A Phase 2, Open-label Extension Study to Evaluate the Long-Term Safety, Clinical Activity, and Pharmacokinetics of ALN-TTRSC in Patients With Transthyretin (TTR) Cardiac Amyloidosis Who Have Previously Received ALN-TTRSC
Phase: PHASE2
Conditions: TTR-mediated Amyloidosis
Sponsor: Alnylam Pharmaceuticals

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
 
 
Alnylam Pharmaceuticals 
Confidential 
Page 1 of 72
 
 
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CLINICAL STUDY PROTOCOL  
ALN-TTRSC-003 
 
A Phase 2, Open-label Extension Study to Evaluate the Long-Term 
Safety, Clinical Activity, and Pharmacokinetics of ALN-TTRSC in 
Patients with Transthyretin (TTR) Cardiac Amyloidosis Who Have 
Previously Received ALN-TTRSC 
 
Original Protocol: 
20 May 2014 
Amendment 1: 
10 July 2014 
Amendment 2: 
23 October 2014  
Amendment 3: 
25 March 2016 
EudraCT Number 
2014-001229-34 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
Sponsor Contact: 
 
Senior Vice President 
Clinical Development 
 
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. 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
 
 
Alnylam Pharmaceuticals 
Confidential 
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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)  
 
 
 
 
 
Sponsor 
Signature 
 
Date 
 
Name (print) 
 
Senior Vice President 
Clinical Development 
 
 
 
 
 
 
 
 
  

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
Confidential  
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Table of Conte nts 
AUTHORIZED SIGNATORIES 
1 
TABLE OF CONTENTS 
2 
LIST OF TABLES 
7 
LIST OF APPENDICES 
7 
PROTOCOL SYNOPSIS 
8 
ABBREVIATIONS 
25 
1. 
INTRODUCTION 
28 
1.1. 
Background and Rationale 
28 
1.1.1. 
Transthyretin Biology 
28 
1.1.2. 
Disease Overview 
28 
1.1.3. 
RNA Interference 
30 
1.1.4. 
Investigational Drug ALN-TTRSC Overview 
31 
1.2. 
Summary of ALN-TTRSC Nonclinical Data 
31 
1.3. 
Summary of Clinical Data with ALN-TTRSC 
32 
1.4. 
Study Hypothesis and Rationale 
33 
1.5. 
Dose Selection and Rationale 
34 
1.6. 
Risk-Benefit Assessment 
34 
1.6.1. 
Injection Site Reactions 
34 
1.6.2. 
Abnormal Liver Function Tests 
34 
1.6.3. 
Vitamin A Lowering 
35 
1.7. 
Urgent Safety Measures 
35 
2. 
STUDY OBJECTIVES 
36 
2.1. 
Primary Objective 
36 
2.2. 
Secondary Objectives 
36 
2.3. 
Tertiary Objectives 
36 
3. 
STUDY PLAN 
37 
3.1. 
Overall Design 
37 
3.2. 
Safety Assessments 
38 
3.3. 
Pharmacodynamic Assessments 
38 
3.4. 
Pharmacokinetic Assessments 
39 
3.5. 
Exploratory Clinical Efficacy Assessments 
39 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
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Other Assessments 
39 
4. 
PATIENT POPULATION 
40 
4.1. 
Eligibility of Patients 
40 
4.2. 
Inclusion Criteria 
40 
4.3. 
Exclusion Criteria 
40 
4.4. 
Patient Withdrawal 
41 
4.4.1. 
Reasons for Withdrawal 
41 
4.4.2. 
Handling of Withdrawals 
42 
4.4.3. 
Replacements 
42 
5. 
STUDY MEDICATION 
43 
5.1. 
Presentation of Study Drug 
43 
5.2. 
Preparation of Study Drug 
43 
5.3. 
Storage of Study Drug 
43 
5.4. 
Labeling and Packaging of Study Drug 
43 
5.5. 
Dose, Route, and Schedule of Study Drug Measurement of Patient 
Compliance 
44 
5.6. 
Criteria for Dose Interruption, Dose Modification, or Discontinuation 
of Study Drug 
44 
5.7. 
Measurement of Patient Compliance 
45 
5.8. 
Study Drug Accountability 
45 
5.9. 
Concomitant Medication / Treatment 
46 
6. 
STUDY ASSESSMENTS 
47 
6.1. 
Demographic Data and Medical History 
47 
6.2. 
Karnofsky Performance Status 
47 
6.3. 
Estimated Glomerular Filtration Rate 
48 
6.4. 
Safety Assessments 
48 
6.4.1. 
Physical Examination 
48 
6.4.2. 
Body Weight and Height 
48 
6.4.3. 
Vital Signs 
48 
6.4.4. 
Electrocardiogram 
48 
6.4.5. 
Clinical Laboratory Tests 
49 
6.4.6. 
Pregnancy Test 
50 
6.4.7. 
Eye Examination 
50 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
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6.4.8. 
Concomitant Medications 
51 
6.4.9. 
Adverse Events 
51 
6.5. 
Pharmacodynamic Assessments 
51 
6.5.1. 
Transthyretin 
51 
6.5.2. 
Vitamin A 
51 
6.6. 
Pharmacokinetic Evaluations 
51 
6.7. 
Clinical Efficacy Assessments 
51 
6.7.1. 
Review of Cardiac Medical History and Treatment Changes 
51 
6.7.2. 
NT-proBNP, Troponin T, and Troponin I 
52 
6.7.3. 
Echocardiography 
52 
6.7.4. 
Six-Minute Walk Test 
52 
6.7.5. 
NYHA Classification 
52 
6.7.6. 
Cardiac Magnetic Resonance Imaging 
52 
6.7.7. 
Modified Body Mass Index 
52 
6.7.8. 
Kansas City Cardiomyopathy Questionnaire 
52 
6.7.9. 
EQ-5D Quality of Life 
53 
6.7.10. 
Technetium Imaging 
53 
6.7.11. 
Fat Pad Aspirates 
53 
6.8. 
Other Assessments 
53 
6.8.1. 
Exploratory Biomarkers and Serology 
53 
6.8.2. 
Pharmacoeconomics Questionnaire 
53 
7. 
REPORTING ADVERSE EVENTS 
54 
7.1. 
Adverse Event Definition 
54 
7.1.1. 
Adverse Events of Clinical Interest 
54 
7.2. 
Serious Adverse Event Definition 
54 
7.3. 
Eliciting Adverse Event Information 
54 
7.4. 
Adverse Event Reporting 
55 
7.5. 
Adverse Event Reporting Period 
56 
7.6. 
Assessment of Causality 
56 
7.7. 
Assessment of Severity 
56 
7.8. 
Serious Adverse Event Reporting 
57 
7.9. 
Contraceptive Requirements 
58 
7.9.1. 
Requirements for Women of Child-bearing Potential 
58 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
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7.9.2. 
Requirements for Male Patients 
59 
7.10. 
Pregnancy Reporting 
59 
8. 
STATISTICAL METHODS 
60 
8.1. 
Sample Size 
60 
8.2. 
Statistical Methodology 
60 
8.2.1. 
Populations to be Analyzed 
60 
8.2.2. 
Baseline Evaluations 
60 
8.2.3. 
Safety Analyses 
60 
8.2.4. 
Clinical Activity Assessments 
61 
8.2.5. 
Healthcare Utilization Assessments 
61 
8.2.6. 
Pharmacodynamics 
61 
8.2.7. 
Pharmacokinetics 
61 
8.2.8. 
Interim Analysis 
61 
8.2.9. 
Missing Data 
61 
9. 
STUDY MANAGEMENT 
63 
9.1. 
Data Handling and Quality Assurance 
63 
9.1.1. 
Case Report Forms 
63 
9.1.2. 
Monitoring 
63 
9.1.3. 
Inspections 
63 
9.2. 
Regulatory Guidelines 
64 
9.2.1. 
Independent Ethics Committee Institutional Review Board 
64 
9.2.2. 
Regulatory Authorities 
64 
9.2.3. 
Modification of the Protocol 
64 
9.2.4. 
Informed Consent Form 
64 
9.2.5. 
Study Reporting Requirements 
65 
9.2.6. 
Financial Disclosure Reporting Obligations 
65 
9.3. 
Ancillary Research 
65 
9.4. 
Study Record Retention 
65 
9.5. 
Discontinuation of the Study by Alnylam 
66 
9.6. 
Confidentiality 
66 
9.7. 
Publications/Reports 
66 
10. 
REFERENCES 
67 
11. 
APPENDICES 
71 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
Confidential  
Page 6 of 72 
 
Appendix 1: Karnofsky Scale 
71 
Appendix 2: New York Heart Association Classification of Heart Failure 
72 
 
 
 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
Confidential  
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List of Tables 
Table 1: 
Schedule of Assessments for Clinic Visits – Year 1 and Year 2 
14 
Table 2: 
Schedule of Assessments for Clinic Visits – Year 3 and Year 4 
19 
Table 3: 
Schedule of Assessments for Weekly Dosing Days between Clinic 
Visits 
22 
Table 4: 
Pharmacokinetic Sampling Schedule 
24 
 
List of Figures 
Figure 1: 
Study Schematic 
38 
 
List of Appendices 
Appendix 1: Karnofsky Scale 
71 
Appendix 2: New York Heart Association Classification of Heart Failure 
72 
 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
Confidential  
Page 8 of 72 
 
PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2, Open-label Extension Study to Evaluate the Long-
Term Safety, Clinical Activity, and Pharmacokinetics of 
ALN-TTRSC in Patients with Transthyretin (TTR) Cardiac 
Amyloidosis Who Have Previously Received ALN-TTRSC 
Indication 
Treatment of patients with mutant or wild-type (WT) TTR 
cardiac amyloidosis. 
Protocol Number 
ALN-TTRSC-003 
Phase of 
Development 
2 
Design 
This is an open-label, extension study designed to evaluate 
the long-term safety, clinical activity, and pharmacokinetic 
(PK) activity of subcutaneously administered ALN-TTRSC 
(International Nonproprietary Name:  revusiran) in patients 
with TTR cardiac amyloidosis who previously completed the 
ALN-TTRSC-002 study. 
Patients must be screened prior to the administration of study 
medication.  Screening/Baseline assessments may be 
performed during several clinic visits.  Patients must have 
completed the ALN-TTRSC-002 study to be eligible for this 
study. 
Eligible, consenting patients will receive 5 daily doses of 
ALN-TTRSC (Day 0, 1, 2, 3, and 4) and a dose at Day 7. 
They will then receive once weekly doses for the duration of 
the study through Day 1337 (or Early Termination [ET]). 
Doses will be administered at the clinic during Days 0 
through 7. Dosing after Day 7 may be administered at home 
by a healthcare professional trained in the protocol or at the 
clinic if dosing coincides with the clinic visit for other 
assessments. At the discretion of the Investigator, after the 
Day 84 dosing visit and if the patient has not previously 
experienced any severe or serious adverse events (SAEs) 
considered related to the study drug within the previous 
12 weeks, patients/caregivers may be trained by the 
Investigator or qualified site staff in the administration of the 
study drug, according to the protocol dosing requirements.  
Clinic visits will be performed for Screening/Baseline, dose 
initiation during Days 0 through 7, and then approximately 
every 12 weeks through the End of Study visit or ET, and 
approximately 28 days following the End of Study visit or ET 
for a Follow-up visit. 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
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Safety will be assessed by collection of adverse events (AEs); 
clinical laboratory tests, including hematology, serum 
chemistry, kidney and thyroid function, coagulation, and 
urinalysis; 12-lead electrocardiograms (ECGs); vital signs, 
eye examinations, and physical examinations.  Safety 
evaluations will be performed as part of Screening and 
approximately every 12 weeks during the treatment period 
with the exception of eye examinations, which will be 
performed once a year. 
Plasma PK samples will be collected at specified time points 
up through Day 336.  During Years 2, 3, and 4 a single PK 
sample will be collected each year. 
Pharmacodynamic (PD) evaluation will include serial 
measurement of serum levels of TTR at specified time points.  
Serum levels of vitamin A will also be evaluated as a 
secondary PD biomarker. 
Clinical efficacy will be explored through mortality, 
hospitalization, and Six-minute Walk Test (6-MWT).  
Additional clinical assessments will be performed including 
echocardiogram, cardiac magnetic resonance imaging 
(CMR), 99m-Technetium (99m Tc) imaging, circulating cardiac 
biomarkers (including N-terminal prohormone of B-type 
natriuretic peptide [NT-proBNP], troponins I and T), amyloid 
quantitation in fat pad aspirates, estimated glomerular 
filtration rate (eGFR), modified body mass index (mBMI), 
the Kansas City Cardiomyopathy Questionnaire (KCCQ), 
occurrence of new onset or recurrence of atrial fibrillation, 
pacemaker placement, change in diuretic regimen, blood 
pressure, New York Heart Association (NYHA) 
classification, and patient-reported quality of life (QoL) 
assessed by EQ-5D.  Evaluations of clinical efficacy will be 
performed as part of Screening and approximately every 
24 weeks during the treatment period. 
Disease burden and healthcare utilization will be assessed 
approximately every 48 weeks using a patient-reported 
pharmacoeconomics questionnaire. 
Blood samples will also be collected to evaluate exploratory 
biomarkers (mutant:  WT TTR levels and additional cardiac 
and hepatic-derived proteins that may include galectin-3 and 
ST2) and serology and anti-drug antibodies (ADAs). 
Study Sites 
This study is to be conducted at approximately 6 study sites. 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
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Investigational Drug 
ALN-TTRSC is comprised of a small interfering RNA 
targeting mutant and WT TTR messenger ribonucleic acid 
with a covalently-attached triantennary N-
acetylgalactosamine (GalNAc) ligand formulated in water for 
injection. 
Dosage, Route of 
Administration and 
Duration of 
Treatment of 
Investigational Drug 
Beginning on Day 0, patients will receive 5 daily 
subcutaneous doses of 500 mg of ALN-TTRSC. The same 
dose will be administered at Day 7 and then weekly from Day 
14 through approximately Day 1337 (or ET). 
Time on Study 
The duration of patient participation in this study is up to 
approximately 4 years (Screening/Baseline through the 
Follow-up visit). 
Primary Objective 
To evaluate the safety and tolerability of long-term dosing 
with ALN-TTRSC. 
Secondary 
Objectives 
Secondary objectives of this study are: 
• To assess the PD effect of long-term dosing of 
ALN-TTRSC on serum levels of TTR. 
• Clinical effects of long-term dosing of ALN-TTRSC, 
including effect on mortality, hospitalization, and 
6-MWT. 
Tertiary Objectives 
The tertiary objectives of this study are: 
• To further characterize the PK of ALN-TTRSC. 
• To assess the clinical effects of long-term dosing of 
ALN-TTRSC including:  echocardiogram, cardiac 
biomarkers (NT-proBNP and troponin T and I), 
quantitation of amyloid in fat pad aspirates, CMR, 
KCCQ, 99mTc imaging, eGFR, NYHA class, blood 
pressure, mBMI, new onset or recurrence of atrial 
fibrillation, pacemaker placement, change in diuretic 
regimen, and EQ-5D QoL. 
• To understand disease burden and healthcare utilization. 
Sample Size 
Approximately 25 patients. 
Inclusion and 
Exclusion Criteria 
Each patient must meet all of the following inclusion criteria 
during the Screening/Baseline period to be eligible for 
enrollment in the study: 
1. Previously received and tolerated ALN-TTRSC in 
Study ALN-TTRSC-002; and completed Study ALN-
TTRSC-002 through the Day 90 visit; 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
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2. Adequate liver function, demonstrated by an aspartate 
transaminase  and alanine transaminase ≤ 2.5 × the 
upper limit of normal, total bilirubin< 2 g/dL (34.2 
µmol/L), and albumin > 3 g/dL (> 4.35 µmol/L); 
3. Women of child-bearing potential (WOCBP) must 
have a negative pregnancy test, cannot be breast 
feeding, and must be willing to use a highly effective 
method of contraception prior to Screening/Baseline, 
throughout study participation, and for 1 month after 
last dose administration; 
4. Males who agree to use appropriate means of 
contraception throughout study participation until 1 
month after last dose administration; 
5. Patient, or patient’s legal representative, is able and 
willing to provide written informed consent and the 
patient is willing to comply with the study 
requirements. 
Each patient must not meet any of the following exclusion 
criteria to be eligible for enrollment in the study:  
1. Estimated Glomerular Filtration Rate 
< 20 mL/min/1.73m2 (using the Modification of Diet 
in Renal Disease [MDRD] formula); 
2. Uncontrolled hypertension; 
3. Uncontrolled ischemic heart disease; 
4. Uncontrolled clinically significant cardiac arrhythmia; 
5. Untreated hypo- or hyperthyroidism; 
6. Prior major organ transplant; 
7. Known or suspected systemic bacterial, viral, 
parasitic, or fungal infection; 
8. Seropositive for hepatitis B virus, hepatitis C virus 
(HCV) or known to be human immunodeficiency 
virus  positive; 
9. Received an investigational agent other than 
tafamidis, diflunisal, doxycycline, or 
tauroursodeoxycholic acid, or an investigational 
device within 30 days prior to first dose of study drug; 
10. Discontinued ALN-TTRSC-002 study due to a 
treatment-related AE; 
11. Metastatic cancer within the past 5 years; 
12. Any conditions which, in the opinion of the 
Investigator, would make the patient unsuitable for 
enrollment or could interfere with the patient’s 
participation in, or completion of, the study. 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
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13. History of allergic reaction to an oligonucleotide or 
GalNAc. 
 
