline visit(s): 
1. Has estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2 (using the 
Modification of Diet in Renal Disease [MDRD] formula). 
2. Has known primary amyloidosis (AL), leptomeningeal amyloidosis, non-FAC hereditary 
cardiomyopathy, hypertensive cardiomyopathy, or cardiomyopathy due to valvular heart 
disease. 
3. Has non-amyloid diseases affecting exercise testing (e.g., severe chronic obstructive lung 
disease, severe arthritis, peripheral vascular disease affecting ambulation). 
4. Has uncontrolled hypertension. 
5. Has uncontrolled ischemic heart disease. 
6. Has uncontrolled clinically significant cardiac arrhythmia. 
7. Had acute coronary syndrome within the past 3 months. 
8. Has a Polyneuropathy Disability score >2. 
9. Has untreated hypo- or hyperthyroidism. 
10. Has a New York Heart Association (NYHA) classification of IV. 
11. Has known or suspected systemic bacterial, viral, parasitic, or fungal infection. 
12. Has known human immunodeficiency virus (HIV) infection. 
13. Current, heavy alcohol use, defined as regular consumption of greater than 2 to 3 
units/day for women and 3 to 4 units/day for men (a unit of alcohol equals 1 glass of wine 
[125 mL], 1 measure of spirits, or ½ pint of beer), or a known history of alcohol abuse 
within the past 2 years. 
14. Has 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. 
15. 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. 
16. Had metastatic cancer within the past 5 years. 


 
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17. History of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc). 
18. Has a history of intolerance to SC injection. 
19. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation. 
20. Has had a heart or liver transplant, or is being considered for a transplant during the study 
period. 
21. Known history of clinically significant chronic liver disease in the opinion of the 
Investigator. 
4.3. 
Study Drug Discontinuation 
The Investigator or designee may discontinue dosing in a patient if the patient: 
• Is in violation of the protocol 
• Experiences a serious or intolerable AE 
• Is found to be considerably non-compliant with the protocol-required visits 
The Investigator will confer with the Sponsor or CRO Medical Monitor before discontinuing 
dosing in the patient.   Patients who are pregnant will be discontinued from dosing immediately. 
Patients who discontinue study drug for any reason will be encouraged to remain on the study 
and complete their remaining clinic visits through the 18-month visit.  Patients who discontinue 
study drug may receive local standard of care treatment for their disease. 
4.4. 
Patient Withdrawal  
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  There will be no replacements of patients who withdraw from this 
study.  Patients may also be withdrawn if the study is terminated. 
If a patient chooses to withdraw from the study, every effort should be made to conduct the Early 
Termination Visit.  When a patient withdraws from the study, the primary reason for 
discontinuation must be recorded in the appropriate section of the electronic case report form 
(eCRF) and all efforts will be made to complete and report the observations as thoroughly as 
possible. 
The withdrawn patient will be asked if they are willing to consent to either be contacted by 
telephone or to allow non-patient contact follow-up (eg, medical record check) 18 months after 
enrolling onto the study to document their overall health status. 


 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Concomitant Medications 
Use of tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid within 14 days prior to 
the first dose of study medication in this protocol or use of any other investigational agent or 
device within 30 days prior to the first dose of study medication is prohibited (see exclusion 
criteria, Section 4.2).  Similarly, these agents or investigational devices are prohibited during the 
study. 
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. 
The 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 from Screening/Baseline through the Follow-up visit will be 
recorded on the patient’s eCRF.  This will include all prescription drugs, herbal preparations, 
OTC medications, vitamins (including the supplemental Vitamin A), and minerals.  Any changes 
in medications during the study will also be recorded on the eCRF. 
Any concomitant medication 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 are recorded on the eCRF.  For coding of concomitant medication, an 
internationally recognized and accepted coding dictionary will be used. 
During the study, patients are also advised not to consume alcohol over the levels stated in the 
exclusion criterion. 
5.2. 
Contraceptive Requirements 
5.2.1. 
Requirements for Women of Child-bearing Potential 
Women of child-bearing potential may be included in this study and include any female who has 
experienced menarche and who is not postmenopausal or permanently sterilized (eg, tubal 
occlusion, hysterectomy, or bilateral salpingectomy). 
Women of child-bearing potential must have a negative pregnancy test and must be using 
1 highly effective method of contraception in combination with a barrier method from the 
signing of the informed consent form (ICF), throughout study participation, and for 28 days after 
the last dose of the study drug. 
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows and should be used per 
availability in each country and local requirements: 
• Hormonal:  established use of oral (except low-dose gestagens [eg, lynestrenol and 
norethisterone]), implantable, injectable, or transdermal methods of contraception in 
conjunction with spermicide, condom, or diaphragm;  


 
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• Placement of an intrauterine device (IUD) in conjunction with spermicide or condom;  
• Placement of an intrauterine system (IUS) (for example, progestin-releasing coil) in 
conjunction with spermicide or condom; 
• Bilateral tubal occlusion in conjunction with spermicide, condom, or diaphragm; 
• 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) in 
conjunction with spermicide, condom, or diaphragm,  
• 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. 
Interaction between ALN-TTRSC and hormonal contraceptives is not anticipated; there were no 
effects of ALN-TTRSC on the reproductive organs (including histopathology) in any of the 
animal (rat and NHP) studies conducted to date.  Moreover, ALN-TTRSC showed no inhibition 
in vitro of cytochrome P450 (CYP)1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 (both 
testosterone and midazolam were used as substrates in human liver microsomes).   
5.2.2. 
Requirements for Male Patients 
Males with partners of child-bearing potential who agree to use appropriate means of 
contraception throughout study participation until 28 days after the last dose of ALN-TTRSC 
may be included in this study. 
It is unknown if ALN-TTRSC poses any potential risk of drug exposure through the ejaculate. 
Male patients (including men who have had vasectomies), particularly those with partners who 
are pregnant, must use a condom, accompanied with spermicidal foam, gel, film, cream, or 
suppository, except in countries where it is not available, as the appropriate means of 
contraception for the duration of the study and until 28 days after the last administration of study 
drug. 
Males should also abstain from sperm donation after the first dose of study drug through study 
participation and for 28 days after the last dose of ALN-TTRSC. 
5.3. 
Treatment Compliance 
Treatment compliance with study drug administration is dependent on the proper preparation and 
administration of SC injections.  Patients will be permitted to miss an occasional dose of study 
drug.  However, if a patient misses multiple consecutive doses, the Investigator, in consultation 
with the CRO Medical Monitor, will discuss whether the patient will be able to continue on the 
study.  If a patient misses a dose of study drug, and remembers prior to their next dose, they 
should receive the missed dose as soon as possible, otherwise the missed dose will not be made 
up.  Patients should never receive more than one dose of study drug a day. 


 
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5.4. 
Randomization and Blinding 
This is a randomized double blind study, and patients will be randomized via an interactive 
response system (IRS). 
5.5. 
Patient Numbering 
Each patient will be uniquely identified in the study by a combination of the site number and 
screening number.  The site number will be assigned by the Sponsor.  Upon signing the ICF, 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 randomization number in the IRS and a study treatment.  A combination of the site number, 
screening number, randomization 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. 
5.6. 
Blinding  
All site personnel and patients will be blinded to study drug treatment.  ALN-TTRSC and 
placebo will be packaged identically and all vial contents will be masked.  The study drug will be 
administered by a healthcare professional (see Section 6.5); prior to withdrawing the study drug 
from the vial, the syringe will be masked.  See the Pharmacy Manual for additional details. 
Injection site reactions have been known to occur in patients receiving both ALN-TTRSC and 
placebo; the consent form will inform patients about the potential for injection site reactions 
regardless of treatment assignment. 
5.7. 
Breaking the Blind 
In the event that the Investigator requests to know a patient’s study treatment assignment, the 
Investigator should attempt to 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 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 Investigator or Sub-investigator should attempt to contact the 
CRO Medical Monitor.  If the CRO Medical Monitor is immediately unreachable, the 
Investigator 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 
should be kept of when the blind was broken, who broke it, and why. 


