HELIOS-A: A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy and Safety of ALN-TTRSC02 in Patients With Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis)
Phase: PHASE3
Conditions: Amyloidosis, Hereditary, Transthyretin Amyloidosis
Sponsor: Alnylam Pharmaceuticals

 
 
Official Title:  
HELIOS-A: A Phase 3 Global, Randomized, Open-label Study to Evaluate the 
Efficacy and Safety of ALN-TTRSC02 in Patients with Hereditary 
Transthyretin Amyloidosis (hATTR Amyloidosis) 
 
NCT Number:   
NCT03759379 
 
Document Date:   
Clinical Study Protocol, 19 February 2021 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
1 
 
CLINICAL STUDY PROTOCOL 
ALN-TTRSC02-002 
 
Protocol Title: 
HELIOS-A:  A Phase 3 Global, Randomized, 
Open-label Study to Evaluate the Efficacy and 
Safety of ALN-TTRSC02 in Patients with 
Hereditary Transthyretin Amyloidosis (hATTR 
Amyloidosis)  
Short Title: 
HELIOS-A:  A Phase 3 Study to Evaluate the 
Efficacy and Safety of ALN-TTRSC02 in Patients 
with hATTR Amyloidosis 
Study Drug: 
ALN-TTRSC02  
EudraCT Number: 
2018-002098-23  
IND Number: 
139086   
Protocol Date: 
Original protocol:  11 October 2018  
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone:  
 
Sponsor Contact:   
 
 
 
 
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. 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
I have read the ALN-TTRSC02-002 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-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
4 
PROTOCOL SYNOPSIS 
 
Protocol Title 
HELIOS-A:  A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy and Safety of 
ALN-TTRSC02 in Patients with Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis) 
Short Title 
HELIOS-A:  A Phase 3 Study to Evaluate the Efficacy and Safety of ALN-TTRSC02 in Patients with 
hATTR Amyloidosis 
Study Drug 
ALN-TTRSC02 
Phase 
3 
Study Centers 
The study will be conducted at up to 80 clinical study centers worldwide. 
Objectives and Endpoints 
The co-primary, and most secondary and exploratory efficacy endpoints are in comparison to the placebo 
arm of the Phase 3 pivotal patisiran-LNP study (ALN-TTR02-004, also referred to as the APOLLO 
study) as specified in the statistical analysis section of the HELIOS-A protocol.  The primary analysis will 
be conducted at Month 9.  An additional analysis of all efficacy endpoints will be conducted at Month 18. 
Objectives 
Endpoints 
Primary  
 
To determine the efficacy of ALN-
TTRSC02 in patients with hATTR 
amyloidosis by evaluating the effect on 
neurologic impairment and on quality of 
life  
Co-Primary: 
 
Change from baseline in the Modified 
Neurologic Impairment Score +7 
(mNIS+7) compared to the placebo arm 
of the APOLLO study 
 
Change from baseline in Norfolk Quality 
of Life Diabetic Neuropathy (Norfolk 
QoL-DN) total score compared to the 
placebo arm of the APOLLO study 
Secondary  
 
To determine the efficacy of ALN-
TTRSC02 on gait speed, nutritional status, 
and disability 
 
To characterize the effect of ALN-
TTRSC02 on serum TTR levels 
 
To evaluate patient mortality and 
hospitalization 
 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study: 
 
Timed 10-meter walk test (10-MWT) 
 
Modified body mass index (mBMI) 
 
Rasch-built Overall Disability Scale 
(R-ODS) 
 
Percent reduction in serum TTR levels in 
the ALN-TTRSC02 arm compared to the 
within-study patisiran-LNP arm  

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
5 
Objectives 
Endpoints 
 
Composite events of all-cause deaths 
and/or all-cause hospitalizations in the 
overall population (over 18 months) 
compared to the placebo arm of the 
APOLLO study 
 
Composite events of all-cause deaths 
and/or all-cause hospitalizations in 
patients with cardiac involvement (over 
18 months) compared to patients with 
cardiac involvement in the placebo arm of 
the APOLLO study 
Exploratory  
 
To determine the effect of ALN-
TTRSC02 on: 
 
Manifestations of cardiac amyloid 
involvement 
 
Other assessment of neurologic 
impairment  
 
Other assessments of quality of life 
 
Disease stage 
 
Performance of daily activities 
 
To characterize the pharmacodynamic (PD) 
effect of ALN-TTRSC02 and patisiran-LNP 
on vitamin A levels  
 
To characterize plasma pharmacokinetics 
(PK) of ALN-TTRSC02 and patisiran-LNP 
 
To assess presence of antidrug antibodies 
(ADA) to ALN-TTRSC02 and patisiran-LNP 
 
Change from baseline in the following 
parameters compared to the placebo arm of 
the APOLLO study: 
 
N-terminal prohormone of B-type 
natriuretic peptide (NT-proBNP) 
levels, echocardiographic parameters, 
Troponin I and T levels, New York 
Heart Association (NYHA) class 
 
Neurologic Impairment Score (NIS) 
 
EuroQoL-5 Dimensions-5 Levels 
(EQ-5D-5L) questionnaire and the 
EuroQoL-Visual Analog Scale (EQ-
VAS)  
 
Familial Amyloidotic 
Polyneuropathy (FAP) stage and 
Polyneuropathy Disability (PND) 
score 
 
Karnofsky Performance Status (KPS) 
 Change from baseline in technetium 
scintigraphy cardiac parameters  
 
Percent reduction in serum vitamin A levels  
 
PK profile of ALN-TTRSC02 and patisiran-
LNP 
 Incidence and titers of ADA to ALN-
TTRSC02 and patisiran-LNP 
Safety 
 
To determine the safety and tolerability of 
ALN-TTRSC02 in patients with hATTR 
amyloidosis 
 
Frequency of adverse events (AE) 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
6 
Study Design 
This is a global, Phase 3 randomized, open-label study designed to evaluate efficacy, safety, and PK/PD 
of ALN-TTRSC02 in adult patients with hATTR amyloidosis.  Patients will be randomized 3:1 to 
ALN-TTRSC02 or patisiran-LNP, a reference comparator. Randomization will be stratified by TTR 
genotype (V30M vs. non-V30M) and baseline NIS score (<50 vs ≥50). 
The study will consist of a Screening Period of up to 42 days, an 18-month Treatment Period, an 
18-month Treatment Extension Period which will include collection of safety and efficacy in patients who 
switch from patisiran-LNP to ALN-TTRSC02 treatment, and up to a 1-year Follow-up Period after the 
last dose of study drug as shown in Figure 1.   
After the Screening period, and at the start of the Treatment Period, eligible patients will be randomized 
3:1 on Day 1 to receive 25 mg of ALN-TTRSC02 administered as a subcutaneous (SC) injection once 
every 3 months (q3M) or patisiran-LNP administered as an intravenous (IV) infusion once every 3 weeks 
(q3w).  During the 18-month Treatment Period, patients will undergo assessments for efficacy and/or 
safety (as outlined in the Schedule of Assessments), with key efficacy assessments being performed prior 
to first dose, at Month 9 (primary efficacy analysis time-point) and at Month 18; samples for TTR 
assessment will be collected more frequently throughout the 18-month Treatment Period.  
During the Treatment Extension Period, starting at Week 84/Month 19, all patients on the patisiran-LNP 
arm will switch to treatment with ALN-TTRSC02 (first dose) and remain on ALN-TTRSC02 q3M 
treatment for the remainder of the study.  During the Treatment Extension Period, patients will undergo 
safety assessments quarterly and efficacy assessments every 9 months at Month 27 and at Month 36.  
During the Follow-up Period, all patients on ALN-TTRSC02 will undergo safety assessments quarterly 
until serum TTR levels return to ≥80% of baseline (for up to 1 year after the last dose of study drug), or 
until the patient starts a TTR lowering regimen as a part of clinical care, whichever comes first; all 
patients will be followed for a minimum of 3 months.  Female patients of child-bearing potential will be 
followed until serum TTR levels return to ≥80% of baseline.  Patients who discontinue treatment early 
while on patisiran-LNP will undergo a follow-up visit 30 days after the last dose of study drug.  
The placebo arm of the APOLLO study will be used as an external control for the primary, most 
secondary, and most exploratory efficacy analyses.  Primary and secondary efficacy evaluations will 
include mNIS+7, Norfolk QoL-DN questionnaire, 10-MWT, mBMI, R-ODS questionnaire, percent TTR 
reduction, and the composite of all cause deaths and/or all cause hospitalizations. Study personnel 
performing the mNIS+7 component assessments will not reference the results of any previous 
assessments.   
Number of Planned Patients 
Approximately 160 patients are planned for enrollment in this study.   
To match the cardiac disease severity with the APOLLO study population, the study plans to enroll no 
more than 15% of patients with NT-proBNP values greater than 3000 ng/L at baseline.   

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
7 
Diagnosis and Main Eligibility Criteria 
This study will include adults age 18 (or age of legal consent, whichever is older) to 85 years of age, with 
a documented TTR mutation, and a confirmed diagnosis of symptomatic hATTR amyloidosis with an 
NIS of 5 to 130 (inclusive), a PND score of ≤3b, and KPS ≥60%. 
Study Drug, Dose, and Mode of Administration 
ALN-TTRSC02 drug product is a subcutaneously (SC) administered N-acetyl galactosamine ligand 
(GalNAc)-conjugated small interfering RNA (siRNA) targeting liver-expressed transthyretin (TTR) 
messenger RNA (mRNA).  
ALN-TTRSC02 will be administered as a 25 mg SC injection q3M (12 weeks). 
Reference Treatment, Dose, and Mode of Administration 
Patisiran-LNP drug product is an intravenously (IV) administered siRNA targeting liver-expressed TTR 
mRNA formulated with lipid excipients (DLin-MC3-DMA, DSPC, cholesterol, and PEG2000-C-DMG) in 
isotonic phosphate buffered saline. 
Patisiran-LNP will be administered as a 0.3 mg/kg IV infusion once every 3 weeks (q3w) ± 3 days.  All 
patients will receive premedication prior to patisiran-LNP infusions as described further in the protocol.   
Duration of Treatment and Study 
The estimated time on study for each patient is approximately 3 years, inclusive of 42 days of Screening, 
and up to 36 months of open-label treatment (including the 18-month Treatment Period plus an 18-month 
Treatment Extension Period). 
During the Follow-up Period, all patients on ALN-TTRSC02 will undergo safety assessments quarterly 
until serum TTR levels return to ≥80% of baseline (for up to 1 year after the last dose of study drug), or 
until the patient starts a TTR lowering regimen as a part of clinical care, whichever comes first; all 
patients will be followed for a minimum of 3 months.  Female patients of child-bearing potential who 
discontinue ALN-TTRSC02 will be followed until serum TTR levels return to ≥80% of baseline. 
Statistical Methods 
A full statistical analysis plan (SAP) will be finalized prior to first patient dosed. 
The co-primary endpoints are changes from baseline at Month 9 for mNIS+7 and Norfolk QoL-DN total 
scores. The co-primary endpoints will each be tested at a significance level of 0.05 and both must be 
significant to declare a positive trial. The primary comparison will be conducted at Month 9 and 
additional analyses will be performed at Month 18. 
For the co-primary endpoint mNIS+7, change in mNIS+7 from baseline at Month 9 will be compared 
between the ALN-TTRSC02 group in this study and the placebo group in the APOLLO study. The 
treatment effect will be estimated based on the least-square (LS) means using an analysis of covariance 
(ANCOVA) model with baseline mNIS+7 score as a covariate and factors including treatment group 
(ALN-TTRSC02 vs placebo), genotype (V30M vs non-V30M), and age of disease onset (<50 vs ≥50 
years old). 
The other co-primary endpoint Norfolk QoL-DN, change in Norfolk QoL-DN total score from baseline at 
Month 9 will be compared between the ALN-TTRSC02 group in this study and the placebo group in the 
APOLLO study. The treatment effect will be estimated based on the least-square (LS) means using an 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
8 
analysis of covariance (ANCOVA) model with baseline score as a covariate and factors including 
treatment group (ALN-TTRSC02 vs placebo), genotype (V30M vs non-V30M), age of disease onset (<50 
vs ≥50 years old), and baseline NIS score (<50 vs ≥50).  
The co-primary endpoints for the patisiran-LNP group in this study will be summarized descriptively. 
Secondary clinical efficacy endpoints will be analyzed similarly. Overall type I error control for 
secondary endpoints will be achieved by a hierarchical testing procedure.    
The TTR percent reduction through Month 9 will be derived as the average trough TTR percent reduction 
from Month 6 to 9 which is the steady state period for both ALN-TTRSC02 and patisiran-LNP. A 
Hodges-Lehmann method stratified by previous TTR stabilizer use (yes vs no) will be used to estimate 
the 95% confidence interval (CI) for the median difference between the ALN-TTRSC02 and patisiran-
LNP groups in this study. Non-inferiority will be declared if the lower limit of the 95% CI for the 
treatment difference is greater than –10%. A sensitivity analysis will be conducted to compare the TTR 
percent reduction between the ALN-TTRSC02 group from this study and the pooled patisiran-LNP 
groups from this Phase 3 study and the APOLLO study.   
The composite endpoint of all-cause hospitalization and death events over 18 months will be analyzed 
using recurrent event method Andersen-Gill model with treatment group (ALN-TTRSC02 vs placebo) as 
an independent variable.  The endpoint will be analyzed for both the overall population and in patients 
with cardiac involvement. 
The analysis of exploratory efficacy endpoint will be described in the SAP. 
Safety data will be summarized descriptively. 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
 
