HELIOS-B: A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)
Phase: PHASE3
Conditions: Transthyretin Amyloidosis (ATTR) With Cardiomyopathy
Sponsor: Alnylam Pharmaceuticals

Clinical Study Protocol ALN-TTRSC02-003
ALN-TTRSC02 (vutrisiran)
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals
Confidential
1 
CLINICAL STUDY PROTOCOL
ALN-TTRSC02-003 
DATED 12 FEBRUARY 2024 
Protocol Title: 
HELIOS-B:  A Phase 3, Randomized, Double-
blind, Placebo-controlled, Multicenter Study to 
Evaluate the Efficacy and Safety of Vutrisiran in 
Patients with Transthyretin Amyloidosis with 
Cardiomyopathy (ATTR Amyloidosis with 
Cardiomyopathy)  
Short Title:
HELIOS-B:  A Study to Evaluate Vutrisiran in 
Patients with Transthyretin Amyloidosis with 
Cardiomyopathy  
Study Drug:
Vutrisiran (ALN-TTRSC02)
EU CT Number:
2023-508366-15 
EudraCT Number:
2019-003153-28 
IND Number:
141923 
Protocol Date: 
Original protocol:  22 August 2019 
Amendment 1:  28 May 2020
Amendment 2: 18 February 2021 
Amendment 3: 13 May 2022
Amendment 4: 22 March 2023 
Amendment 5: 12 February 2024 
Sponsor:
Alnylam Pharmaceuticals, Inc.
300 Third Street 
Cambridge, MA  02142 USA
Telephone:  +1-617-551-8200 
Sponsor Contact:   
Senior Director, Clinical Research
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without expressed written authorization of 
Alnylam Pharmaceuticals, Inc.
PPD

Clinical Study Protocol ALN-TTRSC02-003 
ALN-TTRSC02 (vutrisiran) 
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals 
Confidential 
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SPONSOR PROTOCOL APPROVAL  
 
I have read this protocol and I approve the design of this study. 
 
PPD

Clinical Study Protocol ALN-TTRSC02-003 
ALN-TTRSC02 (vutrisiran) 
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals 
Confidential 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTRSC02-003 protocol and agree to conduct the study in accordance with 
the protocol and all applicable regulations.  I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol. 
 
___________________________________________  
Printed Name of Investigator 
 
___________________________________________  
Signature of Investigator 
 
________________________ 
Date 

Clinical Study Protocol ALN-TTRSC02-003 
ALN-TTRSC02 (vutrisiran) 
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals 
Confidential 
4 
PROTOCOL SYNOPSIS 
Protocol Title 
HELIOS-B:  A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate 
the Efficacy and Safety of Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy 
(ATTR Amyloidosis with Cardiomyopathy)   
Short Title 
HELIOS-B:  A Study to Evaluate Vutrisiran in Patients with Transthyretin Amyloidosis with 
Cardiomyopathy  
Study Drug 
Vutrisiran (ALN- TTRSC02) 
Phase 
Phase 3 
Study Center(s) 
The study will be conducted at approximately 150 clinical study centers worldwide. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of vutrisiran 
compared to placebo on reducing all-cause 
mortality and CV events 
• 
Composite outcome of all-cause mortality and 
recurrent CV events (CV hospitalizations and 
urgent heart failure [HF] visits) in the overall 
population  
• 
Composite outcome of all-cause mortality and 
recurrent CV events (CV hospitalizations and 
urgent HF visits) in the vutrisiran 
monotherapy subgroup (defined as the group 
of patients not on tafamidis at study baseline) 
Secondary 
 
To evaluate the efficacy of vutrisiran compared 
with placebo treatment on: 
• 
Functional capacity  
• 
Patient-reported health status and health-
related quality of life 
• 
All-cause mortality  
• 
Severity of clinical heart failure symptoms  
The following secondary endpoints will be 
defined in both the overall population and the 
vutrisiran monotherapy subgroup: 
• 
Change from baseline in 6-MWT  
• 
Change from baseline in the KCCQ-OS 
• 
All-cause mortality 
• 
Change from baseline in NYHA Class 

Clinical Study Protocol ALN-TTRSC02-003 
ALN-TTRSC02 (vutrisiran) 
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals 
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Objectives 
Endpoints 
Safety 
 
• 
To evaluate the safety and tolerability of 
vutrisiran in patients with ATTR amyloidosis 
with cardiomyopathy 
• 
Frequency of AEs 
 
Study Design 
This is a Phase 3, randomized (1:1), double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of vutrisiran in approximately 600 patients with ATTR amyloidosis with 
cardiomyopathy.  Approximately 20% of the study population is anticipated to have hereditary ATTR 
(hATTR) and 80% wild-type ATTR (wtATTR) amyloidosis with cardiomyopathy.  
At baseline, patients are either: 
• 
Tafamidis-naïve (see inclusion criterion #4 for definition); or 
• 
Currently receiving tafamidis (Note: must be on-label use of commercial tafamidis per an 
approved cardiomyopathy indication in the country of use).   
The study consists of 4 periods (Figure 1): 
1. Screening Period: Up to 45 days during which patients will undergo screening assessments to 
determine eligibility. 
2. Double-Blind Period (DB Period): 
• 
At the start of the DB Period (on Day 1), eligible patients will be randomized in a 1:1 ratio to 
receive blinded doses of 25 mg of vutrisiran or placebo administered as a subcutaneous (SC) 
injection once every 3 months (q3M; every 12 weeks ±7 days) for up to 36 months.  
− 
In addition to study drug, all patients will take the recommended daily allowance of 
vitamin A during their DB Period and Follow-up Period (see below). 
• 
Patients will undergo assessments as outlined in the Schedule of Assessments (Table 1).  
• 
An individual patient’s DB Period visits will end after they complete their Month 36 visit, or 
30 months after the last patient is randomized, whichever comes first. As such, a patient's last 
visit during the DB Period may vary from 30 to 36 months after enrollment.  
− 
The variable length of the DB Period will mean that some patients will not have a 
Month 33 and/or Month 36 visit. For patients whose last visit in the DB Period was 
Month 30 (Week 132), Day 1 in the Open-Label Extension (OLE) Period will occur 
144 weeks (±7 days) after enrollment in the DB Period.  For patients whose last visit in 
the DB Period was Month 33 (Week 144), Day 1 in the OLE Period will occur 156 weeks 
(±7 days) after enrollment in the DB Period. For patients whose last visit in the DB 
Period was Month 36 (Week 156), Day 1 in the OLE Period will occur on the same day 
(since study drug is not administered as part of the Month 36 DB visit). 
− 
The period of DB exposure, defined as the duration prior to first exposure to open-label 
treatment, will be 144 to 156 weeks (33 to 36 months). 

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ALN-TTRSC02 (vutrisiran) 
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals 
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x 
The primary analysis will be conducted after the last patient has completed the period of DB 
exposure or otherwise discontinued. 
3. Open-Label Treatment Extension (OLE) Period  
The study has been amended (Amendment 4) to include an OLE Period in lieu of the Open-Label 
Randomized Treatment Extension Period (previously introduced with Amendment 3). In the OLE Period, 
all patients will receive the 25 mg q3M vutrisiran regimen. 
x 
Upon entry into the OLE, all eligible patients will transition to receive open-label doses of 
25 mg q3M vutrisiran administered as SC injections.  
x 
Patients initially randomized to 
 (under Amendment 3) will transition to receive 
open-label doses of 25 mg q3M vutrisiran administered as SC injections at their next 
scheduled dosing visit (24 weeks after their last dose of 
 vutrisiran). Patients initially 
randomized to 25 mg q3M vutrisiran (under Amendment 3) will continue with the 25 mg 
q3M regimen.  
 
In addition to study drug, all patients will take the recommended daily allowance of 
vitamin A during their OLE Period and Follow-up Period (see below). 
x 
All patients will undergo assessments as outlined in the Schedule of Assessments for the OLE 
Period (Table 2). 
Note: Patients who do not complete the DB Period may not participate in the OLE Period. Consent 
must be signed before any procedures are performed in the OLE Period (Table 2). 
4. Follow-Up Period after the last dose of vutrisiran on study: 
x 
Following completion of the OLE Period (or completion of the DB Period for patients who 
do not continue into the OLE Period; or their last dose of study drug for patients who 
discontinue study drug early), patients will commence follow-up visits every 12 weeks for the 
durations outlined below. 
x 
Prior to unblinding of their treatment from the DB Period, the duration of the Follow-up 
Period for a patient will be 1 year from their last dose of study drug. For women of 
child-bearing potential, the duration of the Follow-up Period will be 18 months from their last 
dose of study drug. Patients will continue vitamin A supplementation during their Follow-up 
Period. 
x 
After unblinding, all patients who were on placebo, and patients who received vutrisiran 
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Follow-up Period, whichever comes first, may discontinue further follow-up and stop taking 
vitamin A. Baseline is defined as the last value prior to first vutrisiran dose (ie, prior to the 
first DB dose for vutrisiran patients in DB Period and prior to the first OLE dose for placebo 
patients). Patients will be followed for a minimum period as listed below during the Follow-
up Period based on the treatment regimen received: 
 
All patients whose last dose of study drug was 25 mg vutrisiran/placebo during DB 
Period or 25 mg vutrisiran during the OLE Period will be followed for a minimum of 
90 days after their last dose of study drug. 
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Clinical Study Protocol ALN-TTRSC02-003 
ALN-TTRSC02 (vutrisiran) 
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals 
Confidential 
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 
Patients whose last dose of study drug was 
 vutrisiran regimen (under 
Amendment 3) will be followed for a minimum of 
 after their last dose of study 
drug during Follow-up Period. 
x 
For any patient who starts a TTR lowering treatment as part of clinical care, and has 
completed a minimum of 90 or 
 (depending on vutrisiran treatment regimen) of 
safety follow-up since their last dose of study drug, further follow-up will be discontinued. 
x 
Patients will undergo assessments as outlined in the Schedule of Assessments (Table 1 and 
Table 2). 
Patients may receive vutrisiran on the study until the end of the OLE Period or until one of the following 
occurs:  1) they meet any of the study discontinuation criteria; 2) vutrisiran is commercially available in 
the patient’s country of residence and vutrisiran is accessible to the patient and the patient has completed 
their OLE Month 12 Visit; or 3) the vutrisiran development program is discontinued.  
Study drug dosing may be allowed outside of the study center (eg, the patient’s home) during the 
DB Period or OLE Period under certain circumstances as specified in Section 5.2.2.  In addition, routine 
assessments and collection of relevant safety information may be collected outside the study center as 
specified in Section 6. 
Number of Planned Patients 
The planned enrollment for this study is 600 patients. 
Diagnosis and Main Eligibility Criteria 
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cardiomyopathy, including those with hATTR or wtATTR amyloidosis and a medical history of HF with 
at least 1 prior hospitalization for HF.  
Study Drug, Dose, and Mode of Administration 
Vutrisiran is a subcutaneously (SC) administered N-acetylgalactosamine (GalNAc)-conjugated small 
interfering RNA (siRNA), which targets liver-expressed messenger RNA (mRNA) for transthyretin 
(TTR).  
Study drug (vutrisiran or placebo) will be administered using a pre-filled syringe and a needle safety 
device.  The outside of the pre-filled syringe barrel will be masked in such a way as to hide the identity of 
the study drug contained within. 
Starting on Day 1 of the DB Period, patients will receive 25 mg of vutrisiran or placebo administered as a 
SC injection once every 3 months (q3M; every 12 weeks; ±7 days) for up to 36 months.   
Under Amendment 4, all patients in the OLE Period will receive SC injections of vutrisiran 25 mg q3M 
(every 12 weeks ±7 days) for up to 2 years; patients initially randomized to receive 
 vutrisiran 
under Amendment 3 will transition to receive 25 mg q3M vutrisiran at their next scheduled dosing visit 
(24 weeks after their last dose of 
 vutrisiran). 
The first dose of study drug should be administered in the clinic on Day 1 of the DB Period (placebo or 
vutrisiran 25 mg) and Day 1 of the OLE Period (vutrisiran 25 mg). If a patient has tolerated at least 1 dose 
of study drug in the clinic, subsequent dosing for the remainder of that period may be administered 
outside the study center (eg, the patient’s home) at all other timepoints where allowed by applicable 
country and local regulations. In these cases, dosing should be administered by a trained healthcare 
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Clinical Study Protocol ALN-TTRSC02-003 
ALN-TTRSC02 (vutrisiran) 
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals 
Confidential 
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professional, with oversight by the Investigator. If the patient is unable to come to the study center, and a 
visit by a home healthcare professional is not possible due to circumstances related to the COVID-19 
pandemic, q3M regimens of study drug (placebo or 25 mg vutrisiran) may be administered by the patient 
or the caregiver under the oversight of the Investigator, and following consultation with the medical 
monitor, as allowed by applicable country and local regulations.  In such cases, the patient or caregiver 
must receive appropriate training on study drug administration.  This measure is intended to remain in 
effect only during periods of time when the COVID-19 pandemic impedes the ability of patients to travel 
to the study site or healthcare professionals to go to patients' homes for dosing.  
Reference Treatment, Dose, and Mode of Administration 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC administration), 
which will be administered at the same dosing interval and volume as the study drug.   
Duration of Treatment and Study Participation 
The planned duration of treatment for each patient is up to approximately 60 months (approximately 
5 years), inclusive of the 30 to 36-month DB Period and a 24-month OLE Period.  
The estimated total time on study for each patient is up to approximately 6 years, including a Screening 
Period of up to 45 days, a DB Period of up to 36 months, an OLE Period of up to 24 months, and a 
Follow-up Period of up to 1 year after the last dose of study drug (18 months for women of child-bearing 
potential). 
Statistical Methods 
For the DB Period, randomization (1:1) will be stratified by:  1) baseline tafamidis use (yes versus no); 2) 
ATTR disease type (hATTR versus wtATTR amyloidosis with cardiomyopathy); and 3) New York Heart 
Association (NYHA) Class I or II and age <75 years versus all other. 
The overall Type I error rate for the two primary endpoints and the secondary endpoints will be controlled 
at a 2-sided 0.05 significance level using a prespecified multiplicity testing procedure. The two primary 
endpoints will be tested at a 2-sided 0.05 significance level using the Hochberg testing procedure, ie, if 
the larger of two p-YDOXHVLVERWKQXOOK\SRWKHVHVZLOOEHUHMHFWHGRWKHUZLVHWKHVPDOOHURIWKH
two p-YDOXHVZLOOKDYHWREHIRUWKHFRUUHVSRQGLQJQXOOK\SRWKHVLVWREHUHMHFWed.  If both primary 
endpoints are statistically significant, the full alpha of 0.05 will be passed to test the secondary endpoints 
defined in both the overall population and the vutrisiran monotherapy subgroup using a pre-specified 
multiple testing procedure described in the statistical analysis plan (SAP).  If one or both of the primary 
endpoints are not statistically significant, secondary endpoint tests will be performed and the results 
summarized, but statistical significance will not be inferred. 
 
 
 
 
 
Patients who undergo heart transplantation and/or left ventricular assist device placement will be treated 
in the same manner as death in the primary analyses of the primary endpoints and mortality-related 
endpoint(s). 
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ALN-TTRSC02 (vutrisiran) 
Amendment 5, 12 February 2024 
Alnylam Pharmaceuticals 
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x 
Dosing decisions may be made based on LFT results (Table 6) collected at the previous dosing visit (up to 14 weeks prior to dosing); in all cases the most recently 
available LFTs should be used.  
x 
When applicable, pregnancy test results must be known prior to dosing.   
x 
When scheduled at the same time points and where feasible, the assessments of vital signs and 
 should be performed before physical examinations, and blood 
sample collections.  
x 
In situations where a study visit is unable to be completed at the site (eg, due to the COVID-19 pandemic limiting the patient’s ability or willingness to access the study 
center or their ability to have received their scheduled doses of study drug), efficacy, safety, and other assessments may be completed up to 3 months after the time point 
(ie, up to Study Month 9, Month 15, Month 21, Month 27, or Month 33, respectively) after consultation with the Medical Monitor.  
a  The variable length of the DB Period will mean that some patients will not have a Month 33 and/or Month 36 visit. For patients whose last visit in the DB Period was Month 30 
(Week 132), Day 1 in the OLE Period will occur 144 weeks (±7 days) after enrollment in the DB Period.  For patients whose last visit in the DB Period was Month 33 (Week 
144), Day 1 in the OLE Period will occur 156 weeks (±7 days) after enrollment in the DB Period.  For patients whose last visit in the DB Period was Month 36 (Week 156), 
Day 1 in the OLE Period will occur on the same day (since study drug is not administered as part of the Month 36 DB visit). 
b  Patients will only enter the Follow-up Period after their last dose of study drug in the DB Period if not continuing into the OLE Period. 
c  When performed on dosing days, the 6-MWT, the KCCQ, safety, and PD assessments will be performed prior to study drug administration. All other efficacy assessments only 
need to be performed prior to study drug administration on Day 1 of the DB Period and Day 1 of the OLE Period.  
 
 
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Clinical Study Protocol ALN-TTRSC02-003 
ALN-TTRSC02 (vutrisiran) 
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Alnylam Pharmaceuticals 
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x 
In situations where a study visit is unable to be completed at the site (eg, due to the COVID-19 pandemic limiting the patient’s ability or willingness to access the study 
center or their ability to have received their scheduled doses of study drug), efficacy, safety, and other assessments may be completed up to 3 months after the time point 
(ie, up to OLE Month 9, OLE Month 15, OLE Month 21, or OLE Month 27, respectively) after consultation with the Medical Monitor. 
a For patients whose last visit in the DB Period was Month 30 (Week 132), Day 1 in the OLE Period will occur 144 weeks (±7 days) after enrollment in the DB Period.  For 
patients whose last visit in the DB Period was Month 33 (Week 144), Day 1 in the OLE Period will occur 156 weeks (±7 days) after enrollment in the DB Period. For patients 
who reach the Month 36 (Week 156) visit of the DB Period prior to the end of the DB Period for the study, this visit will take place on the same day as the Day 1 visit of the 
OLE Period. When this occurs, patients should complete the Scheduled Assessments for both the Month 36 visit of the DB Period and the Day 1 visit of the OLE Period. 
However, where these visits take place on the same day, assessments do not need to be repeated twice on the same day (ie, if an assessment is listed for both the Month 36 visit 
of the DB Period and the Day 1 visit of the OLE Period, the assessment can be performed once).  An informed consent form that has been approved by the appropriate 
Institutional Review Board /Independent Ethics Committee must be signed by the patient before any procedures are performed in the OLE Period. 
b When performed on dosing days, the KCCQ, safety, and PD assessments will be performed prior to study drug administration. All other efficacy assessments only need to be 
performed prior to study drug administration on Day 1 of the DB Period and Day 1 of the OLE Period. 
c  Only females of child-bearing potential.  
d The dosing schedule under Amendment 4 is 25 mg vutrisiran every 12 weeks. Upon entry into the OLE Period (OLE Day 1), all eligible patients will receive open-label doses of 
25 mg q3M vutrisiran administered as SC injections. Patients initially randomized to receive 
 vutrisiran under Amendment 3 will transition to receive 25 mg q3M 
vutrisiran at their next scheduled dosing visit (24 weeks after their last dose of 
 vutrisiran). 
 
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Clinical Study Protocol ALN-TTRSC02-003 
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Table 3: 
Pharmacokinetic Time Points for the Double-blind (DB) Period 
Study Day 
Sampling Time 
(hh:mm) 
Blood PK 
Sample 
Day 1, Week 36, Week 72 
(Month 18), and Week 132 
(Month 30) 
 
Predose (within 60 minutes before 
dosing) 
X 
04:00 (±30 minutes) after dosing 
X 
Abbreviations:  hh=hours; mm=minutes; PK=pharmacokinetics 
Notes: The hour (±range) indicate sample collection timing relative to dosing. Precise PK sample times (hour and 
minute) are recorded.  Refer to Section 6.4  for additional information on PK assessments. 
 
Table 4: 
Pharmacokinetic Time Points for the Open-label Treatment Extension 
(OLE) Period 
Study Day 
Sampling Time 
(hh:mm) 
Blood PK 
Sample 
OLE Day 1 
 
 
03:00 (±30 minutes) after dosing 
X 
06:00 (±30 minutes) after dosing 
X 
Abbreviations:  hh=hours; mm=minutes; OLE=open-label extension; PK=pharmacokinetics. 
Notes: The hour (±range) indicate sample collection timing relative to dosing. Precise PK sample times (hour and 
minute) are recorded.  See Section 6.4  for additional information on PK assessments. 
 