Safety Assessments 
The safety of ALN-TTRSC will be evaluated by: 
• Assessment of AEs 
• Clinical laboratory safety tests (hematology and serum 
chemistry, including liver function tests, thyroid 
function, coagulation, and urinalysis) 
• Vital sign measurements (blood pressure, pulse rate, oral 
body temperature, and respiratory rate) 
• 12-Lead ECG 
• Physical examinations 
• Eye examinations 
Pharmacodynamic 
Assessments 
The PD effect of ALN-TTRSC will include assessment of 
serum TTR and vitamin A levels. 
Pharmacokinetic 
Assessments 
Blood samples for the assessment of ALN-TTRSC 
concentration and possible metabolite analysis will be 
collected predose and at various time points postdose.   
Clinical Efficacy 
Assessments 
Clinical effects of ALN-TTRSC will be explored by: 
• Mortality (cardiovascular-related and all-cause) 
• Hospitalization (cardiovascular-related and heart-failure-
related) 
• 6-MWT 
Additional exploratory clinical assessments include: 
• Echocardiography 
• Cardiac biomarkers (NT-proBNP, troponin T, and 
troponin I) 
• KCCQ 
• mBMI 
• NYHA classification 
• 
99mTc imaging 
• CMR imaging with gadolinium 
• Fat pad aspirates for amyloid quantitation 
• EQ-5D QoL 
• Blood pressure 
• eGFR 
• New onset or recurrent atrial fibrillation 
• Pacemaker placement 
• Changes in diuretic regimen 

ALN-TTRSC (revusiran) 
 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
Confidential  
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Other Assessments 
Other effects of ALN-TTRSC will be evaluated by: 
• Measurement of exploratory biomarkers and serology 
(ADAs) 
• Determination of pharmacoeconomic outcomes through 
disease burden and healthcare utilization questionnaire. 
Statistical Methods 
Statistical analyses will be primarily descriptive in nature.  
Adverse event summaries will include tabulations of all 
treatment-emergent AEs, treatment-related AEs, serious AEs, 
discontinuations due to AEs, and AEs of various grading 
severity.   
Descriptive statistics will be provided for clinical laboratory 
data, vital signs data, and ECG interval data, presented as 
both actual values and changes from baseline relative to each 
on-study evaluation.   
For categorical variables, summary tabulations of the number 
and percentage of patients within each category (with a 
category for missing data) will be presented.  For continuous 
variables, the number of patients, mean, median, standard 
deviation, minimum, and maximum values will be presented. 
 

ALN-TTRSC (revusiran) 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
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Table 1: 
Schedule of Assessments for Clinic Visits – Year 1 and Year 2 
Phase: 
Screeninga/ 
Baseline 
Pre-doseb 
Dose Initiation 
Period 
Treatment Period 
(Doses Administered Weekly between Visitsc,d) 
Year: 
Year 1 
Year 2 
Study Week: 
 
 
Wk  
1 
Wk 
12 
Wk 
24 
Wk 
36 
Wk 
48 
Wk  
60 
Wk  
72 
Wk  
84 
Wk  
96 
Study Day: 
-28 to -1 
0 
0 
1 
2 
3 
4 
7 
84 
168 
252 
336 
420 
504d 
588 
672 
Window (days): 
±1 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
Procedure: 
Informed Consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administrationf,g 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteriag 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serologyi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testj,k 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Karnofsky Performance 
Statusj 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
eGFRj,l 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments: 
Physical Examinationj 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weightj 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsj,m 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj,n 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Serum Chemistry (including 
LFTs), Hematology, 
Urinalysisj 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationj,o 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 

ALN-TTRSC (revusiran) 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
Confidential  
 
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Table 1: 
Schedule of Assessments for Clinic Visits – Year 1 and Year 2 
Phase: 
Screeninga/ 
Baseline 
Pre-doseb 
Dose Initiation 
Period 
Treatment Period 
(Doses Administered Weekly between Visitsc,d) 
Year: 
Year 1 
Year 2 
Study Week: 
 
 
Wk  
1 
Wk 
12 
Wk 
24 
Wk 
36 
Wk 
48 
Wk  
60 
Wk  
72 
Wk  
84 
Wk  
96 
Study Day: 
-28 to -1 
0 
0 
1 
2 
3 
4 
7 
84 
168 
252 
336 
420 
504d 
588 
672 
Window (days): 
±1 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
TSHj 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Eye Examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Review Concomitant 
Medications 
X 
X 
Continuous Monitoring 
Review/Record AEs 
 
 
Continuous Monitoring 
PD Assessments: 
TTRj 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitamin Aj,p 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
PK Assessments: 
Plasma PK Samplingq 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Clinical Efficacy Assessments: 
Review Cardiac Clinical 
Medical History Treatment 
Changesr 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
NT-proBNP, Troponin T, and 
Troponin Ij 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiography by 
Doppler 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
6-MWTj,s 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
NYHA Classification 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
CMRt 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 

ALN-TTRSC (revusiran) 
Clinical Study Protocol ALN-TTRSC-003 
 
 
25 March 2016 
Alnylam Pharmaceuticals 
Confidential  
 
Page 16 of 72 
 
Table 1: 
Schedule of Assessments for Clinic Visits – Year 1 and Year 2 
Phase: 
Screeninga/ 
Baseline 
Pre-doseb 
Dose Initiation 
Period 
Treatment Period 
(Doses Administered Weekly between Visitsc,d) 
Year: 
Year 1 
Year 2 
Study Week: 
 
 
Wk  
1 
Wk 
12 
Wk 
24 
Wk 
36 
Wk 
48 
Wk  
60 
Wk  
72 
Wk  
84 
Wk  
96 
Study Day: 
-28 to -1 
0 
0 
1 
2 
3 
4 
7 
84 
168 
252 
336 
420 
504d 
588 
672 
Window (days): 
±1 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
99mTc Scintigraphy by 3D 
SPECTu 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Fat Pad Aspirate Samples for 
Amyloid Quantificationv 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
mBMI 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
KCCQj 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
EQ-5D QoLj 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Other Assessments: 
Exploratory Biomarkers/ 
Serology (ADA)j,w 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacoeconomics 
Questionnairej 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Abbreviations: 6-MWT = Six-minute Walk Test, 99mTc = 99m-Technetium, ADA = anti-drug antibody, AE = adverse event, aPTT = activated partial thromboplastin time, 
CMR = Cardiac magnetic resonance imaging, ECG = electrocardiogram, eGFR = estimated glomerular filtration rate, ET = early termination, HBsAb – hepatitis B surface 
antibody, HBsAg = hepatitis B surface antigen, HCV Ab = hepatitis C virus antibody, ICF = informed consent form, INR = international normalized ratio, KCCQ = Kansas City 
Cardiomyopathy Questionnaire, LFT = liver function test, LGE = late gadolinium enhancement, mBMI = modified body mass index, MDRD = Modification of Diet in Renal 
Disease, NT-proBNP = N-terminal prohormone of B-type natriuretic peptide, NYHA = New York Heart Association, PD = pharmacodynamic, PK = pharmacokinetic, 
PT = prothrombin time, QoL = quality of life; QTcB = Bazett-corrected QT interval, SPECT = single-photon emission computed tomography, TEAE = treatment-emergent 
adverse event, TSH = thyroid stimulating hormone, TTR = transthyretin, WOCBP = women of child-bearing potential, WT = wild-type 
a 
Screening/Baseline assessments may be performed during several clinic visits.  If the final Day 90 visit in the ALN-TTRSC-002 study is within 28 days of the first dose 
administered in this study, then visit procedures performed as part of the Day 90 visit do not need to be repeated at the Screening/Baseline visit.  If the Day 90 visit in the 
ALN-TTRSC-002 study occurred within 90 days of the first dose administered in this study, the echocardiogram and CMR do not need to be repeated at the 
Screening/Baseline visit. 

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b 
The results from samples collected predose are not needed prior to dosing. 
c 
The 14-day window applies to study assessments.  Dosing is to maintain the weekly schedule (± 2 days). 
d 
Refer to Table 2 for the continued Schedule of Assessments in Years 3 and 4 and for the  End-of-study or Early Termination (ET) visit. For patients who discontinue early and 
provide consent, overall health status will be documented by either telephone contact or non-patient contact follow-up (eg, medical record check) at time points corresponding 
to study Day 504 (Week 72), if applicable, and study Day 1344 (Week 192).   
e 
Prior to Screening/Baseline activities, the patient will sign and date an ICF.  No study procedures should be performed prior to informed consent being obtained.  
f 
During the treatment period, doses will be administered weekly (± 2 days).  Doses may be administered and some assessments may be performed at the clinical site or at 
home according to  Section 5.5.   
g 
Subcutaneous injection of ALN-TTRSC into the abdomen on Day 0 (after completion of all pre-dose evaluations and procedures) and then on subsequent days into other 
quadrants of the abdomen.  The upper arm or thigh may also be used (see the ALN-TTRSC Pharmacy Manual).  Dosing on Days 1, 2, 3, and 4 must be performed 
approximately 24 ±4 hours after the preceding dose of study drug. 
h 
On Day 0 pre-dose, only interval medical history will be collected.  Changes in medical history during the treatment period will be captured as TEAEs or concomitant 
medication(s) as appropriate. 
i 
Serology tests include HBsAb, HBsAg, and anti-HCV Ab. 
j 
Assessment should be performed before dosing. 
k 
The pregnancy test will be performed for WOCBP only.  A serum pregnancy test should be performed at Screening/Baseline.  Urine pregnancy tests at other visits.   
l 
The serum creatinine values should be in mg/dL to 2 decimal places (e.g., 0.95 mg/dL) OR values in µmol/L to the nearest whole number (e.g., 84 µmol/L) when calculating 
eGFR using the MDRD study equation; see http://nkdep.nih.gov/lab-evaluation/gfr-calculators.shtml for an eGFR calculator. 
m 
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.  Vital signs should be collected during any unscheduled 
clinic visit. 
n 
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 electrophysiologic parameters 
assessed will be rhythm, ventricular rate, PR interval, QRS duration, QT interval, ST and T-waves and QTcB. 
o 
Coagulation studies include PT, aPTT, and INR and will be performed on all patients. 
p 
Blood samples for vitamin A will be analyzed by a central laboratory. 
q 
Refer to Table 4 for PK Sampling Schedule.   
r 
Any changes to the patient’s cardiac medical history and treatment regimen changes should be noted, including but not limited to:  onset or recurrence of atrial fibrillation, 
pacemaker placement, and change in diuretic regimen.   
s 
The 6-MWT will include 2 walks at Screening/Baseline, pre- and post-walk assessment of O2 saturation, blood pressure, heart rate, and the Borg scale ratings for fatigue and 
dyspnea. 
t 
Cardiac magnetic resonance imaging with LGE is only to be obtained in patients without contraindications (i.e.  pacemakers, severe renal failure with eGFR< 30 mL/min/1.73 
m2, defibrillators, allergy to gadolinium). 
u 
Each site can use either 99mTc-pyrophosphate as a tracer or 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid.  The tracer should not be changed for the patient during the 
study. 
v 
Additional timepoints may not be collected depending on the status of the screening aspirate samples. 