 
 
 
 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
9 
Figure 1: 
Study Design 
 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
10 
Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Screening 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
 
V1 
V2 
V3 Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day   
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week  
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window  
 
 
 
 
0 
±3D ±3D ±3D 
±3D 
±3D ±3D ±3D 
±3D 
±3D ±3D ±3D ±3D 
NA 
Informed Consent  
Section 6.1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
Section 4.1; 
Section 4.2  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical/Disease 
History 
Section 6.1.3  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs; Physical 
Exam (PE); Weight 
Section 6.5.1; 
Symptom-directed PE 
unless specified as 
Full see Section 6.5.3  
Section 6.5.2 
X 
PE Full 
Vital 
signs 
only 
X 
X - 
No 
PE 
Vital 
signs 
only 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X - 
PE 
Full 
X- No 
PE 
Height 
Section 6.5.2. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mBMI, NYHA 
Class, KPS  
Section 6.2.5 
Section 6.2.10.4 
Section 6.2.11  
X 
 
 
 
 
 
 
 
mBMI 
only 
 
 
 
mBMI 
only 
 
 
 
 
X 
PND Score 
Section 6.2.9 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FAP Stage 
Section 6.2.9 
 
X – Single 
assessment at 
any of these 
visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry, 
Hematology, 
Urinalysis, 
Coagulation 
Section 6.5.6 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 LFT 
See below Table 1 
notes. Results from 
both V1 and V2 must 
meet eligibility 
criteria. Section 6.5.6; 
Section 6.5.6.3  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
11 
Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Screening 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
 
V1 
V2 
V3 Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day   
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week  
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window  
 
 
 
 
0 
±3D ±3D ±3D 
±3D 
±3D ±3D ±3D 
±3D 
±3D ±3D ±3D ±3D 
NA 
FSH (only to 
confirm 
postmenopausal 
status if applicable) 
Section 6.5.6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
At V1 serum 
pregnancy test; after 
V1, either urine or 
serum pregnancy test. 
Section 6.5.6.2 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Cardiac Biomarker 
Samples  
Section 6.2.10.2 
NT-
proBNP 
only 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
TTR Protein; 
Vitamin A 
Section 6.3  
 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
ADA 
On dosing days, 
collect ADA within 1 
hour before dosing, 
Section 6.5.6.1 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
ALN-TTRSC02 
Arm PK Sampling 
See Table 4 for detail 
timepoints 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Patisiran-LNP Arm 
PK Sampling 
See Table 5 for detail 
timepoints 
 
 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Sample for 
Exploratory Analysis Section 6.6 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Norfolk QoL-DN,  
R-ODS 
Section 6.2.3; 
Section 6.2.6; 
 
X– single 
at any of 
these 
visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
12 
Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Screening 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
 
V1 
V2 
V3 Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day   
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week  
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window  
 
 
 
 
0 
±3D ±3D ±3D 
±3D 
±3D ±3D ±3D 
±3D 
±3D ±3D ±3D ±3D 
NA 
EQ-5D-5L and EQ-
VAS;  
C-SSRS; Patient and 
Caregiver Impact 
and Patient 
Experience Surveys 
Section 6.2.8; 
Section 6.5.5; 
Section 6.7.1 
Section 6.7.3   
 
 
X– single 
at any of 
these 
visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NIS, mNIS+7, 
HRdb,  
See below Table 1 
Notes; and 
Section 6.2.1, 
Section 6.2.2  
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
10-MWT 
See below Table 1 
Notes; and 
Section 6.2.4 
 
X – Two 
assessments 
performed at 
any of these 
visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Single (unless 
indicated)  
12-Lead ECG 
Section 6.5.4 
 
X-Triplicate 
performed at 
any of these 
visits 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Echocardiogram 
Section 6.2.10.1 
 
X - Single 
performed at 
any of these 
visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Technetium 
scintigraphy imaging 
(select sites only) 
Section 6.2.10.3  
 
X - Single 
performed at 
any of these 
visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
Window:  -5D prior to 
Day 1 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALN-TTRSC02 
Study Drug Admin. 
Section 5.2.2.1  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
13 
Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Screening 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
 
V1 
V2 
V3 Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day   
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week  
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window  
 
 
 
 
0 
±3D ±3D ±3D 
±3D 
±3D ±3D ±3D 
±3D 
±3D ±3D ±3D ±3D 
NA 
Patisiran-LNP Arm: 
Premedication 
Admin. 
Section 5.2.2.2  
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patisiran-LNP Study 
Drug Admin. 
Section 5.2.2.2 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review/Record 
Hospitalization, 
Urgent care visits; 
Procedures 
Section 6.7.2  
 
X - Collected 
through Day 1 
predose 
Continuous Monitoring 
Review/Record AEs, 
Con. Med,  
Section 6.5.7; 
Section 5.3; 
 
 
Continuous Monitoring 
Abbreviations: AE=adverse event; ADA=antidrug antibodies; Admin.=administration; Con. Med.=concomitant medications; C-SSRS=Columbia-Suicide Severity Rating Scale; 
D=day; ECG=electrocardiogram; EQ-5D-5L= EuroQuality of Life 5-Dimensions 5-Levels; EQ-VAS=EuroQuality of Life-Visual Analog Scale; FAP=Familial Amyloidotic 
Polyneuropathy; FSH=follicle-stimulating hormone; HRdb=heart rate variability with deep breathing; KPS= Karnofsky Performance Status; LFT=liver function test; 
mBMI=modified body mass index; 10-MWT=10-meter walk test; mNIS+7=modified NIS+7; NIS=Neurologic Impairment Score; NT-proBNP= B-type natriuretic peptide; 
NYHA=New York Heart Association; PE=physical exam; PK=pharmacokinetics; PND=Polyneuropathy Disability; QoL-DN= Quality of Life-Diabetic Neuropathy; R-
ODS=Rasch-built Overall Disability Scale; TTR=transthyretin; V=visits 
Table 1 Notes: 
 
The Screening and Baseline visits (V1, V2 and V3) will be performed on separate days and can each occur over multiple days.  V2 (first Baseline NIS, mNIS+7, HRdb 
assessment) must be performed within 21 days prior to the first dose of study drug (Day 1).  V3 (second Baseline NIS, mNIS+7, HRdb assessment) must be conducted 
within approximately 24 hours after Visit 2 but not more than 7 days after.  See Section 6.1 for retesting and re-screening instructions. 
 
Pre-randomization 10-MWT:  Two independent assessments will be performed on separate days (1 assessment on each day); the 2 assessments should be performed 
approximately 24 hours apart from each other but not more than 7 days apart.  
 
LFT for screening:  Day 1 predose LFT does not need to be performed if there are available LFT results within 28 days of first dose.   
 
LFT for after randomization: For the ALN-TTRSC02 cohort, LFTs must be obtained with results available within 28 days before the clinic visit on which ALN-
TTRSC02 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.  
For the patisiran-LNP cohort, LFTs should be performed according to patisiran-LNP visit windows and do not need to be available prior to dosing. 
 
Unless otherwise specified, assessments on dosing days are predose. 
 
For the Month 9, NIS, mNIS+7, HRdb and 10-MWT: Two independent assessments will be performed on separate days (1 assessment on each day); the 2 assessments 
should be performed approximately 24 hours apart from each other but not more than 7 days apart.  Components that are shared between the mNIS+7 and NIS will be 
performed once at each assessment (eg, the weakness component should not be performed more than once on any given day). 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
14 
Table 2: 
Schedule of Assessments – Treatment Period from Month 9 through Month 18 
 
Note 
Treatment Period 
Month 
18 
Efficacy 
Study Day  
 
D274 
D295 
D316 
D337 
D358 
D379 
 
D400 
D421 
D442 
D463 
D484 
D505 
D526 
D547 
D554-D561 
Study Week  
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
±Visit Window  
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
 
Vital signs; 
Physical Exam 
(PE);  
Section 6.5.1; 
Symptom-
directed PE 
Section 6.5.3;  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X - 
weight 
and vitals 
only 
ALN-TTRSC02 
Arm: Weight 
Section 6.5.2 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Patisiran-LNP 
Arm: Weight 
Section 6.5.2. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NYHA class; 
KPS; PND and 
FAP; mBMI  
Section 6.2.10.4; 
Section 6.2.11; 
Section 6.2.9; 
Section 6.2.5 
 
 
 
mBMI 
only 
 
 
 
mBMI 
only 
 
 
 
mBMI 
only 
 
 
X 
Serum Chemistry, 
Hematology, 
Urinalysis, 
Coagulation 
Section 6.5.6 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X-Serum 
chemistry 
only 
LFT 
Section 6.5.6 
Section 6.5.6.3 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Pregnancy Test 
Section 6.5.6.2 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Cardiac 
Biomarker 
Samples 
Section 6.2.10.2 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
TTR Protein 
Vitamin A 
Section 6.3  
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
ADA 
On dosing days, 
collect ADA 
within 1 hour 
before dosing, 
Section 6.5.6.1  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
15 
Table 2: 
Schedule of Assessments – Treatment Period from Month 9 through Month 18 
 
Note 
Treatment Period 
Month 
18 
Efficacy 
Study Day  
 
D274 
D295 
D316 
D337 
D358 
D379 
 
D400 
D421 
D442 
D463 
D484 
D505 
D526 
D547 
D554-D561 
Study Week  
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
±Visit Window  
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
 
ALN-TTRSC02 
Arm PK  
See Table 4 for 
detail timepoints 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Patisiran-LNP 
Arm PK 
See Table 4 for 
detail timepoints 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Samples for 
Exploratory 
Analysis 
Plasma, serum, 
urine; 
Section 6.6 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Norfolk QoL-DN; 
R-ODS; EQ-5D-
5L and EQ-VAS; 
C-SSRS; Patient 
and Caregiver 
Impact and 
Patient 
Experience 
Surveys  
Section 6.2.3; 
Section 6.2.6; 
Section 6.2.8; 
Section 6.5.5; 
Section 6.7.1 
Section 6.7.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NIS; mNIS+7; 
HRdb; 10-MWT 
See below Table 
2 Notes; 
Section 6.2.1; 
Section 6.2.2; 
Section 6.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Single 12-Lead 
ECG 
Section 6.5.4 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram 
Section 6.2.10.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Technetium 
scintigraphy 
imaging (select 
sites only)  
Section 6.2.10.3   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
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Confidential 
 
 
 
 
 
 
 
 
 
16 
Table 2: 
Schedule of Assessments – Treatment Period from Month 9 through Month 18 
 
Note 
Treatment Period 
Month 
18 
Efficacy 
Study Day  
 
D274 
D295 
D316 
D337 
D358 
D379 
 
D400 
D421 
D442 
D463 
D484 
D505 
D526 
D547 
D554-D561 
Study Week  
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
±Visit Window  
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
 
ALN-TTRSC02 
Study Drug 
Administration 
Section 5.2.2.1  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Patisiran-LNP: 
Premedication 
Administration 
Section 5.2.2.2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patisiran-LNP 
Study Drug 
Administration 
Section 5.2.2.2 
X – Dose 
after Month 
9 efficacy 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital status check 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AEs, Con. Med, 
Hospitalization, 
Urgent care visits; 
Procedures 
Section 6.5.7; 
Section 5.3; 
Section 6.7.2  
Continuous Monitoring 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con. Med.=concomitant medications; C-SSRS= Columbia-Suicide Severity Rating Scale; D=day; 
ECG=electrocardiogram; EQ-5D-5L=EuroQuality of Life 5-Dimensions 5-Levels; EQ-VAS=EuroQuality of Life-Visual Analog Scale; FAP=Familial Amyloidotic 
Polyneuropathy; HRdb=heart rate variability with deep breathing; KPS= Karnofsky Performance Status; LFT=liver function test; mBMI=modified body mass index; 10-
MWT=10-meter walk test; mNIS+7=modified NIS+7; NIS=Neurologic Impairment Score; NYHA=New York Heart Association; PE=physical exam; PK=pharmacokinetics; 
PND=Polyneuropathy Disability; QoL-DN=Quality of Life-Diabetic Neuropathy; R-ODS=Rasch-built Overall Disability Scale; TTR=transthyretin  
Table 2 Notes: 
 
Unless otherwise specified, assessments on dosing days are predose. 
 