 

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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................20 
LIST OF TABLES .........................................................................................................................25 
LIST OF FIGURES .......................................................................................................................25 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................26 
1. 
INTRODUCTION ......................................................................................................30 
1.1. 
Disease Overview .......................................................................................................30 
1.2. 
Current Treatments .....................................................................................................30 
1.3. 
RNAi Therapeutics to Reduce TTR Levels ................................................................31 
1.4. 
Clinical Development of Vutrisiran............................................................................32 
1.5. 
Study Design Rationale ..............................................................................................33 
1.6. 
Dose Rationale ............................................................................................................35 
1.7. 
Benefit-Risk Assessment ............................................................................................36 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................38 
3. 
INVESTIGATIONAL PLAN .....................................................................................40 
3.1. 
Summary of Study Design ..........................................................................................40 
3.2. 
Duration of Treatment ................................................................................................42 
3.3. 
Duration of Study Participation ..................................................................................42 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................42 
3.4. 
Number of Planned Patients .......................................................................................42 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................43 
3.6. 
Blinding ......................................................................................................................43 
3.6.1. 
Emergency Unblinding ...............................................................................................43 
3.7. 
Data Monitoring Committee (DMC) ..........................................................................44 
3.8. 
Clinical Events Committee (CEC) ..............................................................................44 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................44 
4.1. 
Inclusion Criteria ........................................................................................................44 
4.2. 
Exclusion Criteria .......................................................................................................46 
4.3. 
Removal from Study Drug or Assessment .................................................................48 

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4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................48 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................49 
4.3.2.1. 
Patient Stops Participation in the Study ......................................................................49 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................50 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................50 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................50 
4.3.3. 
Lost to Follow-Up.......................................................................................................50 
4.3.4. 
Replacement of Study Patients ...................................................................................51 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................51 
5.1. 
Treatments Administered ............................................................................................51 
5.2. 
Study Drug ..................................................................................................................51 
5.2.1. 
Description ..................................................................................................................51 
5.2.2. 
Dose and Administration ............................................................................................52 
5.2.3. 
Dose Modifications .....................................................................................................53 
5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing...........53 
5.2.5. 
Dose Preparation, Handling, and Storage ...................................................................54 
5.2.6. 
Packaging and Labeling ..............................................................................................55 
5.2.7. 
Accountability .............................................................................................................55 
5.3. 
Product Complaints ....................................................................................................55 
5.3.1. 
Definition ....................................................................................................................55 
5.3.2. 
Reporting ....................................................................................................................55 
5.4. 
Concomitant Medications ...........................................................................................55 
5.4.1. 
Concomitant Tafamidis Use .......................................................................................56 
5.5. 
Treatment Compliance ................................................................................................57 
5.6. 
Other Requirements ....................................................................................................57 
5.6.1. 
Contraception ..............................................................................................................57 
5.6.2. 
Alcohol Restrictions ...................................................................................................58 
6. 
STUDY ASSESSMENTS ..........................................................................................58 
6.1. 
Screening Assessments ...............................................................................................59 
6.1.1. 
Retesting .....................................................................................................................60 
6.1.2. 
Rescreening .................................................................................................................61 
6.2. 
Efficacy Assessments .................................................................................................61 
6.2.1. 
Deaths, Hospitalizations, and Urgent Heart Failure Visits .........................................61 

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6.2.2. 
Vital Status Check ......................................................................................................61 
6.2.3. 
6-Minute Walk Test (6-MWT) ...................................................................................61 
6.2.4. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ...............................................62 
6.2.5. 
Cardiac Assessments ..................................................................................................62 
 
 
 
 
 
 
6.2.5.4. 
New York Heart Association (NYHA) Class .............................................................63 
 
 
 
 
 
 
 
 
6.3. 
Pharmacodynamic Assessments .................................................................................64 
6.4. 
Pharmacokinetic Assessments ....................................................................................64 
6.5. 
Safety Assessments .....................................................................................................64 
6.5.1. 
Vital Signs ..................................................................................................................65 
6.5.2. 
Weight and Height ......................................................................................................65 
6.5.3. 
Physical Examination .................................................................................................65 
 
 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................66 
6.5.5.1. 
Assessment for Monoclonal Gammopathy including MGUS ....................................68 
6.5.5.2. 
Immunogenicity ..........................................................................................................68 
6.5.5.3. 
Pregnancy Testing ......................................................................................................69 
6.5.5.4. 
Additional Liver Function Assessments .....................................................................69 
6.5.6. 
Adverse Events ...........................................................................................................70 
6.5.6.1. 
Definitions ..................................................................................................................70 
6.5.6.2. 
Eliciting and Recording Adverse Events ....................................................................72 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................73 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........73 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................74 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................74 
6.5.6.7. 
Pregnancy Reporting ..................................................................................................74 
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6.5.6.8. 
Overdose Reporting ....................................................................................................75 
6.5.7. 
COVID-19 Data Collection ........................................................................................75 
 
 
7. 
STATISTICS ..............................................................................................................76 
7.1. 
Determination of Sample Size ....................................................................................76 
7.2. 
Statistical Methodology ..............................................................................................77 
7.2.1. 
Populations to be Analyzed ........................................................................................77 
7.2.2. 
Examination of Subgroups .........................................................................................77 
7.2.3. 
Handling of Missing Data ...........................................................................................77 
7.2.4. 
Baseline Evaluations ...................................................................................................78 
7.2.5. 
Efficacy Analyses .......................................................................................................78 
7.2.5.1. 
Primary Endpoints ......................................................................................................78 
7.2.5.2. 
Secondary Endpoints ..................................................................................................78 
7.2.5.3. 
Exploratory Endpoints ................................................................................................79 
7.2.6. 
Pharmacodynamic Analysis........................................................................................79 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................79 
7.2.8. 
Safety Analyses ..........................................................................................................79 
7.2.9. 
Immunogenicity Analyses ..........................................................................................80 
7.2.10. 
Interim Analysis ..........................................................................................................80 
 
 
8. 
STUDY ADMINISTRATION ...................................................................................80 
8.1. 
Ethical and Regulatory Considerations ......................................................................80 
8.1.1. 
Informed Consent and Medical Records Release Form .............................................80 
8.1.2. 
Ethical Review ............................................................................................................81 
8.1.3. 
Serious Breach of Protocol .........................................................................................81 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................81 
8.1.5. 
End of Study ...............................................................................................................82 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................82 
8.2. 
Data Quality Control and Quality Assurance .............................................................82 
8.2.1. 
Data Handling .............................................................................................................82 
8.2.2. 
Study Monitoring ........................................................................................................83 
8.2.3. 
Audits and Inspections ................................................................................................83 
8.3. 
Publication Policy .......................................................................................................83 
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9. 
LIST OF REFERENCES ............................................................................................84 
10. 
APPENDICES ............................................................................................................88 
 
 
10.2. 
New York Heart Association Class (NYHA) .............................................................88 
 
 
10.4. 
Amendment History ....................................................................................................89 
10.4.1. 
Amendment 5 Summary of Changes ..........................................................................89 
10.4.2. 
Amendment 4 Summary of Changes ..........................................................................96 
10.4.3. 
Amendment 3 Summary of Changes ........................................................................108 
10.4.4. 
Amendment 2 Summary of Changes ........................................................................120 
10.4.5. 
Amendment 1 Summary of Changes ........................................................................129 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
6-MWT 
6-minute walk test 
99mTc 
Technetium 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALN-65492 
Drug substance in vutrisiran (siRNA targeting TTR mRNA) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APOLLO 
ALN-TTR02-004 pivotal Phase 3 study of patisiran in patients with 
hATTR amyloidosis with polyneuropathy 
APOLLO-B 
ALN-TTR02-011 Phase 3 study of patisiran in patients with ATTR 
amyloidosis with cardiomyopathy 
ASGPR 
Asialoglycoprotein receptor 
AST 
Aspartate aminotransferase 
ATTR 
Amyloid transthyretin 
ATTR-ACT 
Phase 3 study of tafamidis in patients with ATTR amyloidosis with 
cardiomyopathy 
BUN 
Blood urea nitrogen 
CEC 
Clinical Events Committee 
CHF 
Congestive heart failure 
COVID-19 
Coronavirus disease 2019 
CV 
Cardiovascular 
CT 
Computed tomography 
DB 
Double-blind 
DMC 
Data Monitoring Committee 
DPD-Tc 
99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid 
 
 
eCRF 
Electronic case report form 
 
 
ELISA 
Enzyme-linked immunosorbent assay 
ESC 
Enhanced stabilization chemistry 
EU 
European Union 
FAS 
Full Analysis Set 
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Abbreviation  
Definition 
FSH 
Follicle-stimulating hormone 
GalNAc 
N-acetyl galactosamine containing ligand 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
hATTR 
Hereditary ATTR 
HAV 
Hepatitis A virus 
HCV 
Hepatitis C virus 
HEV 
Hepatitis E virus 
HBc 
Hepatitis B virus core 
HBsAg 
Hepatitis B virus surface antigen 
HMDP 
99Tc-hydroxymethylene diphosphonate 
HELIOS-A 
ALN-TTRSC02-002 Phase 3 study of vutrisiran in patients with 
hATTR amyloidosis with peripheral neuropathy 
HELIOS-B 
ALN-TTRSC02-003 Phase 3 study of vutrisiran in patients with ATTR 
amyloidosis with cardiomyopathy (focus of this protocol) 
HF 
Heart failure 
HHV-6 
Human herpes virus 6 
HR 
Hazard ratio 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFE 
Immunofixation Electrophoresis 
IgG 
Immunoglobulin G antibody 
IgM 
Immunoglobulin M antibody 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection-site reaction 
IV 
Intravenous(ly) 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
KCCQ-OS 
KCCQ Overall Summary 
 
 
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Abbreviation  
Definition 
LFT 
Liver function test 
LNP 
Lipid nanoparticle 
LV 
Left ventricular 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGUS 
Monoclonal gammopathy of undetermined significance 
MMRM 
Mixed-effects model repeated measures 
mNIS+7 
Modified Neurologic Impairment Score +7 
MRI 
Magnetic resonance imagery 
mRNA 
Messenger RNA 
 
 
 
 
NYHA 
New York Heart Association 
OLE 
Open-Label Extension 
PC 
Product complaint 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
 
 
PPS 
Per-Protocol Analysis Set 
PT 
Preferred term 
PYP-Tc 
99mTc-pyrophosphate 
q3w 
Once every 3 weeks 
q3M 
Once every 3 months 
 
 
 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
RTE 
Randomized Treatment Extension 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
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Abbreviation  
Definition 
SC 
Subcutaneous 
 
 
siRNA 
Small interfering RNA 
SLA 
Soluble liver antigen 
SMQ 
Standardized MedDRA Query 
SOC 
System organ class 
SPEP 
Serum Protein Electrophoresis 
SUSAR 
Suspected unexpected serious adverse reactions 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
UPEP 
Urine Protein Electrophoresis 
US 
United States 
wt 
Wild-type 
wtATTR 
Wild-type ATTR 
 
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1. 
INTRODUCTION 
Refer to the vutrisiran Investigator’s Brochure (IB) for a detailed overview of transthyretin 
(TTR)-mediated amyloidosis (ATTR amyloidosis), current treatments, and the clinical 
development program for vutrisiran. 
1.1. 
Disease Overview 
ATTR amyloidosis is a rare, serious, life-threatening, multisystemic disease encompassing 
hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis, which 
result from either hereditary (genetic mutation) or nonhereditary (aging) causes, respectively.  
TTR, also known as prealbumin, is a tetrameric protein produced by hepatocytes, the choroid 
plexus, and retina.[Liz 2010]  More than 95% of TTR in the circulation is derived from the liver.  
The primary physiological role of TTR is to serve as a carrier of retinol (also known as vitamin 
A), which involves TTR binding to the retinol binding protein (RBP): vitamin A complex.  
However, there is evidence to suggest that vitamin A transport and tissue uptake can occur in the 
absence of circulating RBP.[Biesalski 1999; Episkopou 1993] 
There are over 120 reported TTR genetic mutations associated with hATTR amyloidosis.[Ando 
2013; Connors 2003]  These inherited mutations in the TTR gene lead to destabilization of the 
tetrameric protein and disassociation of the TTR subunits into dimers and individual mutant and 
wild-type (wt) monomers, which subsequently misfold and form amyloid fibrils and plaques in 
the extracellular space of various tissues.[Hou 2007]  Normal, nonmutant wtTTR alone can also 
be amyloidogenic; this is the basis for the nonhereditary, wtATTR amyloidosis.  This is a 
progressive disease typically seen in patients older than 70 years and is predominantly seen in 
men.[Westermark 2003]  In both hATTR and wtATTR amyloidosis, deposition of TTR amyloid 
fibrils in various organs results in progressive, chronically debilitating morbidity and mortality.  
The most common manifestations of ATTR amyloidosis are cardiomyopathy (ie, ATTR 
amyloidosis with cardiomyopathy) and polyneuropathy (ie, ATTR amyloidosis with 
polyneuropathy). 
In both hereditary and wt disease, cardiac infiltration of the extracellular matrix by TTR amyloid 
fibrils leads to a progressive increase of ventricular wall thickness and a marked increase in 
chamber stiffness, resulting in impaired diastolic function.  Systolic function is also impaired, 
typically reflected by abnormal longitudinal strain despite a normal ejection fraction, which is 
often preserved until late stages of the disease.[Castano 2015; Dungu 2012; Mohty 2013; Ruberg 
2012b]  Cardiac infiltration by amyloid can also lead to conduction disturbances and 
arrhythmias. [Adams 2016; Ando 2013; Benson 2007; Connors 2004]  ATTR amyloidosis 
patients with symptomatic heart failure (HF) experience rapid progression of their 
cardiomyopathy.  Based on natural history data, patients typically experience progressive 
symptoms of HF resulting in hospitalization, with death typically occurring 2.5 to 5 years after 
diagnosis.[Castano 2015; Damy 2015; Dungu 2012; Hawkins 2015] 
1.2. 
Current Treatments 
Historically, palliative/symptomatic therapies directed at specific symptoms, have been the 
mainstay of treatment despite their limited effectiveness.  Recently, several new products for the 
treatment of ATTR amyloidosis have been approved and have become available in some regions.    

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2019]  Currently, patisiran continues to be investigated for the treatment of patients with ATTR 
amyloidosis with cardiomyopathy in the ongoing Phase 3 Study ALN-TTR02-011 
(APOLLO-B). 
Previously, the Sponsor investigated another siRNA therapeutic, revusiran that was also 
conjugated to an N-acetylgalactosamine (GalNAc) containing ligand and administered 
subcutaneously (SC), for use in the treatment of patients with hATTR amyloidosis with 
cardiomyopathy. However, the revusiran program was discontinued (further details can be found 
in the vutrisiran Investigator’s Brochure).  
Presently, the Sponsor is developing a novel synthetic RNAi therapeutic, vutrisiran drug product 
(ALN-TTRSC02; hereafter referred to as vutrisiran) for SC administration for the treatment of 
ATTR amyloidosis, including the treatment of patients with ATTR amyloidosis with 
cardiomyopathy.  Vutrisiran utilizes a mechanism similar to patisiran in that RNAi is used to 
selectively target and degrade TTR mRNA, thus preventing the synthesis of both wt and mutant 
TTR in the liver, the primary source of circulating TTR.  Unlike patisiran, which is formulated as 
an LNP and administered with an IV infusion, vutrisiran is conjugated to a GalNAc and 
administered SC. Rapid and efficient uptake of vutrisiran by the liver occurs via the 
asialoglycoprotein receptor (ASGPR). The ASGPR is a member of the C-type lectin family of 
receptors that recognizes and binds glycoproteins with terminal galactose or GalNAc 
residues.[Ashwell 1974]  It is expressed on the cell surface of hepatocytes at a high copy number 
(0.5-1 million per cell) [Baenziger 1980; Schwartz 1980] and facilitates clearance of desialylated 
glycoproteins from the blood.[Geffen 1992]   
Vutrisiran employs a different ratio of chemical modifications to confer increased stability of the 
siRNA and is thus designed to have greater potency and prolonged duration of action compared 
to current and previous siRNAs evaluated in the clinic for treatment of this disease. This enables 
a much lower dose, lower injection volume, and significantly less frequent dosing with vutrisiran 
compared to other TTR-lowering drugs. Because vutrisiran does not include any LNPs as part of 
its formulation, no premedications are required. 
1.4. 
Clinical Development of Vutrisiran 
Vutrisiran was initially evaluated in a completed Phase 1 study (ALN-TTRSC02-001) in healthy 
patients, and is currently being investigated in an ongoing Phase 3 study (ALN-TTRSC02-002 
[HELIOS-A]) in patients with hATTR amyloidosis with polyneuropathy as described below.   
Study ALN-TTRSC02-001 was a Phase 1, randomized, single-blind, placebo-controlled, single-
ascending dose study evaluating the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of vutrisiran in 80 healthy subjects; 60 subjects received single-doses of 
vutrisiran (from 5 mg to 300 mg) and 20 subjects received placebo.  
Overall, vutrisiran was well tolerated.  There were no serious or severe adverse events (AEs) and 
no subject discontinued from the study due to an AE. Mostly mild, transient, dose-dependent 
increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 
observed in all vutrisiran dose groups, particularly at doses >100 mg.  Two subjects had 
transient, asymptomatic elevations in ALT and/or AST of >3 × the upper limit of normal (ULN).  
None of the ALT or AST elevations were reported as AEs and none were associated with 
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Single SC doses of 25 to 300 mg vutrisiran resulted in robust, and durable reductions in serum 
TTR protein, with the magnitude and duration of TTR reduction being dose-dependent.  At the 
proposed dose of 25 mg vutrisiran, a single dose resulted in mean maximum TTR reduction of 
83%; the nadir was reached at approximately 6 weeks and maintained for 90 days.  Based on the 
results of the Phase 1 Study ALN-TTRSC02-001, vutrisiran 25 mg SC administered once q3M 
was selected for further development (see Section 1.6 for dose rationale). 
HELIOS-A is an ongoing, Phase 3, global, randomized, open-label study to evaluate the efficacy 
and safety of vutrisiran 25 mg SC q3M in patients with hATTR amyloidosis with 
polyneuropathy. Enrollment in this study is complete. Patients were randomized 3:1 to receive 
either 25 mg of vutrisiran (N=122) q3M or 0.3 mg/kg of patisiran (N=42) q3w (as a reference 
comparator) for 18 months. As of Amendment 4, after the 18-month Treatment Period, all 
patients transition into the Randomized Treatment Extension (RTE) Period and are randomized 
1:1 to receive vutrisiran 25 mg q3M or 
 treatment.  The primary endpoint in 
HELIOS-A is change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 
Month 9 and first key secondary endpoint is change from baseline in the 
 total score at Month 9. The primary endpoint and most 
secondary endpoints will be comparisons of vutrisiran to the placebo arm of the Phase 3 
APOLLO study of patisiran. 
Further information on the chemistry, pharmacology, efficacy, and safety of vutrisiran is 
provided in the current edition of the Investigator’s Brochure. 
1.5. 
Study Design Rationale 
The proposed Phase 3 ALN-TTRSC02-003 (HELIOS-B) study is a global, randomized, double-
blind, placebo-controlled study designed to evaluate the efficacy, safety and PK/PD of vutrisiran in 
patients with hATTR and wtATTR amyloidosis with cardiomyopathy.   
Patients will receive treatment with 25 mg vutrisiran or placebo every 3 months (q3M) during 
their Double-blind (DB) Period of the study for up to 36 months (see Section 3.1).  The primary 
analysis will be conducted after the last patient has completed the period of DB exposure 
(defined as the duration prior to first open-label treatment exposure). An Open-label Randomized 
Treatment Extension Period was added with Amendment 3 in which patients who complete 
treatment in the DB Period will be randomized to receive either 25 mg vutrisiran q3M or 
 
vutrisiran 
 in an open-label fashion.  Following implementation of Amendment 4, the 
Randomized Treatment Extension will be replaced with an Open-Label Extension (OLE) where 
all patients who complete treatment in the DB Period will receive vutrisiran 25 mg q3M for up to 
2 years. A Follow-up Period will commence when patients complete the OLE Period (or 
complete the DB Period for patients who do not continue into the OLE Period; or their last dose 
of vutrisiran for patients who discontinue study drug early) and patients will be followed for a 
period of up to 1 year after their last dose of study drug. See also Section 3.1. 
The patient population includes ATTR amyloidosis patients with cardiomyopathy and New York 
Heart Association (NYHA) class I – III heart failure.  However, the study criteria are intended to 
exclude patients with NYHA Class IV heart failure and patients with advanced NYHA Class III 
heart failure based on a biomarker based staging system (
 