 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Presentation of Study Drug 
All study drugs may be dispensed only by the Investigator or trained individual as defined in the 
Pharmacy Manual. 
ALN-TTRSC Solution for Injection (subcutaneous use) is comprised of an siRNA targeting 
mutant and WT TTR mRNA with a covalently attached triantennary GalNAc ligand formulated 
in water for injection.  
ALN-TTRSC will be supplied as a sterile 200 mg/mL solution.  The ALN-TTRSC drug product 
will be packaged in a glass vial.  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 aluminum flip-off cap. 
The control drug for this study will be a placebo (normal saline 0.9% for SC administration). 
Placebo will be packaged identically to ALN-TTRSC. 
6.2. 
Study Drug Packaging and Labeling 
All packaging and labeling as well as the preparation of ALN-TTRSC and placebo will be in 
compliance with Good Manufacturing Practice (GMP) specifications, and any other or local 
applicable regulations. 
6.3. 
Study Drug Storage 
All study drugs will be stored upright and refrigerated at approximately 5±3°C, protected from 
light.  Any deviation from the recommended storage conditions should be reported. 
No special procedures for the safe handling of ALN-TTRSC or placebo are required. 
The Sponsor will be permitted, upon request, to audit the supplies, storage, dispensing 
procedures, and records. 
No study drug may be administered to any person not enrolled in the study. 
Additional storage details are provided in the Pharmacy Manual. 
6.4. 
Study Drug Preparation 
Patients will be randomized using an IRS system to receive either 500mg of ALN-TTRSC or the 
equivalent volume (2.5 mL) of placebo for five daily doses for the first week and then weekly for 
approximately 18 months. 
Study drug supplies will be blinded, and the pharmacist or qualified designee will use the 
pre-labeled study drug vials assigned by the IRS system.  The pharmacist or qualified designee 
managing the study drug will prepare the study drug using aseptic techniques. The procedure for 
preparing study drug is provided in the Pharmacy Manual. 


 
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6.5. 
Administration 
Patients who have met the eligibility criteria will be assigned to either the placebo or 
ALN-TTRSC treatment group based on the randomization code.  As this is a double blinded 
study, neither the Investigator nor the patient will know their group assignment.  Doses will be 
administered as per the dosing scheme (see Table 1-1). 
Study drug injections will be administered under the supervision of the Investigator or healthcare 
professional.  At home dosing may be administered by a healthcare professional.  To maintain 
the blind, the syringes are to be masked prior to study drug withdrawal.  A full description of the 
blinding procedure is included in the Pharmacy Manual. 
The preferred site of SC injection is the abdomen.  Optional additional sites are the upper arms 
and thighs.  The site of injection will be rotated and recorded. 
Detailed instructions can be found in the Pharmacy Manual. 
6.6. 
Dosing Modification Criteria 
During the study, if a patient has an elevation of AST, ALT, or total bilirubin (unless due to 
Gilbert’s Syndrome) >3×ULN, repeat assessments of AST, ALT, and total bilirubin should be 
performed within 72 hours.  The patient should be followed closely, with LFT assessments 
performed weekly, and as medically indicated to guide patient management.  Close monitoring 
may be discontinued when ALT, AST, and total bilirubin return to ≤3×ULN.  Additional, and 
repeat assessments, may be performed at the discretion of the Investigator. 
Dosing will be held for the following LFT abnormalities: 
• AST or ALT elevation of ≥3×ULN in association with either total bilirubin elevation 
of ≥1.5×ULN or gastrointestinal symptoms including nausea, vomiting, and/or 
abdominal pain 
• AST or ALT elevation of ≥5×ULN 
Under these circumstances the contract research organization (CRO) Medical Monitor and 
Investigator, in consultation with a hepatologist as deemed necessary, will decide on appropriate 
action regarding frequency of repeat LFTs and resumption of dosing. 
If a patient experiences an AE considered to be related to study drug, and the Investigator has 
any potential concerns with regard to further dosing, the Medical Monitor and Investigator will 
review all available safety data for the patient.  Based on this review, it may be determined that 
further administration of study drug will be discontinued or study drug administration at the 
same dose may resume. 
If a patient has recurrent or severe ISRs, or clinically significant LFT abnormalities, the 
Investigator and the Medical Monitor should determine whether the patient is a candidate for a 
dose reduction of study drug.  In suitable candidates, dose reduction to 250 mg ALN-TTRSC (or 
placebo equivalent) is allowed.  In patients who have been dose reduced, subsequent 
re-challenge at the full dose may be considered based on the judgment of the Investigator and 
Medical Monitor. 


 
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6.7. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of all 
study drugs including dates of receipt.  In addition, accurate records will be kept by the 
pharmacist or designee of when and how much study drug is dispensed and used by each patient 
in the study.  Any reason for departure from the protocol dispensing regimen must also be 
recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor 
Monitor or designee.  At the completion of the study, there will be a final reconciliation of all 
study drugs. 
Study drug must not be used for any purpose other than the present study.  Study drug which has 
been dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
Further instructions about study drug accountability are detailed in the Pharmacy Manual. 
6.8. 
Study Drug Handling and Disposal 
Remaining study drug (all used, partially used, and unused vials) will be returned to the Sponsor 
or its agent or destroyed at the site according to applicable regulations. 


 
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7. 
STUDY ASSESSMENTS 
The timing of all assessments is found in the Schedule of Assessments (Table 1-1). 
7.1. 
Informed Consent 
The patient (or the patient’s legal guardian) will be given a verbal explanation of the study, 
including information about the study drug and the study procedures, and will have all questions 
adequately addressed.  The patient (or the patient’s legal guardian) must sign and date a consent 
form that has been approved by the appropriate Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) before the Screening/Baseline procedures are initiated.  All patients (or 
their legal guardians) will be given a copy of the signed and dated informed consent form. 
If a patient withdraws from the study, in an attempt to minimize the extent of missing data, they 
will be asked if they would be willing to consent to either be contacted by telephone or to allow 
non-patient contact follow-up (eg, medical record check) 18 months after enrolling onto the 
study to document their overall health status. 
7.2. 
Demographics and Medical History 
Patient demographic data will be obtained at Screening/Baseline.  A complete medical history 
will be obtained at Screening/Baseline. 
7.3. 
Efficacy Assessments 
7.3.1. 
Six-Minute Walk Test 
The 6-MWT will be administered by staff trained in the procedure included in the Site Operation 
Manual.  The staff administering the 6-MWT will be different from the Investigator or designee 
managing the care of the patient.   
The 6-MWT will be performed to assess functional exercise capacity and will include pre- and 
post-walk assessment of O2 saturation, blood pressure, heart rate, and the Borg scale rating for 
dyspnea and fatigue.
25  The Screening/Baseline visit assessment will include a practice and an 
actual 6-MWT at least 1 hour apart and must be done within 28 days prior to randomization.  
The higher of the two values at Screening/Baseline visit will be used for eligibility purposes.  At 
all other visits, the test should be performed only once at approximately the same time of the 
day.  On dosing days, including Day 0, the 6-MWT should be performed prior to study drug 
administration.  Patients who are hospitalized during the course of the study should wait at least 
two weeks after hospitalization before completing a 6-MWT assessment. 
7.3.2. 
Transthyretin 
On scheduled visits, serum samples will be collected within one hour prior to dosing and 
analyzed for total TTR levels using an enzyme linked immunosorbent assay (ELISA) method at 
a central laboratory. 