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w 
Aliquots of serum samples will be taken and frozen, to permit testing of the effect of ALN-TTRSC on the expression of exploratory biomarkers (WT and mutant TTR levels, 
additional cardiac and hepatic-derived proteins that may include galectin-3 and ST2), and serology (ADAs). 

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Table 2: 
Schedule of Assessments for Clinic Visits – Year 3 and Year 4 
Phase: 
Treatment Period 
(Doses Administered Weekly between Visitsa) 
End of Study b 
Follow-up b 
Study Year 
Year 3 
Year 4 
Study Week Wk108 Wk120 Wk132 Wk 144 Wk156 Wk168 
Wk180 
Wk192 
- 
Study Day: 
756 
840 
924 
1008 
1092 
1176 
1260 
1344/ETb 
1372 
Window (days): 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±7 
±14 
Procedure: 
Study Drug Administrationc,d 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Teste,f 
 
X 
 
X 
 
X 
 
X 
X 
Karnofsky Performance Statuse 
 
X 
 
X 
 
X 
 
X 
X 
eGFRe,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments: 
Physical Examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weighte 
 
X 
 
X 
 
X 
 
X 
 
Vital Signse,h 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECGe,i 
 
 
 
X 
 
 
 
X 
 
Serum Chemistry (including LFTs), 
Hematology, Urinalysise 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulatione,j 
 
 
 
X 
 
 
 
X 
X 
TSHe 
 
 
 
X 
 
 
 
X 
 
Eye Examination 
 
 
 
X 
 
 
 
X 
 
Review Concomitant Medications 
Continuous Monitoring 
Review/Record AEs 
Continuous Monitoring 
PD Assessments: 
TTRe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitamin Ae,k 
 
X 
 
X 
 
X 
 
X 
X 
PK Assessments 
Plasma PK Samplingl 
 
X 
 
 
 
X 
 
 
 

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Table 2: 
Schedule of Assessments for Clinic Visits – Year 3 and Year 4 
Phase: 
Treatment Period 
(Doses Administered Weekly between Visitsa) 
End of Study b 
Follow-up b 
Study Year 
Year 3 
Year 4 
Study Week Wk108 Wk120 Wk132 Wk 144 Wk156 Wk168 
Wk180 
Wk192 
- 
Study Day: 
756 
840 
924 
1008 
1092 
1176 
1260 
1344/ETb 
1372 
Window (days): 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±7 
±14 
Clinical Efficacy Assessments: 
Review Cardiac Clinical Medical History 
Treatment Changesm 
X 
X 
X 
X 
X 
X 
X 
X 
 
NT-proBNP, Troponin T, and Troponin Ie 
 
X 
 
X 
 
X 
 
X 
 
Echocardiography by Doppler 
 
X 
 
X 
 
X 
 
X 
 
6-MWTe,n 
 
X 
 
X 
 
X 
 
X 
 
NYHA Classification 
 
X 
 
X 
 
X 
 
X 
 
mBMI 
 
X 
 
X 
 
X 
 
X 
 
KCCQe 
 
X 
 
X 
 
X 
 
X 
 
EQ-5D QoLe 
 
X 
 
X 
 
X 
 
X 
 
Other Assessments: 
Exploratory Biomarkers/ Serology (ADA)e,o 
 
X 
 
X 
 
X 
 
X 
 
Pharmacoeconomics Questionnairee 
 
 
 
X 
 
 
 
X 
 
Abbreviations: 6-MWT = Six-minute Walk Test, 99mTc = 99m-Technetium, ADA = anti-drug antibody, AE = adverse event, aPTT = activated partial thromboplastin time, ECG = 
electrocardiogram, eGFR = estimated glomerular filtration rate, ET = early termination, HBsAb – hepatitis B surface antibody, HBsAg = hepatitis B surface antigen, HCV Ab = 
hepatitis C virus antibody, ICF = informed consent form, INR = international normalized ratio, KCCQ = Kansas City Cardiomyopathy Questionnaire, LFT = liver function test, 
LGE = late gadolinium enhancement, mBMI = modified body mass index, MDRD = Modification of Diet in Renal Disease, NT-proBNP = N-terminal prohormone of B-type 
natriuretic peptide, NYHA = New York Heart Association, PD = pharmacodynamic, PK = pharmacokinetic, PT = prothrombin time, QoL = quality of life; QTcB = Bazett-
corrected QT interval, SPECT = single-photon emission computed tomography, TEAE = treatment-emergent adverse event, TSH = thyroid stimulating hormone, TTR = 
transthyretin, WOCBP = women of child-bearing potential, WT = wild-type 
a 
The 14-day window applies to study assessments.  Dosing is to maintain the weekly schedule (± 2 days). 
b 
The End-of-study or ET visit is scheduled approximately 7 days following the last dose. The Follow-up visit is scheduled approximately 4 weeks following the End-of-study 
or ET visit, if applicable. Patients who discontinue early will be required to report to the clinic for an End of Study visit and a Follow-up visit. For patients who discontinue 

ALN-TTRSC (revusiran) 
Clinical Study Protocol ALN-TTRSC-003 
 
 
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Alnylam Pharmaceuticals 
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early and have provided consent, overall health status will be documented by either telephone contact or non-patient contact follow-up (eg, medical record check) at time 
points corresponding to study Day 504 (Week 72), if applicable, and study Day 1344 (Week 192). 
c 
During the treatment period, doses will be administered weekly (± 2 days).  Doses may be administered at the clinical site or at home according to Section 5.5.   
d 
Subcutaneous injection of ALN-TTRSC into the abdomen.  The upper arm or thigh may also be used (see the ALN-TTRSC Pharmacy Manual).   
e 
Assessment should be performed before dosing. 
f 
The pregnancy test will be performed for WOCBP only.  A serum pregnancy test should be performed at Screening/Baseline.  Urine pregnancy tests at other visits.   
g 
The serum creatinine values should be in mg/dL to 2 decimal places (e.g., 0.95 mg/dL) OR values in µmol/L to the nearest whole number (e.g., 84 µmol/L) when calculating 
eGFR using the MDRD study equation; see http://nkdep.nih.gov/lab-evaluation/gfr-calculators.shtml for an eGFR calculator. 
h 
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.  Vital signs should be collected during any unscheduled 
clinic visit. 
i 
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 electrophysiologic parameters 
assessed will be rhythm, ventricular rate, PR interval, QRS duration, QT interval, ST and T-waves and QTcB. 
j 
Coagulation studies include PT, aPTT, and INR and will be performed on all patients. 
k 
Blood samples for vitamin A will be analyzed by a central laboratory. 
l 
Refer to Table 4 for PK Sampling Schedule.   
m 
Any changes to the patient’s cardiac medical history and treatment regimen changes should be noted, including but not limited to:  onset or recurrence of atrial fibrillation, 
pacemaker placement, and change in diuretic regimen.   
n 
The 6-MWT will include 2 walks at Screening/Baseline, pre- and post-walk assessment of O2 saturation, blood pressure, heart rate, and the Borg scale ratings for fatigue and 
dyspnea. 
o 
Aliquots of serum samples will be taken and frozen, to permit testing of the effect of ALN-TTRSC on the expression of exploratory biomarkers (WT and mutant TTR levels, 
additional cardiac and hepatic-derived proteins that may include galectin-3 and ST2), and serology (ADAs) 
 
 

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Clinical Study Protocol ALN-TTRSC-003 
 
 
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Alnylam Pharmaceuticals 
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Table 3: 
Schedule of Assessments for Weekly Dosing Days between 
Clinic Visits 
Study Day (+14 Days): 
Study Drug 
Administration a,b  
 
Concomitant 
Medication, AEs, and 
Vital Signsc,d 
TTR Sample e 
Serum Chemistry  
and Hematology  
Year 1 
Clinic Visit (Wk 1, Day 7) - See Table 1 
14 
X 
X 
X 
X 
21,35,42,49,63,70,77 
X 
X 
  
  
28,56 
X 
X 
X 
X 
Clinic Visit (Wk 12, Day 84) - See Table 1 
91,98,105,119,126,133,147,154,161 
X 
 
  
  
112,140 
X 
X 
 
 
Clinic Visit (Wk 24, Day 168)  - See Table 1 
175,182,189,203,210,217,231,238,245 
X 
 
  
  
196,224 
X 
X 
 
 
Clinic Visit (Wk 36, Day 252) - See Table 1 
259,266,273,287,294,301,315,322,329 
X 
 
  
  
280,308 
X 
X 
 
 
Clinic Visit (Wk 48, Day 336) - See Table 1 
343,350,357,371,378,385,399,406,413 
X 
 
  
  
364,392 
X 
X 
 
 
Year 2 
Clinic Visit (Wk 60, Day 420) - See Table 1 
427,434,441,455,462,469,483,490,497 
X 
 
  
  
448,476 
X 
X 
 
 
Clinic Visit (Wk 72, Day 504) - See Table 1 
511,518,525,539,546,553,567,574,581 
X 
 
  
  
532,560 
X 
X 
 
 
Clinic Visit (Wk 84, Day 588) - See Table 1 
595,602,609,623,630,637,651,658,665 
X 
 
  
  
616,644 
X 
X 
 
 
Clinic Visit (Wk 96, Day 672) - See Table 2 
679, 686, 693, 707, 714, 721, 735, 742, 749 
X 
 
  
  
700,728 
X 
X 
 
 
Year 3 

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Alnylam Pharmaceuticals 
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Table 3: 
Schedule of Assessments for Weekly Dosing Days between 
Clinic Visits 
Study Day (+14 Days): 
Study Drug 
Administration a,b  
 
Concomitant 
Medication, AEs, and 
Vital Signsc,d 
TTR Sample e 
Serum Chemistry  
and Hematology  
Clinic Visit (Wk 108, Day 756) - See Table 2 
763,770,777,791,798,805,819,826,833 
X 
 
  
  
784,812 
X 
X 
 
 
Clinic Visit (Wk 120, Day 840) - See Table 2 
847,854,861,875,882,889,903,910,917 
X 
 
  
  
868,896 
X 
X 
 
 
Clinic Visit (Wk 132, Day 924) - See Table 2 
931,938,945,959,966,973,987,994,1001 
X 
 
  
  
952,980 
X 
X 
 
 
Clinic Visit (Wk 144, Day 1008) - See Table 2 
1015,1022,1029,1043,1050,1057,1071,1078,1085 
X 
 
  
  
1036,1064 
X 
X 
 
 
Year 4 
Clinic Visit (Wk 156, Day 1092) - See Table 2 
1099,1106,1113,1127,1134,1141,1155,1162, 1169 
X 
 
  
  
1120,1148 
X 
X 
 
 
Clinic Visit (Wk 168, Day 1176) - See Table 2 
1183,1190,1197,1211,1218,1225,1239,1246, 1253 
X 
 
  
  
1204,1232 
X 
X 
 
 
Clinic Visit (Wk 180, Day 1260) - See Table 2 
1267,1274,1281,1295,1302,1309,1323, 1330,1337 
X 
 
  
  
1288,1316 
X 
X 
 
 
Abbreviations:  AE = adverse event, TTR = transthyretin 
a 
During the treatment period, doses will be administered weekly (± 2 days).  Doses may be administered at the 
clinical site or at home according to Section 5.5.   
b 
Subcutaneous  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 (see the ALN-TTRSC Pharmacy Manual).   
c 
Adverse events and concomitant medications information may be collected by the site via phone on a monthly 
basis or by a home healthcare professional. 
d 
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.  Vital signs should be collected prior to each 
weekly dose, up to Day 84. 

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Alnylam Pharmaceuticals 
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e 
TTR  samples should be taken pre-dose.   
 