 
Gillmore 2018]  The population is intended to be broadly representative 
of patients with ATTR cardiomyopathy while avoiding the highest-risk patients who are unlikely 
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to have sufficient time on treatment to derive benefit in the context of a clinical trial of limited 
duration.    
Given that tafamidis is prescribed in some, but not all, regions as standard of care in this patient 
population, at baseline patients will either be on concurrent tafamidis or be considered naïve to 
tafamidis (Section 4.1; Section 5.4.1). As with any active therapy, initiation of tafamidis in naïve 
patients during the study (tafamidis drop-in), impacts the ability to accurately quantify the 
vutrisiran treatment effect relative to placebo, particularly if use is disproportionate between 
treatment arms.  Accordingly, it should be noted that per exclusion criterion #7, tafamidis-naïve 
patients (per inclusion criterion #4a) for whom the Investigator actively plans or anticipates 
commencing treatment with tafamidis either during the Screening Period or the first 12 months 
following randomization should not be enrolled in the trial, taking into consideration clinical 
status, patient preference and/or commercial availability of tafamidis. 
The primary objective of the study is to determine the efficacy and safety of vutrisiran for the 
treatment of cardiomyopathy by evaluating its impact on a composite outcome of mortality and 
recurrent cardiovascular (CV) events. 
The efficacy of vutrisiran will be evaluated in the overall population, which is representative of 
patients with ATTR cardiomyopathy prescribed tafamidis as standard of care, or those newly 
diagnosed. Analysis will also be conducted in the vutrisiran monotherapy subgroup which will 
provide a demonstration of the potential clinical benefit of vutrisiran in the absence of any 
confounding effect of benefit from concomitant tafamidis.  
CV events will include recurrent CV hospitalizations and recurrent non-hospitalized urgent HF 
visits in accordance with the 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical 
Trials.[Hicks 2018] The primary endpoints will provide definitive evidence of a clinically 
meaningful impact in the study population.  Similar endpoints have been used in numerous heart 
failure studies, including the recent Phase 3 ATTR-ACT study of the TTR tetramer stabilizer, 
tafamidis.[Maurer 2018; McMurray 2019] Including urgent HF visits will account for the 
likelihood that the COVID-19 pandemic may increase current trends to reduce hospitalizations 
and shift management of clinically comparable heart failure events to outpatient settings.[Hicks 
2018]  Including urgent HF visits also accounts for regional differences in the criteria for 
hospitalization, which may be further exacerbated by the COVID-19 pandemic.  In addition, data 
support the equivalence of urgent HF visits to HF hospitalizations for predicting 
mortality.[Okumura 2016]   
As a key secondary objective, the study will also evaluate the efficacy of vutrisiran on functional 
capacity (6-minute walk test; 6-MWT) and health status and health-related quality of life 
(Kansas City Cardiomyopathy Questionnaire Overall Summary; KCCQ-OS).  The 6-MWT is a 
clinically relevant assessment of functional capacity that has been used as a primary endpoint in 
pivotal clinical trials in pulmonary arterial hypertension [Gabler 2012] and has been used in the 
evaluation of patients with HF.[Bittner 1993; Flynn 2009; Flynn 2012; Mangla 2013; Masoudi 
2004; Maurer 2018]  The KCCQ-OS has been used as a common assessment in HF 
interventional studies and has been shown to be an independent predictor of prognosis in 
HF.[Heidenreich 2006]   
Both 6-MWT and KCCQ-OS were shown to rapidly and consistently decline over time in 
cardiac ATTR amyloidosis patients and, in the tafamidis Phase 3 ATTR-ACT study, these 

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tested dose (300 mg) were well tolerated.  The selected Phase 3 dosing regimen of 25 mg q3M 
SC is also infrequent, easy to administer, and does not require premedication. Other available 
TTR lowering agents including patisiran, have demonstrated benefit on both neuropathy and 
exploratory assessments of cardiomyopathy as well as on quality of life in patients with hATTR 
amyloidosis.  Based on the clinical data with vutrisiran, taken together with clinical efficacy that 
has been demonstrated with other TTR lowering agents, it is anticipated that TTR reduction with 
vutrisiran will beneficially impact disease progression in patients with ATTR amyloidosis with 
cardiomyopathy. 
Given the target organ of vutrisiran, the available nonclinical and clinical data, and the mode of 
administration, important potential risks for vutrisiran are injection-site reactions (ISRs) and liver 
function test (LFT) abnormalities.  During the study, patients will be closely monitored, 
including evaluation of injections sites.  As vutrisiran is targeted for delivery to the liver, there is 
a potential for development of LFT abnormalities.  Patients presenting with any laboratory result 
considered unacceptable as per exclusion criteria (see Section 4.2) at time of enrollment will be 
excluded from participation in this study, and LFTs will be routinely monitored throughout the 
study per the Schedule of Assessments.  Criteria for dose withholding, modification and stopping 
vutrisiran dosing due to LFT abnormalities are provided in Section 5.2.4.  An external, 
independent Data Monitoring Committee (DMC) will monitor and ensure the safety of trial 
participants (see Section 3.7).  
Nonclinical and clinical data with vutrisiran and patisiran have shown that the lowering of 
circulating vitamin A associated with the reduction in TTR (a carrier of retinol) does not result in 
severe vitamin A deficiency; transport and tissue uptake of vitamin A can occur through 
alternative mechanisms in the absence of retinol binding protein.  However, as the vitamin A 
content of the diet may vary between different individuals, all patients will be instructed to take 
the recommended daily allowance of vitamin A while on the study (see Section 3.1).  Laboratory 
tests for serum vitamin A do not reflect the total amount of vitamin A in the body and should not 
be used to guide vitamin A supplementation beyond the recommended daily dose during 
treatment with vutrisiran. 
Based on the emerging efficacy and available safety data described above, the benefit-risk 
assessment supports the evaluation of vutrisiran in hATTR and wtATTR patients with 
amyloidosis. Detailed information about the known and expected benefits and risks of vutrisiran 
and additional safety information may be found in the current edition of the vutrisiran 
Investigator’s Brochure. 
 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a Phase 3, randomized (1:1), double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety of vutrisiran in approximately 600 patients with ATTR 
amyloidosis (hATTR or wtATTR) with cardiomyopathy.  Approximately 20% of the study 
population is anticipated to have hATTR and 80% wtATTR amyloidosis with cardiomyopathy.  
At baseline, patients are either: 
• Tafamidis-naïve (see inclusion criterion #4 for definition); or 
• Currently receiving tafamidis (Note: must be on-label use of commercial tafamidis 
per an approved cardiomyopathy indication in the country of use).   
The study consists of 4 periods (Figure 1):  
1. Screening Period: Up to 45 days during which patients will undergo screening 
assessments to determine eligibility. 
2. Double-Blind (DB) Period: 
• At the start of the DB Period (on Day 1), eligible patients will be randomized in a 1:1 
ratio to receive blinded doses of 25 mg of vutrisiran or placebo administered as a SC 
injection q3M (every 12 weeks ±7 days) for up to 36 months. 
− In addition to study drug, all patients will take the recommended daily allowance 
of vitamin A during their DB Period and Follow-up Period (see below). 
• Patients will undergo assessments as outlined in the Schedule of Assessments 
(Table 1).  
• An individual patient's DB Period visits will end after they complete their Month 36 
visit, or 30 months after the last patient is randomized, whichever comes first. As 
such, a patient's last visit during the DB Period may vary from 30 to 36 months after 
enrollment. 
− The variable length of the DB Period will mean that some patients will not have a 
Month 33 and/or Month 36 visit. For patients whose last visit in the DB Period 
was Month 30 (Week 132), Day 1 in the OLE Period will occur 144 weeks 
(±7 days) after enrollment in the DB Period.  For patients whose last visit in the 
DB Period was Month 33 (Week 144), Day 1 in the OLE Period will occur 
156 weeks (±7 days) after enrollment in the DB Period. For patients whose last 
visit in the DB Period was Month 36 (Week 156), Day 1 in the OLE Period will 
occur on the same day (since study drug is not administered as part of the 
Month 36 DB visit). 
− The period of DB exposure, defined as the duration prior to first exposure to 
open-label treatment, will be 144 to 156 weeks (33 to 36 months). 
• The primary analysis will be conducted after the last patient has completed the period 
of DB exposure or otherwise discontinued. 

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3. Open-Label Treatment Extension (OLE) Period  
The study has been amended (Amendment 4) to include an OLE Period in lieu of the Open-Label 
Randomized Treatment Extension Period (previously introduced with Amendment 3). In the 
OLE Period, all patients will receive the vutrisiran 25 mg q3M regimen. 
x Upon entry into the OLE, all eligible patients will transition to receive open-label 
doses of 25 mg q3M vutrisiran administered as SC injections.  
x Patients initially randomized to 
 (under Amendment 3) will transition to 
receive open-label doses of 25 mg q3M vutrisiran administered as SC injections at 
their next scheduled dosing visit (24 weeks after their last dose of 
 vutrisiran). 
Patients initially randomized to 25 mg q3M vutrisiran (under Amendment 3) will 
continue with the 25 mg q3M regimen.  
 In addition to study drug, all patients will take the recommended daily allowance 
of vitamin A during their OLE Period and Follow-up Period (see below). 
x All patients will undergo assessments as outlined in the Schedule of Assessments for 
the OLE Period (Table 2). 
Note: Patients who do not complete the DB Period may not participate in the OLE Period. 
Consent must be signed before any procedures are performed in the OLE Period (Table 2). 
4. Follow-Up Period after the last dose of vutrisiran on study: 
x Following completion of the OLE Period (or completion of the DB Period for patients 
who do not continue into the OLE Period; or their last dose of vutrisiran for patients 
who discontinue study drug early), patients will commence follow-up visits every 12 
weeks for the durations outlined below. 
x Prior to unblinding of their treatment from the DB Period, the duration of the Follow-
up Period for a patient will be 1 year from their last dose of study drug. For women of 
child-bearing potential, the duration of the Follow-up Period will be 18 months from 
their last dose of study drug. Patients will continue vitamin A supplementation during 
their Follow-up Period. 
x After unblinding, all patients who were on placebo, and patients who received 
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completed the Follow-up Period, whichever comes first, may discontinue further 
follow-up and stop taking vitamin A. Baseline is defined as the last value prior to first 
vutrisiran dose (ie,  prior to the first DB dose for vutrisiran patients in DB Period and 
prior to the first OLE dose for placebo patients). Patients will be followed for a 
minimum period as listed below during the Follow-up Period based on treatment 
regimen received: 
 All patients whose last dose of study drug was 25 mg vutrisiran/placebo during 
DB Period or 25 mg vutrisiran during the OLE Period will be followed for a 
minimum of 90 days after their last dose of study drug. 
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3.5. 
Method of Assigning Patients to Treatment Groups 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the IRT.  The Investigator or his/her designee will 
contact the IRT to randomize the patient after confirming that the patient fulfills all the inclusion 
criteria and none of the exclusion criteria.  
Randomization for the DB Period: 
Using Interactive Response Technology (IRT), patients will be randomized 1:1 to the vutrisiran 
or placebo arm.  Randomization will be stratified by: 
1. Baseline tafamidis use (yes versus no) 
2. ATTR disease type (hATTR versus wtATTR amyloidosis with cardiomyopathy) 
3. NYHA Class I or II and age <75 years versus all other     
3.6. 
Blinding 
During the DB Period, all site personnel and patients will be blinded to study drug treatment. 
Vutrisiran and placebo will be packaged identically.  The outside of the pre-filled syringe barrel 
will be masked in such a way as to hide the identity of the study drug contained within.  
All study personnel will be blinded to any clinical laboratory results scheduled as part of the 
study that could potentially unblind them, including TTR levels, vitamin A levels, PK data, and 
ADA. 
As it could affect the blind, patients and their physicians are prohibited from obtaining pre-
albumin and vitamin A levels during the DB Period, other than the blinded assessments 
scheduled in the study, unless clinically indicated and after consultation with the Medical 
Monitor.  
During the DB Period, Investigators, study personnel, and the Sponsor will remain blinded to 
treatment assignment until the database lock for the primary analysis. 
During the OLE Period, vutrisiran will be administered in an open-label fashion. 
3.6.1. 
Emergency Unblinding 
During the DB Period, if the treating physician determines that the clinical management of the 
patient requires knowledge of the study drug assignment, the Investigator may break the blind, as 
necessary.  If time permits, clinical study center personnel should contact the Medical Monitor 
before unblinding to discuss the need to unblind the patient but must do so within 1 working day 
after the unblinding event taking care not to share any information about unblinded treatment 
assignment.  Unblinding information should be limited to the fewest number of people on a 
need-to-know basis.  A record of when the blind was broken, who was unblinded, who broke the 
blind, and why it was broken, will be maintained in the trial master file. 
Refer to the IRT instructions for details on emergency unblinding. 

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12. Current or future participation in another investigational device or drug study, scheduled 
to occur during this study, or has received an investigational agent or device within 
30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing 
(Day 1).  In the case of investigational TTR stabilizer drugs, washout for 3 months prior 
to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at 
baseline (per inclusion criterion #4).  
13. Requires treatment with or is unwilling to avoid any concurrent treatment with non-
dihydropyridine calcium channel blockers (eg, verapamil, diltiazem). 
Medical Conditions 
14. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to 
valvular heart disease, or cardiomyopathy due to ischemic heart disease (eg, prior 
myocardial infarction with documented history of cardiac enzymes and ECG changes) 
that the Investigator feels is a significant contributor or the predominant cause of the 
patient’s heart failure. 
15. Unstable congestive heart failure (CHF) (including patients who require adjustment of 
existing diuretics or addition of new diuretics at time of Screening for purposes of 
achieving optimal management of CHF). 
16. Had acute coronary syndrome or unstable angina within the past 3 months. 
17. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.  
18. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a 
pacemaker is indicated but will not be placed. 
19. Has persistent elevation of systolic (˃170 mmHg) or diastolic (˃100 mmHg) blood 
pressure that is considered uncontrolled by physician.  
20. Has untreated hypo- or hyperthyroidism. 
21. Has an active infection requiring systemic antiviral, antiparasitic or antimicrobial therapy 
that will not be completed prior to dosing (Day 1). 
22. Prior or anticipated (during the first 12 months after randomization) heart, liver or other 
organ transplant or implantation of left-ventricular assist device. 
23. History of multiple drug allergies or history of allergic reaction to any component of or 
excipient in the study drug.   
24. History of intolerance to SC injection(s) or significant abdominal scarring that could 
potentially hinder study drug administration or evaluation of local tolerability. 
25. Has other medical conditions or comorbidities (eg, malignancy, neuropsychiatric disorder 
etc…) which, in the opinion of the Investigator, would interfere with study compliance or 
data interpretation.   
Contraception, Pregnancy, and Breastfeeding 
26. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.6.1.  
27. Female patient is pregnant, planning a pregnancy, or breast-feeding.  

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Alcohol Use 
28. Unwilling or unable to limit alcohol consumption throughout the course of the study. 
Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
29. History of alcohol abuse, within the last 12 months before Screening, in the opinion of 
the Investigator. 
30. History of illicit drug abuse within the past 5 years that in the opinion of the Investigator 
would interfere with compliance with study procedures or follow-up visits. 
4.3. 
Removal from Study Drug or Assessment 
Patients are free to discontinue study drug and/or stop protocol procedural assessments, or 
participation in the study as a whole at any time and for any reason, without penalty to their 
continuing medical care.  The Investigator or the Sponsor may discontinue study drug or stop a 
patient’s participation in the study at any time if this is considered to be in the patient’s best 
interest.  Any discontinuation of treatment or the stopping of the patient’s participation in the 
study must be fully documented in the eCRF and should be followed up by the Investigator. 
Discontinuation of study drug or declining procedural assessments is described in Section 4.3.1, 
while the stopping of a patient’s participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
• Significant violation of the protocol 
• Adverse event  
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.6.7 for reporting and follow-up of pregnancy).  A 
positive urine pregnancy test should be confirmed by a serum pregnancy test prior to 
discontinuing the study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study.  In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments so 
that their experience (including, at a minimum, information on vital status, cardiac transplant 

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procedures, left-ventricular assist device placement and hospitalizations for the duration of the 
DB Period of the study) is captured in the final analyses.   
If the patient discontinues study drug early, the Investigator is to discuss with the patient the 
appropriate processes for discontinuation from study drug and must discuss with the patient the 
options for continuation of the Schedule of Assessments (Table 1), including different options 
for follow-up and collection of data (eg, in person, by phone, by mail, through family or friends, 
or from options not involving patient contact, such as communication with other treating 
physicians or from review of medical records), including efficacy endpoints and AEs, and must 
document this decision in the patient’s medical records. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.5.6. When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable. 
Patients who discontinue early from study drug during their treatment in the DB Period will be 
encouraged to: 
• Return for an Early Treatment Discontinuation Visit (Table 1);  
• Remain on the study and complete all remaining DB Period visits at months 6, 12, 18, 
24, 30 and 36, (excluding PK assessments), or until 30 months after the last patient is 
randomized, whichever is earlier; and 
• Complete safety assessments, per the Follow-up Period in the Schedule of 
Assessments (Table 1) as outlined in Section 3.1. 
Patients who discontinue early from study drug during their treatment in the OLE Period will be 
encouraged to: 
• Return for an Early Treatment Discontinuation Visit (Table 2);  
• Complete safety assessments, per the Follow-up Period in the Schedule of 
Assessments (Table 2) as outlined in Section 3.1.  
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient Stops Participation in the Study 
A patient may stop participation in the study at any time.  A patient considering stopping 
participation in the study should be informed that the patient can discontinue study drug and/or 
decline procedural assessments and remain in the study to complete their study assessments, or 
alternatively may complete any minimal assessments for which the patient consents as described 
in Section 4.3.1. If a patient still chooses to discontinue study drug and stop participation in any 
follow-up before the completion of their treatment in the DB Period (defined in Section 3.1) or 
OLE Period, every effort should be made to have the patient return for the Early Study 
Discontinuation Visit within 4 weeks (+1 week) of the last dose of study drug (Table 1 and 
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If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study. Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study. In addition, publicly available data (such as appropriate national or 
regional vital status registry or other relevant databases) can be included after withdrawal of 
consent, where allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data 
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, informing the study doctor at any 
time in writing or in any other form that may be locally required. The Sponsor will continue to 
keep and use the patient’s study information (including any data resulting from the analysis of 
the patient’s biological samples) until the time of withdrawal according to applicable law. The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements.  
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Patients who undergo heart transplant or implantation of a left-ventricular assist device are 
considered to have reached the primary endpoint (treated as death equivalent for primary 
analysis) and should be discontinued from the study. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible.  If a patient’s study participation is stopped due to an AE, 
including SAEs, the event should be followed as described in Section 6.5.6.4. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center.  The following actions 
must be taken if a patient misses a required study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes (for the patient) to continue in the study, 
and/or should continue in the study.  