 
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7.3.3. 
Modified Body Mass Index  
Assessment of nutritional status, which has been linked to autonomic dysfunction will be 
measured by the mBMI.  Since the mBMI takes into account the serum albumin values along 
with BMI (function of height and weight), it corrects for hypoalbuminemia and is considered 
more reflective of nutritional status than BMI alone.  This calculation will be performed by the 
Sponsor on the reported data (ie, whenever body weight is recorded, except end of study) and not 
performed at the site. 
7.3.4. 
Estimated Glomerular Filtration Rate 
Estimated glomerular filtration rate will be calculated using the MDRD formula by the central 
laboratory.  If this parameter met eligibility criteria at Screening/Baseline, then dosing can 
proceed prior to receiving pre-dose Day 0 results. 
7.3.5. 
Fat Pad Biopsy 
Fine-needle aspirates of the abdominal fat pad (FNAFP) for amyloid quantification will be 
collected only at certain sites and in only patients who have provided additional voluntary 
consent.  Subsequent scheduled biopsies may not be collected depending on the status of the 
Screening/Baseline biopsy sample.  Repeat Screening/Biopsy samples may be collected if the 
initial sample is not of sufficient quality.  The voluntary fat pad biopsy should only be obtained 
once during Screening. 
Details on FNAFP collection, processing, and shipment will be in the Site Operations Manual. 
7.3.6. 
Karnofsky Performance Status 
Each patient’s Karnofsky Performance Status (Appendix 2) will be assessed. 
7.3.7. 
Polyneuropathy Disability Score 
Ambulation will be evaluated through the PND score (Appendix 3). 
7.3.8. 
NYHA Classification 
New York Heart Association classification will be recorded.  The NYHA classification scale is 
provided in Appendix 1. 
7.3.9. 
 Imaging 
7.3.9.1. Echocardiography 
An echocardiogram with Doppler will be used for assessment of cardiac structure and function.  
Echoes obtained at the Screening/Baseline visit will be used to assess eligibility criteria. 
Details for image acquisition and upload for central review can be found in the ALN-TTRSC 
Site Operations Manual. 


 
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7.3.9.2. Cardiac Magnetic Resonance Imaging  
Cardiac magnetic resonance imaging with late gadolinium enhancement will only be performed 
on patients without contraindications (ie, pacemakers, severe renal failure with eGFR 
<30 mL/min/1.73 m
2, defibrillators, or allergy to gadolinium).  This test will be performed only 
at select sites and in a subset of patients (up to 60).  Patients are not required to repeat CMR if 
the assessment is performed within 6 months of randomization. 
Details for image acquisition and upload for central review can be found in the ALN-TTRSC 
Site Operations Manual. 
7.3.9.3. Technetium Imaging 
Technetium imaging assessments performed as part of the study are for research and are not 
intended to be used for diagnostic purposes.  
99mTc imaging by 3D SPECT during the study will be performed only at selected sites and in a 
subset of patients (up to 60).  Either PYP-Tc or DPD-Tc can be used as the tracer.  The tracer 
used for a patient should not be changed during the study.  This test will be performed only at 
select sites.  All time points will be evaluated by a central lab.  Patients are not required to repeat 
99mTc scintigraphy if assessment was performed within 6 months of randomization. 
Technetium scintigraphy used to fulfill the inclusion criterion for evidence of cardiac amyloid 
deposition are not performed as part of the study assessments, but will be evaluated by a central 
reader for confirmation of the required cardiac uptake.
26, 27, 28 
Details for the image acquisition and upload for central review can be found in the ALN-TTRSC 
Site Operations Manual. 
7.3.10. Questionnaires 
7.3.10.1. Kansas City Cardiomyopathy Questionnaire 
The KCCQ is a self-administered, 23-item questionnaire that assesses physical function, 
symptoms, social function, self-efficacy and knowledge, and QoL.  Each patient is to complete 
this questionnaire. 
7.3.10.2. EQ-5D Quality of Life 
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.  Each patient is to complete this 
questionnaire. 
7.3.11. NT-proBNP, BNP, Troponin T, and Troponin I 
Blood samples will be collected and analyzed for the quantification of troponin T, troponin I, and 
NT-proBNP (biomarkers of cardiac status).  BNP will only be collected at Screening/Baseline.  
Quantification of these biomarkers will be performed at a central laboratory. 


 
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7.3.12. Mortality and Hospitalization 
All events will be recorded from Day 0 and beyond; reasons for mortality and hospitalization 
will be adjudicated by an independent Clinical Adjudication Committee. 
7.4. 
Pharmacokinetic Assessment 
Blood samples will be taken for the assessment of plasma levels of ALN-TTRSC at the 
following time points during the study:  
• Days 0, Month 6 and Month 12:  within 1 hour predose and 2.5±1 hour postdose 
• A sample will be collected at the Early Termination visit, if applicable. 
Exploratory analyses may also be conducted on plasma samples to evaluate metabolites of ALN-
TTRSC.   
7.5. 
Safety Assessments 
7.5.1. 
Physical Examination 
Routine physical examinations will be performed.  Physical examinations will include the 
examination of the following:  general appearance, head, eyes, ears, nose and throat, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, 
dermatological/skin, thyroid/neck, lymph nodes, and neurological/psychiatric. 
7.5.2. 
Vital Signs 
Vital sign measurements include blood pressure, pulse rate, oral body temperature, and 
respiratory rate.  Vital signs will be measured manually in the supine position after the patient 
has rested comfortably for 10 minutes.  Each patient’s blood pressure should be taken using the 
same arm.  Oral temperature will be obtained in degrees Celsius, heart rate will be counted for a 
full minute and recorded in beats per minute (bpm), and respirations will be counted for a full 
minute and recorded in breaths per minute. 
When vital signs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled time point, and the vitals will be obtained prior to the blood draw.  On 
dosing days, vital signs should be obtained prior to dosing. 
For the safety of the patient, additional vital sign assessments may be added at the discretion of 
the Investigator. 
7.5.3. 
Weight and Height 
Height will be measured only at Screening/Baseline Visit.  
Body weight will be measured in kilograms (kg) at the time points specified in the schedule of 
assessments (SOA). 
7.5.4. 
Electrocardiogram (ECG) 
Standard computerized 12-lead ECG recordings will be obtained.  Each lead shall be recorded 
for at least 3 beats at a speed of 25 mm/sec.  Triplicate recordings will be obtained prior to 


 
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dosing.  The electrophysiological parameters assessed will be rhythm, ventricular rate, PR 
interval, QRS duration, QT interval, ST and T waves, Bazett-corrected QT interval (QTcB) and 
Fredericia-corrected QT interval (QTcF). 
When an ECG is scheduled at the same time as blood draws, the blood draws will be obtained at 
the scheduled time points and the ECG will be obtained prior to the scheduled blood draw. 
The Investigator or designee is responsible for reviewing the ECGs to assess whether the results 
have changed since the Screening/Baseline visit and to determine the clinical significance of the 
results.  These assessments will be recorded on the CRF.  For any clinically significant changes 
from Screening/Baseline (e.g., ischemic ECG changes, wave/interval changes, or arrhythmia), 
the Investigator must contact the CRO Medical Monitor to discuss continued participation of the 
patient in the study. 
7.5.5. 
Laboratory Assessments 
The following clinical laboratory tests will be performed by a central laboratory, unless indicated 
otherwise: 
 