Table 4: 
Pharmacokinetic Sampling Schedule 
Year 
Year 1 
Year 2 
Year 3 
Year 4 
Week 
Wk1 
Wk12 
Wk24 
Wk36 
Wk48 
Wk84 
Wk120 
Wk168 
Study Day 
0 
4 
7 
84 
168 
252 
336 
588 
840 
1176 
PK Collection 
Time 
 
 
 
 
 
 
 
 
 
 
Pre-dose (up to 1 
hr) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
10 min (± 5 min) 
X 
X 
 
 
 
 
 
 
 
 
30 min (±5 min) 
X 
X 
 
 
 
 
 
 
 
 
1 hr (± 10 min) 
X 
X 
 
 
 
 
 
 
 
 
2 hr (± 10 min) 
X 
X 
 
 
 
 
 
 
 
 
4 hr (± 1 hr) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8 hr (±2 hr) 
X 
X 
 
 
 
 
 
 
 
 
Abbreviations:  hr = hour, min = minute, PK = pharmacokinetic 
 

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Clinical Study Protocol ALN-TTRSC-003 
 
 
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Alnylam Pharmaceuticals 
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ABBREVIATIONS 
Abbreviation 
Definition 
6-MWT 
6-minute Walk Test 
99mTc 
99m-Technetium 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AL 
Amyloid light-chain 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
ATTR 
Transthyretin-mediated amyloidosis 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CMR 
Cardiac magnetic resonance imaging (Cardiac MRI) 
CRF 
Case report form 
CRO 
Clinical research organization 
DPD 
99mTc -3,3-diphosphono-1,2-propanodicarboxylic acid 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ET 
Early termination 
EQ-5D-QoL 
EQ-5D Quality of Life questionnaire 
FAC 
Familial amyloidotic cardiomyopathy 
FAP 
Familial amyloidotic polyneuropathy 
FNAFP 
Fine-needle aspirate samples of the abdominal fat pad 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HCV Ab 
Hepatitis C virus antibody 
hr 
Hour 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 

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Alnylam Pharmaceuticals 
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Abbreviation 
Definition 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
LGE 
Late gadolinium enhancement 
LVEF 
Left ventricular ejection fraction 
MAD 
Multiple ascending dose 
mBMI 
Modified body mass index 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mRNA 
Messenger ribonucleic acid 
NHP 
Nonhuman primate 
NOAEL 
No-observed-adverse-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) 
PT 
Prothrombin time 
QoL 
Quality of life 
QTcB 
Bazett-corrected QT interval 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
SPECT 
Single-photon emission computed tomography 
siRNA 
Small interfering RNA 
SSA 
Senile systemic amyloidosis 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
TTR 
Transthyretin 
TRACS 
TTR Amyloidosis Cardiac Study 

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Abbreviation 
Definition 
ULN 
Upper limit of normal 
UK 
United Kingdom 
WBC 
White blood cell 
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); 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.2  In the mouse, TTR 
plays a greater role as a carrier for T4.  Whilst the absence of TTR in the TTR-knockout 
mouse reduces circulating levels of T4, it does not however adversely affect the 
concentration of the hormone in peripheral tissues.3,4  
Vitamin A circulates through the plasma primarily bound to retinol binding protein 
(RBP).1  The clearance of RBP from the circulation is greatly reduced through its binding 
to TTR.  Because vitamin A is lipid-soluble, it can diffuse across the membranes of cells 
and thus, most tissues receive adequate levels of vitamin A obtained normally from the 
diet without it being bound to RBP.  In humans, individuals with mutations in the RBP 
gene leading to complete loss of circulating RBP and very low concentrations of 
circulating vitamin A have not shown any significant signs of vitamin A deficiency other 
than modest retinal dystrophy and decrease in night vision.5  The safety of lowering 
vitamin A through TTR suppression has been further confirmed by the absence of any 
vitamin A deficiency-related adverse events (AEs) in nonhuman primates (NHPs), 
healthy volunteers, and patients with familial amyloidotic polyneuropathy (FAP) treated 
with ALN-TTR02 who experienced > 80% lowering of both TTR and vitamin A. 
1.1.2. 
Disease Overview 
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 mutations6 that phenotypically result in at least 2 distinct clinical syndromes of 
ATTR: familial amyloidotic cardiomyopathy (FAC) and FAP, both of which are 
characterized by amyloid deposits of mutant and wild-type (WT) TTR.7  Following the 
onset of symptoms in these various amyloidosis syndromes, quality of life (QoL) is 
severely impacted and the disease proceeds inexorably to death. 
Familial amyloidotic polyneuropathy, commonly associated with the V30M mutation, 
occurs primarily in families from Portugal, Sweden and Japan, has an early onset (age 
40-50 years), and is characterized initially by peripheral neuropathy leading to sensory 
and motor deficits as well as to profound autonomic dysfunction that produces disabling 

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gastrointestinal pathology, orthostatic hypotension, and bladder dysfunction.8,9  As FAP 
progresses, it is not uncommon for patients with either V30M or non-V30M mutations to 
develop cardiac amyloid deposition leading to conduction defects and symptomatic 
cardiomyopathy.  Median survival after diagnosis of FAP is approximately 10 years.10 
Familial amyloidotic cardiomyopathy is caused predominantly by the V122I mutation 
that is found in up to 4% of African Americans and in over 5% of West African 
populations.11  Occurring predominantly in males, V122I FAC is a late onset (age 
> 60 years) syndrome in which amyloid deposition is largely restricted to the heart and 
manifests as heart wall thickening with diastolic and systolic dysfunction, conduction 
defects, and arrhythmias, leading to congestive heart failure and death; neuropathy is 
uncommon.2  While the rate of disease penetrance in carriers of the mutation remains 
undefined, it is estimated that up to 150,000 older male African Americans in the United 
States carry the V122I gene12, and there could be approximately 40,000 V122I cases 
worldwide.  Another cardiac predominant TTR mutation, T60A, manifests as a disease of 
the heart and the autonomic nerves with less than one quarter of patients suffering from 
sensorimotor neuropathy.13  The T60A mutation affects approximately 1% of the 
population in northwest Ireland, but can also be found in other countries including 
Japan.14,15  Median survival after diagnosis of FAC is approximately 2.5 years for V122I 
and 3.5 years for T60A.13,16 
In addition to FAC, another cause of TTR cardiac amyloidosis where neuropathy is 
uncommon is senile systemic amyloidosis (SSA), a non-hereditary form of ATTR 
occurring when WT TTR deposits as amyloid primarily in heart tissue resulting in 
cardiomyopathy.  This disease is predominantly seen in men older than 70 years17, and 
the clinical presentation is similar to that described for FAC.  The prevalence of SSA is 
unknown, but autopsy studies suggest that up to 22%-25% of individuals > 80 years old 
have TTR amyloid deposits in the heart, although the degree of deposition is mild in the 
majority of cases.18  Median survival after diagnosis of SSA has been reported to be 
approximately 3.5 years.10,19 
The diagnosis of TTR cardiac amyloidosis is made typically through the discovery of 
heart wall thickening and diastolic dysfunction on cardiac echo in patients presenting 
with heart failure symptoms.  These symptoms combined with endomyocardial or 
abdominal fat pad biopsy demonstrating TTR amyloid together with confirmation by 
TTR genotyping lead to the diagnosis of TTR cardiac amyloidosis.  The detection of 
subendocardial late gadolinium enhancement (LGE) on cardiac magnetic resonance 
imaging (CMR) can also assist with making the diagnosis, as can cardiac uptake on 
99mTechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) or 
99mTechnetium -Pyrophosphate imaging, which is able to distinguish TTR from amyloid 
light-chain (AL) in the heart.10, 20,21,22 
There are limited data on the natural history of the disease progression in TTR cardiac 
amyloidosis.  One study in 9 patients reported significant increases in myocardial mass 
(mean increase of 8% by CMR, 22% by echocardiography) after 1 year of observation.23  
The multi-center TTR Amyloidosis Cardiac Study (TRACS) followed disease 
progression in 29 patients and demonstrated declines in left ventricular ejection fraction 
(LVEF) and 6-minute walk distance for both SSA and FAC patients over 18 months.24  

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Both FAC and SSA patients followed on TRACS exhibited a rise in the cardiac 
biomarker N-terminal prohormone of type-B natriuretic peptide (NT-proBNP) over 
18 months.  Elevation of serum biomarkers of heart failure, such as NT-proBNP, 
troponin I, and troponin T, which reflect increased cardiac filling pressures and myocyte 
injury, respectively, have been associated with poor outcome in AL amyloidosis.25  The 
lowering of serum free light chains by chemotherapy in AL amyloidosis is associated 
with a robust decline in NT-proBNP that accompanies clinical improvement well in 
advance of any detectable changes on cardiac echo or CMR.  It is therefore possible that 
the lowering of abnormal circulating TTR monomers through either inhibition of hepatic 
TTR protein production or stabilization of the TTR tetramer could impact NT-proBNP 
and clinical outcome in TTR cardiac amyloidosis patients.   
Patients with TTR cardiac amyloidosis are largely managed with supportive care aimed at 
alleviation of heart failure symptoms, including restriction of salt intake, diuretics, 
pacemakers, and arrhythmia management.  There are currently no approved therapies 
available for TTR cardiac amyloidosis.  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union in 2011 for the treatment of early stage 
neuropathy in ATTR patients.  A single-arm Phase 2 trial of tafamidis in 35 V122I and 
SSA patients has been completed; the study reported a LVEF decline of 4%, left 
ventricular mass increase of 14 g and Six-minute Walk Test (6-MWT) decrease of 
11 meters for the pooled group of FAC and SSA patients after 12 months of treatment.26 
Diflunisal is a generic nonsteroidal anti-inflammatory drug that binds to and stabilizes 
TTR in a manner similar to tafamidis.27  A recently conducted single-arm Phase 2 study 
of diflunisal in 13 patients with TTR cardiac amyloidosis with a mean follow-up of 
approximately one year showed no significant change in cardiac structure/function or 
troponin/ NT-ProBNP levels.  In addition, a decline in renal function was observed.28  
The combination of doxycycline and tauroursodeoxycholic acid, which has activity as a 
TTR amyloid fibril disrupter, is currently undergoing Phase 2 testing in FAP and SSA 
patients.29,30 
Liver transplantation has been used in FAP to eliminate the mutant protein and has been 
shown to slow neuropathy progression in early-stage patients.  However, for FAP patients 
with heart involvement, acceleration of the cardiac disease has been observed 
post-transplantation due to the continued deposition of WT TTR.  For this reason, and 
due to the advanced age of most FAC and SSA patients, liver transplantation is 
contraindicated in TTR cardiac amyloidosis.  While a few heart transplants have been 
performed in patients with cardiac amyloidosis, the procedure is often contraindicated 
due to the advanced age of most FAC patients.  Thus, there exists a high unmet need for 
novel approaches to treat these patients. 
1.1.3. 
RNA Interference 
RNA interference (RNAi) is a naturally occurring cellular mechanism for regulating gene 
expression that is mediated by small interfering ribonucleic acids (siRNAs).31  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 

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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 of the target protein.32  
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.33  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 administration of siRNAs formulated in lipid nanoparticles.34,35 
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 (nM) binding to the hepatic expressed 
asialoglycoprotein receptor  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 
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 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.  The 
proposed indication for ALN-TTRSC is for the treatment of patients with mutant or WT 
TTR cardiac amyloidosis. 
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. 
• Genotoxicity studies (Ames and chromosome aberration assays) were conducted 
in the presence and absence of metabolic activation and demonstrated that 
ALN-TTRSC was neither mutagenic nor clastogenic.  In addition, ALN-TTRSC 
did not induce micronucleus formation in bone marrow of Sprague-Dawley rats. 
• A safety pharmacology study was conducted with SC administered ALN-TTRSC 
in cynomolgus monkeys that demonstrated that the no-observed-effect-level for 
the cardiovascular (electrocardiogram [ECG], QT interval changes, and 
hemodynamics) and respiratory systems was 100 mg/kg ALN-TTRSC (the 
highest dose tested). 

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• The toxicity profile of SC administered ALN-TTRSC was evaluated in 10-dose 
(Days 1 through 5, 8, 15, 22, 29, and 36) toxicology studies in rats and 
cynomolgus monkeys.  Each study included a 4-week nondosing recovery period.  
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.  
 
 
 
  The changes recovered to normal within 4 weeks after the last dose.  
These findings resulted in the no-observed-adverse-effect-level (NOAEL) in rats 
to be conservatively called as 30 mg/kg.  The NOAEL in monkeys was greater or 
equal to the highest dose tested (≥ 300 mg/kg).   
• Results from 6-month rat and 9-month monkey studies indicate that in-life and 
clinical pathology is consistent with results observed in the completed 10-dose 
(6-week) studies in rats and monkeys. 
Further information can be found in the ALN-TTRSC IB. 
1.3. 
Summary of Clinical Data with ALN-TTRSC 
Study ALN-TTRSC-001 was a Phase 1 randomized, double -blind, placebo-controlled, 
study 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 500 or 
600 mg 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.   
Patients completing Study ALN-TTRSC-002 are eligible to enroll into the Phase 2, 
open label, extension study (ALN-TTRSC-003) designed to evaluate the safety and 
tolerability of long-term ALN-TTRSC dosing; additional information will be evaluated 

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including PK, PD, and clinical activity.  Patients will receive 500 mg ALN-TTRSC 
weekly for approximately 4 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 
most common AEs related to study drug have been ISRs, usually characterized by 
transient 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 Hypothesis and Rationale 
The therapeutic hypothesis for treatment with ALN-TTRSC in patients with TTR cardiac 
amyloidosis is that lowering of serum TTR protein through inhibition of hepatic 
production may 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 AL amyloidosis and secondary Amyloid A 
amyloidosis.36  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.37,38  In 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.39  Similarly, studies in FAP patients with 
tafamidis have shown that reducing circulating TTR monomers via stabilization of the 
TTR tetramer results in improved clinical outcomes.40  These precedents suggest that 
direct and potent lowering of circulating TTR with ALN-TTRSC could potentially confer 
clinical benefit in patients with TTR cardiac amyloidosis.   
This is an extension to the first study of ALN-TTRSC in patients with TTR cardiac 
amyloidosis.  The primary objective of this study is to evaluate the safety and tolerability 

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of long-term dosing with ALN-TTRSC administered to patients with TTR cardiac 
amyloidosis.  Secondary objectives include the assessment of the PD effect on total 
serum TTR and the clinical activity of long-term dosing of ALN-TTRSC. 
1.5. 
Dose Selection and Rationale 
Clinical data demonstrate that multiple doses of ALN-TTRSC up to 10 mg/kg and fixed 
doses of 500 mg ALN-TTRSC have been safe and well-tolerated in healthy volunteers. In 
addition, similar PK, PD effects, and safety of ALN-TTRSC was observed in patients 
with TTR cardiac amyloidosis. Based on these data, the proposed 500 mg dose for this 
study is expected to result in sustained TTR reduction ≥ 85%. Patients enrolled in study 
ALN-TTRSC-003 will receive ALN-TTRSC at a fixed dose of 500 mg administered as 
5 daily doses during Week 1, followed by weekly doses for the duration of the study 
through Day 1337 (or Early Termination [ET]). The longer dosing on the extension study 
is supported by the overall favorable benefit/risk profile of ALN-TTRSC to date and the 
absence of new findings in the ongoing long-term toxicology studies in rats and monkeys.  
1.6. 
Risk-Benefit Assessment 
Please see the ALN-TTRSC IB, Guidance to the Investigator for expanded risk/benefit 
assessment. 
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 5.5). Dose 
reduction may be considered in some cases after consultation with the Medical Monitor 
(see Section 5.6). 
1.6.2. 
Abnormal Liver Function Tests 
Elevations of AST and/or ALT 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. 