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5.2.2. 
Dose and Administration 
Detailed instructions for administration are provided in the Pharmacy Manual.  Detailed 
Instructions for Use for the pre-filled syringe will also be provided. 
Starting on Day 1 of the DB Period, patients will receive 25 mg of vutrisiran or placebo 
administered as a SC injection q3M (every 12 weeks ±7 days) for up to 36 months.  
Under Amendment 4, all patients will receive SC injections of 25 mg of vutrisiran q3M (every 
12 weeks ±7 days) for up to 2 years during the OLE Period.  
The first dose of study drug should be administered in the clinic on Day 1 of the DB Period 
(placebo or 25 mg of vutrisiran) and Day 1 of the OLE Period (25 mg of vutrisiran). If a patient 
has tolerated at least 1 dose of study drug in the clinic, subsequent dosing for the remainder of 
that period may be administered outside the study site (eg, the patient’s home) at all other 
timepoints where allowed by applicable country and local regulations. In these cases, dosing 
should be administered by a trained healthcare professional, with oversight by the Investigator.  
If the patient is unable to come to the study site, and a visit by a home healthcare professional is 
not possible due to circumstances related to the COVID-19 pandemic, study drug (placebo or 25 
mg vutrisiran) may be administered by the patient or the caregiver under the oversight of the 
Investigator, and following consultation with the medical monitor, as allowed by applicable 
country and local regulations.  In such cases, the patient or caregiver must receive appropriate 
training on study drug administration. This measure (self- or caregiver administration) is 
intended to remain in effect only during periods of time when the COVID-19 pandemic impedes 
the ability of patients to travel to the study site or healthcare professionals to go to patients' 
homes for dosing. 
The SC injection site may be marked and mapped for later observation.  The preferred site of 
injection is the abdomen.  Optional additional sites are the upper arms and thighs.  If a local 
reaction around the injection site occurs, photographs may be obtained.   
Additional details, including detailed instructions for study drug administration, can be found in 
the Pharmacy Manual. In addition, instructions and procedures related to administration of study 
drug by a patient or caregiver will be provided in the Patient/Caregiver Storage and 
Administration Instructions. 
Missed doses of Study Drug 
If a patient does not receive a dose of study drug within the specified dosing windows, the 
Investigator should contact the Medical Monitor.  After such consultation, the dose may be 
administered as close to the scheduled dosing date as possible with a maximum 8-week delay (to 
be considered a delayed dose).  For patients initially randomized to 
 (under 
Amendment 3), delays beyond 8 weeks may be allowable, but must be discussed with the 
Medical Monitor. Thereafter, the dose will be considered missed and not administered.  If a dose 
is missed or is administered with a delay, the next dose will resume following the original 
schedule. In cases in which a dose is delayed in this manner for issues related to the COVID-19 
pandemic, the Medical Monitor should be informed as soon as possible, but prior consultation is 
not required.  In all cases, the dose should be administered as close as possible to the scheduled 
timepoint. 
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Every effort should be made to avoid missed doses of study drug.  If a patient misses a dose for 
reasons unrelated to the COVID-19 pandemic, the Investigator, in consultation with the Medical 
Monitor, will discuss whether the patient will be able to continue dosing in the study (see also 
Section 4.3). 
5.2.3. 
Dose Modifications 
Dose modifications are not permitted. 
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 study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing  
1. Dosing decisions may be made based on LFT results (Table 6) collected at the previous 
visit (up to 14 weeks prior to dosing); in all cases the most recently available LFTs 
should be used.  All laboratory samples should be sent to the central laboratory; an 
exception is for situations related to the COVID-19 pandemic if central laboratory 
collection is not possible, then a local laboratory may be used.  These local laboratory 
results must be sent to the site for review by the Investigator and entry into the clinical 
database.  
2. For any ALT or AST elevation >3× ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 5. 
3. For any ALT or AST elevation >3× ULN:  
a. Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. If a central laboratory result is not possible due to COVID-19, a 
local laboratory may be used for monitoring in consultation with the Medical 
Monitor; all local laboratory results must be sent to the clinical site for entry into the 
clinical database. 
b. Perform assessments per Table 6 and Table 7. 
c. If an alternative cause is found, provide appropriate care. 
4. For any ALT or AST elevation >3× ULN that is accompanied by clinical symptoms 
consistent with liver injury (eg, nausea, right upper quadrant abdominal pain, jaundice) or 
elevated bilirubin to ≥2× ULN or INR ≥1.5 without alternative cause, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3× ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2× ULN or INR ≥1.5, see Table 5. 

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Table 5: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause 
Identified 
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing   
• 
Evaluate the initial elevation in LFT per the following assessments: 
− 
Table 7 (all assessments to be performed once) 
− 
Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor LFTs at least every two weeks  
• 
If elevation persists for ≥2 months, must discuss with the Medical Monitor before 
continuing dosing 
>5× to 8× ULN 
• 
Hold dosing until recovery to ≤1.5× ULN or baseline; may resume dosing after 
discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
− 
Table 7 (all assessments to be performed once) 
− 
Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor LFTs at least weekly until ALT and/or AST is declining on 2 consecutive 
draws, then may decrease monitoring to biweekly 
• 
If ALT or AST rises to >5× ULN following resumption of dosing, permanently 
discontinue dosing 
>8× ULN 
• 
Permanently discontinue dosing after confirmation of the transaminase value at 
the central laboratory.  
• 
Monitor LFTs at least weekly until ALT and/or AST is declining on 2 consecutive 
draws, then may decrease monitoring to biweekly 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function test(s); 
ULN=upper limit of normal. 
Notes:   In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate. 
5.2.5. 
Dose Preparation, Handling, and Storage 
Staff at each clinical study center, or the home healthcare professional, will be responsible for 
preparation of study drug, according to procedures detailed in the Pharmacy Manual.  In cases 
where study drug is administered outside the study center, dosing may be prepared by the home 
healthcare professional or patient/caregiver according to procedures detailed in the 
Patient/Caregiver Storage and Administration Instructions. No special procedures for the safe 
handling of study drug are required. 
Study drug will be refrigerated at approximately [5±3°C] until dose administration. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage and preparation details will be 
provided in the Pharmacy Manual and Patient/Caregiver Storage and Administration 
Instructions. 

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5.2.6. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, as well as applicable local regulations.  Study drug labels 
and external packaging will include all appropriate information as per local labeling 
requirements.   
During the DB Period, the outside of the pre-filled syringe barrel will be masked in such a way 
as to hide the identity of the study drug contained within (Section 3.6). 
Additional details will be available in the Pharmacy Manual. 
5.2.7. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt.  In addition, accurate records will 
be kept of when and how much study drug is dispensed and administered to each patient in the 
study.  Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.  Used or 
partially unused pre-filled syringes must be disposed of immediately as specified in the 
Instructions for Use for the pre-filled syringe.  
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Product Complaints 
5.3.1. 
Definition 
A product complaint (PC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a product and its packaging after it is released for distribution.   
A PC may be detected prior to use of study drug, during use, or after use.  A PC is typically non-
medical in nature; however, it is possible that complaints could be associated with an AE.  
Examples of a PC include, but are not limited to: illegible label, missing label, damaged syringe, 
empty syringe, contamination of product, and malfunction of syringe needle safety device.  
5.3.2. 
Reporting 
For PCs, the Sponsor or its designee should be notified within 24 hours. PCs that may be 
associated with an AE must be evaluated and reported as indicated in Section 6.5.6 instructions 
on reporting PCs will also be detailed in the Pharmacy Manual.    
In situations where a dose is being administered by a patient or caregiver, instructions to report 
to the study site any issues that could fall under a PC are outlined in the Patient/Caregiver 
Storage and Administration Instructions.  The study site should then notify the Sponsor or 
designee within 24 hours of being informed per above instructions. 
5.4. 
Concomitant Medications 
Use of concomitant medications will be recorded on the patient’s eCRF as specified in the 
Schedule of Assessments (Table 1).  This includes all prescription medications, herbal 

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preparations, over the counter medications, vitamins, and minerals.  Any changes in medications 
during the study will also be recorded on the eCRF.  
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must have 
been able to tolerate them with no previous side effects (eg, gastric distress or bleeding).   
Standard vitamins (including vitamin A supplementation) and topical medications are permitted.  
However, topical steroids must not be applied anywhere near the injection site(s) unless 
medically indicated. 
All patients will take the recommended daily allowance of vitamin A during their DB Period, 
OLE Period, and Follow-up Period as outlined in Section 3.1.  
Use of the following medications/treatments are prohibited during study participation 
(Section 4.2): 
• any investigational agent other than study drug 
• diflunisal 
• ursodeoxycholic acid/tauroursodeoxycholate/doxycycline (Doxycycline is permitted 
if being taken for short-term treatment of infection. Also see exclusion criterion 10). 
• TTR lowering agents (eg., patisiran, inotersen) 
• Non-dihydropyridine calcium channel blockers (eg, verapamil, diltiazem); given they 
are widely recognized to be contraindicated in this patient population  
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator. However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.4.1. 
Concomitant Tafamidis Use 
Per inclusion criterion #4, at baseline patients are either: 1) tafamidis-naïve (defined in inclusion 
criterion #4a) or 2) currently on tafamidis (Note: must be on-label use of commercial tafamidis 
per an approved cardiomyopathy indication and dose in the country of use).  The number of 
patients enrolled on concomitant tafamidis at baseline will be monitored and may result in 
enrollment limitations in certain regions to permit enrollment of tafamidis-naïve patients (no 
baseline concomitant tafamidis) to ensure the study is sufficiently powered and to ensure the 
ability to accurately quantify the vutrisiran monotherapy effect relative to placebo.  
Patients who are on tafamidis at baseline as per inclusion criteria are encouraged, if it is 
medically appropriate in the opinion of the Investigator, to remain on tafamidis for the duration 
of the study. For patients on tafamidis at baseline, the reason why the patient was enrolled while 
already receiving tafamidis (in the opinion of the Investigator) will be recorded in the eCRF.  
Although data with the combination of vutrisiran and TTR tetramer stabilizers, such as tafamidis, 
are not available, the concomitant use of vutrisiran and TTR stabilizers is likely to have an 
acceptable safety and tolerability profile. This assessment is based on complementary 
mechanisms of actions of the 2 agents which would not suggest additional safety concerns when 
used concomitantly. In addition, vutrisiran and TTR stabilizers have non-overlapping 

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pharmacokinetic and drug metabolism properties, which would not result in PK drug-drug 
interactions.  Further, clinical data on the concomitant use of patisiran with TTR tetramer 
stabilizers indicated no drug-drug interaction in the Phase 2 Study ALN-TTR02-003, and the 
overall safety profile of patisiran in patients who used concomitant TTR stabilizers was 
consistent with that observed in patients who did not use concomitant TTR stabilizers. 
While initiating on-label use of tafamidis in previously naïve patients during the study (tafamidis 
drop-in) is not prohibited in countries where tafamidis is commercially available in this patient 
population, it could impact the ability to accurately quantify the vutrisiran treatment effect 
relative to placebo. Accordingly, it should be noted that per exclusion criterion #7, tafamidis-
naïve patients (per inclusion criterion #4a) for whom the Investigator actively plans or 
anticipates commencing treatment with tafamidis either during the Screening Period or the first 
12 months following randomization, taking into consideration clinical status, patient preference 
and/or commercial availability of tafamidis, should not be enrolled in the trial. 
Patients will be monitored for tafamidis use from Screening to completion of the study as 
indicated in the Schedule of Assessments (Table 1 and Table 2).  If, during the study, the 
Investigator decides to begin on-label use of commercial tafamidis per an approved 
cardiomyopathy indication and dose in a patient who is tafamidis-naïve at baseline (ie, tafamidis 
drop-in), prior to commencing concomitant tafamidis the Investigator will perform assessments 
(including primary and select secondary efficacy assessments) at the Pre-tafamidis Drop-in Visit 
as outlined in the Schedule of Assessments (Table 1 and Table 2). 
In all cases, the Pre-tafamidis Drop-in Visit should occur prior to starting concomitant tafamidis.  
Thereafter, the patient will continue with all assessments per the Schedule of Assessments 
(Table 1 and Table 2).  Any efficacy assessments performed within the previous 45 days do not 
need to be repeated at this visit. In addition, at the time of tafamidis drop-in, the reason for 
starting tafamidis will be recorded in the eCRF. 
5.5. 
Treatment Compliance 
Compliance with study drug administration will be verified by study staff. 
5.6. 
Other Requirements 
5.6.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before first dose and until the end of their Follow-up Period (defined 
in Section 3.1). 
Birth control methods which are considered highly effective include:   
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system.  
• Bilateral tubal occlusion. 

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• 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). 
• Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception associated with the inhibition of 
ovulation.  
• True sexual abstinence, when 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.  Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start heterosexual relationships during the study and for up to 90 days after the last 
dose of study drug. 
Investigators should advise females of child-bearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required.  However, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements or at the request of the Sponsor, as described in the corresponding patient informed 
consent forms.   
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.3). 
5.6.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study as indicated in 
Section 4.2. 
6. 
STUDY ASSESSMENTS 
The schedule of study assessments for the DB Period is provided in Table 1 and Table 3 
(pharmacokinetic time points); the schedule of study assessments for the OLE Period is provided 
in Table 2 and Table 4.  
When performed on dosing days, the 6-MWT, the KCCQ, safety, and PD assessments will be 
performed prior to study drug administration. All other efficacy assessments only need to be 
performed prior to study drug administration on Day 1 of the DB Period and Day 1 of the OLE 
Period. Additional information on the collection of study assessments will be detailed in the 
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Where applicable country and local regulations and infrastructure allow, routine assessments 
may be performed outside of the study center (eg, the patient’s home) by a trained healthcare 
professional at all timepoints.  These assessments include the following: vital signs, physical 
exam, weight, 
pregnancy tests, urine collection, blood draws (clinical laboratory 
assessments, ADA, PK; ATTR/vitamin A; exploratory samples), collection of information 
regarding vital status, hospitalizations, urgent care visits, procedures, and concomitant 
medications.  All laboratory samples should be sent to the central laboratory; an exception is for 
situations related to the COVID-19 pandemic when central laboratory assessments are not 
possible, then a local laboratory may be used.  If a local laboratory is used, TTR and vitamin A 
levels should not be tested until after unblinding of treatment assignments (see Section 3.6).  
These local lab results must be sent to the site for review by the Investigator and entry into the 
clinical database. Wherever possible, AE collection associated with visits outside of the clinic 
will be collected by qualified site staff through verbal contact with the patient. 
With the exception of patients unable to come to the site (eg, due to the COVID-19 pandemic 
limiting the patient’s ability or willingness to access the study site), at a minimum, patients 
should visit the site for the scheduled dosing and assessments for the Week 12 (Month 3) visit of 
the DB Period within the study visit window and for efficacy assessments as detailed below. 
If any study assessments are not able to be completed at the site or at home within the study visit 
window, the study physician (or delegate) must, at a minimum, verbally contact the patient 
within the expected window for each study visit to collect relevant safety information (including, 
but not limited to, AEs, concomitant medications, hospitalizations/procedures, and vital status). 
All efficacy assessments associated with the following DB Period visits should be conducted at 
the study center:  Month 6, Month 12, Month 18, Month 24, and Month 30. In addition, dosing 
and efficacy assessments scheduled for Day 1 of the OLE Period should be conducted at the 
study center. In situations where a study visit is unable to be completed at the site (eg, due to the 
COVID-19 pandemic limiting the patient’s ability or willingness to access the study center or 
their ability to have received their scheduled doses of study drug), efficacy, safety, and other 
assessments may be completed up to 3 months after the time point (ie, up to Study Month 9, 
Month 15, Month 21, Month 27, or Month 33, respectively) after consultation with the Medical 
Monitor. 
Further details with regard to visits performed outside of the clinic are provided in the Study 
Reference Manual. 
6.1. 
Screening Assessments 
See the Schedule of Assessments (Table 1) for a list of Screening visit assessments.   
The investigator will notify the Sponsor before screening patients to allow an assessment of the 
ability of the site or any new trial participant to comply with the protocol given COVID-19 
pandemic limitations. 
An ICF that has been approved by the appropriate Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) must be signed by the patient before the Screening procedures are 
initiated.  All patients will be given a copy of the signed and dated ICF.  
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6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
Screening (eg, prohibited medications that were subsequently discontinued), in conjunction with 
the decision of the Medical Monitor(s), may be allowed to rescreen after a minimum of 5 days 
have elapsed from their last screening assessment.  All patients who are rescreened will be re-
consented (ICF and the medical records release form). If a patient is rescreened within the 45-
day Screening window, please consult the medical monitor to determine which screening 
procedures must be repeated.  If rescreening occurs outside of the 45-day Screening window, all 
screening procedures must be repeated. 
For patients who do not meet LFT 
 criteria, rescreening patients once may be 
permitted with consultation of the Medical Monitor after a minimum of 5 days have elapsed 
from a patient’s last laboratory screening assessment.   
Patients who failed Screening due to situations related to the COVID-19 pandemic may be 
allowed to rescreen after consultation with the Medical Monitor.   
6.2. 
Efficacy Assessments 
See the beginning of Section 6 for procedures to follow in situations in which an efficacy visit is 
unable to be completed due to the COVID-19 pandemic limiting the patient’s ability or 
willingness to access the study site. 
6.2.1. 
Deaths, Hospitalizations, and Urgent Heart Failure Visits 
All deaths, hospitalizations and urgent HF visits will be recorded throughout the study as part of 
SAE and AE monitoring (see Section 6.5.6) and per the Schedules of Assessments (Table 1 and 
Table 2). Vital status checks are described in Section 6.2.2.   
All deaths, hospitalizations, and urgent HF visits will be adjudicated by an independent CEC (see 
Section 3.8).  
6.2.2. 
Vital Status Check 
Vital status checks will be performed at the timepoints specified in the Schedules of Assessments 
(Table 1 and Table 2). Given that heart transplantation or left-ventricular assist device 
implantation procedures will be considered deaths for the purposes of the primary analysis, vital 
status checks should include checking for the occurrence of these procedures.  
Also see Section 4.3.2.1 for the collection of vital status after withdrawal of consent and 
Section 4.3.3 for patients who are lost to follow-up.   
6.2.3. 
6-Minute Walk Test (6-MWT) 
Full details regarding the 6-MWT are provided in the relevant study manual. 
The 6-MWT is an assessment of functional exercise capacity.  The 6-MWT will be administered 
by staff trained in the procedure per the relevant study manual.  When possible, the staff 
administering the 6-MWT will be different from the Investigator or designee managing the care 
of the patient. In all cases these staff must be qualified by the central 6-MWT vendor. 
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Table 6: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Carbon dioxide 
Creatinine 
 
Chloride 
Bicarbonate 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Additional Chemistry Assessments  
 
C-reactive protein 
Venous lactate 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy (if clinically indicated) 
Protein 
 
Coagulation  
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time 
 
Hepatic Tests (only at Screening) 
Hepatitis A, including: 
HAV antibody IgM and IgG 
Hepatitis B, including:  
HBs Ag, HBc antibody IgM and IgG 
Hepatitis C, including:  
HCV antibody 
HCV RNA PCR – qualitative and quantitative 
assays 
Hepatitis E, including: 
HEV antibody IgM and IgG 
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Immunogenicity (see Section 6.5.5.1) 
Antidrug antibodies 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.3) 
ȕ-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal 
women only, at Screening only) 
Monoclonal Gammopathy Assessment 
(only at Screening if applicable, see Section 6.5.5.1) 
Serum protein electrophoresis (SPEP) with 
immunofixation electrophoresis (IFE) (or 
documented local results) 
Urine protein electrophoresis (UPEP) with 
Immunofixation electrophoresis (IFE) (or 
documented local results) 
Serum free light chains (or documented local 
results) 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; 
  FSH= follicle-stimulating hormone; 
GGT=gamma glutamyl transferase; HAV=hepatitis A virus; HBsAg=hepatitis B virus surface antigen; 
HBc=hepatitis B virus core; HCV=hepatitis C virus; HEV=hepatitis E virus; IgG=immunoglobulin G antibody; 
IgM=immunoglobulin M antibody; PCR=polymerase chain reaction; RBCs=red blood cells; RNA=ribonucleic acid; 
MDRD=modification of diet in renal disease; SPEP with IFE=serum protein electrophoresis with Immunofixation 
Electrophoresis. 
6.5.5.1. 
Assessment for Monoclonal Gammopathy including MGUS  
As part of the determination of a diagnosis of ATTR amyloidosis, excluding evidence of a 
monoclonal gammopathy at Screening (Table 1) may be necessary (inclusion criterion #2). 
Laboratory assessments associated with this are indicated in Table 6. If available, documented 
local results obtained prior to Screening may be used to fulfill this inclusion requirement. 
Abnormal findings, such as a monoclonal band (M-spike), on SPEP with IFE or serum free light 
chains with an abnormal kappa-to-lambda ratio that are suggestive of an alternative diagnosis, 
such as light chain amyloidosis, will require confirmatory testing using mass spectrometry or 
immunohistochemistry for confirmation of TTR protein deposition.  Specifications for testing 
samples will be provided in the study laboratory manual. The determination of whether abnormal 
findings are suggestive of light chain amyloidosis may be assessed by a clinician experienced in 
the diagnosis of amyloidosis.  
6.5.5.2. 
Immunogenicity 
Blood samples (serum) for ADA testing will be collected at the timepoints specified in the 
Schedules of Assessments (Table 1 and Table 2).  On dosing days, ADA sample collection is 
within 1 hour before dosing.  
ADA will be assessed using a validated ELISA method. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Study Laboratory Manual. 
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6.5.5.3. 
Pregnancy Testing 
Pregnancy tests will be performed for females of child-bearing potential at the timepoints 
specified in the Schedules of Assessments (Table 1 and Table 2) and at any time pregnancy is 
suspected.  
A serum pregnancy test will be performed at Screening and urine or serum pregnancy tests will 
be performed thereafter. The results of the pregnancy test must be known before study drug 
administration.  More frequent pregnancy testing may be performed where required per local 
requirements. 
Patients who are pregnant at Screening are not eligible for study participation.  Any woman with 
a positive urine pregnancy test, subsequently confirmed by a positive serum pregnancy test, 
during the study will be discontinued from study drug but will continue to be followed for safety.  
Patients determined to be pregnant while on study will be followed at least until the pregnancy 
outcome is known (see Section 6.5.6.7 for follow-up instructions). 
In situations where a study visit is unable to be completed at the site due to the COVID-19 
pandemic impacting activities at the study site or patient ability or willingness to access the site, 
pregnancy testing may be performed by a healthcare professional or the patient/caregiver (and 
confirmed by the site) where applicable country and local regulations and infrastructure allow. 
Follicle-stimulating hormone testing will be performed in all post-menopausal women to confirm 
suspected post-menopausal status. 
6.5.5.4. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.4.  Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 7 will 
be performed one time, as well as hematology, serum chemistry, LFT, and coagulation 
assessments from Table 6, and other assessments or evaluations per Investigator discretion, as 
appropriate.  
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in Section 5.2.4. 