 
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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 Chemistry 
• Sodium 
• Potassium 
• Blood urea nitrogen (BUN) 
• Phosphate 
• Creatinine 
• Albumin 
• Uric acid 
• Calcium 
• Lactate dehydrogenase (LDH) 
• Carbon dioxide 
• Glucose 
• Chloride 
Liver Function Tests 
 
• AST 
• Alkaline phosphatase (ALP) 
• ALT 
• Bilirubin (total and direct) 
Coagulation Studies 
• Prothrombin time (PT) 
• International Normalized Ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
Thyroid Function Test 
• Thyroid stimulating hormone (TSH) 
 
Serology Parameters 
• Hepatitis B surface antigens (HBsAg) 
• Hepatitis B surface antibodies (HBsAb) 
• Anti-hepatitis C virus antibodies (HCV Ab) 
 
Urinalysis 
• Visual inspection for appearance and color 
• Bilirubin 
• pH (dipstick) 
• Nitrite 
• Specific gravity 
• RBCs 
• Ketones 
• Urobilinogen 
• Protein 
• Leukocytes 
• Glucose 
• Microscopy (if clinically indicated) 
Pregnancy Testing (WOCBP only) 
• β-human chorionic gonadotropin 
Other 
• Vitamin A 
• Serum SPEP with IFE (or documented local results 
within last year) 
• Urine SPEP with IFE (or documented local 
results within last year) 
• Serum FLC (or documented local results within 
last year) 


 
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WOCBP = women of child bearing potential 
Additional and repeat testing may be performed at the discretion of the Investigator. 
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. 
7.5.5.1. Anti-drug Antibodies 
Serum samples will also be collected at scheduled time points prior to dosing to evaluate ADAs. 
7.5.5.2. Pregnancy Screen 
A serum pregnancy test will be performed for women of child bearing potential (WOCBP) at 
Screening/Baseline.  A urinary pregnancy test will be performed any time pregnancy is 
suspected, and in accordance with the SOA.  Urine pregnancy test may also be performed more 
frequently (monthly) based on local country requirements.  The results of the pregnancy test 
must be known prior to administration of study drug.  Patients who are pregnant are not eligible 
for study participation.  Patients determined to be pregnant while on study will be followed until 
the pregnancy outcome is known (see Section 8.10). 
7.5.6. 
Ophthalmologic Examination 
An ophthalmologic examination will be performed at Screening/Baseline and in accordance with 
the Table 1-1.  Patients are not required to repeat the ophthalmologic examination if the 
assessment was performed within 90 days of randomization.  Visual acuity should be evaluated 
at the beginning of each specified visit (ie, prior to slit-lamp examination).  Manifest refraction 
will be performed at each specified visit, where possible, 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 and be tested in bright and dim light conditions.  
Further details regarding the ophthalmologic examinations will be provided in the Site 
Operations Manual. 
7.5.7. 
Concomitant Medications 
All medications the patient receives during the Screening/Baseline period through the Follow-up 
Visit will be recorded.  The indication for the medication must be assessed to determine if a new 
AE is present.  See Section 5.1 for more details on prohibited and acceptable concomitant 
medications. 
7.5.8. 
Adverse Events 
Starting on Day 0, adverse events will be assessed and recorded.  The reporting guidelines are 
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7.6. 
Other Assessments 
7.6.1. 
Exploratory Biomarkers 
Where local regulations permit, blood samples will also be collected at scheduled time points 
prior to dosing to evaluate exploratory biomarkers (mutant: WT TTR levels and additional 
cardiac and hepatic-derived proteins that may include galectin 3 and ST2).  Aliquots of plasma 
and serum samples will be taken and frozen, to permit testing of the effect of ALN-TTRSC on 
the expression of these exploratory biomarkers. 
Collection of samples for exploratory biomarker analysis will be subject to discretionary 
approval from each site’s IRB/IEC.  Samples will be stored by the Sponsor or designee in a 
secure and controlled environment until analysis, and will be destroyed by the Sponsor or 
designee after all worldwide obligations have been met, or sooner if required by local 
regulations. 
7.6.2. 
DNA Sample 
Where local regulations permit and subject to discretionary approval from each center’s 
IRB/IEC, a voluntary blood sample for DNA extraction will be collected from each patient at 
Screening/Baseline.  The voluntary DNA sample should only be obtained once during Screening.  
The results may be used as part of a later analysis, which could include a determination of the 
spectrum of TTR mutations in patients with ATTR and the relationship between TTR gene 
mutation and the safety and efficacy of ALN-TTRSC.  The Sponsor will only analyze DNA 
sequences within genes relevant to the mode of action and response to ALN-TTRSC.  No 
additional testing will be performed on the samples collected in the study.  
DNA samples will be stored by the Sponsor, or designee, in a secure, monitored, and controlled 
environment until analysis, and will be destroyed by the Sponsor after all worldwide obligations 
have been met, or sooner if required by local regulations. 
7.6.3. 
Pharmacoeconomics Questionnaire 
Disease burden and healthcare utilization will be assessed using a patient reported 
pharmacoeconomics questionnaire.  


 
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8. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
8.1. 
Adverse Events 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. 
All injection site reactions will be recorded as AEs. 
8.1.1. 
Adverse Events of Clinical Interest 
The following events are considered to be AEs of clinical interest: 
• ISRs 
• Hepatic AEs, including LFT abnormalities considered clinically significant by the 
Investigator 
8.2. 
Serious Adverse Event (SAE) 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 in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality 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 and may require intervention to 
prevent one of the other outcomes listed in the definition above (e.g.  events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias, 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). 


 
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In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, ECG changes, or other findings that are 
relevant to patient safety. 
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 the end of the reporting 
periods defined in Section 8.5. 
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 after the first dose of study 
drug, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ eCRF, 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). 
For AEs that are considered AEs of clinical interest, additional clinical information may be 
collected based upon the severity or nature of the event.  If a patient has ISRs meeting any of the 
following criteria, the Investigator, or delegate, should contact the Medical Monitor and submit a 
supplemental ISR eCRF: 
• ISRs that are recurrent and/or demonstrate a pattern of increasing severity 
• Any ISR that is determined to be severe and/or a cause for study drug discontinuation  
• Any ISR which, in the opinion of the Investigator, requires further medical evaluation or 
treatment 
In some cases, where it is medically appropriate, further evaluation may include photographs, 
referral to a dermatologist, skin biopsy, or other laboratory testing.  If a biopsy was obtained, the 
Sponsor may request that the biopsy also be reviewed by a central dermatopathologist.   
For patients with hepatic AEs, local laboratory results may be collected to monitor LFT levels or 
other laboratory parameters. 
Refer to the CRF completion guidelines for details on reporting events in the supplemental AE of 
clinical interest eCRF form(s).  When the form(s) is/are completed, 
 
 personnel will be notified electronically and may 
follow-up with queries. 
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, Week 82.  All AEs that occur after the start of study drug administration on 
Day 0 must be reported in detail on the appropriate eCRF page and followed to 
satisfactory resolution, or through the End of Study Visit after the last dose of study 
drug administration.  Serious AEs will be followed through the End of Study Visit, or 


 
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until satisfactory resolution, or until the SAE is considered by the Investigator to be 
chronic or the patient is stable. 
• For patients who withdraw from the study early, ongoing AEs will be followed until 
resolution or 28 days from last dose, whichever occurs first.  Serious AEs will be 
followed through 28 days from the last dose of study drug, or until satisfactory 
resolution, or until the SAE is considered by the Investigator to be chronic or the 
patient is 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 normal daily activities. 
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 