For the Month 18 NIS; mNIS+7; HRdb and 10-MWT: Two independent assessments will be performed on separate days (1 assessment on each day); the 2 assessments 
should be performed approximately 24 hours apart from each other but not more than 7 days apart.  Components that are shared between the mNIS+7 and NIS will be 
performed once at each assessment (eg, the weakness component should not be performed more than once on any given day). 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
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Confidential 
 
 
 
 
 
 
 
 
 
17 
Table 3: 
Schedule of Assessments:  Treatment Extension Period, Other Visits, and Follow-up Period 
 
Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy 
Visits for Patients 
Who Discontinue 
Treatment before 
Month 18 
FU 
Period 
 
 
Last Patisiran-
LNP Dosing 
Visit 
ALN-
TTRSC02 
Dosing Visits 
Every 12 
Weeks 
Month 27 
Efficacy 
and Dosing 
Visit 
Month 36 
Efficacy Visit 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
 
81 
84, 96, 108, 
120, 132, 144, 
and 156 
120 
160 
- 
36-39 
79-80 
- 
±Visit Window 
 
±3D 
±7D 
±2 weeks 
±2 weeks 
- 
- 
- 
- 
NYHA class; KPS; 
PND and FAP; 
mBMI  
Section 6.2.10.4; 
Section 6.2.11; 
Section 6.2.9; 
Section 6.2.5 
 
 
X 
X 
X 
X 
X 
 
Vital Signs 
Section 6.5.1 
X 
X 
X 
X 
 
 
 
 
Full Physical 
Examination (PE); 
Weight,  
Section 6.5.3; 
Section 6.5.2  
 
 
X 
X 
X 
X 
X 
X 
NIS; mNIS+7; 
HRdb 
See below Table 3 
Notes; Section 6.2.1; 
Section 6.2.2;  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
 
10-MWT 
Section 6.2.4  
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Questionnaires: 
Norfolk QoL-DN; 
R-ODS; EQ-5D-5L 
and EQ-VAS; C-
SSRS; all 
Pharmacoeconomic 
assessments 
Section 6.2.3; 
Section 6.2.6;; 
Section 6.2.8; 
Section 6.5.5 
Section 6.7 
 
 
X 
X 
X - No Patient 
Preference 
Survey 
X – No  
C-SSRS 
X – No  
C-SSRS 
 
Single 12-Lead 
ECG 
Section 6.5.4; 
 
 
 
 
X 
 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
18 
Table 3: 
Schedule of Assessments:  Treatment Extension Period, Other Visits, and Follow-up Period 
 
Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy 
Visits for Patients 
Who Discontinue 
Treatment before 
Month 18 
FU 
Period 
 
 
Last Patisiran-
LNP Dosing 
Visit 
ALN-
TTRSC02 
Dosing Visits 
Every 12 
Weeks 
Month 27 
Efficacy 
and Dosing 
Visit 
Month 36 
Efficacy Visit 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
 
81 
84, 96, 108, 
120, 132, 144, 
and 156 
120 
160 
- 
36-39 
79-80 
- 
±Visit Window 
 
±3D 
±7D 
±2 weeks 
±2 weeks 
- 
- 
- 
- 
Echocardiogram 
Section 6.2.10.1 
 
 
X 
X 
X 
 
 
 
Technetium 
scintigraphy 
imaging (select 
sites only) 
Section 6.2.10.3 
 
 
X 
X 
X 
 
 
 
Serum Chemistry, 
Hematology, 
Urinalysis, 
Coagulation and 
Liver Function 
Tests 
Section 6.5.6; 
Section 6.5.6.3. 
LFT only; 
applies to both 
arms 
X 
X 
X 
X 
Serum 
Chemistry 
and LFTs 
only 
Serum 
Chemistry 
and LFTs 
only 
X 
Pregnancy Test  
Section 6.5.6.2. 
 
X 
X 
X 
X 
X 
X 
X 
Cardiac Biomarker 
Samples 
Section 6.2.10.2 
 
X - Every 24 weeks starting at  
Week 96 
X 
X 
X 
 
TTR Protein; 
Vitamin A 
Prior to each dose on 
dosing days Section 6.3 
 
X 
X 
X 
X 
X 
X 
X  
ADA 
On dosing days, collect 
within 1 hour before 
dosing, Section 6.5.6.1;  
 
X -Every 24 weeks starting at Week 96 
X 
 
 
 
ALN-TTRSC02 
PK  
See Table 4 for PK 
collection timepoints 
 
 
 
 
X 
X 
X 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
19 
Table 3: 
Schedule of Assessments:  Treatment Extension Period, Other Visits, and Follow-up Period 
 
Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy 
Visits for Patients 
Who Discontinue 
Treatment before 
Month 18 
FU 
Period 
 
 
Last Patisiran-
LNP Dosing 
Visit 
ALN-
TTRSC02 
Dosing Visits 
Every 12 
Weeks 
Month 27 
Efficacy 
and Dosing 
Visit 
Month 36 
Efficacy Visit 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
 
81 
84, 96, 108, 
120, 132, 144, 
and 156 
120 
160 
- 
36-39 
79-80 
- 
±Visit Window 
 
±3D 
±7D 
±2 weeks 
±2 weeks 
- 
- 
- 
- 
Samples for 
Exploratory 
Analysis 
Section 6.6 
 
 
X 
X 
X 
 
 
 
AEs; Con. Meds; 
Hospitalizations, 
Urgent care visits 
and Procedures 
Section 6.5.7; 
Section 5.3; 
Section 6.7.2 
 
X 
X 
X 
X 
X 
X 
X -
Through 
week 12 
after 
last 
dose 
ALN-TTRSC02 
Study Drug 
Administration 
Section 5.2.2.1  
 
X - Every 12 weeks starting at 
Week 84 to EOT Week 156 
 
 
 
 
 
Patisiran-LNP: 
Premedication 
Administration 
Section 5.2.2.2  
X 
 
 
 
 
 
 
 
Patisiran-LNP 
Study Drug 
Administration 
Section 5.2.2.2 
X 
 
 
 
 
 
 
 
Vital status check  
See note below Table 3 
 
 
 
 
 
 
X 
 
Abbreviations:  ADA=antidrug antibodies; AE=adverse event; Con. Med.=concomitant medications; C-SSRS= Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
EOT=End of Treatment; EQ-5D-5L=EuroQuality of Life 5-Dimensions 5-Levels; EQ-VAS= EuroQuality of Life-Visual Analog Scale; FAP=Familial Amyloidotic 
Polyneuropathy; FU=Follow-up; HRdb=heart rate variability with deep breathing; KPS= Karnofsky Performance Status; LFT=liver function test; mBMI=modified body mass 
index; 10-MWT=10-meter walk test; mNIS+7=modified NIS+7; NIS=Neurologic Impairment Score; NYHA=New York Heart Association; PE=physical exam; 
PK=pharmacokinetics; PND=Polyneuropathy Disability; QoL-DN=Quality of Life-Diabetic Neuropathy; R-ODS=Rasch-built Overall Disability Scale; TTR=transthyretin  

Clinical Study Protocol ALN-TTRSC02-002 
 
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Original, 11 October 2018 
 
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Confidential 
 
 
 
 
 
 
 
 
 
20 
Table 3 Notes: 
 
For the NIS; mNIS+7; HRdb;10-MWT performed as part of the Early Drug Discontinuation Visit and the Modified Month 9 and 18 Efficacy Visit(s): Two independent 
assessments will be performed on separate days (1 assessment on each day); the 2 assessments should be performed approximately 24 hours apart from each other but not 
more than 7 days apart.   
 
See Section 4.3 for instructions on early discontinuation of study drug procedures.  
 
Follow-up for patients who discontinued ALN-TTRSC02:  All patients on ALN-TTRSC02 will undergo safety assessments quarterly until serum TTR levels return to 
≥80% of baseline (for up to 1 year after the last dose of study drug), or until the patient starts a TTR lowering regimen as a part of clinical care, whichever comes first; all 
patients will be followed for a minimum of 3 months.  Female patients of child-bearing potential will be followed until serum TTR levels return to ≥80% of baseline.  
The frequency of follow-up visits will be as follows: 
o 
Patients who discontinue study treatment early will be requested to follow the planned visit schedule and will be asked to complete the Month 9 and Month 18 
efficacy assessment visits as described in Section 4.3.1 as per the Modified Efficacy Visits for Patients Who Discontinue Treatment before Month 18 column, 
and also completing the assessments in the Follow-Up column. 
o 
Patients who complete the study will be followed every 12 weeks, completing the assessments in the Follow-Up column. 
 
Follow-up for patients who discontinue patisiran-LNP:  Patients will undergo a follow-up visit 30 days after the last dose of study drug (completing the assessments in 
the Follow-Up column).  
 
Vital status:  All patients who discontinue study drug will have a vital status check approximately 18 months after the first dose of study drug either in person during the 
modified Month 18 visit or , as appropriate, by utilizing different follow options including 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.  
 
SAE, AECI will be collected throughout the Follow-up Period; AEs will be collected until 3 months after the last dose of study drug.  

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
 
 
 
 
 
 
 
 
 
21 
Table 4: 
Pharmacokinetic Time Points: ALN-TTRSC02 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood (Plasma) 
Day 1 and Day 253±3 days  
Predose (within 60 minutes before dosing) 
X 
03:00 (±1 hr) 
X 
06:00 (±1 hr) 
X 
24:00 (±2 hr) 
X 
Day 85 and Day 169 (±3 days) 
Predose (within 60 minutes before dosing) 
X 
 
03:00 (±1 hr) 
X 
Day 337, Day 421, and Day 505 (±3 days) 
Predose (within 60 minutes before dosing) 
X 
 
03:00 (±1 hr) 
X 
Early Drug Discontinuation Visit 
Collect any time within the visit window 
X 
Modified Efficacy Visits for Patients Who Discontinue 
Treatment before Month 18 
Collect any time within the visit window 
X 
 
Table 5: 
Pharmacokinetic Time Points: Patisiran-LNP 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood (Plasma) 
Day 1 and Day 253±3 days  
Predose (within 60 minutes before dosing) 
X 
00:30 (±5 min) 
X 
06:00 (±1 hr) 
X 
24:00 (±2 hr) 
X 
Day 22, Day 127, Day 274, Day 379, and Day 547 
(±3 days) 
Predose (within 60 minutes before dosing) 
X 
03:00 (±1 hr) 
X 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
22 
TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................22 
LIST OF TABLES .........................................................................................................................27 
LIST OF FIGURES .......................................................................................................................27 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................28 
1. 
INTRODUCTION ......................................................................................................32 
1.1. 
Disease Overview .......................................................................................................32 
1.2. 
Current Treatments .....................................................................................................33 
1.3. 
RNAi Therapeutics to Reduce TTR Levels ................................................................34 
1.4. 
Clinical Experience with Patisiran-LNP and ALN-TTRSC02 ...................................35 
1.4.1. 
The APOLLO Study ...................................................................................................35 
1.4.2. 
ALN-TTRSC02-001 Phase 1 Clinical Study ..............................................................35 
1.5. 
Study Design Rationale ..............................................................................................36 
1.6. 
Dose Rationale ............................................................................................................37 
1.7. 
Benefit-Risk Assessment ............................................................................................38 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................39 
3. 
INVESTIGATIONAL PLAN .....................................................................................41 
3.1. 
Summary of Study Design ..........................................................................................41 
3.2. 
Duration of Treatment ................................................................................................42 
3.3. 
Duration of Study .......................................................................................................42 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................42 
3.4. 
Number of Planned Patients .......................................................................................43 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................43 
3.6. 
Blinding ......................................................................................................................43 
3.7. 
Data Monitoring Committee .......................................................................................43 
3.8. 
Adjudication Committee .............................................................................................43 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................43 
4.1. 
Inclusion Criteria ........................................................................................................43 

Clinical Study Protocol ALN-TTRSC02-002 
 
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Original, 11 October 2018 
 
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23 
4.2. 
Exclusion Criteria .......................................................................................................44 
4.3. 
Removal from Therapy or Assessment.......................................................................46 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................46 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................47 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................47 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................48 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................48 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................48 
4.3.3. 
Lost to Follow-Up.......................................................................................................48 
4.3.4. 
Replacement of Study Patients ...................................................................................49 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................49 
5.1. 
Treatments Administered ............................................................................................49 
5.2. 
Study Drug ..................................................................................................................49 
5.2.1. 
Description ..................................................................................................................49 
5.2.2. 
Dose and Administration ............................................................................................50 
5.2.2.1. 
ALN-TTRSC02 ..........................................................................................................50 
5.2.2.2. 
Patisiran-LNP .............................................................................................................50 
5.2.2.3. 
Switching from Patisiran-LNP to ALN-TTRSC02 After Month 18 ..........................52 
5.2.3. 
LFT Criteria for Withholding, Monitoring and Stopping ALN-TTRSC02 
Dosing .........................................................................................................................52 
5.2.4. 
Preparation, Handling, and Storage ............................................................................53 
5.2.5. 
Packaging and Labeling ..............................................................................................54 
5.2.6. 
Accountability .............................................................................................................54 
5.3. 
Concomitant Medications ...........................................................................................54 
5.4. 
Treatment Compliance ................................................................................................55 
5.5. 
Other Requirements ....................................................................................................55 
5.5.1. 
Contraception ..............................................................................................................55 
5.5.2. 
Alcohol Restrictions ...................................................................................................56 
6. 
STUDY ASSESSMENTS ..........................................................................................56 
6.1. 
Screening Assessments ...............................................................................................57 
6.1.1. 
Retesting .....................................................................................................................57 
6.1.2. 
Rescreening .................................................................................................................57 
6.1.3. 
Demographic and Medical History/Disease History ..................................................57 