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Dose reduction may be considered in some cases after consultation with the Medical 
Monitor (see Section 5.6). 
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.41  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.42  Provided there is adequate vitamin A in the 
diet, tissue stores of vitamin A should not be affected by the lowering of TTR and RBP.  
However, as the vitamin A content of the diet may vary between different countries and 
different individuals within a country, all patients on the study will be asked to take a 
supplement containing the recommended daily allowance of vitamin A of 2500-3000 IU. 
1.7. 
Urgent Safety Measures 
In accordance with UK Law (Medicines for Human Use [Clinical Trials] as amended: 
Statutory Instrument 1031 Part 4 Section 30) the Sponsor and Investigator may take 
appropriate urgent safety measures in order to protect the subjects of a clinical trial 
against any immediate hazard to their health or safety.  If such measures are taken, the 
Sponsor shall immediately (no later than 3 days from the date the measures are taken) 
give written notice to the licensing authority and the relevant Independent Ethics 
Committee (IEC) of the measures taken and the circumstances giving rise to those 
measures. 

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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of long-term 
dosing with ALN-TTRSC. 
2.2. 
Secondary Objectives 
Secondary objectives of this study are to assess the PD effect of long-term dosing of 
ALN-TTRSC on serum levels of TTR and the clinical effects of long-term dosing of 
ALN-TTRSC, including effect on mortality, hospitalization, and 6-MWT. 
2.3. 
Tertiary Objectives 
Tertiary objectives of the study are: 
• To further characterize the PK of ALN-TTRSC. 
• To assess the clinical effects of long-term dosing of ALN-TTRSC including:  
echocardiogram, cardiac biomarkers (NT-proBNP and troponin T and I), quantitation 
of amyloid in fat pad aspirates, CMR, Kansas City Cardiomyopathy Questionnaire 
(KCCQ), 99m-Technetium (99mTc) imaging, estimated glomerular filtration rate 
(eGFR), New York Heart Association (NYHA) class, blood pressure, modified body 
mass index (mBMI), new onset or recurrence of atrial fibrillation, pacemaker 
placement, change in diuretic regimen, and EQ-5D Quality of Life (EQ-5D-QoL) 
questionnaire. 
• To understand disease burden and healthcare utilization. 

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3. 
STUDY PLAN 
3.1. 
Overall Design 
Protocol ALN-TTRSC-003 is an open-label, extension study designed to evaluate the 
long-term safety, clinical activity, and PK of subcutaneously administered ALN-TTRSC 
in patients with TTR cardiac amyloidosis who previously completed the 
ALN-TTRSC-002 study.   
The study will be conducted either at newly added study sites or at the same study sites 
where patients completed participation in Study ALN-TTRSC-002. 
Eligible, consenting patients will receive 5 daily doses of ALN-TTRSC (Day 0, 1, 2, 3, 
and 4) and a dose at Day 7.  They will then receive once weekly doses for the duration of 
the study through Day 1337 (or ET).  Doses will be administered at the clinic during 
Days 0 through 7.  Dosing after Day 7 may be administered at home by a healthcare 
professional trained in the protocol, or at the clinic if dosing coincides with the clinic visit 
for other assessments.  At the discretion of the Investigator, after the Day 84 dosing visit, 
and if the patient has not experienced any severe adverse events or SAEs considered 
related to the study drug within the previous 12 weeks, patients/caregivers may be trained 
by the Investigator or qualified site staff in the administration of the study drug, 
according to the protocol dosing requirements.   
Patients must be screened prior to administration of study medication under this protocol.  
Screening/Baseline assessments may be performed during several clinic visits.  Patients 
must have completed the ALN-TTRSC-002 study to be eligible for this study.  If the final 
(Day 90) visit in the ALN-TTRSC-002 study is within 28 days of the first dose 
administered in this study, then visit procedures performed as part of the Day 90 visit do 
not need to be repeated at the Screening/Baseline visit.  If the final (Day 90) visit in the 
ALN-TTRSC-002 study occurred within 90 days of the first dose administered in this 
study, the echocardiogram and CMR do not need to be repeated at the Screening/Baseline 
visit.  Assessments not conducted as part of the ALN-TTRSC-002 Day 90 visit must be 
completed at the Screening/Baseline visit. 
Clinic visits will be performed for Screening/Baseline, dose initiation during Days 0 
through 7, and then approximately every 12 weeks through the End of Study visit (or 
ET), and at approximately 28 days following the End of Study visit (or ET) for a Follow-
up visit. 
A schematic of the protocol design is presented in Figure 1. 
 
 

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Figure 1: 
Study Schematic 
 
3.2. 
Safety Assessments 
Safety evaluations will be performed as part of Screening/Baseline and approximately 
every 12 weeks during the treatment period (with the exception of eye examinations, 
which will be performed once a year).  Some safety evaluations such as vital sign 
measurement and clinical laboratory tests will be performed more frequently. 
Safety monitoring will include assessment of AEs, clinical laboratory tests (hematology, 
serum chemistry, thyroid function, coagulation, and urinalysis), 12-lead ECGs, vital signs 
(blood pressure, pulse rate, oral body temperature, and respiratory rate), eye 
examinations, and physical examinations. 
3.3. 
Pharmacodynamic Assessments 
Pharmacodynamic evaluation will include serial measurement of serum levels of TTR at 
specified time points.  Serum levels of vitamin A will also be evaluated as a secondary 
PD biomarker. 
D-28 to D-1
D0 to D4
D7
D14 to D77
D91-D161
D84
D168
D175 to D245
D252
D259 to D329
D343 to D413
D336
D427 to D497
D420
D504
D511 to D581
D588
D595 to D665
D672
Screening
Study Days in Study 
ALN-TTRSC-003
Dose Initiation 
Period
Weekly Treatment 
Period
Completion of Study ALN-
TTRSC-002 through Day 90
Year 1
Year 2
D763-D833
D756
D840
D847 to D917
D924
D931 to D1001
D1015 to D1085
D1008
D1099 to D1169
D1092
D1176
D1183 to D1253
D1260
D1267-to D1337
D1344
End-of-Study or Early 
Termination (ET)
Follow-up
Study Days in 
Study ALN-
TTRSC-003
Weekly Treatment 
Period
Denotes weekly dosing, 
which may be conducted at home
Denotes clinic visits
Year 3
Year 4
28 days after End 
of Study or ET
D679 to D749

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3.4. 
Pharmacokinetic Assessments 
Samples for assessment of plasma concentration of ALN-TTRSC and possible metabolite 
analysis will be collected at various time points. 
3.5. 
Exploratory Clinical Efficacy Assessments 
Clinical efficacy will be explored through mortality, hospitalization, and 6-MWT.  
Additional clinical assessments will be performed including echocardiogram, CMR, 
99mTc imaging, circulating cardiac biomarkers (including NT-proBNP, troponins I and T), 
amyloid quantitation in fat pad aspirates, eGFR, mBMI, KCCQ, new onset or recurrence 
of atrial fibrillation, pacemaker placement, change in diuretic medication regimen, blood 
pressure, NYHA classification, and patient-reported QoL assessed by EQ-5D.  
Evaluations of clinical efficacy will be performed as part of Screening and approximately 
every 24 through 48 weeks during the treatment period. 
Other Assessments 
Blood samples will also be collected to evaluate exploratory biomarkers (mutant:  
WT TTR levels and additional cardiac and hepatic-derived proteins that may include 
galectin-3 and ST2) and serology (anti-drug antibody [ADAs]). 
Aliquots of serum samples will be taken and frozen, to permit testing of the effect of 
ALN-TTRSC on the expression of these exploratory biomarkers and serology. 
Disease burden and healthcare utilization will be assessed approximately every 48 weeks 
using a patient reported pharmacoeconomics questionnaire. 

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4. 
PATIENT POPULATION 
4.1. 
Eligibility of Patients 
Approximately 25 patients who completed participation in Study ALN-TTRSC-002 are 
expected to be enrolled in this extension study. 
4.2. 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria during the 
Screening/Baseline period to be eligible for enrollment in this study: 
1. 
Previously received and tolerated ALN-TTRSC in Study ALN-TTRSC-002; and 
completed Study ALN-TTRSC-002 through the Day 90 visit; 
2. 
Adequate liver function, demonstrated by an AST and ALT ≤2.5 × ULN, total 
bilirubin< 2 g/dL (34.2 µmol/L), and albumin > 3 g/dL (> 4.35 µmol/L);  
3. 
Women of child-bearing potential (WOCBP) must have a negative pregnancy 
test, cannot be breast feeding, and must be willing to use a highly effective 
method of contraception (see Section 7.9.1) prior to Screening/Baseline, 
throughout study participation, and for 1 month after last dose administration; 
4. Males who agree to use appropriate means of contraception (see Section 
7.9.2) throughout study participation until 1 month after last dose 
administration; 
5. 
Patient, or patient’s legal representative, is able and willing to provide written 
informed consent and the patient is willing to comply with the study 
requirements. 
4.3. 
Exclusion Criteria 
Each patient must not meet any of the following exclusion criteria to be eligible for 
enrollment in the study: 
1. 
Estimated Glomerular Filtration Rate < 20 mL/min/1.73 m2 (using the 
Modification of Diet in Renal Disease [MDRD] formula); 
2. 
Uncontrolled hypertension; 
3. 
Uncontrolled ischemic heart disease; 
4. 
Uncontrolled clinically significant cardiac arrhythmia; 
5. 
Untreated hypo- or hyperthyroidism;   
6. 
Prior major organ transplant;  
7. 
Known or suspected systemic bacterial, viral, parasitic, or fungal infection; 
8. 
Seropositive for hepatitis B virus, hepatitis C virus (HCV) or known to be HIV 
positive; 

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9. 
Received an investigational agent other than tafamidis, diflunisal, doxycycline, or 
tauroursodeoxycholic acid, or an investigational device within 30 days prior to 
first dose of study drug; 
10. 
Discontinued ALN-TTRSC-002 due to a treatment-related AE; 
11. 
Metastatic cancer within the past 5 years; 
12. 
Any conditions which, in the opinion of the Investigator, would make the patient 
unsuitable for enrollment or could interfere with the patient’s participation in, or 
completion of, the study. 
13. 
History of allergic reaction to an oligonucleotide or GalNAc. 
14. 
 Blinding Procedure 
This is an open-label, multi-dose study; all patients will receive ALN-TTRSC.  No 
blinding procedures are needed. 
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.  For those patients who withdraw early, every 
effort should be made to complete the ET visit (see Section 4.4.2 for handling of patients 
who withdraw). 
4.4.1. 
Reasons for Withdrawal 
The Investigator or designee may withdraw a patient from the study if the patient: 
• Is in violation of the protocol. 
• Experiences a serious or intolerable AE. 
• Becomes pregnant. 
• Requests to be withdrawn from the study (patient withdrawal of consent). 
• Is found to be considerably non-compliant with the protocol-required ALN-TTRSC 
dosing visits. 
A patient may also be withdrawn from the study if, in the Investigator’s opinion, he or 
she is unable to continue.  The Investigator will also withdraw the patient from the study 
upon the request of Alnylam, including if Alnylam terminates the study.  Upon 
occurrence of a serious or intolerable AE, the Investigator or designee will make every 
possible attempt to confer with Alnylam before discontinuing the patient. 
Missing an occasional dose of study medication will not necessarily result in the patient 
being withdrawn from the study.  However, if a patient misses 2 consecutive doses of 
study medication, the Investigator at the site and the Medical Monitor will discuss the 
appropriate management measures up to and including withdrawal from the study. 

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4.4.2. 
Handling of Withdrawals 
In the event a patient withdraws or is withdrawn from the study, the Investigator will 
inform the Medical Monitor at the clinical research organization (CRO) and Alnylam 
immediately.  If there is a medical reason for withdrawal, the patient will remain under 
the supervision of the Investigator for protocol-specified safety follow up procedures.   
When a patient withdraws or is withdrawn from the study, every effort should be made to 
conduct a complete ET visit as soon as possible following the patient’s withdrawal, as 
described in Table 2. 
If a patient is withdrawn for an AE, appropriate medical care should be provided and, if 
possible, the AE should be followed until resolution. 
A patient who fails to return for final evaluations will be contacted by the site in an 
attempt to have the patient comply with the protocol.  The site will follow up by 
telephone at least twice and send a registered letter to any patient who fails to return for 
the final evaluation. 
When a patient withdraws from the study, the primary reason for discontinuation must be 
recorded in the appropriate section of the case report form (CRF) and all efforts will be 
made to complete and report the observations as thoroughly as possible. 
For patients who discontinue early and have provided consent, overall health status will 
be documented by telephone contact or non-patient contact follow-up (eg, medical record 
check) at the scheduled time points. 
4.4.3. 
Replacements 
No replacements will be allowed for patients who withdraw early from the study. 