 
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require documentation of the start and stop of each incidence.  When changes 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. 
Coding of Adverse Events 
The Medical Dictionary of Regulatory Activities (MedDRA) will be used to code AEs. 
8.9. 
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 seriousness criteria above (Section 8.2) must be reported to 
the CRO 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, and  
• Preliminary assignment of causality to study drug 
To report the SAE, complete the paper SAE form and fax it to 
 (fax number is 
provided in the Site Operations Manual) within 24 hours of awareness.  SAE information must 
also be entered into the EDC system on the Adverse Events page within 5 calendar days of 
awareness. 
Follow-up information must be provided to 
 using the paper SAE report (fax 
number is provided in the Site Operations Manual) within 24 hours of the information becoming 
available.   The Investigator should also submit any supporting documentation such as a patient 
discharge summary or autopsy reports.  Updated/follow-up SAE information must also be 
entered into the EDC system on the Adverse Events page within 5 calendar days of receiving the 
information.    
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. 
8.9.1. 
Notifying the IRB/IEC 
SAEs will be reported to the IRB/IEC per their institutional policy by the Investigator or Sponsor 
(or Sponsor designee) according to country requirements.  Copies of each report and 
documentation of IRB/IEC notification and acknowledgement of receipt will be kept in the 
Investigator’s study file. 


 
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8.9.2. 
Sponsor Reporting: Notifying Regulatory Authorities 
The Sponsor or its representative is required to report certain study events in an expedited 
manner to the FDA, the European Medicines Agency’s EudraVigilance electronic system 
according to Directive 2001/20/EC, and to all country Regulatory Authorities where the study is 
being conducted, according to local applicable regulations. 
The following describes the safety reporting timeline requirements for suspected unexpected 
serious adverse reactions (SUSARs) and other reportable events: 
Immediately and within 7 calendar days 
• Any suspected adverse reaction that is:  associated with the use of the study drug, 
unexpected, and fatal or life threatening.  Follow-up information must be reported in the 
following 8 days. 
Immediately and within 15 calendar days 
• Any suspected adverse reaction that is:  associated with the use of the study drug, 
unexpected, and serious, but not fatal or life threatening, and there is evidence to suggest 
a causal relationship between the study drug and the reaction. 
• Any finding from tests in laboratory animals that:  suggest a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• Any event in connection with the conduct of the study or the development of the study 
drug that may affect the safety of the trial subjects. 
In addition, periodic safety reporting to regulatory authorities will be done by the Sponsor or its 
representative according to national and local regulations. 
8.9.3. 
Sponsor Reporting: Notifying Participating Investigators 
All Investigators will be informed by the Sponsor or its representative of relevant clinical safety 
findings from this or other clinical studies, as well as any new findings from tests in laboratory 
animals that significantly impact the benefit/risk to patients in this study.  All reports should be 
transmitted to the IEC/IRB that approved the study. 
8.10. 
Pregnancy Reporting 
A female patient with a positive pregnancy test at Screening/Baseline is ineligible for this study.  
If a female patient becomes pregnant during the course of this study (or during the first month 
following the last dose of study drug), the patient must be instructed to stop all study drug 
administration, and the Investigator must 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. 
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 


 
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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 as outlined in Section 8.9. 
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. 
STATISTICS 
9.1. 
Sample Size 
For the 6-MWT primary endpoint, a sample size of 180 with a 2:1 treatment allocation (N=120 
on ALN-TTRSC and N=60 on placebo) has 90% power to detect a treatment difference of 
0.55 standard deviations using a Finkelstein and Schoenfeld analysis with a significance level of 
0.05.29  This assumes 20% of placebo patients and 13% of ALN-TTRSC patients die before the 
18 month assessment (ie, Hazard Ratio [HR]=0.6).  Assuming a standard deviation of 70 meters 
in change from baseline, this would correspond to 90% power to detect a treatment effect of 
39 meters in the 6-MWT.  Assuming a 10% patient dropout rate, approximately 200 patients will 
be enrolled in the study.  Note that power for the comparison of percent reduction in serum TTR 
between treatment groups is expected to be >90% for a significance level of 0.05; sustained 
knockdown of serum TTR levels >85% has been observed in healthy volunteers and patients 
receiving ALN-TTRSC (Section 1.3).  For this reason, overall power to establish efficacy is 
expected to be approximately 90% under the assumptions described above. 
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) will be evaluated and used for presentation 
of the data: 
• Modified intent to treat (mITT) population:  all patients who were randomized and 
received at least 1 dose of ALN-TTRSC or placebo. 
• Per protocol (PP) population:  all patients who did not have any major protocol 
violations; and completed the 18-month 6-MWD assessment or died on-study. 
• Safety population:  All patients who received at least 1 dose of ALN-TTRSC or 
placebo (analyzed as treated, not as randomized). 
The primary population for efficacy analyses will be the mITT population; the key efficacy 
results will also be analyzed 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. 


 
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9.2.3. 
Efficacy Analyses 
9.2.3.1. Primary Efficacy Endpoint 
There are two co-primary endpoints.  The first co-primary endpoint is change from baseline (in 
meters) for a 6-MWD conducted 18 months after randomization.  The primary efficacy analysis 
for the comparison of 6-MWD between treatment groups will be conducted using Wilcoxon 
Mann Whitney-based test statistics that will take into account informative missingness due to 
death and the loss of the ability to perform the test.
29  Briefly, in this stratified non-parametric 
rank sum analysis, all pairs of patients within a stratum are compared.  A pair of patients is 
compared first on time to death (if death occurs before 18 months); second on time until the 
inability to perform the test (if it cannot be determined as to which patient in a pair lived longer); 
and third on the change from baseline in 6-MWD at the time of the last assessment shared by 
both patients (if it cannot be determined as to which patient in a pair lived longer and which 
retained the ability to perform the 6-MWD longer).  The analysis will be stratified based on the 
stratification parameters that are used for randomization.  
The second co-primary endpoint is percent reduction from baseline in serum TTR using enzyme-
linked immunosorbent assay.  The area under the effect curve (eAUC) for percent reduction from 
baseline in serum TTR over time, where the y-axis is percent reduction and the x-axis is time 
since randomization, will be compared across groups using Analysis of Covariance (ANCOVA), 
in which the stratification variables and baseline serum TTR level will be included in the model 
as covariates.  The eAUC will be computed using the trapezoidal method, where assessments 
missing due to death or discontinuation will be imputed using the baseline level, i.e., the percent 
reduction will be assumed to be 0%. 
The study will have demonstrated efficacy if the p-value for each of the co-primary endpoints is 
≤0.05 (2-sided). 
Sensitivity analyses for each co-primary endpoints, including different methods for handling of 
the missing data, will assess the robustness of the primary analysis for the mITT population. 
9.2.3.2. Secondary Efficacy Endpoints 
The secondary composite of CV mortality and CV hospitalization, as well as change in NYHA 
class and change in KCCQ, will also be compared across treatment groups using stratified 
Finkelstein and Schoenfeld Joint Rank Tests.  CV mortality and all-cause mortality will be 
compared across treatment groups using stratified log-rank tests.  CV hospitalizations will be 
compared using the stratified Anderson-Gill model for recurrent events.  Analyses will be 
stratified using the stratification parameters that are used for randomization. 
Type I error control for secondary endpoints will be achieved by a hierarchical ordering 
procedure.  Endpoints will be compared across treatment groups in the following pre-specified 
order:  
• Composite CV mortality and CV hospitalization 
 
• New York Heart Association (NYHA) class (Appendix 1) 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) 


 
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• Cardiovascular (CV) mortality 
• CV hospitalization 
• All-cause mortality 
If and only if a comparison is significant at p<0.05, the next endpoint in the hierarchy may be 
formally tested.  
9.2.4. 
Safety Analyses 
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. 
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. 
Pharmacokinetic Analyses 
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.  
Plasma PK will be summarized and descriptive statistics conducted for each time point. 
Inferential statistics of efficacy and PK/PD relationships will be conducted where possible. 
PK-PD data will be analyzed via a population PK-PD model in order to leverage the sparse 
nature of the dataset.  Details regarding the PKPD methods will be provided in a 
Pharmacokinetic Analysis Plan (PAP). 
9.2.6. 
Interim Analysis 
An unblinded interim analysis for futility may be conducted once approximately half the patients 
have completed the study.  Further details will be included in the Statistical Analysis Plan (SAP). 
 