Clinical Study Protocol ALN-TTRSC02-002 
 
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24 
6.2. 
Efficacy Assessments .................................................................................................58 
6.2.1. 
Neurologic Impairment Assessments .........................................................................58 
6.2.1.1. 
Modified Neurological Impairment Score +7 (mNIS+7) ...........................................58 
6.2.1.2. 
Neurologic Impairment Score (NIS) ..........................................................................58 
6.2.1.3. 
Personnel and Procedures to Ensure Quality and Consistency of NIS and 
mNIS+7 Scoring .........................................................................................................58 
6.2.2. 
Heart Rate Response to Deep Breathing (HRdb) .......................................................59 
6.2.3. 
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) ............................59 
6.2.4. 
Ten-meter Walk Test (10-MWT) ...............................................................................59 
6.2.5. 
Modified Body Mass Index (mBMI) ..........................................................................60 
6.2.6. 
Rasch-built Overall Disability Scale (R-ODS) ...........................................................60 
6.2.7. 
Deaths and Hospitalizations .......................................................................................60 
6.2.8. 
European Quality of Life-5 Dimensions 5-Levels (EQ-5D-5L) and EQ-
Visual Analog Scale (EQ-VAS) .................................................................................60 
6.2.9. 
PND Score and FAP Stage .........................................................................................60 
6.2.10. 
Cardiac Assessments ..................................................................................................61 
6.2.10.1. 
Echocardiogram ..........................................................................................................61 
6.2.10.2. 
Cardiac Biomarkers ....................................................................................................61 
6.2.10.3. 
Technetium Scintigraphy Imaging .............................................................................61 
6.2.10.4. 
New York Heart Association (NYHA) Class .............................................................62 
6.2.11. 
Karnofsky Performance Status (KPS) ........................................................................62 
6.3. 
Pharmacodynamic Assessments .................................................................................62 
6.4. 
Pharmacokinetic Assessments ....................................................................................62 
6.5. 
Safety Assessments .....................................................................................................62 
6.5.1. 
Vital Signs ..................................................................................................................63 
6.5.2. 
Weight and Height ......................................................................................................63 
6.5.3. 
Physical Examination .................................................................................................63 
6.5.4. 
Electrocardiogram .......................................................................................................63 
6.5.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................64 
6.5.6. 
Clinical Laboratory Assessments ...............................................................................64 
6.5.6.1. 
Immunogenicity ..........................................................................................................67 
6.5.6.2. 
Pregnancy Testing ......................................................................................................67 
6.5.6.3. 
Additional Liver Function Assessments .....................................................................67 

Clinical Study Protocol ALN-TTRSC02-002 
 
ALN-TTRSC02 
Original, 11 October 2018 
 
Alnylam Pharmaceuticals 
Confidential 
25 
6.5.7. 
Adverse Events ...........................................................................................................68 
6.5.7.1. 
Definitions ..................................................................................................................68 
6.5.7.2. 
Eliciting and Recording Adverse Events ....................................................................70 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................71 
6.5.7.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........71 
6.5.7.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................72 
6.5.7.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................72 
6.5.7.7. 
Pregnancy Reporting ..................................................................................................72 
6.5.7.8. 
Overdose Reporting ....................................................................................................73 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................73 
6.7. 
Pharmacoeconomic Assessments ...............................................................................74 
6.7.1. 
Patient and Caregiver Impact Survey .........................................................................74 
6.7.2. 
Hospitalization, Urgent Healthcare Visits, Surgeries, and Procedures ......................74 
6.7.3. 
Patient Experience Survey ..........................................................................................74 
6.7.4. 
Patient Preference Survey ...........................................................................................74 
7. 
STATISTICS ..............................................................................................................74 
7.1. 
Determination of Sample Size ....................................................................................74 
7.2. 
Statistical Methodology ..............................................................................................75 
7.2.1. 
Populations to be Analyzed ........................................................................................75 
7.2.2. 
Examination of Subgroups .........................................................................................75 
7.2.3. 
Handling of Missing Data ...........................................................................................76 
7.2.4. 
Baseline Evaluations ...................................................................................................76 
7.2.5. 
Efficacy Analyses .......................................................................................................76 
7.2.5.1. 
Co-Primary Endpoint ..................................................................................................76 
7.2.5.2. 
Secondary Endpoints ..................................................................................................77 
7.2.5.3. 
Exploratory Endpoints ................................................................................................78 
7.2.6. 
Pharmacodynamic Analysis........................................................................................78 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................78 
7.2.8. 
Safety Analyses ..........................................................................................................78 
7.2.9. 
Immunogenicity Analyses ..........................................................................................78 
7.2.10. 
Other Analyses ............................................................................................................78 
7.2.11. 
Interim Analysis ..........................................................................................................79 

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8. 
STUDY ADMINISTRATION ...................................................................................79 
8.1. 
Ethical and Regulatory Considerations ......................................................................79 
8.1.1. 
Informed Consent .......................................................................................................79 
8.1.2. 
Ethical Review ............................................................................................................79 
8.1.3. 
Serious Breach of Protocol .........................................................................................80 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................80 
8.1.5. 
End of Study ...............................................................................................................80 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................80 
8.2. 
Data Quality Control and Quality Assurance .............................................................81 
8.2.1. 
Data Handling .............................................................................................................81 
8.2.2. 
Study Monitoring ........................................................................................................81 
8.2.3. 
Audits and Inspections ................................................................................................81 
8.3. 
Publication Policy .......................................................................................................81 
9. 
LIST OF REFERENCES ............................................................................................83 
10. 
APPENDICES ............................................................................................................86 
10.1. 
mNIS+7 Components and Scoring .............................................................................86 
10.2. 
PND Scores and FAP Stages ......................................................................................88 
10.3. 
New York Heart Association (NYHA) Class .............................................................89 
10.4. 
Karnofsky Performance Status (KPS) Scale ...............................................................90 

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LIST OF TABLES 
Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 ...............10 
Table 2: 
Schedule of Assessments – Treatment Period from Month 9 through Month 
18 ................................................................................................................................14 
Table 3: 
Schedule of Assessments:  Treatment Extension Period, Other Visits, and 
Follow-up Period ........................................................................................................17 
Table 4: 
Pharmacokinetic Time Points: ALN-TTRSC02 .........................................................21 
Table 5: 
Pharmacokinetic Time Points: Patisiran-LNP ............................................................21 
Table 6: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................53 
Table 7: 
Clinical Laboratory Assessments ...............................................................................66 
Table 8: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............68 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Antidrug antibodies  
AE 
Adverse event 
ALN-TTRSC02 
Name of study drug product 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
APOLLO 
Name of patisiran-LNP pivotal Phase 3 clinical study ALN-TTR02-004 
ASGPR 
Asialoglycoprotein receptor  
AST 
Aspartate transaminase 
ATTR 
Amyloid transthyretin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CAS 
Central Assessment Sites 
CASE 
Computer Aided Sensory Evaluator 
CI 
Confidence Interval 
CHMP 
Committee for Medicinal Products for Human Use 
CMAP 
Compound muscle action potential 
Cmax 
Observed peak concentration 
Con. Med 
Concomitant medication 
CRF 
Case Report Form 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicine Agency 

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Abbreviation 
Definition 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQoL 5-Dimensions 5-Levels 
EQ-VAS 
EuroQoL visual analogue scale 
EU 
European Union 
FAC 
Familial amyloidotic cardiomyopathy, also known as hATTR amyloidosis 
with cardiomyopathy 
FAP 
Familial amyloidotic polyneuropathy, also known as hATTR amyloidosis with 
polyneuropathy 
GalNAc 
N-acetyl galactosamine ligand 
GCP 
Good Clinical Practice 
H1 
Histamine 1 receptor 
H2 
Histamine 2 receptor 
hATTR 
Hereditary ATTR 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency virus 
HRdb 
Heart rate variability with deep breathing 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRR 
Infusion related reaction 
IRS 
Interactive Response System 
ISR 
Injection site reaction 
IV 
Intravenous 
KPS 
Karnofsky Performance Status 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LS 
Least-square 

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Abbreviation 
Definition 
LV 
Left ventricle 
mBMI 
Modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of Diet in Renal Disease Study 
mITT 
Modified Intent-to-Treat 
10-MWT 
10-meter walk test 
mNIS+7 
Modified Neurologic Impairment Score +7 
mRNA 
Messenger RNA 
NCS 
Nerve conduction studies 
NCS Σ5 
NCS sum of 5 attributes 
NIS 
Neurologic Impairment Score 
NIS-R 
NIS reflexes 
NIS-S 
NIS sensation 
NIS-W 
NIS weakness 
Norfolk QoL-DN Norfolk Quality of Life-Diabetic Neuropathy 
NT-proBNP 
B-type natriuretic peptide 
NYHA 
New York Heart Association 
OLT 
Orthotopic Liver Transplantation 
Patisiran-LNP 
Name of patisiran drug product; patisiran-lipid nanoparticles 
PCS 
Patient Care Sites 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PND 
Polyneuropathy Disability 
PT 
Prothrombin time 
q3M 
Once every 3 months 
q3w 
Once every 3 weeks 
QoL or QOL 
Quality of life 
QST 
Quantitative sensory testing 
QST-BSAHP 
QST heat pain by body surface area 
QST-BSATP 
QST touch pressure by body surface area 

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Abbreviation 
Definition 
QTc 
Corrected QT interval 
QTcF 
QT obtained using Fridericia's formula  
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RISC 
RNA-induced silencing complex 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
siRNA 
Small interfering ribonucleic acid 
SNAP 
Sensory nerve action potential 
SOC 
System organ class 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T3 
Triiodothyronine 
T4 
Thyroxine 
tmax 
Time of observed maximum concentration 
TTR 
Transthyretin 
TUDCA 
Tauroursodeoxycholic acid 
ULN 
Upper limit of normal 
US 
United States 
USA 
United States of America 
V30M 
Valine to methionine mutation at position 30 
V122I 
Valine to isoleucine mutation at position 122 
WHO 
World Health Organization 
wt 
Wild type 
 

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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Hereditary ATTR amyloidosis (hATTR amyloidosis) is a rare, life-threatening, autosomal 
dominant, multi-systemic disease caused by mutations in the transthyretin (TTR) gene that 
results in rapidly progressive, debilitating morbidity and high mortality.  The cardinal 
manifestations of hATTR amyloidosis are polyneuropathy and cardiomyopathy. 
TTR, also known as prealbumin, is a tetrameric protein predominantly produced by hepatocytes 
(>95% of circulating TTR is liver-derived), with a smaller fraction produced by the choroid 
plexus and retina (Liz, Mar et al. 2010).  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. TTR also serves as a minor carrier for thyroxine (T4).  
In hATTR amyloidosis, 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.  These misfolded TTR monomers can 
then self-assemble into oligomers and form amyloid fibrils and plaques in the extracellular space 
of various tissues (Hou, Aguilar et al. 2007), including the peripheral nervous system, heart, 
gastrointestinal tract, kidney, central nervous system and eye, leading to cellular injury and organ 
dysfunction with corresponding clinical manifestations. Since almost all patients are 
heterozygous for the mutated TTR allele, the amyloid fibrils typically consist of both mutant and 
wt TTR.  There are over 120 reported TTR genetic mutations associated with hATTR (Connors, 
Lim et al. 2003; Ando, Coelho et al. 2013). The disease is most often caused by the valine to 
methionine mutation at position 30 in the human TTR gene (V30M)primarily in families with 
heritage from Portugal, Sweden, Japan, and Brazil (Parman, Adams et al. 2016). Another 
common genotype is the isoleucine substitution for valine at position 122 (V122I).  This 
mutation occurs in up to 4% of African Americans and in over 5% of West African populations 
(Jacobson, Pastore et al. 1997). 
Historically, due to incomplete understanding of etiology and pathogenesis, 2 clinical syndromes 
of hATTR amyloidosis have been described in the medical literature: hATTR amyloidosis with 
polyneuropathy (previously known as familial amyloidotic polyneuropathy, or FAP) and hATTR 
amyloidosis with cardiomyopathy (previously known as familial amyloidotic cardiomyopathy, or 
FAC), both of which are characterized by amyloid deposits comprised of both mutant and wt 
TTR (Yazaki, Tokuda et al. 2000).  However, while patients with hATTR amyloidosis may 
present with predominantly polyneuropathy or cardiomyopathy, most patients with hATTR 
amyloidosis manifest signs and symptoms of both polyneuropathy and cardiomyopathy over the 
course of their disease.  Therefore, hATTR amyloidosis is increasingly viewed as a single 
hereditary disease with a spectrum of clinical manifestations rather than 2 distinct syndromes 
(Swiecicki, Zhen et al. 2015). 
The clinical manifestations of the length-dependent, symmetrical polyneuropathy are the result 
of amyloid-mediated injury to large and small peripheral nerve fibers (Benson and Kincaid 2007; 
Plante-Bordeneuve and Said 2011; Ando, Coelho et al. 2013).  Sensory abnormalities include 
painful dysesthesias in the feet and hands, as well as loss of sensation leading to thermal burns in 
these areas and to joint injury in the lower limbs.  Progressive muscle atrophy and motor 