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5. 
STUDY MEDICATION 
5.1. 
Presentation of Study Drug 
The study drug, 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 ALN-TTRSC Solution for Injection will be supplied as a sterile 200 mg/mL solution 
and packaged in a glass vial.  The container closure system consists of a United States 
Pharmacopeia/European Pharmacopoeia Type I borosilicate glass vial, a Teflon-faced 
butyl rubber stopper and an aluminum flip-off cap. 
5.2. 
Preparation of Study Drug 
The study drug will be prepared by investigational site staff, a healthcare professional, 
the patient, or caregiver according to the procedures detailed in the Pharmacy Manual.   
5.3. 
Storage of Study Drug 
Study drug may be dispensed only by the Investigator, by a staff member specifically 
authorized by the Investigator, or by a pharmacist, as appropriate.  If a patient will 
receive weekly doses between visits at home, arrangements should be made to allow the 
required number of vials to be stored either at the site, a homecare health agency, or the 
patient’s home for storage between doses. 
All study drug will be stored upright, refrigerated, and protected from light in the storage 
area of the site pharmacy, homecare health agency, or in a patient’s home.  Any deviation 
from the recommended storage conditions should be reported. 
No special procedures for the safe handling of ALN-TTRSC are required. 
Alnylam, or a designee, will be permitted, upon request, to audit the supplies, storage, 
dispensing procedures, and records, as applicable. 
No study drug may be administered to any person not enrolled in the trial. 
Additional storage details are provided in the Pharmacy Manual. 
5.4. 
Labeling and Packaging of Study Drug 
All packaging and labeling as well as the preparation of ALN-TTRSC will be in 
compliance with Good Manufacturing Practice specifications, as described in the 
Manufacture of Investigational Medicinal Products Volume 4 Annex 13, and any other or 
local applicable regulations. 
Study drug labels for use at study sites will include all appropriate local labeling 
requirements on the vial and external packaging.  Sample labels will be submitted to 
health authorities, per local country submission requirements. 

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5.5. 
Dose, Route, and Schedule of Study Drug Measurement of 
Patient Compliance 
Patients meeting the eligibility criteria will initially receive a daily SC dose of 500 mg of 
ALN-TTRSC over 5 consecutive days (Days 0, 1, 2, 3, and 4).  Doses should be 
administered 24 ±4 hours apart. 
Patients will then receive the same dose of ALN-TTRSC on Day 7 and then weekly from 
Day 14 through approximately Day1337 (or ET).  The Day 7 dose should be 
administered within ±1 day of the planned dosing date.  The weekly doses starting on 
Day 14 should be administered within ±2 days of the planned dosing date.   
Study drug injection during clinic visits will be administered by qualified site staff under 
the supervision of the Investigator or designee.  Dosing after Day 7 may be administered 
at home by a healthcare professional trained in the protocol, or at the clinic if dosing 
coincides with the clinic visit for other assessments.  The preferred site of injection is the 
abdomen.  Optional additional sites are the upper arms and thighs.  The site of injection 
will be rotated.  If a local reaction around the injection site occurs, photographs may be 
taken.   
At the discretion of the Investigator, after the Day 84 dosing visit, and if the patient has 
not experienced any severe or serious AEs considered related to the study drug within the 
previous 12 weeks, patients/caregivers may be trained by the Investigator or qualified site 
staff in the administration of the study drug, according to the protocol dosing 
requirements.  Training of the patient/caregiver in study dosing should be recorded in the 
site source documentation.    
Detailed instructions can be found in the Pharmacy Manual. 
5.6. 
Criteria for Dose Interruption, Dose Modification, or 
Discontinuation of Study Drug 
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 liver function test 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 ≥5 ×ULN 
Under these circumstances, the Medical Monitor and Investigator will decide on the 
appropriate action regarding frequency of repeat liver function tests and resumption of 
dosing. 

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Dose-modification criteria: 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the Medical Monitor and Investigator will 
review all available safety data for that patient and for all other patients enrolled in the 
study.  Based on this review it may be decided to discontinue further administration of 
ALN-TTRSC, or, if the Investigator concurs, the patient may resume ALN-TTRSC at the 
same dose or, at a lower dose of 250 mg. 
Missed doses: 
If a patient misses a dose of study drug and is able to take the dose 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. 
5.7. 
Measurement of Patient Compliance 
Treatment compliance with study drug administration is dependent on the proper 
preparation and administration of SC injections by study site personnel, the patient’s 
home healthcare professional, or the patient/caregiver who has been trained in study drug 
administration, as well as attendance by the patient to the clinic.  Patients/caregivers will 
be provided with a diary with which to record study drug administration between clinic 
visits.  Patients will be permitted to miss an occasional dose of study drug.  However, if a 
patient misses 2 consecutive doses, the Investigator, in consultation with the Medical 
Monitor, will discuss whether the patient will be able to continue on the study.  
Patients/caregivers who are administering study drug at home should be instructed to 
contact the study site if 2 consecutive doses are missed. 
5.8. 
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 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. 
Patients/caregivers who have been trained to administer study drug at home between 
clinic visits will be dispensed an adequate supply of ALN-TTRSC.  The number of vials 
dispensed to the patient will be recorded in the study drug accountability log.  At each 
subsequent clinic visit, patients will be required to return all used and unused study drug 
vials to the site and the number of bottles will be recorded in the study drug 
accountability log by the site staff. 
Drug accountability records and inventory will be available for verification by the 
Alnylam Monitor or designee.  At the completion of the study, there will be a final 
reconciliation of all study drugs.  Remaining study drug (all used, partially used, and 
unused vials) will be returned to Alnylam or its agent or destroyed at the site according to 
applicable regulations. 

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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 ALN-TTRSC 
Pharmacy Manual. 
5.9. 
Concomitant Medication / Treatment 
Use of any investigational agent other than tafamidis, diflunisal, doxycycline, or 
tauroursodeoxycholic acid, or an investigational device within 30 days prior to the first 
dose of study medication in this protocol is prohibited during study participation. 
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, and advise patients to limit heavy 
alcohol consumption. 
Use of all concomitant medications from Screening/Baseline through the Follow-up visit 
will be recorded on the patient’s CRF.  This will include all prescription drugs, herbal 
preparations, OTC medications, vitamins, and minerals.  Any changes in medications 
during the study will also be recorded on the CRF. 
Any concomitant medication 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 CRF.  For coding of concomitant 
medication, an internationally recognized and accepted coding dictionary will be used. 

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6. 
STUDY ASSESSMENTS 
Details of the timing of each assessment are presented in the Schedule of Assessments for 
Clinic Visits for Year 1 and Year 2 (Table 1 ), the Schedule of Assessments for Clinic 
Visits for Year 3 and Year 4 (Table 2), the Schedule of Assessments for Weekly Dosing 
Days Between Clinic Visits (Table 3), and the Pharmacokinetic Sampling Schedule 
(Table 4). 
Screening/Baseline assessments may be performed during several clinic visits.  If the 
final Day 90 visit in the ALN-TTRSC-002 study is within 28 days of the first dose 
administered in this study, then visit procedures performed as part of the Day 90 visit do 
not need to be repeated at the Screening/Baseline visit.  If the Day 90 visit in the 
ALN-TTRSC-002 study occurred within 90 days of the first dose administered in this 
study, the echocardiogram and CMR do not need to be repeated at the Screening/Baseline 
visit.  The results from samples collected predose are not needed prior to dosing. 
The 14-day window for clinic visits applies to study assessments.  Dosing is to maintain 
the weekly schedule (± 2 days). 
The End-of-study or ET visit is scheduled approximately 7 days following the last dose.  
The Follow-up visit is scheduled approximately 4 weeks following the End-of-study or 
ET visit, if applicable.  Patients who discontinue early will be required to report to the 
clinic for an End-of-study visit and a Follow-up visit. 
6.1. 
Demographic Data and Medical History 
Patient demographic data will be obtained at Screening/Baseline.  A complete medical 
history will be obtained at Screening/Baseline and will include past or present conditions 
of the following:  general, head and neck, eyes, ears, nose and throat, chest/respiratory, 
heart/cardiovascular, gastrointestinal/liver, gynecological/urogenital, 
musculoskeletal/extremities, dermatological/skin, neurological/psychiatric, 
endocrine/metabolic, hematologic/lymphatic, allergies/drug sensitivities, past surgeries, 
substance abuse, or any other disease or disorder.  The patient’s HIV status will also be 
obtained. 
Any AEs from the previous study (ALN-TTRSC-002) that are ongoing on Day 0 will be 
considered as part of the medical history and recorded as such on the CRF. 
On Day 0 pre-dose, the medical history for each patient will be updated with any changes 
during the interval since the last recording.  Any changes in medical history will be 
evaluated against the inclusion and exclusion criteria to determine the patient’s continued 
eligibility for the study.   
6.2. 
Karnofsky Performance Status 
At the scheduled time points, each patient’s Karnofsky Performance Status will be 
assessed before study drug dosing; see Appendix 1 for a sample of the Karnofsky Scale.43 

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6.3. 
Estimated Glomerular Filtration Rate 
Estimated glomerular filtration rate will be calculated using the MDRD formula.  If this 
parameter met eligibility criteria at Screening/Baseline, then dosing can proceed prior to 
receiving pre-dose Day 0 results. 
The formula is as follows: 
GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) 
× (1.212 if African American) (conventional units) 
This formula estimates GFR using 4 variables (serum creatinine, age, ethnicity, and 
gender).  For precision, the serum creatinine values should be in mg/dL to 2 decimal 
places (eg, 0.95 mg/dL) OR values in µmol/L to the nearest whole number 
(e.g., 84 µmol/L).44   The following eGFR calculator can be used to determine eGFR:  
http://nkdep.nih.gov/lab-evaluation/gfr-calculators.shtml. 
6.4. 
Safety Assessments 
All safety assessment measures will be recorded in the patient’s medical record and CRF. 
6.4.1. 
Physical Examination 
At the scheduled time points, physical examinations should be performed before study 
drug dosing and 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. 
6.4.2. 
Body Weight and Height 
At the scheduled time points, body weight (measured in kilograms [kg]) will be obtained 
before study drug dosing; height will also be measured. 
6.4.3. 
Vital Signs 
At the scheduled time points, vital signs will be measured before study drug dosing.  
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, and respirations 
will be counted for a full minute and recorded in breaths per minute. 
Vital signs should also be collected during any unscheduled clinic visit, and before 
dosing at home, up to Day 84.  For the safety of the patient, additional vital signs may be 
added at the discretion of the Investigator. 
6.4.4. 
Electrocardiogram 
At the scheduled time points, standard computerized 12-lead ECG recordings will be 
obtained in triplicate before study drug dosing.  Each lead shall be recorded for at least 3 

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beats at a speed of 25 mm/sec.  The electrocardiographic parameters assessed will be 
rhythm, ventricular rate, PR interval, QRS duration, QT interval, ST and T waves, and 
Bazett-corrected QT interval (QTcB).   
The Investigator or designee is responsible for reviewing the ECGs to assess whether the 
results are within normal limits and to determine the clinical significance of the results.  
These assessments will be recorded on the CRF.  For any clinically significant abnormal 
results (eg, ischemic ECG changes, wave/interval changes, or arrhythmia), the 
Investigator must contact the Medical Monitor to discuss continued participation of the 
patient in the study. 
6.4.5. 
Clinical Laboratory Tests 
At the scheduled time points, samples for clinical laboratory tests will be collected before 
study drug dosing.  The following clinical laboratory tests will be performed by each 
study site’s local laboratory or a central laboratory:  
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 
• 
Phosphate 
• 
Potassium 
• 
Albumin 
• 
Blood urea nitrogen (BUN) 
• 
Calcium 
• 
Creatinine 
• 
Carbon dioxide 
• 
Uric acid 
• 
Chloride 
• 
Lactate dehydrogenase (LDH) 
 
• 
Glucose 
 
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) 

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Thyroid Function Test 
 
• 
Thyroid stimulating hormone (TSH) 
 
Serology Parameters 
 
• 
Hepatitis B surface antigens (HBsAg) 
• 
Hepatitis B surface antibody (HBsAb) 
• 
Anti-hepatitis C virus antibody (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) 
Urine Pregnancy Testing (WOCBP only) 
• 
-human chorionic gonadotropin 
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. 
6.4.6. 
Pregnancy Test 
A serum pregnancy test should be performed at Screening/Baseline for WOCBP and a 
urine pregnancy test may be used at all other visits; urine pregnancy tests will be 
performed at the study site.  Samples for the pregnancy test should be collected before 
study drug dosing.  The results of the pregnancy test at Screening/Baseline 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 7.10). 
6.4.7. 
Eye Examination 
At the scheduled time points, an eye examination will be performed.  These examinations 
will include assessment of visual acuity and slit-lamp evaluation and visual field, where 
possible.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Visual acuity testing should be done with best 
(most recent) correction.  Further details regarding the eye examinations will be provided 
in the Study Reference Manual. 

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6.4.8. 
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.  After Day 84, the site should contact the patient by 
phone at least monthly to collect information on concomitant medications between clinic 
visits.  See Section 5.9 for more details on prohibited and acceptable concomitant 
medications. 
6.4.9. 
Adverse Events 
Adverse events will be collected beginning with the first dose of study drug and through 
the Follow-up visit.  After Day 84, the site should contact the patient by phone at least 
monthly to collect information on adverse events between clinic visits.  See Section 7 for 
more details on the collection and reporting of AEs. 
6.5. 
Pharmacodynamic Assessments 
Details of how samples will be collected, processed, and stored will be in the Study 
Laboratory Manual. 
6.5.1. 
Transthyretin 
At the scheduled time points, blood for serum total TTR levels will be collected before 
study drug dosing and assessed using an enzyme linked immunosorbent assay method. 
6.5.2. 
Vitamin A 
At the scheduled time points, blood for serum vitamin A levels will be collected before 
study drug dosing and analyzed at a central laboratory. 
6.6. 
Pharmacokinetic Evaluations 
Blood samples for assessment of ALN-TTRSC concentration and possible metabolite 
analysis will be collected as noted in the Pharmacokinetic Sampling Schedule (Table 4). 
Please refer to the Study Laboratory Manual for details on the sample collection and 
processing for plasma PK samples. 
6.7. 
Clinical Efficacy Assessments 
The clinical efficacy assessments are briefly described below.  Further details on 
performing clinical efficacy assessments will be provided in the Study Reference Manual. 
6.7.1. 
Review of Cardiac Medical History and Treatment Changes 
Any changes to the patient’s cardiac medical history and treatment regimen changes 
should be recorded.  Changes to be documented may include, but are not limited to, onset 
or recurrence of atrial fibrillation, pacemaker placement, and change in diuretic regimen. 