 
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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. Electronic Case Report Forms 
The Investigator and designees agree to maintain accurate eCRFs 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. 
The Sponsor or CRO will supply eCRFs for each patient. Case report forms must be completed 
only by persons designated by the Investigator.  Corrections must be made so as to not obliterate 
the original data and must be identified and dated by the person who made the correction.  All 
data entered into the eCRF must also be available in the source documents.  The Investigator will 
allow designated Sponsor representatives and regulatory bodies to have direct access to the 
source documents to verify the data reported in the eCRFs. 
Each completed eCRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed eCRF will be the records maintained by the Sponsor.  A copy of the 
eCRF will remain in the Investigator
's files. 
10.1.2. Monitoring 
The clinical monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the monitor will visit the Investigator and site 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 the Sponsor 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 the Sponsor 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 the Sponsor, representatives from the Sponsor, or 
regulatory agencies access to all study records. 


 
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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) 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 the Sponsor 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 the Sponsor 
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 the Sponsor 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. 


 
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The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  The site-specific ICF must be reviewed and approved by the 
Sponsor 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 the Sponsor.  Revisions to the ICF required 
during the study must be agreed upon, and a copy of the revised ICF provided to the Sponsor. 
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 the Sponsor 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 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 DMC will not stop the trial for efficacy.  
The membership of the DMC and reporting structure are defined in the DMC Charter. 
10.3.2. Independent Clinical Adjudication Committee 
An independent clinical adjudication committee will perform a blinded adjudication of the 
causes of hospitalization and death, with the goal to identify cause of mortality (CV and 


 
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all-cause) and hospitalization (CV and HF).  Each review will follow procedures detailed 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 the Sponsor. 
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 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 the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The International Conference on Harmonisation 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 the Sponsor 
The Sponsor 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 the Sponsor 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. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor 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 the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (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 the Sponsor, thereby allowing no unwarranted access to the 
information.  When reporting results for interim safety assessment and at the end of the study, 
the code will be shared per standard operating procedures with the responsible member of the 


 
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Biostatistical and Data Management Departments of the CRO.  The numbering code will also be 
held for samples in storage until marketing approval of ALN-TTRSC in the countries where this 
study was conducted, or until clinical development of ALN-TTRSC is halted.   
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.  The Sponsor must approve 
any transfer of information not directly involved in the study. 
10.8. 
Publications/Reports 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A copy of any proposed manuscript 
must be provided and confirmed received at Alnylam at least 30 days prior to its submission, and 
according to any additional publication details in the Investigator Agreement.  


 
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11. 
LIST OF REFERENCES 
1. Stangou, A.J. and P.N. Hawkins, Liver transplantation in transthyretin-related familial 
amyloid polyneuropathy. Curr Opin Neurol, 2004. 17(5): p. 615-20. 
2. Connors LH, Lim A, Prokaeva T,Costello CE. Tabulation of human transthyretin (TTR) 
variants. Amyloid. 2003 Sep;10(3):160-84. 
3. Yazaki M, Tokuda T, Nakamura A, Higashikata T, Koyama J, Higuchi K, et al. Cardiac 
amyloid in patients with familial amyloid polyneuropathy consists of abundant wild-type 
transthyretin. Biochem Biophys Res Commun. 2000 Aug 11;274(3):702-6. 
4. Westermark P, Bergstrom J, Solomon A, et al. Transthyretin-derived senile systemic 
amyloidosis: clinicopathologic and structural considerations. Amyloid 2003;10 Suppl 
1:48-54. 
5. Jacobson DR, Pastore RD, Yaqhoubian R, Kane I, Gallo G, Buck FS, et al. Variant sequence 
transthyretin (isleucine 122) in late-onset cardiac amyloidosis in black americans. N Engl 
J Med, 1997 Feb 13;336(7):466-73.  
6. Dharmarajan K, Maurer M. Transthyretin cardiac amyloidoses in older North Americans. J 
Am Geriatr Soc. 2012 Apr;60(4):765-74. 
7. Sattianayagam PT, Hahn AF, Whelan CJ, Gibbs SD, Pinney JH, Stangou AJ, et al. Cardiac 
phenotype and clinical outcome of familial amyloid polyneuropathy associated with 
transthyretin alanine 60 variant. Eur Heart J. 2012 May;33(9):1120-7 
8. Connors L, Prokaeva T, Lim A, Théberge R, Falk RH, Doros G, et al. Cardiac amyloidosis in 
African Americans: comparison of clinical and laboratory features of transthyretin V122I 
amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009 
Oct;158(4):607-14 
9.  Connors L.H., Doros, G., Sam, F., Badiee, A., Seldin, D., and Skinner, M. (2011). Amyloid. 
Informa Healthcare, 3. 
10. Ruberg, F.L., Maurer, M.S., Judge, D.P., Zeldenrust, S., Skinner, M., Kim, A.Y., Falk, R.H., 
Cheung, K.N., Patel, A.R., Pano, A., et al. Prospective evaluation of the morbidity and 
mortality of wildtype and V122I mutant transthyretin amyloid cardiomyopathy: the 
Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J 2012; 164, 222-228 
e221. 
11. Vaishnaw AK, Gollob J, Gamba-Vitalo C, Hutabarat R, Sah D, Meyers R, et al. A status 
report on RNAi therapeutics. Silence. 2010 Jul 8;1(1):14. 
12.  Elbashir SM, Lendeckel W, Tuschi T. RNA interference is mediated by 21- and 22-
nucleotide RNAs. Genes Dev. 2001 Jan 15;15(2):188-200. 
13. Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, et al. Therapeutic 
silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 
2004 Nov 11;432:173-8. 