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weakness in both lower and upper limbs leads to impaired ambulation (progressing from the use 
of one stick to two for ambulation, followed by needing to use a wheel chair and then becoming 
bed-ridden over just a few years), and inability to perform other activities of daily living.  
Autonomic dysfunction results in debilitating orthostatic hypotension, severe gastrointestinal 
symptoms, and bladder dysfunction with recurrent urinary tract infections.   
Polyneuropathy stage or severity is classified by FAP stage or Polyneuropathy Disability (PND) 
score, both of which are based on ambulatory ability.  The degree of neurologic impairment has 
historically been measured using the Neurologic Impairment Score (NIS), which has been shown 
to be correlated with FAP stage and PND score; an increase from baseline in NIS score signifies 
worsening in neurologic impairment, which in turn correlates with a higher FAP stage 
designation and PND score (Adams, Coelho et al. 2015). The maximum impairment score for the 
NIS is 244 points, and a change from baseline of 10 to 14 points per year has been observed in 
untreated patients based on data from an hATTR amyloidosis clinical study and an observational 
natural history study (Berk, Suhr et al. 2013; Adams, Coelho et al. 2015). This is in contrast to 
patients with diabetic polyneuropathy where NIS progression is <1 point/year (Ziegler, Low et 
al. 2011). For clinical studies, the modified NIS+7 (mNIS+7) score, a more sensitive measure 
with a scale from 0 to 304 points, has been developed to provide a more comprehensive measure 
of polyneuropathy in patients with hATTR amyloidosis (Suanprasert, Berk et al. 2014).  
Cardiac infiltration with amyloid leads to heart wall thickening and cardiomyopathy 
characterized by clinical heart failure due to both diastolic and systolic dysfunction, as well as 
cardiac conduction disturbances and arrhythmias (Carvalho, Alves et al. 1992; Connors, 
Yamashita et al. 2004; Soares, Coelho et al. 2005; Benson and Kincaid 2007; Ando, Coelho et al. 
2013).  Patients with symptomatic heart failure experience rapid progression of their amyloid 
cardiomyopathy, with substantial worsening of echocardiographic and biomarker measures of 
cardiac function, ambulation, and quality of life seen over a period of 18 months or less (Ruberg 
and Berk 2012).   
1.2. 
Current Treatments 
The treatment of hATTR amyloidosis requires a multidisciplinary approach primarily involving 
neurology, gastroenterology, and cardiology specialties.  Palliative/symptomatic therapies 
directed at specific symptoms such as pain, nausea/vomiting and diarrhea have been the mainstay 
of treatment.   
Two treatment approaches that have historically been used for the treatment of hATTR 
amyloidosis are orthotopic liver transplantation (OLT), which serves to eliminate mutant TTR 
from the circulation, but does not affect the hepatic production of wt TTR (Okamoto, Wixner et 
al. 2009; Carvalho, Rocha et al. 2015; Ericzon, Wilczek et al. 2015), and TTR tetramer 
stabilizers (including tafamidis and diflunisal), which have been shown in clinical studies to 
reduce neuropathy in patients with early stage polyneuropathy (Coelho, Maia et al. 2012; Berk, 
Suhr et al. 2013). However, these therapies are restricted to a small subset of patients with 
hATTR amyloidosis with early stage neuropathy. Furthermore, the majority of patients receiving 
tafamidis continue to experience neuropathy progression with a steady decline in quality of life, 
ability to walk, and to perform activities of daily living (Barroso, Judge et al. 2017).  

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Recently, the antisense oligonucleotide inotersen and the short interfering ribonucleic acid 
(siRNA) patisiran-LNP were shown in randomized controlled studies to significantly reduce 
neurologic impairment and improve quality of life compared with placebo in patients with 
hATTR amyloidosis (Adams, Suhr et al. 2017; Dyck PJ 2017; Wang et al. 2017).  Both novel 
therapies, albeit through different mechanisms, aim at reducing the expression of TTR messenger 
RNA (mRNA), and the amount of circulating amyloidogenic protein in patients with hATTR 
amyloidosis.   
1.3. 
RNAi Therapeutics to Reduce TTR Levels  
Patisiran-LNP (ONPATTRO™) developed by Alnylam, which targets the production of hepatic 
TTR, is approved in the US for the treatment of the polyneuropathy of hATTR amyloidosis in 
adults and in the EU for the treatment of hATTR amyloidosis in adult patients with stage 1 and 
stage 2 polyneuropathy.  The recommended dose of patisiran-LNP is 0.3 mg/kg administered via 
intravenous (IV) infusion once every 3 weeks (q3w).  To minimize the risk of infusion related 
reactions (IRRs), all patients must receive pre-medication including corticosteroids (10 mg 
dexamethasone IV), histamine 1 (H1) and histamine 2 (H2) blockers, and paracetamol or 
equivalents 60 minutes prior to the infusion. 
Patisiran-LNP utilizes the mechanism of RNA interference to selectively degrade TTR mRNA 
and thereby reduce the expression of its corresponding protein (Bumcrot, Manoharan et al. 
2006). Patisiran-LNP is an siRNA that is formulated as lipid nanoparticles (LNP) to target 
delivery to hepatocytes in the liver, the primary source of TTR protein in circulation.  Following 
IV infusion, opsonization of the LNP by apolipoprotein E facilitates binding to the low-density 
lipoprotein receptor on hepatocytes and subsequent endocytosis.  Fusion of the ionizable lipid 
component of the LNP with the endosomal membrane then leads to release of the siRNA into the 
cytoplasm where it can bind to and activate the RNA-induced silencing complex (RISC). Upon 
binding and activation of RISC in the cytoplasm within hepatocytes, the siRNA duplex unwinds 
and the antisense strand specifically binds to a genetically conserved sequence in the 3’ 
untranslated region of wt and mutant TTR mRNA.  The Argonaute-2 endonuclease within the 
RISC/siRNA enzyme complex catalytically degrades wt and mutant TTR mRNA, resulting in a 
reduction of wt and mutant TTR protein.   
Alnylam had also developed another siRNA-conjugate therapeutic, revusiran, primarily for the 
treatment of patients with hATTR amyloidosis with cardiomyopathy; however, this program was 
discontinued as described further in the ALN-TTRSC02 Investigator’s Brochure (IB).   
ALN-TTRSC02 is in clinical development for the treatment of ATTR amyloidosis. This 
molecule is 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.  ALN-
TTRSC02 has the same nucleotide sequence as revusiran but employs a different ratio of 
chemical modifications to confer increased stability of the siRNA.   
ALN-TTRSC02 drug product comprises the drug substance ALN-65492, an siRNA targeting 
TTR mRNA that is conjugated to an N-acetyl galactosamine ligand (GalNAc) to facilitate 
delivery to the liver, formulated in 10 mM sodium phosphate, 110 mM sodium chloride at pH 7 
for subcutaneous (SC) injection.  Uptake of ALN-TTRSC02 occurs via the asialoglycoprotein 
receptor (ASGPR), a member of the C-type lectin family of receptors that recognizes and binds 

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glycoproteins with terminal galactose (Gal) or GalNAc residues (Ashwell and Morell 1974; Nair, 
Willoughby et al. 2014). It is expressed on the cell surface of hepatocytes at a high copy number 
(0.5-1 million per cell) (Baenziger and Fiete 1980; Schwartz, Rup et al. 1980), and facilitates 
clearance of desialylated glycoproteins from the blood (Geffen and Spiess 1992). Binding of the 
carbohydrate ligand to the ASGPR leads to receptor-mediated endocytosis of the ligand-receptor 
complex followed by release of its cargo in the endocytic pathway, and subsequent recycling of 
the receptor to the cell surface for successive rounds of uptake. 
ALN-TTRSC02 has been shown to have increased potency and duration of TTR reduction in 
nonclinical species and in a clinical study in healthy volunteers described in Section 1.4.2, 
enabling a much lower dose, lower injection volume, and significantly less frequent dosing for 
patients compared to other TTR-lowering drugs. 
1.4. 
Clinical Experience with Patisiran-LNP and ALN-TTRSC02 
1.4.1. 
The APOLLO Study 
The safety and efficacy of patisiran-LNP was shown in a Phase 3 multicenter, multinational, 
randomized, double-blind, placebo-controlled study (ALN-TTR02-004, APOLLO) that met the 
primary and all secondary endpoints (Adams, Gonzalez-Duarte et al. 2018).  This study 
demonstrated that in patients with hATTR amyloidosis, who exhibited a broad range of disease 
severity and TTR genotypes, treatment with patisiran-LNP leads to a significant improvement in 
neuropathy (mNIS+7) relative to placebo at 18 months (primary analysis), as well as significant 
improvement in quality of life (Norfolk QoL-DN, key secondary analysis) relative to placebo at 
18 months.  Significant improvement in neuropathy and quality of life were also observed at 
Month 9.  This study furthermore demonstrated that treatment with patisiran-LNP is associated 
with an improvement in overall health (gait speed, nutritional status, and disability), with 
improvement in these endpoints seen as early as at Month 9.  Patisiran-LNP treatment was also 
associated with improvement compared to placebo in exploratory cardiac endpoints including 
key echocardiographic parameters and the biomarker NT-proBNP (Solomon 2018).  In post-hoc 
analyses, patisiran-LNP demonstrated a reduction in the composite event rate of hospitalization 
and mortality. 
In the patisiran-LNP group, the mean TTR percent reduction from baseline was 82.6% and 
84.3% at Month 9 and Month 18, respectively.  TTR percent reduction was maintained over the 
duration of the study.  A correlation (Pearson’s r, 0.59; 95% CI, 0.49-0.68) was observed 
between the degree of TTR reduction from baseline and the change in the mNIS+7 at 18 months. 
Patisiran-LNP showed an acceptable safety profile in the APOLLO study.  Common adverse 
events (AEs) occurring more frequently with patisiran-LNP compared to placebo included 
peripheral edema (30% versus 22%) and infusion related reactions (IRRs) (19% versus 9%, 
respectively). 
1.4.2. ALN-TTRSC02-001 Phase 1 Clinical Study  
ALN-TTRSC02 has been evaluated in a recently completed Phase 1 study (study ALN-
TTRSC02-001).  ALN-TTRSC02-001 was a randomized, single-blind, placebo controlled single-
ascending dose study to evaluate the safety and tolerability, pharmacokinetics (PK) and 
pharmacodynamics (PD) of ALN-TTRSC02 in healthy subjects and in healthy subjects of 

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Japanese descent.  Single doses of 5, 25, 50, 100, 200 or 300 mg ALN-TTRSC02 were 
administered by SC injection to cohorts of 8 subjects (6:2 ratio ALN-TTRSC02 to placebo). 
Subjects remained blinded to treatment assignment through Day 90. Eighty healthy volunteers 
were randomized in 10 cohorts and followed for up to 314 days.  
ALN-TTRSC02 reduced serum TTR in a dose dependent fashion with higher doses of ALN-
TTRSC02 achieving deeper and longer duration of serum TTR reduction.  At the proposed dose 
of 25 mg ALN-TTRSC02, a single dose resulted in maximum TTR reduction of 94% and mean 
maximum TTR reduction of 83% that was maintained for 90 days (n=12). Consistent with the 
expected PD effect, vitamin A levels were also reduced following a single dose of ALN-
TTRSC02. Similar PD effects were observed in the subjects of Japanese descent, as compared to 
the subjects in the non-Japanese cohorts. 
AEs were reported in 77% and 50% of ALN-TTRSC02 and placebo treated subjects, 
respectively.  Among ALN-TTRSC02 treated patients, the majority of AEs were mild.  ALN-
TTRSC02 drug-related AEs included injection site reactions in 4 subjects that were mild and 
transient including bruising (50 mg), erythema (200 mg) and pain (200 mg and 300 mg); there 
were no drug-related AEs in patients receiving ALN-TTRSC02 doses ≤25 mg.  There were no 
severe or serious AEs; no subject discontinued from the study due to an AE. A dose-dependent 
pattern in transaminase elevations was observed across the ALN-TTRSC02 doses tested, in 
particular at doses ≥100 mg; the majority were mild, transient, and none were reported as AEs.  
Most alanine transaminase (ALT) and aspartate transaminase (AST) elevations were ≤3 x upper 
limit of normal (ULN); 1 subject receiving ALN-TTRSC02 50 mg had AST >3 x ULN and 1 
subject receiving ALN-TTRSC02 200 mg had ALT and AST >3 x ULN, which were 
asymptomatic and resolved to <ULN without intervention.  There were no concurrent elevations 
in bilirubin or alkaline phosphatase. There were no clinically significant changes in renal 
function or hematologic parameters, including platelets and no clinically significant changes in 
electrocardiogram (ECG), vital signs or physical exam. 
Further information on the chemistry, pharmacology, efficacy, and safety of ALN-TTRSC02 is 
provided in the current edition of the Investigator’s Brochure. 
1.5. 
Study Design Rationale 
This is a global Phase 3 open-label study designed to evaluate the efficacy, safety, and PK/PD 
profile of ALN-TTRSC02 in adult patients with hATTR amyloidosis.  Patients will be 
randomized 3:1 to ALN-TTRSC02 or patisiran-LNP.  Patisiran-LNP is the reference comparator 
arm.  All patients randomized to patisiran-LNP will be transitioned to ALN-TTRSC02 after 
completion of the 18-month Treatment Period. 
The study will consist of a Screening Period of up to 42 days, an 18-month Treatment Period, an 
18-month Treatment Extension Period, and up to a 1-year Follow-up Period after the last dose of 
study.   
The proposed development plan for ALN-TTRSC02 builds upon learnings from the previous 
development of another siRNA that targets TTR, patisiran-LNP (described in Section 1.4). The 
completed patisiran-LNP Phase 3 APOLLO study, which enrolled a similar patient population to 
the current study and incorporated similar endpoints to the current study, will be used as an 
external control for efficacy analysis. The co-primary endpoints in this study, change from 