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6.7.2. 
NT-proBNP, Troponin T, and Troponin I 
At the scheduled time points, blood samples for the quantification of troponin T, troponin 
I, and NT-proBNP (biomarkers of cardiac status) will be collected before study drug 
dosing.  Quantification of these biomarkers will be performed at a central laboratory. 
6.7.3. 
Echocardiography 
An echocardiogram with Doppler will be used for assessment of cardiac structure and 
function.  Echocardiography will be performed.  Details for image acquisition and upload 
for central review can be found in the Echocardiogram Site Instruction Manual. 
6.7.4. 
Six-Minute Walk Test 
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.  The Screening/Baseline assessment will include a 
practice and an actual 6-MWT test 1 hour apart; at subsequent visits the 6-MWT should 
be performed before study drug dosing.  Attempts should be made to perform the test 
approximately the same time of the day during the visits. 
The 6-MWT will be administered by staff trained in the protocol, as per the American 
Thoracic Society guidelines.45 
6.7.5. 
NYHA Classification 
NYHA classification will be recorded; the NYHA classification scale is provided in 
Appendix 2. 
6.7.6. 
Cardiac Magnetic Resonance Imaging  
Cardiac MRI with LGE will be performed on patients without contraindications (ie, 
pacemakers, severe renal failure with eGFR < 30 mL/min/1.73 m2, defibrillators, or 
allergy to gadolinium). 
Details for image acquisition and upload for central review can be found in the MRI 
Instruction Manual. 
6.7.7. 
Modified Body Mass Index  
Assessment of nutritional status will be measured by the mBMI, which has been linked to 
autonomic dysfunction.  Since the mBMI takes into account the serum albumin values 
along with body mass index (BMI; function of height and weight), it corrects for 
hypoalbuminemia and is considered more reflective of nutritional status than BMI alone.   
6.7.8. 
Kansas City Cardiomyopathy Questionnaire  
The KCCQ is a self-administered, 23-item questionnaire developed to provide a better 
description of health-related QoL in patients with chronic heart failure.46  The KCCQ 
assesses physical function, symptoms, social function, self-efficacy, and knowledge, and 
QoL.  At the scheduled time points, this questionnaire should be completed before study 
drug dosing.   

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6.7.9. 
EQ-5D Quality of Life 
Quality of life will be assessed through the use of the EQ-5D-5L, a standardized 
5 question instrument for use as a measure of health outcomes.  At the scheduled time 
points, This questionnaire should be completed before study drug dosing. 
6.7.10. 
Technetium Imaging 
Technetium (99mTc) imaging by 3D single-photon emission computed tomography 
(SPECT) will be performed, where possible, depending upon availability of the 99mTc 
imaging tracer.  99m-Tc-Pyrophosphate or DPD can be used as a tracer.  The tracer should 
not be changed for the patient during the study. 
Details for the procedure can be found in the Technetium Site Imaging Manual. 
6.7.11. 
Fat Pad Aspirates 
At the scheduled time points, two fine-needle aspirate samples of the abdominal fat pad 
(FNAFP) for amyloid quantification will be collected.  Additional timepoints may not be 
collected depending on the status of the screening aspirate samples.  Details on FNAFP 
collection, processing, and shipment will be in the Study Reference Manual. 
6.8. 
Other Assessments 
6.8.1. 
Exploratory Biomarkers and Serology  
At the scheduled time points, aliquots of serum samples will be taken before study drug 
dosing and frozen to permit testing of the effect of ALN-TTRSC on the expression of 
exploratory biomarkers (mutant:  WT TTR levels, additional cardiac and hepatic-derived 
proteins that may include galectin-3 and ST2) and serology (ADA).   
Mutant and WT TTR will be assessed using a mass spectrometry (MS) method. 
Details of how samples will be collected, processed, and stored will be in the Study 
Laboratory Manual. 
Biological samples for biomarker research can be retained on behalf of Alnylam for a 
maximum of 15 years following the last patient’s last visit in the study. 
6.8.2. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  At the scheduled time points, this questionnaire 
should be completed before study drug dosing. 

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7. 
REPORTING ADVERSE EVENTS 
7.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
Because reductions in TTR and vitamin A are expected responses to ALN-TTRSC, 
reductions in these parameters will not be considered AEs.  While circulating vitamin A 
levels will be lowered, this is not expected to result in signs or symptoms of severe 
vitamin A deficiency. 
7.1.1. 
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 
7.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly or birth defect; 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient and may require intervention 
to prevent one of the other outcomes listed above.  Examples of such 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. 
7.3. 
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 

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prescription and OTC).  Between clinic visits, the Investigator or designated study site 
staff should contact the patient by telephone on at least a monthly basis to collect 
additional information about any medically relevant health changes that may have 
occurred since the study visit.  The patient should also be instructed to contact the study 
site to report any changes in health status. 
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. 
7.4. 
Adverse Event Reporting 
The Investigator is responsible for reporting all AEs that are observed or reported after 
the first dose of study drug through the Follow-up visit regardless of their relationship to 
study drug or clinical significance. 
Any medical condition that is present when a patient is screened and does not deteriorate 
is captured as medical history and should not be reported as an AE.  However, if it does 
deteriorate at any time during the study, it should be reported as an AE. 
All AEs that occur after the first dose of study drug must be reported in detail on the 
appropriate CRF page and recorded in the site’s source records.  The description of the 
AE will include the onset time and date, duration, severity, seriousness (see Section 7.8) 
relationship to study drug, action taken, and outcome (including time and date of 
resolution, if applicable).  Adverse events resulting from concurrent illnesses, 
concomitant medications, or progression of disease states must also be reported.  The 
Medical Dictionary for Regulatory Activities (MedDRA®) will be used to code AEs. 
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 designee, 
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. To better understand the safety profile of the study drug, 
additional analysis of biopsy tissue may be performed as allowed by local regulations.  
For patients with hepatic AEs, additional information, including, clinical history, course 
of event, and local laboratory results  to monitor LFT levels or other laboratory 
parameters, may be collected. 

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7.5. 
Adverse Event Reporting Period 
All AEs that occur after the first dose of study drug must be followed to satisfactory 
resolution or for a period of 28 days from the last dose of study drug, whichever is the 
shorter, or the AE is deemed by the Investigator to be chronic or the patient to be stable. 
Serious AEs will be followed until resolved or until the SAE is considered by the 
Investigator to be chronic or the patient to be stable. 
7.6. 
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. 
7.7. 
Assessment of Severity 
The severity of each AE is to be classified as mild, moderate, severe, or life threatening 
according to the following criteria: 
Mild: 
Mild events are those which require minimal or no treatment and 
do not interfere with the patient’s daily activities. 
Moderate: 
Moderate events are those which cause sufficient discomfort to 
interfere with normal everyday activities and may require minor 
analgesics or antiemetics. 

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Severe: 
Severe events are those which interrupt a patient’s usual daily 
activity and may require systemic drug therapy or other therapy. 
Life Threatening: 
Life threatening events put the patient’s life at risk. 
Changes in severity should be documented in the medical record to allow assessment of 
the duration of the event at each level of severity.  Adverse events characterized as 
intermittent require documentation of the start and stop of each incidence.  When changes 
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). 
7.8. 
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 7.2) must 
be reported to Alnylam, or designee, within 24 hours from the time that site personnel 
first learn of the event, using the Serious Adverse Event Report provided.  All SAEs must 
be reported regardless of the relationship to study drug.  The SAE must also be recorded 
on the standard CRF pages. 
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. 
In the first instance, AE reporting will be via electronic data capture (EDC).  For names, 
addresses, telephone, and fax numbers for SAE reporting (eg, in case the EDC system is 
down), see information included in the SAE Reporting Procedure. 
If follow up is required, new information should be provided to Alnylam, or designee, as 
it becomes available using the Serious Adverse Event Report.  Copies of discharge 
summaries, consultant reports, autopsy reports, and any other relevant documents may 
also be requested. 
Appropriate remedial measures should be taken by the Investigator or Sub-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 or Sub-investigator until satisfactory 
resolution or the Investigator or Sub-investigator deems the SAE to be chronic or stable.  
Clinical, laboratory, and diagnostic measures should be employed by the Investigator or 
Sub-investigator as needed to adequately determine the etiology of the event. 

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The Investigator will be responsible for reporting all SAEs to the IEC/Institutional 
Review Board (IRB).  Alnylam, or designee, will be responsible for reporting of all 
relevant events to the regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and 
the Ethics Committees in the concerned Member States will be notified of fatal and life-
threatening Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as 
possible but no later than 7 calendar days after Alnylam or its representative has first 
knowledge of the minimum criteria for expedited reporting.  Non-fatal and non-life-
threatening SUSARs should be reported no later than 15 calendar days after Alnylam or 
its representative has first knowledge of them. 
The Investigator may be informed by Alnylam or its representatives of SAEs from other 
Investigators or clinical studies that may have relevance to this clinical trial.  These SAEs 
should also be reported promptly to the IEC/IRB that approved this study.  All SAE 
reports should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a 
copy of that transmittal should be maintained in the Investigator’s files and forwarded to 
Alnylam as part of the trial master file on study completion. 
7.9. 
Contraceptive Requirements 
7.9.1. 
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 1 
month after the last dose of ALN-TTRSC. Highly effective methods of birth control 
result in a low failure rate (ie, less than 1% per year).47  
For the purpose of this study, one of the following combinations of contraceptive 
methods must be used by WOCBP: 
• Hormonal: established use of oral (except low-dose gestagens [eg, lynestrenol and 
norethisterone]), implantable, injectable, or transdermal methods of conception in 
conjunction with spermicide, condom, or diaphragm;  
• Placement of an intrauterine device in conjunction with spermicide or condom;  
• Placement of an intrauterine system in conjunction with spermicide or condom; 
• Bilateral tubal occlusion in conjunction with spermicide or condom; 
• 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;  

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• Sexual true abstinence:  when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, 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). 
7.9.2. 
Requirements for Male Patients 
Males who agree to use appropriate means of contraception throughout study 
participation until 1 month after the last dose of ALN-TTRSC may be included in this 
study (see Section 7.9.1). 
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, should use condoms (accompanied with spermicidal 
foam, gel, film, cream, or suppository) as the appropriate means of contraception for the 
duration of the study and until 1 month after study drug administration. 
Males should also abstain from sperm donation after the first dose of study drug through 
study participation and for 1 month after the last dose of ALN-TTRSC. 
7.10. 
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 this study, the patient must be 
instructed to stop all study drug administration.  The Investigator or Sub-investigator 
must report a patient pregnancy (or a pregnancy of the partner of a patient participating in 
the study if consent has been obtained from the partner) to Alnylam or its agency within 
24 hours of being notified of the pregnancy.  Details of the pregnancy will be reported on 
a pregnancy report form.  The patient/partner shall receive any necessary counseling 
regarding the risks of continuing the pregnancy and the possible effects on the fetus. 
Monitoring of the patient/partner by the Investigator will continue until the conclusion of 
the pregnancy, and the Investigator will document the outcome of the pregnancy, which 
will be reported to Alnylam.  If the outcome of the pregnancy meets the criteria for an 
SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), then the Investigator should follow the procedures for reporting an 
SAE outlined above. 

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8. 
STATISTICAL METHODS 
8.1. 
Sample Size 
Approximately 25 patients who completed Study ALN-TTRSC-002 will be enrolled in 
this extension study.   
8.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature.  Adverse event summaries will 
include tabulations of all TEAEs, treatment-related AEs, SAEs, discontinuations due to 
AEs, and AEs of various grading severity.   
Descriptive statistics will be provided for clinical laboratory data, vital signs data, and 
ECG interval data, presented as both actual values and changes from baseline relative to 
each on-study evaluation.   
For categorical variables, summary tabulations of the number and percentage of patients 
within each category (with a category for missing data) will be presented.  For continuous 
variables, the number of patients, mean, median, standard deviation, minimum, and 
maximum values will be presented. 
A full statistical analysis plan will be finalized prior to database lock. 
8.2.1. 
Populations to be Analyzed 
The following populations (ie,  analysis sets) will be identified: 
• Safety Analysis Set:  All patients who receive at least one dose of ALN-TTRSC 
will be included in the safety analysis. 
• PD Analysis Set: All patients who received at least one dose of ALN-TTRSC and 
have at least one blood sample post-dose assessment. 
• PK Analysis Set:  All patients who receive at least one dose of ALN-TTRSC and 
have at least one blood draw postdose to determine plasma concentrations of 
ALN-TTRSC will be included in PK analyses. 
8.2.2. 
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. 
8.2.3. 
Safety Analyses 
Adverse events will be summarized by MedDRA® system organ class and preferred term.  
Separate tabulations will be produced for all TEAEs, treatment-related AEs (those 
considered by the Investigator as at least possibly drug related), SAEs, discontinuations 
due to AEs, and AEs of various grading severity.   
Descriptive statistics will be provided for clinical laboratory data and vital signs data, 
presented as both actual values and changes from baseline relative to each on-study 
evaluation and to the last evaluation on study. 