 
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14. Coelho T, Silva A, Suhr OB, et al.  Final Phase 1 safety, pharmacokinetic and 
pharmacodynamics results for ALN-TTR01, a novel RNAi therapeutic for the treatment 
of transthyretin amyloidosis. 13th International Symposium of Amyloidosis, 2012 Oral 
Presentation. 
15. Fitzgerald K, Frank-Kamenetsky M, Mant T, et al. Phase I safety, pharmacokinetic and 
pharmacodynamics results for ALN PCS02, a novel RNAi therapeutic for the treatment 
of hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology 2012 
Scientific Sessions. Oral Presentation. 
16. Alahdab, M.T., Mansour, I.N., Napan, S., and Stamos, T.D. Six minute walk test predicts 
longterm all-cause mortality and heart failure rehospitalization in African-American 
patients hospitalized with acute decompensated heart failure. J Card Fail 2009; 15, 130-
135.  
17. Mangla, A., Kane, J., Beaty, E., Richardson, D., Powell, L.H., and Calvin, J.E., Jr. 
Comparison of predictors of heart failure-related hospitalization or death in patients with 
versus without preserved left ventricular ejection fraction. Am J Cardiol 2013; 112, 1907-
1912. 
18. Ahmed, A., Aronow, W.S., and Fleg, J.L. Higher New York Heart Association classes and 
increased mortality and hospitalization in patients with heart failure and preserved left 
ventricular function. Am Heart J 2006; 151, 444-450. 
19.  Bittner, V., Weiner, D.H., Yusuf, S., Rogers, W.J., McIntyre, K.M., Bangdiwala, S.I., 
Kronenberg, M.W., Kostis, J.B., Kohn, R.M., Guillotte, M., et al. Prediction of mortality 
and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. 
SOLVD Investigators. JAMA 1993; 270, 1702-1707 
20. Herlenius, G., Wilczek, H.E., Larsson, M., and Ericzon, B.G. Ten years of international 
experience with liver transplantation for familial amyloidotic polyneuropathy: results 
from the Familial Amyloidotic Polyneuropathy World Transplant Registry. 
Transplantation 2004; 77, 64-71. 
21. Sharma, P., Perri, R.E., Sirven, J.E., Zeldenrust, S.R., Brandhagen, D.J., Rosen, C.B., 
Douglas, D.D., Mulligan, D.C., Rakela, J., Wiesner, R.H., et al. Outcome of liver 
transplantation for familial amyloidotic polyneuropathy. Liver Transpl 2003; 9, 1273-
1280. 
22. Tashima, K., Ando, Y., Terazaki, H., Yoshimatsu, S., Suhr, O.B., Obayashi, K., Yamashita, 
T., Ando, E., Uchino, M., and Ando, M. Outcome of liver transplantation for 
transthyretin amyloidosis: followup of Japanese familial amyloidotic polyneuropathy 
patients. J Neurol Sci 1999; 171, 19-23. 
23. Lachmann, H.J., Gallimore, R., Gillmore, J.D., Carr-Smith, H.D., Bradwell, A.R., Pepys, 
M.B., and Hawkins, P.N. 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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24. Lachmann, H.J., Goodman, H.J., Gilbertson, J.A., Gallimore, J.R., Sabin, C.A., Gillmore, 
J.D., and Hawkins, P.N. Natural history and outcome in systemic AA amyloidosis. N 
Engl J Med 2007; 356, 2361-2371. 
25. Am J Respir Crit Care Med Vol 166. pp 111–117, 2002. 
http://www.thoracic.org/statements/resources/pfet/sixminute.pdf 
26. Maurer M.S., Falk R.H., Merlini G., Damy T., et. Al.  Diagnosis of cardiac transthyretin 
amyloidosis in the absence of histology. Gillmore J.D., Manuscript submitted for 
publication. 
27. Bokhari, S., Castaño, A., Pozniakoff, T., Deslisle, S., Latif, F., Maurer, M.S.  99mTc-
Pyrophosphate Scintigraphy for Differentiating Light-Chain Cardiac Amyloidosis From 
the Transthyretin-Related Familial and Senile Cardiac Amyloidoses.  Circ Cardiovasc 
Imaging. 2013;6:195-201. 
28. Perugini E., Guidalotti P.L., Salvi F., Cooke Cinzia Pettinato R.M.T., Riva L., et. Al.  
Noninvasive Etiologic Diagnosis of Cardiac Amyloidosis Using 99mTc-3,3-Diphosphono-
1,2-Propanodicarboxylic Acid Scintigraphy.  J Am Coll Cardiol 2005;46:1076–84. 
29. Finkelstein, D.M., and Schoenfeld, D.A. Combining mortality and longitudinal measures in 
clinical trials. Stat Med 1999; 18, 1341-1354. 


 
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12. 
APPENDICES 
APPENDIX 1. 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 2. 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 3. 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. 
 

SAP_001.pdf: 
Alnylam Pharmaceuticals 
Protocol No.: ALN-TTRSC-004 
A Phase 3 Multicenter, Multinational, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
ALN-TTRSC in Patients with Transthyretin (TTR) Mediated Familial 
Amyloid otic Cardiomyopathy (F 
AC) 
STATISTICAL ANALYSIS PLAN 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 
Version: 1.0 
Date of Issue: 21 October 2015 
 CONFIDENTIAL 
Page 1 of45 


Statistical Analysis Plan 
Version: 1.0 
Date oflssue: 21 October 2015 
AlnylamProtocol No. ALN-TTRSC-004 
APPROVALS 
The undersigned agree that all required reviews of this document are complete, and approve this Statistical 
Analysis Plan as final. 
 Approval: 
Signature 
Date 
 Senior Manager, Biostatistics 
Printed Name/Title 
Signature 
Date 
 Senior Manager, Health Economics and Outcomes Research 
Printed Name/Title 
Alnylam Approval: 
Signature 
 Senior Manager, Biostatistics 
.; Senior Director, Biometrics 
Printed N arne/Title 
 Senior Dire tor, Clinical Development 
d Name/Title 
Signature 
Date 
Senior Vice Presi 
Printed Name/Title 
 CONFIDENTIAL 
Page 2 of45 


Statistical Analysis Plan 
Version: 1.0 
Date of-Issne: 21 October 2015 
AlnylamProtocol No. ALN-TTRSC-004 
APPROVALS 
The undersigned agree that all required reviews of this document are complete, and approve this Statistical 
Analysis Plan as final. 
 
Approval: 
s
 
Date 
Senior Manager, Biostatistics 
Printed Name!ritle 
Signature 
. Date 
Senior Manager, Health Economics and Outcomes Research 
Printed N arne/Title 
Alnylam Approval: 
Signature 
Date 
MA; Senior Manager, Biostatistics 
Printed Name/Title 
Signature 
Date 
 Senior Director, Biometrics 
Printed Name/Title 
Signature 
Date 
Senior Director, Clinical Development 
Printed Name/Title 
Signature 
Date 
Senior Vice President, Clinical Development 
Printed Name/Title 
 CONFIDENTIAL 
Page 2 of45 




Statistical Analysis Plan 
Version: 1.0 
Date oflssue: 21 October 2015 
Alnylam Protocol No. ALN-TTRSC-004 
APPROVALS 
The undersigned agree that all required reviews of this document are complete, and approve this Statistical 
Analysis Plan as final. 
Approval: 
Signature 
Date 
Senior Manager, Biostatistics 
P
_,...=O_c_f---==Z:::....:J,_-f'h_~2c.-:O:....:..../-=-~--
s
 
D•« 
 Senior Manager, Health Economics and Outcomes Research 
Printed Name/Title 
Alnylam Approval: 
Signature 
Date 
Senior Manager, Biostatistics 
Printed Name/Title 
Signature 
Date 
Senior Director, Biometrics 
Printed Name/Title 
Signature 
Date 
Senior Director, Clinical Development 
Printed Name/Title 
Signature 
Date 
 Senior Vice President, Clinical Development 
Printed Name/Title 
 CONFIDENTIAL 
Page 2 of45 