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baseline in mNIS+7 score and Norfolk QoL-DN total score at Month 9, will be compared with 
the placebo group from the APOLLO study at Month 9 as the primary analysis.  An additional 
analysis of efficacy is planned at Month 18.   
The use of an external control for comparison is supported by the principles outlined in the EMA 
guideline on clinical trials in small populations (CHMP/EWP/83561/2005), ICH E10 guidance 
on control groups in clinical trials, as well as the USA's 21st Century Cures Act (Section 3012 
Targeted Drugs for Rare Diseases).  Based on these guidelines, an external comparison is an 
appropriate clinical study design for diseases occurring in small populations, with well 
understood natural history of disease course.  The natural history of hATTR amyloidosis has 
been well-characterized in several, large, randomized clinical trials, including the APOLLO 
study, as well as natural history studies.  Importantly, these studies all demonstrate similar rates 
of disease progression despite having been conducted at substantially different points in time and 
in patients with different disease characteristics across different geographies (Berk, Suhr et al. 
2013; Adams, Coelho et al. 2015; Maurer, Elliott et al. 2017; Adams, Gonzalez-Duarte et al. 
2018).   The patisiran-LNP reference comparator arm will help to validate the use of the external 
control for the primary and secondary efficacy analyses both by allowing descriptive comparison 
of the clinical efficacy endpoints between treatment arms within this study and by establishing 
similar (non-inferior) level of TTR reduction is achieved for ALN-TTRSC02 and patisiran-LNP. 
Secondary and exploratory endpoints in this study assessing the clinical manifestations of 
hATTR amyloidosis are similar to those in the APOLLO study.  A composite of all-cause death 
and/or all-cause hospitalizations has also been included to assess the impact of ALN-TTRSC02 
on patient outcomes in the overall study population and in patients with cardiac involvement.  
Additional cardiac assessments are included in this study as exploratory endpoints. These 
endpoints will all be assessed in comparison to the placebo group in the APOLLO study. 
Safety will be assessed by monitoring of AEs, laboratory data including liver function tests, 
changes in physical exam, vital signs, and ECG.  Safety data will not be compared to the 
APOLLO study. 
1.6. 
Dose Rationale 
The proposed dose of ALN-TTRSC02 for this study is 25 mg SC given q3M. This dose was 
well-tolerated in the Phase 1 study (see Section 1.4.2 ) and is expected to provide efficacy similar 
to patisiran-LNP based on the anticipated magnitude of TTR lowering.   
Modeling and simulation predict that the proposed 25 mg dose of ALN-TTRSC02 administered 
SC q3M will lead to substantial and persistent serum TTR reduction, comparable to TTR 
lowering observed with patisiran-LNP in the Phase 3 APOLLO study. At steady state, which is 
achieved by approximately 6 months, 25 mg SC q3M regimen of ALN-TTRSC02 is predicted to 
achieve median trough TTR reductions of 86%, which is similar to patisiran-LNP. This 
magnitude of TTR lowering is expected to lead to durable clinical benefit as evidenced by the 
statistically significant difference in mNIS+7 and all the secondary endpoints, including Norfolk 
QoL-DN, in the patisiran-LNP arm compared to placebo in the pivotal Phase 3 APOLLO study.  
Furthermore, on the Phase 3 APOLLO study, this magnitude of TTR lowering was associated 
with an acceptable safety profile. 

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Overall, available nonclinical and clinical data suggest the selected dose will appropriately 
balance safety and efficacy in the broad hATTR patient population.    
1.7. 
Benefit-Risk Assessment 
Based on available nonclinical and clinical data, with evidence of TTR reduction in the healthy 
subject study, TTR reduction by ALN-TTRSC02 is anticipated to beneficially impact disease 
progression in patients with hATTR amyloidosis, as has been shown with other available TTR 
lowering agents including patisiran-LNP and inotersen.   The q3M SC regimen is infrequent, 
easy to administer, and does not require premedication, and thus may maximize convenience and 
minimize overall burden of care.  In the Phase 1 clinical study in healthy subjects, single SC 
doses up to the highest tested dose (300 mg) of ALN-TTRSC02 were well tolerated.   
Given the biological target of ALN-TTRSC02, the available nonclinical and clinical data, and 
the mode of administration, important potential risks for ALN-TTRSC02 are injection site 
reactions (ISRs), liver function test (LFT) abnormalities, and consequences of vitamin A 
deficiency.  During the study, patients will be closely monitored, including evaluation of 
injections sites.  As ALN-TTRSC02 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) 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 ALN-
TTRSC02 dosing due to LFT abnormalities are provided in Section 5.2.3.  Detailed information 
about the known and expected benefits and risks of ALN-TTRSC02 and additional safety 
information may be found in the current edition of the ALN-TTRSC02 Investigator’s Brochure. 
For patisiran-LNP, important identified risks include infusion related reactions (IRRs).  All 
patients must receive premedication with a corticosteroid, paracetamol/acetaminophen, and H1 
and H2 blockers prior to patisiran-LNP administration to reduce the risk of IRRs (see 
Section 5.2.2.2).  Potential risks include consequences of vitamin A deficiency and severe 
hypersensitivity (eg, anaphylaxis) to the active substance or any of the excipients. Detailed 
information about the known and expected benefits and risks of patisiran-LNP and additional 
safety information may be found in the current edition of the patisiran-LNP Investigator’s 
Brochure or, where approved, in the ONPATTRO prescribing/product information. 
Nonclinical and clinical data with ALN-TTRSC02 and patisiran-LNP 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 5.2).  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 ALN-TTRSC02 and patisiran-LNP. 

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2. 
OBJECTIVES AND ENDPOINTS 
The co-primary, and most secondary and exploratory efficacy endpoints are in comparison to the 
placebo arm of the Phase 3 pivotal patisiran-LNP study (ALN-TTR02-004, also referred to as the 
APOLLO study) as specified in the statistical analysis section of the HELIOS-A protocol.  The 
primary analysis will be conducted at Month 9.  An additional analysis of all efficacy endpoints 
will be conducted at Month 18. 
Objectives 
Endpoints 
Primary 
 
To determine the efficacy of ALN-
TTRSC02 in patients with hATTR 
amyloidosis by evaluating the effect on 
neurologic impairment and on quality of 
life  
Co-Primary: 
 
Change from baseline in the Modified 
Neurologic Impairment Score +7 
(mNIS+7) compared to the placebo arm 
of the APOLLO study 
 
Change from baseline in Norfolk Quality 
of Life-Diabetic Neuropathy (Norfolk 
QoL-DN) total score compared to the 
placebo arm of the APOLLO study 
Secondary 
 
To determine the efficacy of ALN-
TTRSC02 on gait speed, nutritional status, 
and disability 
 
To characterize the effect of ALN-
TTRSC02 on serum TTR levels 
 
To evaluate patient mortality and 
hospitalization 
 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study: 
 
Timed 10-meter walk test (10-
MWT); 
 
Modified body mass index (mBMI) 
 
Rasch-built Overall Disability Scale 
(R-ODS) 
 Percent reduction in serum TTR levels in 
the ALN-TTRSC02 arm compared to the 
within-study patisiran-LNP arm  
 
Composite events of all-cause deaths 
and/or all-cause hospitalizations in the 
overall population (over 18 months) 
compared to the placebo arm of the 
APOLLO study 
 Composite events of all-cause deaths 
and/or all-cause hospitalizations in 
patients with cardiac involvement (over 
18 months) compared to patients with 
cardiac involvement in the placebo arm of 
the APOLLO study 

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Objectives 
Endpoints 
Exploratory  
 
To determine the effect of ALN-
TTRSC02 on: 
 
Manifestations of cardiac amyloid 
involvement 
 
Other assessment of neurologic 
impairment  
 
Other assessments of quality of life 
 
Disease stage 
 
Performance of daily activities 
 
To characterize the pharmacodynamic (PD) 
effect of ALN-TTRSC02 and patisiran-LNP 
on vitamin A levels  
 
To characterize plasma pharmacokinetics 
(PK) of ALN-TTRSC02 and patisiran-LNP 
 
To assess presence of antidrug antibodies 
(ADA) to ALN-TTRSC02 and patisiran-LNP 
 
Change from baseline in the following 
parameters compared to the placebo arm of 
the APOLLO study: 
 
N-terminal prohormone B-type 
natriuretic peptide (NT-proBNP) 
levels, echocardiographic parameters, 
Troponin I and T levels, New York 
Heart Association (NYHA) class 
 
Neurologic Impairment Score (NIS) 
 
EuroQoL-5 Dimensions-5 Levels 
(EQ-5D-5L) questionnaire and the 
EuroQoL-Visual Analog Scale (EQ-
VAS) 
 
Familial Amyloidotic 
Polyneuropathy (FAP) stage and 
Polyneuropathy Disability (PND) 
score 
 
Karnofsky Performance Status (KPS) 
 Change from baseline in technetium 
scintigraphy cardiac parameters  
 Percent reduction in serum vitamin A 
levels  
 
PK profile of ALN-TTRSC02 and patisiran-
LNP 
 Incidence and titers of ADA to ALN-
TTRSC02 and patisiran-LNP 
Safety 
 
To determine the safety and tolerability of 
ALN-TTRSC02 in patients with hATTR 
amyloidosis 
 
Frequency of adverse events (AE) 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a global Phase 3 randomized, open-label study designed to evaluate efficacy, safety, and 
PK/PD of ALN-TTRSC02 in adult patients with hATTR amyloidosis.  Patients will be 
randomized 3:1 to ALN-TTRSC02 or patisiran-LNP, a reference comparator.  
The study will consist of a Screening Period of up to 42 days, an 18-month Treatment Period, an 
18-month Treatment Extension Period which will include collection of safety and efficacy in 
patients who switch from patisiran-LNP to ALN-TTRSC02 treatment, and up to a 1-year Follow-
up Period after the last dose of study as shown in Figure 1.   
After the Screening period at the start of the Treatment Period, eligible patients will be randomized 
3:1 on Day 1 to receive 25 mg of ALN-TTRSC02 administered as a SC injection on q3M or 
patisiran-LNP administered as an IV infusion q3w; patients in the patisiran-LNP arm will also 
receive premedications prior to each dose (see Section 5.2.2.2).    During the 18-month Treatment 
Period, patients will undergo assessments for efficacy and/or safety (as outlined in the Schedule 
of Assessments), with key efficacy assessments being performed prior to first dose, at Month 9 
(primary efficacy analysis time-point) and at Month 18; samples for TTR assessment will be 
collected more frequently throughout the 18-month Treatment Period.  
All ALN-TTRSC02 doses will be administered at the clinic during scheduled study assessment 
visits through Month 18. For patients randomized to the ALN-TTRSC02 arm, after Month 9, non-
dosing visits for routine assessments (eg, vital signs and blood collection) may be performed 
outside the clinic (eg, at home) by a trained healthcare professional where applicable country and 
local regulations and infrastructure allow.   
All patisiran-LNP doses will be administered at the clinic during the scheduled study assessment 
visits through Month 9.  After Month 9, visits for patisiran-LNP dosing, as well as routine 
assessments (eg, vital signs and blood collection), may be performed outside of the clinic (eg, at 
home) by a trained healthcare professional where applicable country and local regulations and 
infrastructure allow, with the exception of the patisiran-LNP dosing visits at Weeks 48, 60 and 72 
which must be performed in the clinic. 
For both ALN-TTRSC02 and patisiran-LNP treated patients, wherever possible, AE collection 
associated with visits performed outside of the clinic will be collected by a phone call from 
qualified site staff.  In addition, ad hoc visits may be performed outside the clinic (eg, at home) 
throughout the study in cases where, for example, a blood sample needs to be redrawn.  In all 
cases, the Month 9 and Month 18 efficacy visits will be performed in the clinic.  Further details 
with regard to visits performed outside of the clinic are provided in the Study Reference Manual. 
During the Treatment Extension Period, starting at Week 84/Month 19, patients who are tolerating 
their ALN-TTRSC02 injections as determined by the Investigator and where applicable country 
and local regulations allow, may have ALN-TTRSC02 administered outside the clinic (eg, home) 
by a healthcare professional trained on study drug administration. Also, starting at Week 84/Month 
19, all patients on the patisiran-LNP arm will switch to treatment with ALN-TTRSC02 (first dose) 
and remain on ALN-TTRSC02 q3M treatment for the remainder of the study. For patients in the 
patisiran-LNP arm who transition to ALN-TTRSC02 during the Treatment Extension period, 

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ALN-TTRSC02 may be administered outside of the clinic (eg, at home) as outlined above after 
they have received, and tolerated, at least one dose in the clinic. During the Treatment Extension 
Period, patients will undergo safety assessments quarterly and efficacy assessments every 9 
months at Month 27 and at Month 36.   
During the Follow-up Period, all patients on ALN-TTRSC02 will undergo safety assessments 
quarterly until serum TTR levels return to ≥80% of baseline (for up to 1 year after the last dose of 
study drug), or until the patient starts a TTR lowering regimen as a part of clinical care, whichever 
comes first; all patients will be followed for a minimum of 3 months.  Female patients of child-
bearing potential will be followed until serum TTR levels return to ≥80% of baseline.  Patients 
who discontinue treatment early while on patisiran-LNP will undergo a follow-up visit 30 days 
after the last dose of study drug.  
The placebo arm of the APOLLO study will be used as an external control for the primary, most 
secondary, and most exploratory efficacy analysis.  Primary and secondary efficacy evaluations 
will include mNIS+7, Norfolk QoL-DN questionnaire, 10-MWT, mBMI, R-ODS questionnaire, 
percent TTR reduction, and the composite of all-cause deaths and/or all-cause hospitalizations. 
Study personnel performing the mNIS+7 component assessments will not reference the results of 
any previous assessments.  
3.2. 
Duration of Treatment  
The treatment duration in this study is up to 36 months inclusive of the 18-month Treatment 
Period and the 18-month Treatment Extension Period. 
Refer to Section 4.3.1 for information on early treatment discontinuation. 
3.3. 
Duration of Study 
The estimated time on study for each patient is approximately 3 years, inclusive of 42 days of 
Screening, and up to 36 months of open-label treatment (including the 18-month Treatment 
Period plus the 18-month Treatment Extension Period). 
The Follow-up Period is until serum TTR levels return to ≥80% of baseline (for up to 1 year after 
the last dose of study drug), or until the patient starts a TTR lowering regimen as a part of 
clinical care, whichever comes first; all patients will be followed for a minimum of 3 months.  
Female patients of child-bearing potential who discontinue ALN-TTRSC02 will be followed 
until serum TTR levels return to ≥80% of baseline. 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if: 
 the patient has completed the Month 36 Efficacy Visit, or  
 the patient has completed the ALN-TTRSC02 Follow-up Period, until serum TTR levels 
return to ≥80% of baseline (for a maximum of up to 1 year after the last dose of study 
drug), or until the patient starts a TTR lowering regimen as a part of clinical care, 
whichever comes first; all patients will be followed for a minimum of 3 months. Female 
patients of child-bearing potential who discontinue ALN-TTRSC02 will be followed until 
serum TTR levels return to ≥80% of baseline. 