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Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBsAg, HBc antibody IgM and IgG 
Parvovirus B19 
HAV antibody IgM 
HHV-6 
HCV antibody 
Anti-nuclear antibodies 
HCV RNA PCR – qualitative and quantitative 
Anti-smooth muscle antibodies 
HEV antibody IgM 
Anti-LKM1 antibody 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Anti-mitochondrial antibodies 
Herpes Zoster Virus IgM, IgG 
Anti-SLA 
Epstein-Barr Virus antibodies, IgM and IgG 
Ferritin 
Cytomegalovirus antibodies, IgM, IgG 
Ceruloplasmin 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption and drugs of abuse   
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E is 
endemic 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; 
IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; LKM1=liver/kidney microsome-1 antibody 
MRI=magnetic resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid; SLA=soluble liver 
antigen 
Note: 
• 
All Extended Hepatic Panel assessments will be measured in central laboratory. The full panel of assessments 
should only be performed once; individual assessments may be repeated, as needed. 
6.5.6. 
Adverse Events 
6.5.6.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an adverse event 
(AE) is any untoward medical occurrence in a patient or clinical investigational subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
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Serious Adverse Event 
A 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 or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
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). 
Adverse Events of Clinical Interest 
The following are considered to be AEs of clinical interest:  
• ALT or AST >3 × ULN 
• Severe or serious injection site reactions (ISRs); ISRs that are associated with a recall 
phenomenon (reaction at the site of a prior injection with subsequent injections), or 
those that lead to temporary dose interruption or permanent discontinuation of 
vutrisiran. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  A systemic reaction which includes the 
injection site, eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site is not considered an ISR.  
For information on recording and reporting of AEs of clinical interest, see Section 6.5.6.2 and 
Section 6.5.6.3, respectively. 

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Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental activities of daily living (eg, preparing 
meals, shopping for groceries or clothes, using the telephone, managing 
money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention 
indicated; OR death related to an adverse event. 
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). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?”  A “yes” response indicates that the event is considered as related to 
the study drug. 
6.5.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient, if applicable, should be asked about medically relevant changes in the patient’s 
health since the last visit.  The patient if applicable, should also be asked if the patient has been 
hospitalized, had any accidents, used any new medications, or changed concomitant medication 
routines (both prescription and over-the-counter).  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. 

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Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
study drug through the end of study.  Non-serious AEs will be followed until the end of study.  
Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1), while AEs that occur after study drug administration, and  
baseline events that worsen after study drug administration, must be recorded as AEs.   
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study drug 
through the end of study.  SAEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed.  Additional clinical and laboratory information may 
be collected.  Refer to eCRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit an Injection Site Reaction Signs or 
Symptoms eCRF, recording additional information regarding each injection site reaction that is 
entered on the AE eCRF (eg, symptom(s), injection site location, follow-up actions taken, etc.). 
If patients develop ocular symptoms suggestive of vitamin A deficiency, for example reduced 
night vision or night blindness, the Investigator should consult with the Medical Monitor, and 
consider referral to an ophthalmologist if, in the opinion of the Investigator, it is medically 
appropriate. Any information collected during an ophthalmological assessment should be 
recorded in the eCRF and reports or images of ophthalmological assessments should be collected 
as well. 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the Sponsor or its designee 
should be notified within 24 hours using the appropriate eCRF. 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.5.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 

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The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form. Within 24 hours of 
receipt of follow-up information, the Investigator must update the eCRF and, as applicable, the 
SAE form.  SAEs must be reported using the contact information provided in the Study Manual. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
If the Investigator becomes aware of an SAE with a suspected causal relationship to the study 
drug that occurs after a patient withdraws from the study, the Investigator shall report the SAE to 
the Sponsor or designee within 24 hours of first awareness of the event. 
If the Investigator becomes aware of an SAE in a patient with a suspected causal relationship to 
the study drug that occurs after the end of the study, the Investigator shall report the SAE to the 
Sponsor within 24 hours of first awareness of the event using the paper SAE form. 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Clinical Trials Regulation (EU) No 536/2014 (CTR), and to all country 
Regulatory Authorities where the study is being conducted, according to local applicable 
regulations. 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.5.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through the end of their Follow-up Period 
(defined in Section 3.1), the Investigator must report the pregnancy to the Sponsor or designee 
within 24 hours of being notified of the pregnancy.  Details of the pregnancy will be recorded on 
the pregnancy reporting form.  The patient should receive any necessary counseling regarding 

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7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses for 
the primary analysis, conducted at the completion of the DB Period (Section 3.1).  Changes to 
the methods described in the final SAP will be described and justified as needed in the clinical 
study report.  For information on study endpoints, see Section 2. 
Additional analyses and data summaries will be outlined in the SAP. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
• Full Analysis Set (FAS): All patients who were randomized and received any 
amount of study drug (vutrisiran or placebo). 
• Vutrisiran Monotherapy Subgroup FAS: All patients who were not on tafamidis at 
the study baseline in the FAS. 
• Safety Analysis Set: All patients who received any amount of study drug.  
• Vutrisiran Monotherapy Subgroup Safety Analysis Set: All patients  who were 
not on tafamidis at the study baseline in the Safety Analysis Set. 
• PK Analysis Set: All patients who received at least one full dose of study drug and 
have at least one non-missing postdose PK assessment and evaluable PK data. 
• PD Analysis Set:  All patients who received at least one full dose of study drug and 
have an evaluable baseline and at least one evaluable postbaseline sample for TTR 
assessment. 
The FAS and vutrisiran monotherapy subgroup FAS will be used for the analysis of efficacy 
endpoints. Safety analyses will be based on the Safety Analysis Set and vutrisiran monotherapy 
subgroup Safety Analysis Set. PK and PD analyses will be based on PK Analysis Set and PD 
Analysis Set, respectively.  
All by-treatment analyses based on the FAS and vutrisiran monotherapy subgroup FAS will be 
according to the randomized treatment arm. Safety analyses will be analyzed according to the 
treatment actually received.  
7.2.2. 
Examination of Subgroups 
Subgroup analyses will be conducted for the primary and secondary efficacy endpoints. Efficacy 
subgroup analyses will be conducted for age group (<75 versus ≥75), baseline tafamidis use (Yes 
versus No) (overall population endpoints only), ATTR disease type (hATTR; wtATTR) and 
NYHA Class (I/II; III). Safety subgroup analyses will be conducted for at least the following 
variables:  age group, gender, race, geographic region, and NYHA class. Additional variables 
may be included and the details will be provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 

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allowed by local regulations, for the purpose of obtaining information on vital status, cardiac 
transplant procedures, left-ventricular assist device placement (Section 6.2.2), and 
hospitalizations (Section 6.2.1) from patients who discontinue early from the study. 
The signing of this medical records release form is in addition to the ICF.  
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study (except those that support the need to remove an apparent immediate 
hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.5.6.4.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB or IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug.  The Sponsor 
or designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a potential 
breach of the protocol.  A serious breach is a breach that is likely to affect to a significant degree 
the safety and rights of a study participant or the reliability and robustness of the data generated 
in the clinical trial. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory or as locally required, whichever is longer.  If it becomes necessary for the 

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Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable regulatory authorities to 
review or audit any documentation relating to the study, the Investigator must permit direct 
access to all source documents/data.  Records will not be destroyed without informing the 
Sponsor in writing and giving the Sponsor the opportunity to store the records for a longer period 
of time at the Sponsor’s expense. 
The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document.  Documents not for submission to the Sponsor 
(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, whose use is for the purpose of conducting the study. The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time.  Conditions that may warrant this action may include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• The decision on the part of the Sponsor to suspend or discontinue treatment with the 
study drug 
Should the study be terminated, and/or the site closed for whatever reason, all documentation and 
study drug pertaining to the study must be returned to the Sponsor or its representative, and the 
Investigators, IRB/IEC 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. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor.  Case report forms must be completed only by persons 

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designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system.  All data entered into the eCRF must 
also be available in the source documents.  Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  The Monitor will visit the Investigator and clinical study center periodically 
and will 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. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately. The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The Investigator should contact the Sponsor and designee immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A copy of any proposed 
publication (eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this 
study, must be provided and confirmed received at the Sponsor at least 30 days before its 
submission.  The Clinical Trial Agreement will detail the procedures for publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 

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10. 
APPENDICES 
10.2. 
New York Heart Association Class (NYHA) 
  
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs does not 
cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, in cold weather, in wind or when under 
emotional stress causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to two blocks on the 
level and climbing more than one flight of stairs in normal conditions causes undue fatigue 
or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or dyspnea. 
 
 
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10.4. 
Amendment History 
10.4.1. 
Amendment 5 Summary of Changes 
The primary purpose for this global protocol amendment is to expand the analysis of the existing 
primary endpoint to both the overall population and the vutrisiran monotherapy subgroup 
(defined as the subgroup of patients not on tafamidis at study baseline).  Changes included in this 
amendment concern the method of data analyses and do not impact study execution or the patient 
experience. 
Establishing the efficacy of vutrisiran in the overall population is important because it is 
representative of current treatment practice, wherein many patients with ATTR amyloidosis 
(hereditary and wt) with cardiomyopathy are prescribed tafamidis as it is the only currently 
approved treatment available. 
The rationale for analyzing the primary endpoint in the vutrisiran monotherapy subgroup is to 
enable demonstration of the potential clinical benefit of vutrisiran without any confounding 
effect of benefit from tafamidis.  Patients already prescribed tafamidis for the approved 
cardiomyopathy indication were permitted to enroll in HELIOS-B, and there was no eligibility 
requirement that these patients needed to have manifested disease progression on tafamidis. 
Thus, patients on tafamidis at baseline, comprising approximately 40% of the enrollment into 
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HELIOS-B, are likely to have been receiving some degree of CV benefit from this medication 
throughout the trial. For this reason, the results from a pre-specified analysis in the vutrisiran 
monotherapy subgroup would provide the clearest demonstration of the potential clinical benefit 
of vutrisiran, without any confounding effect of benefit from concomitant tafamidis.  
This amendment also restructures the existing secondary and exploratory endpoints such that 
specific endpoints were moved from exploratory to secondary and from secondary to exploratory 
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Table 8: 
Protocol Amendment 4 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Amendment 4 are indicated.  The corresponding text has been 
revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Remove reference to the RTE Period and the 
 dosing regimen, clarify the duration of the Double-Blind Period 
relative to a patient starting in the OLE Period, and adjust follow-up time between dosing. 
The primary change occurs in Section 3.1 Summary of Study Design 
Revised text: 
The study consists of 4 periods (Figure 1):  
1. Screening Period: Up to 45 days during which patients will undergo screening assessments to determine eligibility. 
2. Double-Blind (DB) Period: 
x At the start of the DB Period (on Day 1), eligible patients will be randomized in a 1:1 ratio to receive blinded doses of 25 mg 
of vutrisiran or placebo administered as a SC injection q3M (every 12 weeks ±7 days) for up to 36 months. 
 In addition to study drug, all patients will take the recommended daily allowance of vitamin A during their DB Period 
and Follow-up Period (see below). 
x Patients will undergo assessments as outlined in the Schedule of Assessments (Table 1).  
x An individual patient’s DB Period will end after they complete their Month 36 Visit, or 30 months after the last patient is 
randomized, whichever comes first. As such, the length of each patient’s intended treatment during the DB Period may vary 
from 30 to 36 months. 
x The variable length of the DB Period will mean that some patients will not have a Month 33 and/or Month 36 visit. For those 
patients, the Day 1 visit of their Open-label Treatment Extension (OLE) Period should be 3 months after their last planned visit 
(at Month 30 or Month 33 [±7 days]). For patients whose last visit in the DB Period was Month 30 (Week 132), Day 1 in 
the Open-Label Extension (OLE) Period will occur 144 weeks (±7 days) after enrollment in the DB Period.  For patients 
whose last visit in the DB Period was Month 33 (Week 144), Day 1 in the OLE Period will occur 156 weeks (±7 days) 
after enrollment in the DB Period. 
x The primary analysis will be conducted after the last patient has completed the Month 30 Visit or otherwise discontinued. 
3. Open-Label Randomized Treatment Extension (OLE RTE) Period  
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The study has been amended (Amendment 4) to include an OLE Period in lieu of the Open-Label Randomized Treatment 
Extension Period (previously introduced with Amendment 3). In the OLE Period, all patients will receive the 25 mg q3M 
vutrisiran regimen. 
x On or before the date of their last planned visit of the DB Period, patients will be randomized to treatment in RTE Period as 
described below and receive their first dose of open label vutrisiran at this visit (RTE Day 1).  
x At the start of Upon entry into the OLE Period (RTE Day 1), eligible patients will be randomized in a 1:1 ratio transition to 
receive open-label doses of 25 mg q3M vutrisiran or 
 administered as SC injections. 
x Patients initially randomized to 
 (under Amendment 3) will transition to receive open-label doses of 25 mg 
q3M vutrisiran administered as SC injections at their next scheduled dosing visit (24 weeks after their last dose of 
 
vutrisiran). Patients initially randomized to 25 mg q3M vutrisiran (under Amendment 3) will continue with the 25 mg 
q3M regimen. 
 In addition to study drug, all patients will take the recommended daily allowance of vitamin A during their RTE OLE 
Period and Follow-up Period (see below). 
x All patients will undergo assessments as outlined in the Schedule of Assessments for the RTE OLE Period (Table 2). 
Note: Patients who do not complete the DB Period may not participate in the RTE OLE Period. Consent must be signed before any 
procedures are performed in the RTE OLE Period (Table 2). 
4. Follow-Up Period after the last dose of vutrisiran on study: 
x Following completion of the RTE OLE Period (or completion of the DB Period for patients who do not continue into the RTE 
OLE Period; or their last dose of vutrisiran for patients who discontinue study drug early), patients will commence follow-up 
visits every 12 weeks for the durations outlined below. 
x Prior to unblinding of their treatment from the DB Period, the duration of the Follow-up Period for a patient will be 1 year 
from their last dose of study drug. For women of child-bearing potential, the duration of the Follow-up Period will be 18 
months from their last dose of study drug. Patients will continue vitamin A supplementation during their Follow-up Period. 
x After unblinding, all patients who were on placebo, and patients who received vutrisiran whose serum TTR level has returned 
WRRIEDVHOLQHRUZKRKDYHFRPSOHWHGWKH)ROORZ-up Period, whichever comes first, may discontinue further follow-up 
and stop taking vitamin A. Baseline is defined as the last value prior to first vutrisiran dose (ie,  prior to the first DB dose for 
vutrisiran patients in DB Period and prior to the first OLE dose for placebo patients). Patients will be followed for a minimum 
period as listed below during the Follow-up Period based on treatment regimen received: 
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 All patients whose last dose of study drug was 25 mg vutrisiran/placebo during DB Period or 25 mg vutrisiran during 
the RTE OLE Period will be followed for a minimum of 90 days after their last dose of study drug. 
 Patients whose last dose of study drug was 
 vutrisiran regimen (under Amendment 3) will be followed 
for a minimum of 
 after their last dose of study drug during Follow-up Period. 
x For any patient who starts a TTR lowering treatment as part of clinical care, and has completed a minimum of 90 or 
 
(depending on vutrisiran treatment regimen) of safety follow-up since their last dose of study drug, further follow-up will be 
discontinued. 
x Patients will undergo assessments as outlined in the Schedule of Assessments (Table 1 and Table 2). 
Patients may receive vutrisiran on the study until the end of the RTE OLE Period or until one of the following occurs:  1) they meet 
any of the study discontinuation criteria; 2) vutrisiran is commercially available in the patient’s country of residence and vutrisiran is 
accessible to the patient and the patient has completed their RTE OLE Month 12 Visit; or 3) the vutrisiran development program is 
discontinued. 
Study drug dosing may be allowed outside of the study center (eg, the patient’s home) during the DB Period or RTE OLE Period 
under certain circumstances as specified in Section 5.2.2.  In addition, routine assessments and collection of relevant safety 
information may be collected outside the study center as specified in Section 6. 
Sections also reflecting this change:  
x Synopsis 
x Table 2, Schedule of Assessments: Open-Label Treatment Extension (OLE) and Follow-Up Periods 
Purpose:  Update the study design figure to reflect Amendment 4 
The primary change occurs in Synopsis 
Revised figure:   
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 For patients enrolled under Amendment 3, the visit schedule remains the same following implementation of 
Amendment 4, with no changes to the visit weeks noted in Table 2. For example, if Amendment 4 was 
implemented after a patient had completed Week 24 under Amendment 3, their first visit under Amendment 4 
will be Week 36.  
 The dosing schedule under Amendment 4 is 25 mg vutrisiran every 12 weeks; however, patients initially 
randomized to receive 
 vutrisiran under Amendment 3 will transition to receive 25 mg q3M 
vutrisiran at their next scheduled dosing visit (24 weeks after their last dose of 
 vutrisiran). 
x Revised footnote a, Table 2:  
 
a For patients whose last visit in the DB Period was Month 30 (Week 132), Day 1 in the OLE will occur 144 
weeks (±7 days) after enrollment in the DB Period.  For patients whose last visit in the DB Period was Month 
33 (Week 144), Day 1 in the OLE will occur 156 weeks (±7 days)  after enrollment in the DB Period. For 
patients who reach the Month 36 (Week 156) visit of the DB Period prior to the end of the DB Period for the 
study, this visit will take place on the same day as the Day 1 visit of the OLE Period. When this occurs, patients 
should complete the Scheduled Assessments for both the Month 36 visit of the DB Period and the Day 1 visit of the 
OLE Period. However, where these visits take place on the same day, assessments do not need to be repeated twice 
on the same day (ie, if an assessment is listed for both the Month 36 visit of the DB Period and the Day 1 visit of the 
OLE Period, the assessment can be performed once).  An informed consent form that has been approved by the 
appropriate Institutional Review Board /Independent Ethics Committee must be signed by the patient before any 
procedures are performed in the OLE Period. 
x Added footnote d, Table 2:  
 
d The dosing schedule under Amendment 4 is 25 mg vutrisiran every 12 weeks. Upon entry into the OLE Period 
(OLE Day 1), all eligible patients will receive open-label doses of 25 mg q3M vutrisiran administered as SC 
injections. Patients initially randomized to receive 
 vutrisiran under Amendment 3 will transition 
to receive 25 mg q3M vutrisiran at their next scheduled dosing visit (24 weeks after their last dose of 
 
vutrisiran). 
Purpose:  To clarify the impact to study design rationale based on Amendment 4. 
The primary change occurs in Section 1.5, Study Design Rationale 
Revised text:   
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Patients will receive treatment with 25 mg vutrisiran or placebo every 3 months (q3M) during their Double-blind (DB) Period of the 
study for up to 36 months. The primary analysis will be conducted 30 months after the last patient is randomized.  As such, the length 
of each patient’s intended treatment during the DB Period may vary from 30 to 36 months. In addition, an An Open-label 
Randomized Treatment Extension Period (hereafter referred to as the RTE Period) was added with Amendment 3 in which patients 
who complete treatment in the DB Period will be randomized to receive either 25 mg vutrisiran q3M or 
 in an 
open label fashion.  Following implementation of Amendment 4, the Randomized Treatment Extension will be replaced with an 
Open-Label Treatment Extension where all patients who complete treatment in the DB Period will receive vutrisiran 25 mg 
q3M for up to 2 years. A Follow-up Period will commence when patients complete the OLE Period (or complete the DB Period for 
patients who do not continue into the OLE Period; or their last dose of vutrisiran for patients who discontinue study drug early) and 
patients will be followed for a period of up to 1 year after their last dose of study drug. See also Section 3.1. 
The RTE OLE Period is designed to evaluate the longterm efficacy, safety and efficacy , PK, and PD of the 
 dosing 
regimen in comparison to the 25 mg q3M dosing regimen of vutrisiran. 
Purpose:  Remove modeling statements and planned analysis for the 
 dose regimen 
The primary change occurs in Section 1.6, Dose Rationale 
Revised text:  
The vutrisiran regimen of 25 mg q3M SC is proposed for the DB Period of this Phase 3 Study ALN-TTRSC02-003 (HELIOS-B) to be 
conducted in patients with hATTR or wtATTR amyloidosis with cardiomyopathy.  In addition to the 25 mg q3M dose, a dose of 
 