Statistical Analysis Plan 
Version: 1.0 
Date oflssue: 21 October 2015 
Alnylam Protocol No. ALN-TTRSC-004 
TABLE OF CONTENTS 
APPROVALS ............................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................................... 5 
1 SOURCE DOCUMENTS ...................................................................................................................... 7 
2 PROTOCOL DETAILS ........................................................................................................................ 7 
2.1 Study Objectives ............................................................................................................................ 7 
2.2 Overall Study Design .................................................................................................................... 7 
2.3 Sample Size and Power ................................................................................................................. 7 
3 EFFICACY AND SAFETY VARIABLES .......................................................................................... 8 
3.1 Primacy Efficacy Endpoints ......................................................................................................... 8 
3.2 Secondary Efficacy Endpoints ..................................................................................................... 8 
3.3 Exploratory Efficacy Endpoints .................................................................................................. 8 
3.4 Safety-Variables ............................................................................................................................. 9 
3.5 Other Variables ............................................................................................................................. 9 
4 PHARMACOKINETIC/PHARMACODYNAMIC VARIABLES ................................................... 9 
5 ANALYSIS POPULATIONS ................................................................................................................ 9 
5.1 Modified Intent-to-Treat .............................................................................................................. 9 
5.2 Safety-.............................................................................................................................................. 
9 
5.3 Per-Protocol ................................................................................................................................... 
9 
5.3.1 Protocol Deviations Leading to Exclusion from the PP Analysis ..................................... 10 
6 DATA HANDLING ............................................................................................................................. 11 
6.1 Time Points and Visit Windows ................................................................................................. 11 
6.2 Handling of Dropouts or Missing Data ..................................................................................... 12 
6.2.1 
6.2.2 
Efficacy Analysis .............................................................................................................. 12 
Safety Analysis ................................................................................................................. 12 
7 STATISTICAL METHODS ............................................................................................................... 13 
7.1 General Principles ....................................................................................................................... 13 
7.2 Subject Disposition and Data Sets Analyzed ............................................................................ 13 
7.3 Protocol Deviations ..................................................................................................................... 14 
7.4 Demographics and Other Baseline Characteristics ................................................................. 14 
7.4.1 Medical History ................................................................................................................. 15 
7.4.2 Previous and Concomitant Medications ............................................................................ 15 
7.5 Extent ofExposure ...................................................................................................................... 15 
7.6 Efficacy ......................................................................................................................................... 16 
7.6.1 Primary Efficacy Analysis ................................................................................................ 16 
7.6.1.1 
Change from Baseline in 6-MWD at Month 18 .......................................................... 16 
 CONFIDENTIAL 
Page 3 of46 


Statistical Analysis Plan 
Version: 1.0 
Date of Issue: 21 October 2015 
Protocol No. ALN-TTRSC-004 
7.6.1.2 
Sensitivity Analyses for Change in 6-MWD from Baseline at Month 18 ................... 17 
7.6.1.3 
Percent reduction in serum TTR from Baseline over 18 months ................................ 18 
7 .6.1.4 
Sensitivity Analyses for Percent Reduction in Serum TTR from Baseline over 18 
months ......................................................................................................................... 18 
7.6.1.5 
Subgroup Analysis ...................................................................................................... 19 
7.6.2 Secondary Efficacy Analysis ............................................................................................ 19 
7.6.2.1 
Composite CV Mortality and CV Hospitalization ....................................................... 20 
7.6.2.2 
Change in NYHA from Baseline ................................................................................. 20 
7 .6.2.3 
Change in overall summary score from Baseline-KCCQ ......................................... 21 
7.6.2.4 
CV Mortality ............................................................................................................... 21 
7.6.2.5 
CV Hospitalization ...................................................................................................... 21 
7.6.2.6 
All-cause Mortality ...................................................................................................... 22 
7.6.3 Exploratory Efficacy Analysis .......................................................................................... 22 
7.6.3.1 
Echocardiogram (ECHO) Parameters ......................................................................... 22 
7.6.3.2 
Karnofsky Performance Status .................................................................................... 22 
7. 6.3 .3 
Troponin T and I, and NT proBNP Levels .................................................................. 22 
7.6.3.4 
Cardiac Magnetic Resonance (CMR) Imaging Parameters ......................................... 22 
7.6.3 .5 
Technetium-99m Scintigraphy Parameters .................................................................. 23 
7.6.3.6 
Amyloid in Abdominal Wall Fat Pad Aspirates .......................................................... 23 
7.6.3.7 
Polyneuropathy Disability Score ................................................................................. 23 
7.6.3.8 
Modified Body Mass Index ......................................................................................... 23 
7.6.3.9 
Estimated Glomerular Filtration Rate (eGFR) ............................ 
: 
............................... 24 
7 .6.3 
.1 0 Heart Failure (HF) Hospitalization .............................................................................. 24 
7.6.3.11 EQ-5D-5L .................................................................................................................... 24 
7.6.3.12 Pharmacoeconomic Questionnaire (PEQ) ................................................................... 24 
7. 7 Safety ............................................................................................................................................ 25 
7. 7.1 Adverse Events .................................................................................................................. 25 
7. 7.2 Laboratory Evaluations ..................................................................................................... 26 
7. 7.3 Ophthalmologic Examination ........................................................................................... 26 
7.7.4 Vital Signs, Body Weight and BMI .................................................................................. 27 
7.7.5 Electrocardiograms ........................................................................................................... 27 
7.7.6 Physical Examination ........................................................................................................ 27 
7.7.7 Anti-Drug Antibodies (ADA) ........................................................................................... 27 
7. 7.8 Exploratory Biomarkers .................................................................................................... 28 
7.8 Interim Analysis .......................................................................................................................... 28 
8 REFERENCES ..................................................................................................................................... 28 
9 APPENDICES ...................................................................................................................................... 29 
Appendix I 
Appendix II 
Appendix III 
Appendix IV 
AppendixV 
Appendix VI 
Appendix VII 
Details for Co-primary and Secondary Endpoints ................................................. 29 
Computational Procedure of Finkelstein and Schoenfeld Joint Rank Test ......... 36 
Kansas City Cardiomyopathy Questionnaire (KCCQ) Measure and Scoring .... 38 
EQ-SD-SL Measure and Scoring .............................................................................. 43 
Selected ECHO Parameters ...................................................................................... 44 
Selected CMR Parameters ........................................................................................ 45 
Laboratory Parameters ............................................................................................. 46 
 CONFIDENTIAL 
Page 4 of46 


Statistical Analysis Plan 
Version: 1.0 
Date of Issue: 21 October 2015 
Alnylam Protocol No. ALN-TTRSC-004 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
6-MWD 
Six-minute walk distance 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ANCOVA 
Analysis of covariance 
BMI 
Body mass index 
bpm 
Beats per minute 
EQ-5D-5L 
EuroQoL 5 Domains, 5 Levels of response 
CAC 
Clinical Adjudication Committee 
CMR 
Cardiac magnetic resonance imaging (Cardiac MRI) 
cv 
Cardiovascular 
DMC 
Data Monitoring Committee 
eAUC 
Area under the effect curve 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FAC 
Familial amyloidotic cardiomyopathy 
HF 
Heart failure 
HR 
Heart rate 
ISR 
Injection site reaction 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
KM 
Kaplan-Meier 
MAR 
Missing At Random 
mBMI 
Modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
miTT 
Modified intent-to-treat 
MMRM 
Mixed-effects model repeated measures 
NTproBNP 
N-terminal prohormone ofB-type natriuretic peptide 
NYHA 
New York Heart Association 
PEQ 
Pharmacoeconomics Questionnaire 
PK 
Pharmacokinetic( s) 
PND 
Polyneuropathy Disability 
pp 
Per protocol 
PRO 
Patient Reported Outcome 
PT 
Preferred term 
QTcB 
Bazett-corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
RBP 
Retinol binding protein 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
 CONFIDENTIAL 
Page 5 of46 


Statistical Analysis Plan 
Version: 1.0 
Date of Issne: 21 October 2015 
Alnylam Protocol No. ALN-TTRSC-004 
SD 
Standard deviation 
soc 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
 CONFIDENTIAL 
Page 6 of46