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3.4. 
Number of Planned Patients 
Approximately 160 patients are planned for enrollment in this study.   
To match the cardiac disease severity with the APOLLO study population, the study plans to 
enroll no more than 15% of patients with NT-proBNP values greater than 3000 ng/L at baseline.   
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the Interactive Response System (IRS), patients will be randomized 3:1 to the ALN-
TTRSC02 or patisiran-LNP arm.  Randomization will be stratified by TTR genotype (V30M vs. 
non-V30M) and baseline NIS score (<50 vs ≥50). 
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 IRS. The Investigator or his/her designee will 
contact the IRS to randomize the patient after confirming that the patient fulfills all the inclusion 
criteria and none of the exclusion criteria. 
3.6. 
Blinding 
Not applicable, this is an open-label, controlled study. 
3.7. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will oversee the safety and overall conduct 
of this study through the Treatment Period (through Month 18), providing input to the Sponsor.  
The DMC will operate under the rules of a charter that will be reviewed and approved at the 
organizational meeting of the DMC.  The DMC has the responsibility for reviewing safety data 
and analyses and making recommendations to the Sponsor.  The DMC will perform periodic 
reviews of data during the course of the clinical trial through the Treatment Period, and on an ad 
hoc basis for review of emergent safety data.  Details are provided in the DMC Charter. 
3.8. 
Adjudication Committee 
An independent Adjudication Committee will review deaths and hospitalizations and will 
attribute a cause according to the responsible underlying disease process rather than the 
immediate mechanism.  Deaths and hospitalizations will be classified as specified in the 
Adjudication Committee Charter. 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Each patient must meet all of the following eligibility criteria at Screening Visit 1 (except where 
specified) to be eligible for enrollment in the study. 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all of the following criteria apply: 
Age and Sex 

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1. Male or female age 18 (or age of legal consent, whichever is older) to 85 years of age  
Patient and Disease Characteristics 
2. Have a diagnosis of hATTR amyloidosis with documented TTR mutation  
3. Have an NIS of 5 to 130 (inclusive; this criterion must be met at the Screening Visit 2) 
4. Have a PND score of ≤3b (this criterion must be met at the Screening Visit 2) 
5. Have a Karnofsky Performance Status (KPS) of ≥60% 
Informed Consent 
6. Patient is willing and able to comply with the study requirements and to provide written 
informed consent   
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Has had a liver transplant or is likely, in the opinion of the Investigator, to undergo liver 
transplantation during the 18-month Treatment Period of the study 
2. Has known other (non-hATTR) forms of amyloidosis or clinical evidence of 
leptomeningeal amyloidosis 
3. Has a New York Heart Association heart failure classification >2 
Laboratory Assessments 
4. Has any of the following laboratory parameter assessments:  
a. ALT and/or AST >1.5× upper limit of normal reference range (ULN) 
b. Total bilirubin >ULN (>1.5 ULN in patients with Gilbert's Syndrome) 
c. International normalized ratio (INR) >1.2 (patients on anticoagulant therapy with an 
INR of ≤3.5 will be allowed) 
(Note: ALT, AST, and total bilirubin laboratory criteria must be met at both Screening 
Visit 1 and Screening Visit 2) 
5. Platelet count <50,000/μL  
6. Absolute neutrophil count (ANC) <1500 cells/mm³ 
7. Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73m2 (using the Modification 
of Diet in Renal Disease [MDRD] formula) 
8. Has vitamin B12 levels below the lower limit of normal (LLN) 
9. Has known human immunodeficiency virus (HIV) infection; or evidence of acute or 
chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection 
Prior/Concomitant Therapy 
10. 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 

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days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing (Day 
1) 
11. Received prior TTR-lowering treatment or participated in a gene therapy trial for hATTR 
amyloidosis 
12. Is currently taking tafamidis, doxycycline, or tauroursodeoxycholic acid; if previously on 
any of these agents, must have completed a 14-day wash-out prior to dosing (Day 1) 
13. Is currently taking diflunisal; if previously on this agent, must have at least a 3-day wash-
out prior to dosing (Day 1) 
Medical Conditions 
14. Has other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune 
disease, monoclonal gammopathy) that the treating physician believes to be contributing 
to the neuropathy 
15. Had acute coronary syndrome within the past 3 months 
16. Has uncontrolled clinically significant cardiac arrhythmia or unstable angina 
17. Has known type 1 diabetes 
18. Has had type 2 diabetes mellitus for ≥5 years 
19. Has untreated hypo- or hyperthyroidism 
20. Has had a major surgery within the past 3 months or has a major surgery planned during 
the study through Month 18 
21. Has an active infection requiring systemic antiviral, antiparasitic or antimicrobial therapy 
that will not be completed prior dosing (Day 1) 
22. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix that has been successfully treated 
23. Anticipated survival is less than 2 years, in the opinion of the Investigator 
24. History of multiple drug allergies; or history of allergic reaction to an oligonucleotide or 
GalNAc; or had a prior severe reaction to a liposomal product or any component of 
patisiran-LNP (ALN-TTR02) 
25. Is unable to take the required premedications (see Section 5.2.2.2) 
26. History of intolerance to subcutaneous (SC) injection(s) or significant abdominal scarring 
that could potentially hinder study drug administration or evaluation of local tolerability 
27. Any condition (eg, medical concern), which in the opinion of the Investigator, would 
make the patient unsuitable for dosing or which could interfere with the study 
compliance, the patient’s safety and/or the patient’s participation through the Month 18 
visit of the study.  This includes significant active and poorly controlled (unstable) 
cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric disorders 
unrelated to hATTR identified by key laboratory abnormalities or medical history 
Contraception, Pregnancy, and Breastfeeding 

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28. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.5.1.  
29. Female patient is pregnant or breastfeeding 
Alcohol Use 
30. 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]) 
31. History of alcohol abuse, within the last 12 months before screening, in the opinion of the 
Investigator 
4.3. 
Removal from Therapy or Assessment 
Patients or their legal guardians 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 and recorded in the 
electronic case report form (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-adverse event) 
 Or, the study is terminated by the Sponsor 
The Investigator will confer with the Sponsor or Medical Monitor before discontinuing dosing of 
the patient.  Patients who are pregnant will be discontinued from study drug dosing immediately 
(see Section 6.5.7.7 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 is captured in the final analyses.   

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If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the subject the options for continuation of 
the Schedule of Assessments (Table 3), 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 endpoints and adverse events, and must document this decision in 
the patient’s medical records. 
If a patient discontinues dosing due to an AE, including serious adverse events (SAEs), the event 
should be followed as described in Section 6.5.7. When a patient discontinues study drug dosing, 
the primary reason must be recorded in the electronic case report form (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 study drug early for any reason during the Treatment Period (defined as 
the time the first dose of study drug is administered on Study Day 1 through completion of the 
Month-18 assessments) should complete the Early Drug Discontinuation visit and will be 
encouraged to remain on the study to complete the modified Month 9 and Month 18 efficacy 
assessments visits, prioritizing the primary and secondary assessments, where possible so that 
their experience is captured in the final analyses. If a patient discontinues study drug and 
completes the Early Drug Discontinuation visit within 3 months of Month 9 or Month 18 and 
remains on the study, they will not be required to complete the modified Efficacy Assessments at 
Month 9 and/or Month 18, as applicable depending on the time they discontinue study drug 
(Table 3). 
Patients who discontinue study drug, but who remain on study, may receive treatment consistent 
with local standard practice for their disease per Investigator judgment, as applicable.  For 
patients who discontinue study drug and remain in the study, all AEs will be collected for 90 
days after the last dose, thereafter, SAEs and AEs of clinical interest (see definition in 
Section 6.5.7.1) will be collected for the remainder of their participation in the study. 
Patients who discontinue study drug during the Treatment Extension period will be asked to 
return for their next scheduled visit to complete the Early Drug Discontinuation visit.   
All patients who discontinue study drug will also be asked to complete safety follow-up visits, 
per the Follow-up Period schedule (see Table 3) until serum TTR levels return to ≥80% of 
baseline (for up to 1 year after the last dose of study drug), or until the patient starts a TTR 
lowering regimen as a part of clinical care, whichever comes first; all patients will be followed 
for a minimum of 3 months. Female patients of child-bearing potential who discontinue ALN-
TTRSC02 will be followed until serum TTR levels return to ≥80% of baseline. 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  Patients 
considering stopping their participation in the study should be informed that they can discontinue 
study drug and/or decline procedural assessments and remain in the study for the collection of 
important study data as described in Section 4.3.1. If a patient still chooses to discontinue study 

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drug and stop participation in all follow-up, every effort should be made to conduct the Early 
Drug Discontinuation Visit assessments within 4 weeks of the last dose (Table 3).   
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’s 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, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and 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, 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. 
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 6.5.7. 
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 fails to return to the clinic for 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 to continue in the study and/or should 
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 Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, 
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the patient’s 
medical record. 
 Should the patient continue to be unreachable, the patient will be considered to have 
stopped participation in the study. 
 For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status.  This 
ensures that the outcome of the study is as comprehensive as possible. 
4.3.4. 
Replacement of Study Patients  
Patients who discontinue the study drug or stop participation in the study will not be replaced. 
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of ALN-TTRSC02 
and patisiran-LNP is provided in the Pharmacy Manual. 
All patients will be instructed to take the recommended daily allowance of vitamin A while on 
the study. 
5.2.1. 
Description 
ALN-TTRSC02 will be supplied as a sterile solution containing 50 mg/mL of siRNA ALN-
65492 free acid (equivalent to 53 mg/mL sodium salt) in phosphate buffered saline for SC 
injection.  The drug product does not contain preservatives and is intended for single use.  See 
the Pharmacy Manual for further details of solution concentration and fill volume.   
The comparator drug for this study will be patisiran-LNP that contains 2 mg/mL of drug 
substance ALN-18328 (siRNA) and lipid excipients DLin-MC3-DMA, DSPC, cholesterol, and 
PEG2000-C-DMG formulated as lipid nanoparticles (LNPs) in isotonic phosphate buffered saline 
for IV administration.  Patisiran-LNP will be provided by the Sponsor.   

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5.2.2. 
Dose and Administration 
5.2.2.1. 
ALN-TTRSC02 
ALN-TTRSC02 25 mg SC injection will be administered q3M (12 weeks ±3 days during the 
Treatment Period and ±7 days during the Treatment Extension Period).  Study drug SC injections 
will be administered under the supervision of the Investigator or healthcare professional.   
All ALN-TTRSC02 doses will be administered at the clinic during scheduled study assessment 
visits during the Treatment Period on Day 1 through Month 18.  During the Treatment Extension 
Period, starting at Week 84/Month 19, patients who are tolerating their ALN-TTRSC02 
injections as determined by the Investigator and where applicable country and local regulations 
allow, may have ALN-TTRSC02 administered outside the clinic (eg, home) by a healthcare 
professional trained on study drug administration.   
Method of Administration of ALN-TTRSC02 
ALN-TTRSC02 is for SC use and should be administered by a healthcare professional. 
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. 
Missed Doses of ALN-TTRSC02 
If a patient does not receive a dose of ALN-TTRSC02 within the specified dosing window, the 
Investigator should contact the Medical Monitor.  After such consultation, the dose may be 
administered with up to a 6-week delay (to be considered a delayed dose).  Thereafter, the dose 
will be considered missed and not administered.  If a dose is administered with a delay, the next 
dose will resume following the original schedule. 
During the Treatment Period, every effort should be made to avoid missed doses of 
ALN-TTRSC02.  During the Treatment Period, if a patients misses a dose, the Investigator, in 
consultation with the Medical Monitor, will discuss whether the patient will be able to continue 
in the study (see also Section 4.3).   
5.2.2.2. 
Patisiran-LNP 
Patisiran-LNP 0.3 mg/kg IV infusion will be administered once every 3 weeks (q3w) ±3 days.  
The amount (in mg) of study drug to be administered should be determined based on the patient's 
weight (kg).  Dosing is based on actual body weight. For patients weighing ≥ 100 kg, the 
maximum recommended dose is 30 mg. 
All patisiran-LNP doses will be administered at the clinic during the scheduled study assessment 
visits through Month 9.  After Month 9, patisiran-LNP dosing may be performed at home by a 
trained healthcare professional where applicable country and local regulations and infrastructure 
allow, with the exception of the patisiran-LNP dosing visits at Weeks 48, 60, and 72, which must 
be performed in the clinic during scheduled study assessment visits through Month 18. 
Required premedication for patients in the patisiran-LNP arm 