SC given 
is included as a treatment arm during the RTE Period. These doses are This dose is also being evaluated for the 
treatment of patients with hATTR amyloidosis with polyneuropathy in the ongoing Phase 3 Study ALN-TTRSC02-002 (HELIOS-A) 
described in Section 1.4. 
In addition to the 25 mg dose of vutrisiran, modeling and simulation predict that the 
 and 25 mg q3M regimens of 
vutrisiran achieve comparable average TTR reductions with the same cumulative annual dose (100 mg).  Addition of the 
 
dose in the RTE Period of this study will provide data to further assess the extent of TTR reduction and the overall safety, PD, and 
efficacy of a 
 dose compared to a 25 mg q3M dose of vutrisiran. 
Purpose:  Remove justification for addition of 
 dosing regimen. 
The primary change occurs in Section 1.7, Benefit-Risk Assessment 
Deleted text:   
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Patients with ATTR amyloidosis often suffer substantial loss in ambulatory ability and mobility that significantly impact activities of 
daily living and can make healthcare visits challenging. The addition of a 
 dose regimen aims to further minimize the need 
for frequent healthcare visits and further mitigate patient burden. This is consistent with global trends toward decreased healthcare 
encounters, the importance of which has been further highlighted by the COVID 19 pandemic. 
Purpose:  To remove description of the process for randomization during the treatment extension. 
The primary change occurs in Section 3.5, Method of Assigning Patients to Treatment Groups 
Deleted text:   
Randomization for the RTE Period: 
Using Interactive Response Technology (IRT), patients will be randomized 1:1 to the 25 mg vutrisiran q3M or 
 
arm. Randomization will be stratified by: 
1. Tafamidis use (yes versus no) (assessed on Day 1 of the RTE Period) 
2. ATTR disease type (hATTR versus wtATTR amyloidosis with cardiomyopathy)  
3. NYHA Class I or II and age <75 years versus all other (assessed on Day 1 of the RTE Period) 
Sections also reflecting this change:  
x Synopsis 
Purpose: Remove description of the 
 dose. 
The primary change occurs in Section 5.2.1, Description (of study drug) 
Deleted text:  
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC administration). Study drug (vutrisiran or placebo) 
will be administered using single-use prefilled syringes. Each prefilled syringe will be filled with either a 25 mg dose of vutrisiran or 
placebo with a fill volume of 0.5 mL. Two pre filled syringes (each with a 25 mg dose of vutrisiran and a volume of 0.5 mL) will be 
administered sequentially for patients randomized to the 
 dose during the RTE Period. Each pre-filled syringe includes a needle 
safety device which will be engaged to cover the exposed needle after injection. 
Purpose:  Specify dose administration for patients enrolled under Amendment 3 and those under Amendment 4. 
The primary change occurs in Section 5.2.2, Dose and Administration 
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Revised text:  
Starting on Day 1 of the DB Period, patients will receive 25 mg of vutrisiran or placebo administered as a SC injection q3M (every 12 
weeks ±7 days) for up to 36 months.  
Starting on Day 1 of the RTE Period Under Amendment 4, all patients will receive SC injections of 25 mg of vutrisiran q3M (every 
12 weeks ±7 days) or 
 for up to 2 years during the OLE Period. 
The first dose of study drug should be administered in the clinic on Day 1 of the DB Period (placebo or 25 mg of vutrisiran) and Day 1 
of the OLE Period (25 mg of vutrisiran or 
 of vutrisiran). If a patient has tolerated at least 1 dose of study drug in the clinic, 
subsequent dosing for the remainder of that period may be administered outside the study site (eg, the patient’s home) at all other 
timepoints where allowed by applicable country and local regulations. In these cases, dosing should be administered by a trained 
healthcare professional, with oversight by the Investigator. 
If the patient is unable to come to the study site, and a visit by a home healthcare professional is not possible due to circumstances 
related to the COVID-19 pandemic, q3M regimens of study drug (placebo or 25 mg vutrisiran) may be administered by the patient or 
the caregiver under the oversight of the Investigator, and following consultation with the medical monitor, as allowed by applicable 
country and local regulations.  In such cases, the patient or caregiver must receive appropriate training on study drug administration. 
This measure (self- or caregiver administration) is intended to remain in effect only during periods of time when the COVID-19 
pandemic impedes the ability of patients to travel to the study site or healthcare professionals to go to patients' homes for dosing.  The 
 vutrisiran regimen introduced in the RTE Period must be administered by a healthcare professional. 
Missed doses of Study Drug 
If a patient does not receive a dose of study drug within the specified dosing windows, the Investigator should contact the Medical 
Monitor.  After such consultation, the dose may be administered as close to the scheduled dosing date as possible with a maximum 8-
week delay (to be considered a delayed dose).  For patients in the initially randomized to 
 treatment arm (under 
Amendment 3), delays beyond 8 weeks may be allowable, but must be discussed with the Medical Monitor. Thereafter, the dose will 
be considered missed and not administered.  If a dose is missed or is administered with a delay, the next dose will resume following 
the original schedule. In cases in which a dose is delayed in this manner for issues related to the COVID-19 pandemic, the Medical 
Monitor should be informed as soon as possible, but prior consultation is not required.  In all cases, the dose should be administered as 
close as possible to the scheduled timepoint. 
Sections also reflecting this change:  
x Synopsis 
Purpose: Clarify Patient/Caregiver Storage and Administration Instructions 
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10.4.3. 
Amendment 3 Summary of Changes 
The primary purpose for this protocol amendment is to add an Open-label Randomized 
Treatment Extension (RTE) Period to allow a descriptive comparison of 2 vutrisiran dosing 
regimens administered during the RTE Period.   
During the RTE period, patients will be randomized 1:1 to receive treatment with 1 of 2 different 
treatment regimens for up to 2 years. Patients in one arm will receive 25 mg vutrisiran once 
every 3 months (q3M). Patients in the other arm will receive an alternative dosing regimen 
 This amendment will enable a descriptive 
comparison of the alternate dosing regimen with the current dosing regimen with respect to 
safety, pharmacodynamic (PD), pharmacokinetic (PK), and efficacy. The proposed 
 
regimen is the same cumulative annual dose (100 mg) relative to the 25 mg q3M and the dosing 
regimens are predicted to have similar safety, transthyretin (TTR) reduction (PD), and efficacy.   
The 
 regimen, being administered only twice a year, is a potentially important 
alternative option for patient care that may further reduce treatment burden for patients and 
caregivers. Patients with ATTR amyloidosis often suffer substantial loss in ambulation and 
mobility that significantly impact activities of daily living and can make healthcare visits 
challenging.  The ongoing coronavirus disease 2019 (COVID-19) pandemic has demonstrated 
the potential benefit of a less frequent dosing option for patients with ATTR amyloidosis to 
minimize the need for healthcare visits and mitigate the associated risk of missed doses for a 
serious and life-threatening condition. The addition of the 
 regimen aims to provide 
an option that can reduce treatment visits by half (from 4 to 2 times a year) and further mitigate 
patient burden, consistent with global trends toward decreased healthcare encounters.  The 
benefit of reduced healthcare encounters, while highlighted recently by the COVID-19 
pandemic, will substantially benefit patients post-pandemic as well. 
The rationale for the 
 regimen of vutrisiran is based on predictions from modeling 
and simulation of TTR reduction data from the Phase 1 vutrisiran study (ALN-TTRSC02-001) 
and data through Month 18 from the Phase 3 ALN-TTRSC02-002 (HELIOS-A) study in patients 
with hATTR amyloidosis with polyneuropathy.   The safety, PD, PK, and efficacy of the 
vutrisiran 
 regimen is also being explored in patients with hATTR with 
polyneuropathy in the RTE of the ongoing HELIOS-A study. 
In addition to achieving the same cumulative annual dose of 100 mg as tested in the treatment 
period in HELIOS-A, observed data from the single-dose Phase 1 study (ALN-TTRSC02-001) 
and PK/PD modeling show that the 
 and 25 mg q3M regimens of vutrisiran are 
expected to achieve comparable average TTR reductions (see Table 9). 
x The 
 regimen is expected to achieve slightly higher median peak lowering 
with lower variability compared with the 25 mg q3M regimen (89.3 % vs 87.8%). 
x The 25 mg q3M and 
 regimens are predicted to achieve median trough 
TTR reduction of 86.4% and 82.5% which are similar to the observed median trough 
TTR reductions of 81.2% for patisiran at Month 18 of the APOLLO study. [Adams 
2018]   
x Importantly, the steady state average TTR lowering of both 25 mg q3M and 
 
 are expected to be similar (87.1% vs 86.7%).  
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The TTR lowering expected with 25 mg q3M or 
 dosing regimens of vutrisiran is 
similar to that observed with patisiran in APOLLO, and hence is expected to translate into 
similar clinical efficacy.  
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Table 9: 
Summary of Observed and Predicted Median TTR Reductions (%) for 
 25 mg q3M Vutrisiran, and 0.3 mg/kg q3W Patisiran Regimens   
 
Vutrisiran  
(Model-predicted) 
HELIOS-A 
Vutrisiran 
(Observed) 
APOLLO 
Patisiranc 
(Observed) 
Serum TTR 
% change 
from baseline 
25 mg q3Ma 
 
25 mg q3M 
0.3 mg/kg q3W 
Peak 
-87.8  
(-97.8, -51.7) 
-89.3  
(-97.9, -57.0) 
 -90.8d 
  (-97.7, -63.4) 
-88.5  
(-95.4, -56.8) 
Trough 
-86.4  
(-97.7, -43.7) 
-82.5  
(-97.5, -31.4) 
-86.2e 
  (-97.3, -41.8) 
-81.2  
(-94.2, -49.9) 
Average 
-87.1  
(-97.7, -48.6) 
-86.7  
(-97.7, -46.9) 
 -86.9f 
 (-97.5, -42.1) 
-83.1  
(-93.7, -56.5) 
Abbreviations: q3M=once every 3 months; 
; q3W=once every 3 weeks; 
TTR=transthyretin. 
The numbers in table are median and 5th and 95th percentiles of simulations (vutrisiran) or observed data 
(patisiran)  
a The average TTR reduction was computed over a dosing interval (Month 15 to Month 18), while peak and trough 
TTR reduction was at Week 66 and Week 72, respectively. 
b The average TTR reduction was computed over a dosing interval (Month 12 to Month 18), while peak and trough 
TTR reduction was at Week 56 and Week 72, respectively. 
c For APOLLO observed data (Month 18), the peak and trough percent TTR change was at Month 18 and Day 546, 
respectively, while the average percent TTR change represents the mean of assessments at Day 546, Month 18 and 
Day 567.  
d Day 211 and Day 547 samples for vutrisiran. 
e Day 253 and Day 505 samples for vutrisiran. 
f Represents the mean of assessments between Month 6 and Month 9 (Day 169, 211 and 253) and Month 15 to 
Month 18 (Day 421, 465 and 505) for vutrisiran. 
Importantly, the available safety data in healthy volunteers, as well as exposure-response 
modeling, suggest the two regimens will result in similar safety profiles.  In the Phase 1 study, 
vutrisiran demonstrated an acceptable safety profile at single doses up to 300 mg.  The data to 
date in HELIOS-A also support that vutrisiran continues to have an acceptable safety profile.   
In summary, the adjustment of the study design to include an RTE Period will facilitate a 
descriptive comparison of safety, PD, PK, and efficacy of the 
 regimen relative to the 
25 mg q3M dose regimen.  The 
 regimen has the same annual dose (100 mg) and an 
expected therapeutic effect and safety comparable to the 25 mg q3M regimen.  
Changes to the protocol are outlined below. 
Changes Related to the Addition of the RTE Period and a 
 Dosing Regimen 
x Patients must sign an informed consent form for the RTE Period before any 
procedures can be performed in the RTE Period. 
x The study design has been revised to include the open-label RTE Period described 
above. This includes modification of the study design figure, addition of new 
schedules of assessments for the RTE Period (Table 2 and Table 4), and other 
relevant modifications throughout the protocol.  
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• Updated liver function test (LFT) monitoring and pregnancy reporting text to align 
with updates made to the Sponsor protocol template reflecting current Sponsor 
standards.  
• Clarified definitions of the PK Analysis Set and PD Analysis Set to include all 
patients who received at least 1 complete dose of study drug. Removed Per-Protocol 
Analysis Set. 
A detailed summary of changes is provided in Table 10.  The following changes are not detailed: 
administrative changes, corrections to typographical errors, punctuation, grammar, abbreviations, 
and formatting. 

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Table 10: 
Protocol Amendment 3 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 3 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  To add the Randomized Treatment Extension (RTE) Period.  
The primary change occurs in Section 3.1, Summary of Study Design 
Revised text: 
The study consists of 3 4 periods (Figure 1): 
6. Screening Period: Up to 45 days during which patients will undergo screening assessments to determine eligibility. 
7. Double-Blind (DB) Period (DB Period): 
x At the start of the DB Period (on Day 1), eligible patients will be randomized in a 1:1 ratio to receive blinded doses of 
25 mg of vutrisiran or placebo administered as a SC injection q3M for up to 36 months. 
 In addition to study drug, all patients will take the recommended daily allowance of vitamin A during their DB Period 
and Follow-up Period (see below). 
x Patients will undergo assessments as outlined in the Schedule of Assessments (Table 1).  
x An individual patient’s DB Period will end after they complete their Month 36 Visit, or 30 months after the last patient is 
randomized, whichever comes first. As such, the length of each patient’s intended treatment during the DB Period may 
vary from 30 to 36 months. 
x The variable length of the DB Period will mean that some patients will not have a Month 33 and/or Month 36 visit. 
For those patients, the Day 1 visit of their RTE Period should be 3 months after their last planned visit (at Month 30 
or Month 33 [±7 days]). 
x The primary analysis will be conducted after the last patient has completed the Month 30 Visit or otherwise discontinued. 
8. Open-Label Randomized Treatment Extension (RTE) Period  
x On or before the date of their last planned visit of the DB Period, patients will be randomized to treatment in RTE 
Period as described below and receive their first dose of open-label vutrisiran at this visit (RTE Day 1).  
x At the start of the RTE Period (RTE Day 1), eligible patients will be randomized in a 1:1 ratio to receive open-label 
doses of 25 mg of vutrisiran q3M or 
 administered as SC injections for up to 2 years. 
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 In addition to study drug, all patients will take the recommended daily allowance of vitamin A during their RTE 
Period and Follow-up Period (see below). 
x Patients will undergo assessments as outlined in the Schedule of Assessments for the RTE Period (Table 2). 
Note: Patients who do not complete the DB Period will not participate in the RTE Period. Consent must be signed 
before any procedures are performed in the RTE (Table 2). 
9. Follow-Up Period after the last dose of vutrisiran on study: 
x Following completion of the RTE Period (or completion of the DB Period for patients who do not continue into the 
RTE Period; or their last dose of vutrisiran in the DB Period, for patients who discontinue study drug early), patients 
will commence follow-up visits every 12 weeks for the durations outlined below. 
x Prior to unblinding of their treatment from the DB Period, the duration of the Follow-up Period for a patient will be 
1 year from their last dose of study drug. For women of child-bearing potential, the duration of the Follow-up Period will 
be 18 months from their last dose of study drug. Patients will continue vitamin A supplementation during their Follow-up 
Period. 
x After unblinding, all patients who were on placebo, and patients who received vutrisiran whose serum TTR level has 
UHWXUQHGWRRIEDVHOLQHRUZKRKDYHFRPSOHWHGWKH)ROORZ-up Period, whichever comes first, may discontinue further 
follow-up and stop taking vitamin A; all patients will be followed for a minimum of 3 months. Baseline is defined as the 
last value prior to first vutrisiran dose (ie, prior to the first DB dose for vutrisiran patients in DB Period and prior 
to the first RTE dose for placebo patients). Patients will be followed for a minimum period as listed below during 
the Follow-up Period based on treatment regimen received: 
 All patients who received only a q3M study drug regimen (25 mg vutrisiran/placebo during DB Period and/or 
25 mg vutrisiran during the RTE Period) will be followed for a minimum of 90 days after their last dose of study 
drug. 
 All patients who received the 
 vutrisiran regimen (during the RTE Period) will be followed for a 
minimum of 
 after their last dose of study drug during Follow-up Period. 
x For any patient who starts a TTR lowering treatment as part of clinical care, and has completed a minimum of 3 months 
90 or 
 (depending on vutrisiran treatment regimen) of safety follow-up since their last dose of study drug, 
further follow-up will be discontinued. 
x Patients will undergo assessments as outlined in the Schedule of Assessments (Table 1 and Table 2). 
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Upon completion of the DB Period for each individual patient, in the case where there are no commercially available treatment 
options, the Sponsor will aim to provide access to vutrisiran via the means available (eg, open label extension study, named patient 
sales programs, charitable access programs, or other means). 
Patients may receive vutrisiran on the study until the end of the RTE Period or until one of the following occurs:  1) they meet 
any of the study discontinuation criteria; 2) vutrisiran is commercially available in the patient’s country of residence and 
vutrisiran is accessible to the patient and the patient has completed their RTE Month 12 Visit; or 3) the vutrisiran 
development program is discontinued. 
Study drug dosing may be allowed outside of the study center (eg, the patient’s home) during the DB Period or RTE Period under 
certain circumstances as specified in Section 5.2.2.  In addition, routine assessments and collection of relevant safety information may 
be collected outside the study center as specified in Section 6.  
Sections also reflecting this change:  
• Synopsis 
• Study Design Figure 1 
• Schedule of Assessments, Table 1, Table 2, and Table 4 
• Section 1.4, Clinical Development of Vutrisiran 
• Section 1.5, Study Design Rationale 
• Section 1.6, Dose Rationale 
• Section 1.7, Benefit-Risk Assessment 
• Section 3.2, Duration of Treatment 
• Section 3.3, Duration of Study Participation 
• Section 3.3.1, Definition of End of Study for an Individual Patient 
• Section 3.5, Method of Assigning Patients to Treatment Groups 
• Section 3.6, Blinding 
• Section 4.3.1, Discontinuation of Study Drug or Declining Procedural Assessments 
• Section 4.3.2.1, Patient Stops Participation in the Study 

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• Section 5.2 (and subsections within), Study Drug 
• Section 5.4 (and subsections within), Concomitant Medications 
• Section 6 (and subsections within), Study Assessments 
• Section 7.2, Statistical Methodology 
Purpose:  To specify that efficacy assessments other than the 6-MWT and KCCQ only need to be performed prior to study drug 
administration on Day 1 of the DB Period and Day 1of the RTE Period. 
The primary change occurs in Section 6, Study Assessments 
Revised text:   
When performed on dosing days, efficacy the 6-MWT, the KCCQ, safety, and PD assessments will be performed prior to study drug 
administration. All other efficacy assessments only need to be performed prior to study drug administration on Day 1 of the DB 
Period and Day 1 of the RTE Period. 
Sections also reflecting this change:  
• Schedule of Assessments, Table 1 and Table 2 
Purpose:  To specify starting a TTR-lowering regimen meets end of study criteria for an individual patient. 
The primary change occurs in Section 3.3.1, Definition of End of Study for an Individual Patient 
Revised text:  
A patient is considered to have reached the end of the study if they have: 
• completed the DB Period and the Follow-up Period (if the patient does not continue into the RTE Period); or  
• completed the DB Period, the RTE Period, and the Follow-up Period;  
• completed the Early Study Discontinuation Visit; or  
• started a TTR-lowering regimen as a part of clinical care 
Note that a patient is considered to have completed the study only if they have completed the DB Period and the Follow up Period. 
Purpose:  To remove wording that the sponsor may perform a sample size re-assessment (SSR). 
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Sections also reflecting this change:  
x Schedule of Assessments, Table 1 and Table 2 
Purpose: To clarify pregnancy reporting requirements.  
The primary change occurs in Section 6.5.6.7, Pregnancy Reporting 
Revised text:   
If a female patient becomes pregnant during the study through the end of their Follow-up Period (defined Section 3.1) 90 days 
following the last dose of study drug, or through their last visit in the study (whichever is later), the Investigator must report the 
pregnancy to the Sponsor or designee within 24 hours of being notified of the pregnancy.  Details of the pregnancy will be recorded on 
the pregnancy reporting form.  The patient should receive any necessary counseling regarding the risks of continuing the pregnancy, 
the possible effects on the fetus, and be counseled to not breastfeed for 90 days after the last dose of study drug (q3M treatment arm) 
or 
 
Purpose: To clarify the definitions of the PK analysis set and PD analysis and to remove the Per-Protocol Analysis Set.  
The primary change occurs in newly added Section 7.2.1, Populations to be Analyzed 
Revised Text: 
The populations (analysis sets) are defined as follows:  
x Full Analysis Set (FAS): all patients who were randomized and received any amount of study drug (vutrisiran or placebo).   
x Per-Protocol Analysis Set (PPS): all patients in the FAS set who do not have major violations of inclusion/exclusion 
criteria or other protocol deviations considered to impact the interpretation of the primary efficacy analysis. Classification 
of patients into (or exclusions from) the PPS will be determined prior to database lock and study unblinding. 
x Safety Analysis Set: includes all patients who received any amount of study drug.  
x PK Analysis Set: All randomized patients who received any amount of study drug at least one full dose of vutrisiran and 
have at least 1 post dose blood sample for one non-missing postdose PK parameters and have evaluable PK data 
assessment. 
x PD Analysis Set:  All patients who received any amount of study drug and who have an evaluable baseline and at least 1 
evaluable post baseline serum TTR measurement will be included in the PD analyses at least one full dose of study drug. 
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The FAS will be used for the analysis of all efficacy endpoints. The primary endpoint will also be analyzed for the PPS. Safety 
analyses will be based on the Safety Analysis Set. PK and PD analyses will be based on PK Analysis Set and PD Analysis Set, 
respectively.  
Purpose: To clarify subgroup analyses. 
The primary change occurs in Section 7.2.2, Examination of Subgroups 
Revised Text: 
Subgroup analyses will be conducted for the primary and selected secondary efficacy endpoints. Subgroup Efficacy subgroup 
analyses will be conducted for age group (<75 versus ≥75), baseline tafamidis use (Yes verse No), ATTR disease type (hATTR; 
wtATTR) and NYHA Class (I/II; III). Safety subgroup analyses will be conducted for at least the following variables:  age group, 
gender, race, geographic region, and NYHA class. Additional variables may be included and the details will be provided in the SAP. 
 