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Descriptive statistics will be provided for ECG interval data and presented as both actual 
values and changes from baseline relative to each on-study evaluation and to the last 
evaluation on study.  Details of any abnormalities will be included in patient listings. 
Details of any abnormalities will be included in patient listings. 
8.2.4. 
Clinical Activity Assessments 
Change from baseline by time point for 6-MWT will be summarized, where change from 
baseline is predose value (or final assessment from ALN-TTRSC-002, if a pre-dose 
assessment in this study is not required).  Change from baseline will also be summarized 
where baseline is derived from predose assessments in ALN-TTRSC-002.   
Frequency of hospitalization, cardiovascular hospitalization, and heart failure 
hospitalization will be summarized.  All-cause mortality and cardiovascular mortality 
will be summarized using Kaplan-Meier curves. 
Descriptive statistics will be presented for all clinical activity variables (NT-proBNP, 
troponin I, troponin T concentrations; selected echocardiography parameters; mBMI; 
NYHA classification; CMR imaging parameters).  Patient reported QoL and disease 
burden will be assessed by summary statistics for the EQ-5D and KCCQ.  Summary 
statistics will be provided for observed values and changes from baseline. 
8.2.5. 
Healthcare Utilization Assessments 
The observed values and changes from baseline in a health care utilization questionnaire 
will be summarized. 
8.2.6. 
Pharmacodynamics 
Summary tables and graphical displays of observed values and changes from baseline in 
serum TTR will be used to assess the durability of suppression over the course of the 
study.  Similar analyses will be performed for the secondary PD biomarker (vitamin A). 
8.2.7. 
Pharmacokinetics 
Pharmacokinetic parameters will be calculated, when feasible, by noncompartmental 
methods using standard modeling software.  Pharmacokinetic parameters will be 
summarized and presented, and mean (± standard error of the mean) concentration-time 
profiles will be generated by dose. 
8.2.8. 
Interim Analysis 
There is no formal interim analysis planned for this study.  Interim data examinations 
may be performed, but these will be of a descriptive nature and will not involve any 
formal hypothesis testing. 
8.2.9. 
Missing Data 
For continuous and categorical variables, data will be analyzed as reported, unless 
otherwise specified.  No imputation will be performed unless clearly identified. 

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For time-to-event variables, such as overall survival, subjects missing death will be 
right-censored. 

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9. 
STUDY MANAGEMENT 
The Investigator is accountable for the conduct of the trial.  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. 
9.1. 
Data Handling and Quality Assurance 
9.1.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source 
documentation as part of these case histories.  Source documents are the originals of any 
documents used by the Investigator or hospital/institution that allow verification of the 
existence of the patient and substantiate the integrity of the data collected during the trial. 
Alnylam will supply CRFs for each patient.  Case report forms must be completed only 
by persons designated by the Investigator.  Corrections must be made so as not to 
obliterate original data and must be identified and dated by the person who made the 
correction.  All data entered into the CRF must also be available in the source documents.  
The Investigator will allow designated Alnylam representatives and regulatory bodies to 
have direct access to the source documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a 
timely manner.  The completed CRF will be the records maintained by Alnylam.  A copy 
of the CRF will remain in the Investigator’s files.  
9.1.2. 
Monitoring 
The clinical monitor, as a representative of Alnylam, has an obligation to follow the study 
closely.  In doing so, the monitor will visit the 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 Alnylam or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice 
(GCP) and current standard operating procedures. 
9.1.3. 
Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB 
and/or Regulatory Authorities, providing direct access to source data/documents.  The 
study may be subject to audit by Alnylam or its representatives or by regulatory 
authorities.  If such an audit occurs, the Investigator must agree to allow access to the 
required patient records.  In the event of an audit, the Investigator agrees to allow 
Alnylam, representatives from Alnylam, or regulatory agencies access to all study 
records. 

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9.2. 
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 
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, and all other applicable medical 
privacy laws and regulations. 
9.2.1. 
Independent Ethics Committee Institutional Review Board 
National regulations and ICH require that approval be obtained from an IEC or an IRB 
prior to participation of patients in research studies.  Prior to the study onset, the protocol, 
any protocol amendments, informed consent forms (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 IEC or IRB. 
All IEC and IRB approvals must be dated and contain IEC/IRB Chairman or designee 
authorization and must identify the IEC/IRB (eg, 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 IEC/IRB authorization 
has been received by Alnylam or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at 
least annually or more often if specified by the IEC or IRB.  The Investigator must supply 
Alnylam with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IEC or IRB is constituted and 
operates in accordance with Federal and ICH GCP and any local regulations. 
9.2.2. 
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. 
9.2.3. 
Modification of the Protocol 
Major changes in this research activity, except those to remove an apparent immediate 
hazard to the patient, must be reviewed and approved by Alnylam and the IEC or IRB 
that approved the study.  Amendments to the protocol must be submitted in writing to the 
Investigator’s IEC or IRB and the Regulatory Authority for approval prior to patients 
being enrolled under the amended protocol. 
9.2.4. 
Informed Consent Form 
Written informed consent in compliance with ICH and local regulations 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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Alnylam will provide an ICF template to the Investigator for use in developing a 
site-specific ICF.  Prior to submission of the site-specific ICF to the IEC/IRB, the 
site-specific ICF must be reviewed and approved by Alnylam.  Any changes requested by 
the IEC/IRB must also be approved by Alnylam.  The final IEC/IRB approved ICF must 
be provided to Alnylam.  Revisions to the ICF required during the study must be 
approved by Alnylam, and a copy of the revised ICF provided to Alnylam. 
Before recruitment and enrollment, each prospective patient will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured 
that the patient understands the commitments of participating in the study, the patient 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. 
For patients who discontinue early and have provided consent, overall health status will 
be documented by telephone contact or non-patient contact follow-up (eg, medical record 
check) at the scheduled time points in an attempt to minimize the extent of missing data. 
9.2.5. 
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 IEC/IRB per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be 
made available to Alnylam or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the 
Alnylam or designee 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 Alnylam. 
9.2.6. 
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. 
9.3. 
Ancillary Research 
Research ancillary to this main protocol may not be performed by individual study sites 
without prior discussion and approval by Alnylam. 
9.4. 
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 

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Investigators, copies of the completed CRFs, signed ICFs, IEC/IRB approval and all 
related correspondence, financial agreements, regulatory approval, drug accountability, 
study correspondence, and patient identification codes.  Records will not be destroyed 
without informing Alnylam in writing and giving Alnylam the opportunity to store the 
records for a longer period of time at Alnylam’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after 
the completion or discontinuation of the study. 
9.5. 
Discontinuation of the Study by Alnylam 
Alnylam reserves the right to discontinue the study for clinical or administrative reasons 
at any time.  Should the study be terminated and/or the site closed for whatever reason, 
all documentation and study drug pertaining to the study must be returned to Alnylam or 
its representative, and the Investigators, IEC/IRB, and Regulatory Authorities will be 
promptly informed of the termination and the reason for the decision.  The Investigator 
should promptly inform the patients and assure appropriate therapy and follow-up. 
9.6. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the 
CRFs or other documents submitted to Alnylam or designees, patients should not be 
identified by their names, but by the assigned patient number and initials.  If patient 
names are included on copies of documents submitted to Alnylam or designees, the 
names (except for initials) will be obliterated and the assigned patient number added to 
the document.  Documents not for submission to Alnylam (eg,  signed ICFs) should be 
maintained by the Investigator in strict confidence. 
The Investigator must treat all of the information related to the study and the compiled 
data as confidential, the use of which is for the purpose of conducting the study.  Alnylam 
must approve any transfer of information to any person(s) or entities not directly involved 
in the study. 
9.7. 
Publications/Reports 
Following completion of the study, the data may be considered for publication in a 
scientific journal or for reporting at a scientific meeting.  A copy of the manuscript must 
be provided and confirmed received at Alnylam at least 30 days prior to its submission. 
No submission of a manuscript may be made until the results from all of the study sites 
have been received and analyzed by Alnylam, or the study has been terminated at all 
centers.  A separate, individual publication of the results of the study will be delayed until 
initial publication of the results of the multicenter study, or a decision not to publish is 
made.  If an initial draft is not produced within 18 months of completion of the study at 
all centers, or the timeframe for publication is not satisfactory, the Investigator may 
disclose the results after providing a copy and Alnylam confirms receipt of the 
manuscript 30 days prior to submission.    

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10. 
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Palha JA, Hays MT, Morreale de Escobar G, Gottesman ME, Saraiva MJ, et al. 
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Biesalski HK, Frank J, Beck SC, et al. Biochemical but not clinical vitamin A 
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Connors LH, Lim A, Prokaeva T,Costello CE. Tabulation of human transthyretin 
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Yazaki M, Tokuda T, Nakamura A, Higashikata T, Koyama J, Higuchi K, et al. 
Cardiac amyloid in patients with familial amyloid polyneuropathy consists of 
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Carvalho M, Alves M, Luis ML. Octreotide--a new treatment for diarrhoea in 
familial amyloidotic polyneuropathy. J Neurol Neurosurg Psychiatry. 1992 Sep 
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Soares M, Coelho T, Sousa A, Batalov S, Conceição I, Sales-Luís ML, et al. 
Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid 
polyneuropathy: complexity in a single-gene disease. Hum Mol Genet. 2005 Feb 
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Ruberg F, Berk J. Transthyretin (TTR) Cardiac Amyloidosis. Circulation. 
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Variant sequence transthyretin (isleucine 122) in late-onset cardiac amyloidosis in 
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12  
Dharmarajan K, Maurer M. Transthyretin cardiac amyloidoses in older North 
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Sattianayagam PT, Hahn AF, Whelan CJ, Gibbs SD, Pinney JH, Stangou AJ, et 
al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy 
 
 

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associated with transthyretin alanine 60 variant. Eur Heart J. 2012 
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Reilly M, Staunton H, Harding A. Familial amyloid polyneuropathy (TTR ala 60) 
in north west Ireland: a clinical, genetic, and epidemiological study. J Neurol 
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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 
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Am Heart J. 2009 Oct;158(4):607-14. 
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Westermark P, Bergström J, Solomon A, Murphy C, Sletten K. . Transthyretin-
derived senile systemic amyloidosis: clinicopathologic and structural 
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presenting with heart failure - a comparison with light chain-associated 
amyloidosis. Arch Intern Med. 2005 Jun 27;165(12):1425-9. 
20  
Ando Y, Coelho T, Berk J, Cruz MW, Ericzon BG, Ikeda S, et al. Guideline of 
transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 
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21  
Meier-Ewert H, Sanchorawala V, Berk J, Ruberg FL. Cardiac amyloidosis: 
evolving approach to diagnosis and management. Curr Treat Options Cardiovasc 
Med. 2011 Dec;13(6):528-42. 
22  
Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-
pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis 
from the transthyretin-related familial and senile cardiac amyloidoses. Circ 
Cardiovasc Imaging. 2013 Mar 1;6(2):195-201. 
23  
Benson MD, Teague SD, Kovacs R, Feigenbaum H, Jung J, Kincaid JC. Rate of 
progression of transthyretin amyloidosis. Am J Cardiol 2011 Jul 15;108(2):285-9. 
24  
Ruberg F, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. 
Prospective evaluation of the morbidity and mortality of wild-type and V122I 
mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis 
Cardiac Study (TRACS). Am Heart J 2012 Aug 16;164(2):222-8. 
25  
Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. 
Prognostication of survival using cardiac troponins and N-terminal pro-brain 
 

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natriuretic peptide in patients with primary systemic amyloidosis undergoing 
peripheral blood stem cell transplantation. Blood. 2004 Sep 15;104(6):1881-7. 
26  
ClinicalTrial.gov Identifier NCT00694161. The effects of Fx-1006A on 
transthyretin stabilization and clinical outcome measures in patients with V122I 
or Wild-Type TTR amyloid cardiomyopathy 
http://clinicaltrials.gov/ct2/show/NCT00694161?term=NCT00694161&rank=1 
Accessed on 30 Jul 2013. 
27  
Sekijima Y, Dendle MA, KellyJW. Orally administered diflunisal stabilizes 
transthyretin against dissociation required for amyloidogenesis. Amyloid. 2006 
Dec;13(4):236-49. 
28  
Castano A, Helmke S, Alvarez J, et al. Diflunisal for ATTR cardiac amyloidosis. 
Congest Heart Fail. 2012Nov-Dec;18(6):315-9. 
29  
ClinnicalTrial.gov Identifier NCT01855360 
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Accessed 07 Aug 2013. 
30  
ClinnicalTrial.gov Identifier NCT01171859 
http://clinicaltrials.gov/ct2/show/NCT01171859?term=NCT01171859&rank=1 
Accessed 07 Aug 2013. 
31  
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. 
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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. 
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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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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. 
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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. 
36  
Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore 
JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J 
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37  
Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, et al. 
High-dose melphalan and autologous stem-cell transplantation in patients with 
AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. 
 

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38  
Lachmann HJ, Gallimore R, Gilmore JD, Carr-Smith HD, Bradwell AR, Pepys 
MB, et al. Outcome in systemic AL amyloidosis in relation to changes in 
concentration of circulating free immunoglobulin light chains following 
chemotherapy. Br J Haematol, 2003 Jul;122(1):78-84. 
39  
Bergethon PR, Sabin TD, Lewis D, Simms RW, Cohen AS, Skinner M. 
Improvement in the polyneuropathy associated with familial amyloid 
polyneuropathy after liver transplantation. Neurology, 1996 Oct. 47(4):44-51. 
40  
Coelho T, Maia L, Martins da Silva A, Waddington Cruz M, Planté-Bordeneuve 
V, Lozeron P, et al. Tafamidis for transthyretin familial amyloid polyneuropathy, 
a randomized, controlled trial. Neurology. 2012 Aug 21;79(8):785-92. 
41  
Coutinho P, DeSilva AM, Lima JL, Barbosa AR. Forty years of experience with 
type I amyloid neuropathy: review of 483 cases. In: Glenner GG, Pinho P, Costa 
E, Falcao de Freitas A, Eds. Amyloid and Amyloidosis. Amsterdam: Excerpta 
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Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a 
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43  
Yates JW, Chalmer B, McKegney FP. Evaluation of patients with advanced 
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http://www.thoracic.org/statements/resources/pfet/sixminute.pdf. Accessed 28 
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Green CP, Porter CB, Bresnahan DR, Spertus JA.Development and evaluation of 
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2010. Accessed 30 July 2013. 

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11. 
APPENDICES 
Appendix 1: 
Karnofsky Scale 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.   
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.   
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
 

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