References 
Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi Therapeutic, for Hereditary 
Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21. 
 

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x To protect blinding, added an instruction that TTR and vitamin A levels should not be 
tested when a local laboratory must be used when use of a central laboratory is not 
possible due to COVID-19 restrictions. This is consistent with the instructions on 
Vitamin A testing in Section 3.6 (Blinding) of the protocol. 
x Added instructions to indicate that all patients who are rescreened must be 
reconsented and that if a patient is within the 45-day screening window, the medical 
monitor should be contacted to determine which screening procedures should be 
repeated. 
x Adjusted requirements for vital sign collection to indicate they can be collected after 
approximately 10 minutes of rest and that blood pressure should be taken from the 
same arm when possible. 
 
 
x Added the guidance that symptom-directed physical examinations may be deferred to 
the next on-site visit, when they cannot be performed during a home visit. 
x In addition to the requirement that pregnancies be reported through 90 days following 
the last dose of study drug, further clarified that pregnancies should also be reported 
through a patient’s last study visit (whichever is later). This change was made to 
ensure pregnancy reporting continues during the Follow-up Period. 
x Simplified process of overdosing reporting to indicate that when an overdose is 
suspected, the Investigator should inform the Medical Monitor. Removed instructions 
about recording an actual dose associated with an overdose in the electronic case 
report form. 
x Made edits to the summary of the HELIOS-A study in the introduction to align with 
recent study protocol amendments and completion of enrollment. 
A detailed summary of changes is provided in Table 11.  The following changes are not detailed: 
administrative changes, changes associated with administrative letters ([between protocol 
amendments 1 and 2), and corrections to typographical errors, punctuation, grammar, 
abbreviations, and formatting. 
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b. Wild-type ATTR (wtATTR) amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria: 
iv. 
If the patient has evidence of a MGUS (Section 6.5.5.1) based on serum and urine protein electrophoresis and 
serum free light chains, the following is required: documentation of TTR protein in cardiac tissue with 
immunohistochemistry or mass spectrometry is required; OR, documentation of TTR protein in noncardiac 
tissue (eg, fat pad aspirate, salivary gland, median nerve connective sheath) with immunohistochemistry or 
mass spectrometry AND Grade 2 or 3 cardiac uptake on technetium scintigraphy per item 2biii above.    
Purpose:   Additional clarifications were made that align with the original scope of the changes to the assessment of monoclonal 
gammopathy outlined in HELIOS-B Protocol Administrative Letter 3 dated 10 September 2020. 
The primary change occurs in Section 6.5.5.1. (Assessment for Monoclonal Gammopathy including MGUS) 
Revised text: 
As part of the determination of a diagnosis of ATTR amyloidosis, excluding evidence of a monoclonal gammopathy at Screening 
(Table 1) may be necessary (inclusion criterion #2). Laboratory assessments associated with this are indicated in Table 4. If available, 
documented local results obtained within 1 year prior to Screening may be used to fulfill this inclusion requirement. 
Abnormal findings, such as a monoclonal band (M-spike), on SPEP with IFE or serum free light chains with an abnormal kappa-to-
lambda ratio that are suggestive of an alternative diagnosis, such as light chain amyloidosis, will require confirmatory testing 
using mass spectrometry or immunohistochemistry for confirmation of TTR protein deposition.  Specifications for testing samples 
will be provided in the study laboratory manual. 
The determination of whether abnormal findings are suggestive of light chain amyloidosis may be assessed by a clinician 
experienced in the diagnosis of amyloidosis.  
Section(s) also reflecting this change:  
• Table 1 (Schedule of Assessments) 
• Table 4 (Clinical Laboratory Assessments) 
Purpose:   Added further guidance confirming rules already in place that specify when performed on dosing days, efficacy, safety, and 
PD assessments will be performed prior to study drug administration. 
The primary changes occur in Table 1 (Schedule of Assessments) 
Moved the rows related to study drug administration and randomization to the end of the Schedule of Assessments. 
Added a link to Table 2 to direct reviewers the detailed schedule for predose and postdose PK samples that were already in place. 

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Added note to cell in the “Study Drug Administration” row and the “See Table/Section for Details” column: 5.2.2; to be 
administered after efficacy, safety, and PD assessments during applicable visits 
Modified the following existing footnote and moved it to the top of the footnote list. Also added references to this footnote in the 
Efficacy Assessments, Safety Assessments and Pharmacodynamic Assessments rows:  
•a When performed on dosing days, efficacy, safety, and PD assessments will be performed prior to study drug 
administration. Unless otherwise specified, assessments are to be performed prior to dosing. 
Section(s) also reflecting this change:  
• Section 6 (Study Assessments) 
• Section 6.2.4. (Kansas City Cardiomyopathy Questionnaire [KCCQ]) 
Purpose:   Added a visit window of ±10 days for visits during the Follow-up Period. 
The primary change occurs in Table 1 (Schedule of Assessments) 
Added text: ±10-day window added to the column titled “Follow-up Period Visits Every 12 Weeks” 
Purpose:   To protect blinding, added an instruction that TTR and vitamin A levels should not be tested when a local laboratory must 
be used when use of a central laboratory is not possible due to COVID-19 restrictions. 
The primary change occurs in Section 6 (Study Assessments) 
Revised text (relevant text only): All laboratory samples should be sent to the central laboratory; an exception is for situations related 
to the COVID-19 pandemic when central laboratory assessments are not possible, then a local laboratory may be used.  If a local 
laboratory is used, TTR and vitamin A levels should not be tested (see Section 3.6). 
Purpose:   Added instructions to indicate that all patients who are rescreened must be reconsented and that if a patient is within the 
45-day screening window, the medical monitor should be contacted to determine which screening procedures should be repeated. 
The primary change occurs in Section 6.1.2. Rescreening 
Revised text (relevant text only): 
A patient who does not meet all study eligibility criteria due to a transient condition observed at Screening (eg, prohibited medications 
that were subsequently discontinued), in conjunction with the decision of the Medical Monitor(s), may be allowed to rescreen after a 
minimum of 5 days have elapsed from their last screening assessment.  A patient All patients who are rescreened will be re-
consented (ICF and the medical records release form), if). If a patient is rescreened within the 45-day screening window, please 
consult the medical monitor to determine which screening procedures must be repeated.  If rescreening occurs outside of the 45-
day screening window.  In this case, all screening procedures must be repeated. 

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Purpose:   Adjusted requirements for vital sign collection to indicate they can be collected after approximately 10 minutes of rest and 
that blood pressure should be taken from the same arm when possible. Confirmed that triplicate ECGs will be only conducted at 
Screening. 
The primary changes occur in the following sections (relevant revised text indicated): 
6.5.1. Vital Signs 
Vital signs should be measured predose in the seated or supine position, after the patient has rested comfortably for approximately 10 
minutes.  Blood pressure should be taken using the same arm, when possible.   
 
   
Purpose:   Added the guidance that symptom-directed physical examinations may be deferred to the next on-site visit, when they 
cannot be performed during a home visit. 
The primary change occurs in Section 6.5.3. (Physical Examination) 
Added text: In situations in which symptom-directed physical examinations cannot be performed during a home visit, they may 
be deferred to the next on-site visit. 
Purpose:   In addition to the requirement that pregnancies be reported through 90 days following the last dose of study drug, further 
clarified that pregnancies should also be reported through a patient’s last study visit (whichever is later). 
The primary change occurs in Section 6.5.6.7. (Pregnancy Reporting) 
Revised text: If a female patient becomes pregnant during the study through 90 days following the last dose of study drug, or through 
their last visit in the study (whichever is later), the Investigator must report the pregnancy to the Sponsor or designee within 
24 hours of being notified of the pregnancy. 
Purpose:   Simplified process of overdosing reporting to indicate that when an overdose is suspected, the Investigator should contact 
the Medical Monitor within 24 hours to discuss the event. Removed instructions about recording an actual dose associated with an 
overdose in the electronic case report form. 
The primary change occurs in Section 6.5.6.8. (Overdose Reporting) 
Revised text: 
An overdose is defined as any dose of study drug administered to or taken by a patient (accidentally or intentionally) that exceeds the 
highest daily dose, or is at a higher frequency, than included in the protocol.  The Investigator will decide whether a dose is to be 
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Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. Tafamidis Treatment for Patients with 
Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep 13;379(11):1007-16. 
Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM, et al. Screening for Transthyretin Amyloid Cardiomyopathy in 
Everyday Practice. JACC Heart Fail. 2019 Aug;7(8):709-16. 
 

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10.4.5. 
Amendment 1 Summary of Changes 
The primary purpose for this protocol amendment is to incorporate Urgent Safety Measures 
(USMs) that were communicated to investigators at active study centers (Canada, Latvia, 
Lithuania, Slovenia, and US) in a Dear Investigator Letter dated 07 April 2020 to assure the 
safety of study participants while minimizing risks to study integrity amid the COVID-19 
pandemic. These changes were to be immediately adopted by the investigator site per the Dear 
Investigator Letter and are in line with guidance from both the European Medicines Agency and 
the United States Food and Drug Administration on the conduct of clinical trials during the 
COVID-19 pandemic.[EMA 2020; FDA 2020] 
This protocol amendment also incorporates several other changes including: modification of 
study endpoints, changes in inclusion/exclusion criteria based on feedback from regulators and 
sites, and allowance for diagnostic testing in countries where necessary screening tests are not 
standard of care. A detailed summary of protocol changes is provided in Table 12 and Table 13; 
the changes will not be implemented until appropriate Health Authority and Ethics Committee 
(EC) and/or Institutional Review Board (IRB) approval. 
Urgent Safety Measures due to the Impact of the COVID-19 Pandemic 
Urgent Safety Measures were implemented by the Sponsor, as mentioned above, to ensure the 
safety of study participants and the integrity of study data in response to the impact of the 
COVID-19 pandemic. The changes are outlined below.  
• Study Drug Dosing at a Location other than the Study Center (eg, the patient’s 
home) 
Administration of study drug will be permitted outside the study center (eg, the 
patient’s home) by a home healthcare professional at all timepoints provided the 
patient has tolerated at least 1 dose of study drug administered in the study center 
(previously required study drug administration in the study center for all dosing 
visits).  
• Dosing Outside the Study Center by Patient or Caregiver 
Following appropriate training on study drug administration, dosing may be permitted 
by the patient or caregiver at all dosing timepoints under the oversight of the 
Investigator and following consultation with the Medical Monitor. This measure is 
intended to remain in effect only during periods of time when the COVID-19 
pandemic impedes the ability of patients to travel to the study site or healthcare 
professionals to go to patients' homes for dosing. In addition, added references to 
patient/caregiver instructions for administration, storage of study drug, and reporting 
of product complaints. 
• Expanded Dosing Window After Which a Dose Will be Considered Delayed 
If a patient does not receive a dose of study drug within the specified dosing window, 
the dose may be administered with up to an 8-week delay (previously 6 weeks) to be 
considered a delayed dose. If the delay in dose is related to COVID-19, the Medical 
Monitor should be informed of any delayed doses (previously consultation with the 
Medical Monitor was required prior to administration of the delayed dose). 

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This change has been implemented to provide greater flexibility amid travel and other 
restrictions related to the COVID 19 pandemic, in order to minimize the number of 
missed doses on study. Given the long activity of vutrisiran resulting in sustained 
suppression of TTR as observed in Phase 1 study, an occasional delay of 8 weeks in 
dosing is expected to have minimal impact on the TTR suppression (decrease of only 
7% in TTR suppression relative to vutrisiran original scheduled dosing) as predicted 
by the Sponsor’s PK/PD modeling. Resumption of dosing as per the original dosing 
schedule is expected to be tolerated based on the safety data from the Phase 1 study 
which evaluated, and demonstrated an acceptable safety profile, at doses as high as 
300 mg (12× higher than the therapeutic dose of 25 mg administered quarterly).   
• Screening Patients 
The requirement that the Investigator notify the Sponsor before screening patients 
was added to allow an assessment of the ability of the study center or any new trial 
participant to comply with the protocol given the COVID-19 limitations. 
In addition, patients who failed screening due to situations related to the COVID-19 
pandemic may be allowed to rescreen after consultation with the Medical Monitor. 
• Assessments Performed Outside the Study Center 
Routine assessments may be performed outside of the study center (eg, the patient’s 
home) by a trained healthcare professional at all timepoints.  These assessments 
include the following: vital signs, physical exam, weight, ECGs, pregnancy tests, 
urine collection, blood draws (clinical laboratory assessments, ADA, PK; 
ATTR/vitamin A; exploratory samples), collection of information regarding vital 
status, hospitalizations, urgent care visits, procedures, and concomitant medications.  
Wherever possible, AE collection associated with visits outside of the clinic will be 
collected by qualified site staff through verbal contact with the patient. All laboratory 
samples should be sent to the central laboratory. Exception added that local 
laboratory assessments are permitted in cases when assessment at central laboratory is 
not possible due to complications related to the COVID-19 pandemic. 
With the exception of patients unable to come to the site due to the COVID-19 
pandemic limiting the patient’s ability or willingness to access the study site, at a 
minimum, patients should visit the site for the scheduled dosing and assessments for 
the Week 12 (Month 3) visit within the study visit window and for efficacy 
assessments as detailed below. 
If any study assessments are not able to be completed at the site or at home within the 
study visit window, the study physician (or delegate) must verbally contact the patient 
to collect relevant safety information (including, but not limited to, AEs, concomitant 
medications, hospitalizations/procedures, and vital status). 
• Elimination of the Week 18 Visit 
The Week 18 visit, including all associated assessments, has been removed.   
This change was implemented to reduce the frequency of patient visits to the study 
center, and therefore reduce potential exposure to COVID-19, while maintaining 

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continuity of study drug dosing. The removal of the Week 18 visit is considered 
appropriate as the visit is a non-dosing visit and not necessary for safety monitoring.  
After Week 12, the patients will have study visits every 12 weeks.  The current safety 
profile for vutrisiran from the ongoing HELIOS-A study supports removal of the 
Week 18 visit.  As per the protocol, Investigators will always be required to report 
any known adverse events, hospitalizations or changes in vital status that occur 
between Week 12 and Week 24 as they would between any other study visits. 
• Liver Function Tests (LFTs)  
Removed the requirement for a pre-dose LFT assessment within 14 days of each 
dose. Dosing decisions may be made based on LFT results collected at the previous 
dosing visit  (up to 14 weeks prior to dosing) or screening, as applicable; in all cases 
the most recently available LFTs should be used. 
These changes were implemented in order to limit the number of times a patient 
needs to visit the site/interact with home healthcare professionals and reduce potential 
exposure to COVID-19.   The changes are based on the available safety data from the 
prior Phase 1 study (ALN-TTRSC02-001) and the ongoing HELIOS-A study (ALN-
TTRSC02-002), which support that vutrisiran continues to have an acceptable safety 
profile.   
In the HELIOS-A study, as of 08 April 2020, 120 patients had received a total of 305 
doses of vutrisiran 25 mg every 3 months (mean 2.5 doses, range: 1-5 doses).  This 
provides a mean exposure of 130.4 days (range: 1 to 339 days) and most patients (101 
out of 120) have had at least 2 doses of vutrisiran.  No subjects in the ongoing 
HELIOS-A study have had laboratory elevations of >3×ULN for ALT or AST and no 
subjects have required interruption of study drug due to elevations in liver 
transaminases, bilirubin or adverse hepatic events. Thus, with increasing exposure in 
HELIOS-A, vutrisiran continues to have an acceptable hepatic safety profile.   
The Sponsor acknowledges that liver transaminase elevations remain an important 
potential risk based on the mechanism of action of vutrisiran, as well as findings in 
pre-clinical studies and early-phase clinical trials.  The specific rules for monitoring 
and dosing in the setting of transaminase elevations outlined in the protocol are 
unchanged (Section 5.2.4 Table 3 [Monitoring and Dosing Rules for Asymptomatic 
Patients with Confirmed Isolated Elevations of ALT and/or AST >3× ULN, with No 
Alternative Cause Identified]).  
Given the available safety data for vutrisiran, the degree of risk of COVID-19 
exposure related to the additional visits is considered in excess of the degree of risk 
mitigation obtained by more frequent LFT monitoring.  With the current changes, a 
robust LFT monitoring schedule of every 12 weeks, is maintained and the results will 
be regularly reviewed by the Medical Monitor and the Data Monitoring Committee 
(DMC).  Continuous monitoring of adverse events will also allow for detection of any 
clinically relevant events and additional LFTs may be obtained at any time at the 
discretion of the investigator. 

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• Use of Local Laboratories for Analysis due to COVID-19 
Confirmed that the intention during normal operations is that all laboratory samples 
are sent to a central laboratory. Added an exception that in situations related to the 
COVID-19 pandemic when central laboratory assessments are not possible, a local 
laboratory may be used. These local lab results must be sent to the site for review by 
the Investigator and entry into the clinical database. 
• Addition of Infrared to the List of Acceptable Body Temperature Collection 
Methods 
Added as a non-contact method of temperature collection to limit contact between 
patients and study or home healthcare professionals. 
• Performance of Efficacy Assessments and Delays Due to COVID-19 
Clarified that all efficacy assessments associated with the following visits should be 
conducted at the study center:  Month 6, Month 12, Month 18, Month 24, and Month 
30. In situations where an efficacy assessment study visit is unable to be completed at 
the site due to the COVID-19 pandemic limiting the patient’s ability or willingness to 
access the study center or their ability to have received their scheduled doses of study 
drug, efficacy assessments may be completed up to 3 months after the time point (ie, 
up to Study Month 9, Month 15, Month 21, Month 27, or Month 33, respectively). 
This change was implemented to allow for collection of critical efficacy data while 
limiting unnecessary patient exposure to COVID 19 and to ensure, to the extent 
possible, that study integrity is maintained amid travel and other restrictions related to 
the COVID-19 pandemic.   
• Collection of Information Related to COVID-19 
Information related to the impact of the COVID-19 pandemic on patient participation 
in the study will be collected for each patient in order to enable analysis of the impact 
of the COVID-19 global pandemic on clinical trial data.   
• Updates to Study Administration Text 
Text was updated to provide clarification of Investigator responsibilities regarding 
communication of new study information to patients and IRB/IECs. 
Changes Not Related to Urgent Safety Measures 
The following additional changes are being implemented as outlined below, and a detailed 
summary is provided in Section 2.2. 
• Objectives and Endpoints   
The primary and secondary objectives and endpoints were revised to include non-
hospitalized urgent heart failure (HF) visits (urgent HF visits).  Urgent HF visits must 
satisfy criteria developed by the Standardized Data Collection for Cardiovascular 
Trials Initiative and the US Food and Drug Administration[Hicks 2017] and will be 
adjudicated by the independent Clinical Events Committee (CEC). 

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Specifically, the primary composite endpoint of “all-cause mortality and recurrent CV 
hospitalizations” will be changed to “all-cause mortality and recurrent CV events.” 
Recurrent CV events includes CV hospitalizations and urgent HF visits.   
Similarly, the composite secondary endpoint of “all-cause mortality and recurrent all-
cause hospitalizations” will be revised to also include urgent HF visits. The secondary 
endpoint of “recurrent CV hospitalizations will be revised to “recurrent CV events” to 
include urgent HF visits.  
Including urgent HF visits will account for the likelihood that the COVID-19 
pandemic may increase current trends to reduce hospitalizations and shift 
management of clinically comparable heart failure events to outpatient settings.[Hicks 
2017]  Including urgent HF visits also mitigates regional differences in the criteria for 
hospitalization, which may be further exacerbated by the COVID-19 pandemic. 
Urgent HF visits are well defined endpoints in regulatory guidances 
(CPMP/EWP/235/95, Rev.2, Guideline on clinical investigation of medicinal 
products for the treatment of chronic heart failure, Committee for Medicinal Products 
for Human Use, 2017; Guidance for Industry, Treatment for Heart Failure: Endpoints 
for Drug Development, US Food and Drug Administration, 2019).   
• Exclusion of deaths and hospitalizations due to COVID-19 
Deaths  and hospitalizations due to COVID-19 will be excluded from all-cause deaths 
and hospitalizations, respectively, in the primary analyses of primary and applicable 
secondary endpoints. 
As of April 29, 2020, according to the World Health Organization, the COVID-19 
pandemic has led to over 3,000,000 confirmed cases and over 200,000 deaths 
worldwide.[WHO 2020]  The effects of the pandemic on global health are 
unprecedented and due to the novel SARS-CoV2 circulating in a population with no 
prior immunity.[Jin 2020]  As the COVID-19 pandemic will have a confounding 
effect on the number of death and hospitalization events in the study, we will exclude 
events due to COVID-19 from analyses for all-cause deaths or hospitalizations.  
• Allowance for Diagnostic Testing at Screening 
Confirmed that diagnostic tests required to confirm eligibility per inclusion criterion 2 
are intended to be historical and will not be performed as part of the study. However, 
an allowance was added for diagnostic testing in countries where necessary screening 
tests are not standard of care.  This will enable diagnostic testing to confirm 
transthyretin amyloidosis with cardiomyopathy in the event these results are not 
available for the assessment of eligibility. This change is necessary to accommodate 
enrollment in regions of the world where certain diagnostic tests may not be standard 
of care.   
• Revised Subgroup Analysis Description 
Based on feedback from a regulatory authority, added a statement that subgroup 
analyses will be conducted for at least the following variables: age group, gender, 
race, geographic region, and NYHA class. 

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reasonable amount of time to avoid any confounding effects from diflunisal on the 
baseline assessments. 
• Exclusion Criteria 10 and 11, Prohibited TTR lowering agents  
Added ursodeoxycholic acid to the list of TTR lowering agents to be avoided during 
the study. The exclusion now excludes patients unwilling to avoid any concurrent 
treatment with diflunisal, ursodeoxycholic acid/ tauroursodeoxycholate/ doxycycline , 
or TTR lowering agents (eg, patisiran, inotersen). 
• Exclusion Criterion 23, History of Drug Allergies/Reaction to Study Drug 
Exclusion criteria widened to include a history of allergic reaction to any component 
of or excipient in the study drug based on a request from a regulatory authority. 
• Doxycycline Use 
Added a clarification that doxycycline use is permitted if taken for short-term 
treatment of infection; use of doxycycline is otherwise excluded.  
The following changes are not detailed: administrative changes, changes associated with 
administrative letters (since the original protocol was finalized), and corrections to typographical 
errors, punctuation, grammar, abbreviations, and formatting. 

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Protocol Amendment 1 Detailed Summary of Changes 
Table 12: 
Protocol Amendment 1 Urgent Safety Measure COVID-19-related Changes to be Adopted Immediately 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 1 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  The following changes were made related to administration of study drug: 
• Expanded study drug Dosing Outside the Study Center 
• Study Drug Dosing at a Location other than the Study Center (eg, the patient’s home) 
• Dosing Outside the Study Center by Patient or Caregiver 
• Expanded Dosing Window After Which a Dose Will be Considered Delayed 
• Modified other dose, administration, and product complaint sections to match new administration strategy 
The primary changes occur in Section 5.2.2 (Dose and Administration) 
5.2.2. Dose and Administration 
Detailed instructions for administration are provided in the Pharmacy Manual.  Detailed Instructions for Use for the pre-filled syringe 
will also be provided. 
Starting on Day 1, patients will receive 25 mg of vutrisiran or placebo administered as a SC injection q3M (every 12 weeks ±7 days) 
for up to 36 months.  Study drug will be administered under the supervision of the Investigator or designee. 
If a patient has tolerated at least 1 dose of study drug in the clinic, subsequent dosing may be administered outside the study 
site (eg, the patient’s home) at all timepoints where allowed by applicable country and local regulations. In these cases, dosing 
should be administered by a trained healthcare professional, with oversight by the Investigator. If the patient is unable to 
come to the study site, and a visit by a home healthcare professional is not possible due to circumstances related to the 
COVID-19 pandemic, study drug may be administered by the patient or the caregiver under the oversight of the Investigator, 
and following consultation with the medical monitor, as allowed by applicable country and local regulations.  In such cases, 
the patient or caregiver must receive appropriate training on study drug administration. This measure (self- or caregiver 
administration) is intended to remain in effect only during periods of time when the COVID-19 pandemic impedes the ability 
of patients to travel to the study site or healthcare professionals to go to patients' homes for dosing. 
The SC injection site may be marked and mapped for later observation.  The preferred site of injection is the abdomen.  Optional 
additional sites are the upper arms and thighs.  If a local reaction around the injection site occurs, photographs may be obtained.   

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Additional details, including detailed instructions for study drug administration, can be found in the Pharmacy Manual. In addition, 
instructions and procedures related to administration of study drug by a patient or caregiver will be provided in the 
Patient/Caregiver Storage and Administration Instructions. 
Missed doses of Study Drug 
If a patient does not receive a dose of study within the specified dosing windows, the Investigator should contact the Medical Monitor.  
After such consultation, the dose may be administered as close to the scheduled dosing date as possible with a maximum 6 week 8-
week delay (to be considered a delayed dose).  Thereafter, the dose will be considered missed and not administered.  If a dose is 
missed or is administered with a delay, the next dose will resume following the original schedule. In cases in which a dose is delayed 
in this manner for issues related to the COVID-19 pandemic, the Medical Monitor should be informed as soon as possible, but 
prior consultation is not required.  In all cases, the dose should be administered as close as possible to the scheduled timepoint. 
Every effort should be made to avoid missed doses of study drug.  If a patient misses a dose, for reasons unrelated to the COVID-19 
pandemic, the Investigator, in consultation with the Medical Monitor, will discuss whether the patient will be able to continue dosing 
in the study (see also Section 4.3). 
Sections also reflecting this change:   
• Synopsis 
• Table 1, Schedule of Assessments 
• Section 3.1 Summary of Study Design 
• Section 5.2.5, Dose Preparation, Handling, and Storage 
• Section 5.3.2, Reporting 
Purpose:  The requirement that the Investigator notify the Sponsor before screening patients was added to allow an assessment of the 
ability of the study center or any new trial participant to comply with the protocol given the COVID-19 limitations. 
The primary changes occur in Section 6.1 (Screening Assessments) 
Added text: The investigator will notify the Sponsor before screening patients to allow an assessment of the ability of the site or 
any new trial participant to comply with the protocol given COVID-19 pandemic limitations. 

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Purpose:  The following changes have been made relating to expanding the ability to perform assessments outside of the study center: 
x Clarified and expanded on language already in the protocol related to performing routine assessments outside of the clinic 
(eg, at home) at all timepoints.  These assessments include the following: vital signs, physical exam, weight, ECGs, 
pregnancy tests, urine collection, blood draws (clinical laboratory assessments, ADA, PK; ATTR/vitamin A; exploratory 
samples), collection of information regarding vital status, hospitalizations, urgent care visits, procedures, and concomitant 
medications.   
x Confirmed that the intention during normal operations is that all laboratory samples are sent to a central laboratory. 
Added an exception that in situations related to the COVID-19 pandemic when central laboratory assessments are not 
possible, a local laboratory may be used.  These local lab results must be sent to the site for review by the Investigator and 
entry into the clinical database. 
x Added guidance that with the exception of patients unable to come to the site due to the COVID-19 pandemic limiting the 
patient’s ability or willingness to access the study site, at a minimum, patients should visit the site for the scheduled dosing 
and assessments for the Week 12 (Month 3) visit within the study visit window and for efficacy assessmentsas detailed 
below. 
x If any study assessments are not able to be completed at the site or at home within the study visit window, the study 
physician (or delegate) must verbally contact the patient to collect relevant safety information (including, but not limited 
to, AEs, concomitant medications, hospitalizations/procedures, and vital status). 
x 
. 
x Added option for pregnancy testing by the patient or caregiver in situations a study visit is unable to be completed at the 
site due to the COVID-19 pandemic 
The primary changes occur in Section 6 (Study Assessments), 
), and Section 6.5.6.2 (Pregnancy 
Testing) 
6. STUDY ASSESSMENTS 
During the study, where applicable country and local regulations and infrastructure allow, assessments that may be conducted by a 
qualified home healthcare professional include but are not limited to: blood draws, vital signs, physical exam, collection of 
information regarding hospitalizations, procedures and concomitant medications.  Wherever possible, AE collection associated with 
visits outside of the clinic will be collected by a phone call from qualified site staff. Further details with regard to visits performed 
outside of the clinic are provided in the Study Manual. 
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Added text: 
In situations where a study visit is unable to be completed at the site due to the COVID-19 pandemic impacting activities at the 
study center or patient ability or willingness to access the study center, pregnancy testing may be performed by a healthcare 
professional or the patient/caregiver (and confirmed by the site) where applicable country and local regulations and 
infrastructure allow. 
Sections also reflecting this change:   
• Synopsis 
• Table 1, Schedule of Assessments 
• Section 3.1 Summary of Study Design 
• Section 4.3.3. Lost to Follow-Up 
• Section 6.2. Efficacy Assessments 
• Section 6.5. Safety Assessments 
• Section 6.5.5. Clinical Laboratory Assessments 
Purpose:  The Week 18 visit, including all associated assessments, has been removed.  
• Elimination of the Week 18 Visit 
The primary changes occur in Table 1 (Schedule of Asessments) 
Description of change: The Week 18 visit, including all associated assessments, has been deleted. 
Purpose: The following changes were made related to performance of liver function tests: 
• Removed the requirement for a pre-dose LFT assessment within 14 days of each dose.  
• Dosing decisions may be made based on LFT results collected at the previous dosing visit  (up to 14 weeks prior to 
dosing); in all cases the most recently available LFTs should be used. 
The primary changes occur in Table 1 and Section 5.2.4 (LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing) 
Table 1 (Schedule of Assessments) – footnotes: 

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• LFTs before the first dose of study drug (Day 1): Day 1 predose LFT does not need to be performed if there are available 
LFT results within 14 days of first dose.  
• LFTs after the first dose of study drug (Day 1): LFTs must be obtained with results available within 14 days before each 
clinic visit on which vutrisiran dosing is scheduled. LFTs can be analyzed locally, but if a local assessment is drawn, a 
sample must also be drawn for analysis at the central laboratory. 
• Dosing decisions may be made based on LFT results (Table 4) collected at the previous dosing visit (up to 14 weeks 
prior to dosing); in all cases the most recently available LFTs should be used.  
5.2.4. LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing 
Revised text (relevant text only) 
1. LFT results (Table 4) are to be obtained within 14 days prior to study drug dosing and results are to be reviewed prior to each dose 
of study drug.  Dosing decisions may be made based on LFT results (Table 4) collected at the previous dosing visit (up to 14 
weeks prior to dosing); in all cases the most recently available LFTs should be used.  Central laboratory results are preferable.  
If not available, local laboratory results may be used; however, if a local assessment is drawn, a serum chemistry sample must also 
be drawn for analysis at the central laboratory. All laboratory samples should be sent to the central laboratory; an exception is 
for situations related to the COVID-19 pandemic if central laboratory collection is not possible, then a local laboratory 
may be used.  These local laboratory results must be sent to the site for review by the Investigator and entry into the 
clinical database. 
2. For any ALT or AST elevation >3× ULN, central laboratory results should be used to guide subsequent monitoring as detailed in 
Table 3.  
3. For any ALT or AST elevation >3× ULN:  
a. Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but no later than 7 days. If a central 
laboratory result is not possible due to COVID-19, a local laboratory may be used for monitoring in consultation with the 
Medical Monitor; all local laboratory results must be sent to the clinical site for entry into the clinical database. 
b. Perform assessments per Table 4 and Table 5. 
c. If an alternative cause is found, provide appropriate care. 
Sections also reflecting this change:   
• Section 6.5.5, Clinical Laboratory Assessments 

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Purpose: Addition of Infrared to the List of Acceptable Body Temperature Collection Methods. 
The primary change occurs in Section 6.5.1 (Vital Signs) 
Revised text:  
Body temperature in degrees Celsius will be obtained via oral or, tympanic, or infrared methods.   
Purpose:  Made the following changes related to performance of efficacy assessments and delays due to COVID-19: 
• Clarified that all efficacy assessments associated with the following visits should be conducted at the study center:  Month 
6, Month 12, Month 18, Month 24, and Month 30.  
• Specified that in situations where an efficacy assessment study visit is unable to be completed at the site due to the 
COVID-19 pandemic limiting the patient’s ability or willingness to access the study center or their ability to have received 
their scheduled doses of study drug, efficacy assessments may be completed up to 3 months after the time point (ie, up to 
Study Month 9, Month 15, Month 21, Month 27, or Month 33, respectively). 
The primary change occurs in Section 6 (Study Assessments) 
Added text: 
All efficacy assessments associated with the following visits should be conducted at the study center:  Month 6, Month 12, 
Month 18, Month 24, and Month 30. In situations where an efficacy assessment study visit is unable to be completed at the site 
due to the COVID-19 pandemic limiting the patient’s ability or willingness to access the study center or their ability to have 
received their scheduled doses of study drug, efficacy assessments may be completed up to 3 months after the time point (ie, up 
to Study Month 9, Month 15, Month 21, Month 27, or Month 33, respectively). 
Sections also reflecting this change:   
• Synopsis 
• Table 1 Schedule of Assessments 
• Section 3.1 Summary of Study Design 

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Purpose:  Added collection of information related to the impact of the COVID 19 pandemic on patient participation in the study for 
each patient.  
The primary change occurs in newly added Section 6.5.7 (COVID-19 Data Collection) 
Added text:   
Information on the COVID-19 infection status of the patient, if known, and other information on the impact of the COVID-19 
pandemic on the patient's participation in the study will be collected. 
Sections also reflecting this change:   
• Section 7.2 Statistical Methodology 
Purpose:  Updated study administration text.   
The primary change occurs in Section 8.1.1, Informed Consent and Medical Records Release Form and Section 8.1.2, Ethical Review 
8.1.1. Informed Consent and Medical Records Release Form (relevant changed text only) 
Added text:   
The Investigator will inform the patient/legal guardian if new information becomes available that may be relevant to the 
patient’s/legal guardian’s willingness to continue participation in the study.  Communication of this information should be 
documented. 
8.1.2. Ethical Review (relevant changed text only) 
Added text:   
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol in accordance with local requirements.  
In addition, the IRB or IEC must approve all patient materials for the study (except those that support the need to remove an 
apparent immediate hazard to the patient).    

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Sections also reflecting this change:   
• Synopsis 
• Section 1.5 (Study Design Rationale) 
• Section 3.8 (Clinical Events Committee (CEC)) 
• Section 7.1 (Determination of Sample Size) 
• Section 7.2.5.1 (Primary Endpoint) 
• Section 7.2.5.2 (Secondary Endpoints) 
Purpose: Deaths  and hospitalizations due to COVID-19 will be excluded from all-cause deaths and hospitalizations, respectively, in 
the primary analyses of primary and applicable secondary endpoints 
The primary change occurs in Section 7.2.5 (Efficacy Analyses): 
Added text: Deaths and hospitalizations due to COVID-19 will be excluded from all-cause deaths and hospitalizations, respectively, in 
the primary analyses of primary and applicable secondary endpoints. 
Sections also reflecting this change:   
• Synopsis 
Purpose: Added allowance for diagnostic testing in countries where necessary screening tests are not standard of care.   
The primary change occurs in Section 6.1 (Screening Assessments): 
Added text:  
The diagnostic tests required to confirm eligibility per inclusion criterion 2 are intended to be historical, as part of the 
patient’s clinical care and diagnosis, and will not be performed as part of the study except as described below.    
If a diagnostic result that confirms ATTR Amyloidosis is not available at Screening for the assessment of eligibility (Section 
4.1, inclusion criterion 2a/b), testing may be conducted at a laboratory or diagnostic center selected by the site, in consultation 
with the Medical Monitor, in countries in which this test is not standard of care.  For TTR mutation testing, a blood sample 
may be drawn at Screening and sent for genotype testing at the central lab, in countries in which genotyping is not available at 
a local laboratory.  

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Purpose: Added a statement that subgroup analyses will be conducted for at least the following variables: age group, gender, race, 
geographic region, and NYHA class. 
The primary change occurs in Section 7.2.2: 
Revised text: 
Subgroup analyses may will be conducted for the primary and selected secondary efficacy endpoints.  List of subgroup variables and 
endpoints for which subgroup analysis will be performed, as well as methodology for interaction test (if needed), will be provided in 
the SAP. Subgroup analyses will be conducted for at least the following variables: age group, gender, race, geographic region, 
and NYHA class. Additional variables may be included and the details will be provided in the SAP. 
Purpose: Inclusion Criterion 2b, iv, Clarified that documentation of TTR protein in cardiac tissue with immunohistochemistry or mass 
spectrometry is required. Clarification provided to maintain consistency with Inclusion Criterion 2b, iii. 
The primary change occurs in Section 4.1, Inclusion Criteria 
Revised text: 
2b, iv. If the patient has evidence of a MGUS based on serum and urine protein electrophoresis and serum free light chains, 
documentation of TTR protein in cardiac tissue with immunohistochemistry or mass spectrometry is required. 
Purpose: Inclusion Criterion 4b, Clarified that tafamidis treatment at study entry must be on-label use of commercial tafamidis per an 
approved cardiomyopathy indication and dose in the country of use. Changes made throughout the protocol to maintain a consistent 
statement. 
The primary changes occurs in Section 4.1 (Inclusion Criteria) and Section 5.4.1 (Concomitant Tafamadis Use): 
Revised text: 
Section 4.1 (Inclusion Criteria) 
Revised text: 
4b, On tafamidis (Note: must be on-label use of commercial tafamidis per the an approved cardiomyopathy indication and dose in 
the country of use) 
5.4.1. Concomitant Tafamidis Use 
Revised text: 

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Revised text: 
9. Is currently taking diflunisal; if previously on this agent, must have at least a 3 month 30-day wash-out prior to dosing (Day 1). 
Purpose: Exclusion Criteria 10 and 11, Added ursodeoxycholic acid to the list of TTR lowering agents to be avoided during the study. 
The primary change occurs in Section 4.2, Exclusion Criteria 
Revised text: 
10. Is currently taking doxycycline, ursodeoxycholic acid, or tauroursodeoxycholic acid; if previously on any of these agents, must 
have completed a 30-day wash-out prior to dosing (Day 1).  
11. Unwilling to avoid any concurrent treatment with diflunisal, ursodeoxycholic acid/tauroursodeoxycholate/doxycycline, or TTR 
lowering agents (eg, patisiran, inotersen) 
Sections also reflecting this change:   
• Section 5.4 (Concomitant Medications) 
Purpose: Exclusion Criterion 23, Exclusion criteria widened to include a history of allergic reaction to any component of or excipient 
in the study drug 
The primary change occurs in Section 4.2, Exclusion Criteria 
23. History of multiple drug allergies; or history of allergic reaction to any component of or excipient in the study drug an 
oligonucleotide or GalNAc. 
Purpose: Added a clarification that doxycycline use is permitted if taken for short-term treatment of infection; use of doxycycline is 
otherwise excluded. 
The primary change occurs in Section 5.4 (Concomitant Medications) 
Revised text (also includes revisions described above relate to ursodeoxycholic acid) 
Use of the following medications/treatments are prohibited during study participation (Section 4.2): 
• any investigational agent other than study drug 
• diflunisal   
• ursodeoxycholic acid/tauroursodeoxycholate/doxycycline (Doxycycline is permitted  if being taken for short-term 
treatment of infection Also see exclusion criterion 10). 

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• TTR lowering agents (eg., patisiran, inotersen) 
• calcium channel blockers (eg, verapamil, diltiazem) or digitalis; given they are widely recognized to be contraindicated in 
this patient population 

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References 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic, 
(20/03/2020; updated 27/03/2020; updated 28/04/2020). 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf  
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: 
Guidance for Industry, Investigators, and Institutional Review Boards (03/2020; updated 
16/04/2020). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-
guidance-conduct-clinical-trials-medical-products-during-covid-19-pandemic 
Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, et al. 2017 
Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. Circulation. 
2018;137(9):961-72. 
World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report - 100.2020 
29 April 2020.  
Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, Epidemiology, Pathogenesis, 
and Control of COVID-19. Viruses. 2020 Mar 27;12(4).