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All patients should receive premedication prior to patisiran-LNP administration to reduce the risk 
of infusion-related reactions (IRRs). Each of the following medicinal products should be given 
on the day of patisiran-LNP infusion at least 60 minutes prior to the start of infusion: 
 Intravenous corticosteroid (dexamethasone 10 mg, or equivalent) 
 Oral paracetamol (500 mg) 
 Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent)  
 Intravenous H2 blocker (ranitidine 50 mg, or equivalent) 
For premedications not available or not tolerated intravenously, equivalents may be administered 
orally.  Modifications to lower the corticosteroid dose may be made to the premedication 
regimen for either of the following 2 reasons: 
 If a patient is having difficulty tolerating the corticosteroid premedication regimen (eg, 
patient develops uncontrolled hyperglycemia, altered mental status, or other 
complication), then lowering of the corticosteroid premedication may be allowed for that 
patient after consultation with the medical monitor.   
 If a patient has tolerated 3 or more infusions of patisiran-LNP with their current 
corticosteroid premedication regimen (ie, patient has not had IRRs during the past 3 or 
more infusions), then lowering of the corticosteroid premedication is recommended.   
Corticosteroid tapering should be performed in the clinic. Steps to lower corticosteroid dosing 
are provided in the Pharmacy Manual.   
Additional or higher doses of one or more of the premedications may be administered to reduce 
the risk of IRRs, if needed.  Guidelines for management of IRRs can be found in the Pharmacy 
Manual.   
Method of Administration of patisiran-LNP 
Patisiran-LNP is for IV use and should be administered by a healthcare professional.  
Weight from previous visit may be used for calculating dose.  Weight must be collected predose. 
The patient’s infusion site should be assessed for signs of any localized reaction during the 
infusion and for 30 minutes after the end of the infusion.  The patient will remain at the study site 
for 1 hour following completion of dosing for observation and completion of assessments. 
Detailed instructions for study drug preparation and administration can be found in the Pharmacy 
Manual. 
Missed Doses of patisiran-LNP   
If a patient does not receive a dose of patisiran-LNP within the dosing window (±3 days), the 
dose will be considered missed and not administered. 
A dose will be considered completed if 80% or more of the total volume of the IV solution has 
been administered to the patient.  Patients will be permitted to miss an occasional dose of study 
drug.  However, if a patient misses 2 consecutive doses, the Investigator, in consultation with the 
Medical Monitor, will discuss whether the patient will be able to continue in the study. 

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5.2.2.3. 
Switching from Patisiran-LNP to ALN-TTRSC02 After Month 18 
On Week 84, patients in the patisiran-LNP arm will be switched to ALN-TTRSC02 treatment 
and will receive the first ALN-TTRSC02 dose.  The last dose of patisiran-LNP will be at Week 
81, and patients should receive treatment with ALN-TTRSC02 3 weeks later on Week 84 and 
thereafter q3M (12 weeks ±7 days) for the remainder of the study. 
5.2.3. 
LFT Criteria for Withholding, Monitoring and Stopping ALN-TTRSC02 Dosing  
1. LFT results (Table 7) are to be obtained within 28 days prior to ALN-TTRSC02 dosing 
and results are to be reviewed prior to each dose of ALN-TTRSC02.  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. 
2. For any ALT or AST elevation >3× ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 6.  
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. 
b. Perform assessments per Table 6 and Table 8. 
c. If an alternative cause is found, provide appropriate care. 
4. For any ALT or AST elevation >3× ULN without alternative cause 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, 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 6 
(below). 

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Table 6: 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 8 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT and coagulation per Table 7  
• 
Monitor at least every two weeks (LFT and coagulation per Table 7)  
• 
If elevation persists for ≥2 months, must discuss with the medical monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold ALN-TTRSC02 dosing until recovery to ≤1.5× ULN; may resume 
dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
• 
Table 8 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 7  
• 
Monitor at least weekly (LFT and coagulation per Table 7) until ALT 
and/or AST is declining on two 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 
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; INR=international normalized ratio; 
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. 
5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of ALN-TTRSC02 and patisiran-LNP doses, according to procedures detailed in the 
Pharmacy Manual.  No special procedures for the safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately [5±3°C] until dose 
preparation.  Deviations from the recommended storage conditions should be reported to the 
Sponsor and use of the study drug halted until authorization for its continued use has been 
provided by the Sponsor or designee, as described in the Pharmacy Manual. 
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 will be provided in the 
Pharmacy Manual. 

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5.2.5. 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. Additional details will be available in the Pharmacy Manual. 
5.2.6. 
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, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study center according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications 
Use of concomitant medications will be recorded on the patient’s eCRF as specified in the 
Schedule of Assessments (see Table 1 to Table 3).  This includes all prescription medications, 
herbal 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 NSAIDs 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.   
Prohibited medications during the study include inotersen, tafamidis, diflunisal, and 
doxycycline/TUDCA (see Section 4.2 for prior medication washout requirements before first 
dose of study drug).  Use of patisiran-LNP outside of the protocol specified administration is also 
prohibited.  Any investigational agent other than ALN-TTRSC02 is not permitted during the 
study. 
For other permitted concomitant medications administered subcutaneously, do not administer in 
same injection site area as the study drug, for 2 weeks after the last dose of study drug.  
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 CRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
If available, information from a cardiac technetium scan or liver biopsy prior to study enrollment 
or during the study (as part of standard of care) should be collected and recorded as part of 
concomitant procedure information. 

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5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals. 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females of child-bearing potential must be willing to use acceptable methods of contraception 
from 14 days before first ALN-TTRSC02 dose, throughout study participation, and for 90 days 
after last dose administration.   
Females of child-bearing potential taking patisiran-LNP must use acceptable methods of 
contraception prior to dosing and for 12 weeks after the last dose of patisiran-LNP in this study if 
they do not switch and continue treatment with ALN-TTRSC02 starting at Day 337 (Week 48). 
Birth control methods which are considered highly effective include: 
 Placement of an intrauterine device. 
 Placement of an intrauterine hormone-releasing system.  
 Bilateral tubal occlusion. 
 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 for low dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. Females of child-bearing potential 
who use hormonal contraceptives as a method of contraception must also use a barrier 
method (condom or occlusive cap [diaphragm or cervical/vault cap] in conjunction 
with spermicide [eg, foam, gel, film, cream, or suppository]).   
 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 childbearing 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.  

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For male patients, no contraception is required.  However, contraception use by males should be 
consistent with local regulations 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 6.5.6.2). 
5.5.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1 (Screening through Treatment Period 
Month 9), Table 2 (Treatment Period from Month 9 through Month 18), Table 3 (Treatment 
Extension Period, Other Visits, and Follow-up Period), Table 4  (ALN-TTRSC02 PK Time 
Points) and Table 5 (Patisiran-LNP PK Time Points). Additional information on the collection of 
study assessments will be detailed in the Study Reference Manual.  In this study there are 2 types 
of study centers:  
 Patient Care Sites (PCS) can screen, dose, and manage the well-being of patients and 
collect safety assessments, and can administer efficacy assessments that include, but are 
not limited to, completion of a questionnaire or collection of blood samples for 
assessment of TTR and other PD biomarkers, as well as cardiac biomarkers, but will not 
perform the following efficacy assessments: NIS, mNIS+7, HRdb, 10-MWT, FAP and 
PND, KPS, echocardiogram.  
 Central Assessment Sites (CAS) can perform all efficacy assessments and perform the 
same assessments as at a PCS (as stated above).  Efficacy assessments (NIS, mNIS+7, 
HRdb, 10-MWT, FAP and PND, KPS, echocardiogram) in this study may require special 
training as described further in Section 6.2; therefore, all patients must be sent to a CAS 
to collect these efficacy assessments during screening and predose baseline assessments, 
Month 9, Month 18, and during the Treatment Extension period at Month 27 and Month 
36.  Assessors who will perform efficacy assessments at a CAS will be different from site 
personnel who monitor the administration of study drug during the study and monitor the 
well-being of the patient during the study.  This is instituted to minimize the influence 
patient management and AEs may have on efficacy assessment evaluation(s). 
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, urgent care visits, 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 Reference Manual. 

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6.1. 
Screening Assessments 
An informed consent form (ICF) or assent form that has been approved by the appropriate 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) must be signed by the 
patient (or legal guardian) before the Screening procedures are initiated.  All patients (or their 
legal guardians) will be given a copy of the signed and dated ICF and/or assent form. 
See Table 1 for a list of Screening visit assessments.   
Patients will complete the following 3 visit types prior to randomization:  the informed consent 
form (ICF) will be obtained at the Visit 1 (Screening), and all inclusion/exclusion criteria will be 
assessed except for the NIS and PND score criteria; see Section 4.1); the NIS and PND score 
inclusion criteria will be assessed at Visit 2 (Baseline first assessment); other baseline 
assessments will be completed at Visit 3 or at Day 1 prior to first dose.  Visits 1, 2 and 3 may 
each occur over multiple days.   
6.1.1. Retesting 
If screening laboratory abnormalities, in the Investigator’s judgement, are felt likely to be 
transient, then the laboratory tests may be repeated. The Investigator’s rationale should be 
documented.  Laboratory values can be retested once during screening provided that the patient 
can be evaluated for eligibility and randomized within the allowed Screening period. Qualifying 
LFTs (AST, ALT and bilirubin) are an exception to this rule and may not be repeated. 
6.1.2. Rescreening 
For patients who do not meet LFT or NIS eligibility 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 screening assessment. 
6.1.3. Demographic and Medical History/Disease History 
Medical history will be collected during screening Visit 1 (including any cardiac disorders, any 
eye disorders or previous ophthalmology test results, and prior medications).  Documented 
technetium scintigraphy and/or tissue biopsy testing for amyloidosis performed prior to study 
enrollment should be collected and recorded as part of medical history. Information on prior 
medications, hospitalization, and procedures through 1 year prior to first dose should be 
collected and recorded. 
At screening Visit 2 and Visit 3, only additional medical history changes since Visit 1 will be 
collected. 
Also, technetium scintigraphy scans and/or tissue biopsy testing for amyloidosis performed as 
part of clinical care during the study should be collected and recorded as part of concomitant 
procedure information.   

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6.2. 
Efficacy Assessments 
6.2.1. 
Neurologic Impairment Assessments  
6.2.1.1. 
Modified Neurological Impairment Score +7 (mNIS+7)  
The mNIS+7 assessment tool is a 304-point composite measure of neurologic impairment which 
includes the following measures and components (Suanprasert, Berk et al. 2014):  
 Physical exam of lower limbs, upper limbs and cranial nerves to assess motor 
strength/weakness and determine the following component scores:  
 NIS-weakness (NIS-W)  
 NIS-reflexes (NIS-R) 
 Electrophysiologic measures of small and large nerve fiber function to determine the 
5 NCS component score that includes assessment of the ulnar CMAP, ulnar SNAP, 
sural SNAP, tibial CMAP, peroneal CMAP  
 Sensory testing to determine the quantitative sensory testing (QST) score included 
assessing touch pressure by body surface area (QST-BSATP) and heat pain by body 
surface area (QST-BSAHP).  A Computer Aided Sensory Evaluator (CASE) IV 
device will be used for this assessment. 
 Postural blood pressure is measured to assess autonomic function. Postural blood 
pressure is measured sitting down and standing up.  Points are assigned based on the 
change in blood pressure with standing. 
A summary of the scoring of the components of the mNIS+7 is provided in Section 10.1. 
6.2.1.2. 
Neurologic Impairment Score (NIS) 
The NIS assessment is a 244-point composite measure of neurologic impairment which includes 
a physical exam of lower limbs, upper limbs and cranial nerves to assess motor 
strength/weakness and determine the following component scores: 
 NIS-W 
 NIS-R 
 NIS-sensation (NIS-S) 
6.2.1.3. 
Personnel and Procedures to Ensure Quality and Consistency of NIS and 
mNIS+7 Scoring 
The NIS and mNIS+7 will be evaluated at the timepoints specified in the Schedule of 
Assessments (Table 1 to Table 3).  The NIS-W and NIS-R assessments obtained for NIS 
calculation do not need to be repeated for the mNIS+7 calculation. 
As per the Schedule of Assessments, 2 independent assessments will be performed on separate 
days (1 assessment on each day); the 2 assessments should be performed approximately 24 hours 
apart from each other but not more than 7 days apart.  Each site should make every effort to have 
these assessments performed by the same assessor.  

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NIS and QST assessments will be performed by certified staff trained on the use of the CASE IV 
device.  NCS studies will be performed by trained staff.   
Study personnel performing the mNIS+7 component assessments will not reference the results of 
any previous assessments. 
All site staff performing the mNIS+7 will be trained and certified by the peripheral neuropathy 
laboratory at the 
, USA.  The peripheral neuropathy laboratory at the 
 
also serves as the central laboratory that will assess the mNIS+7 score.  All data will be 
transmitted to the 
 where qualified personnel will assess the quality and acceptability 
of all test scores.  The peripheral neuropathy laboratory at the 
 can request a site to 
repeat testing of mNIS+7 components per the 
 Standard Operating Procedures (SOP) 
if the quality was not acceptable at any time point. 
Data acquisition, storage, and transfer guidelines will be provided in the Study Reference 
Manual.  
6.2.2. 
Heart Rate Response to Deep Breathing (HRdb) 
The HRdb test evaluates small nerve fiber autonomic function by the cardio-vagal response.  
This assessment will be performed by a certified trained staff at the timepoints specified in the 
Schedule of Assessments (Table 1 to Table 3).  The average heart rate difference while taking 
eight deep breaths will be measured using a CASE IV device.   
As per the Schedule of Assessments, 2 independent assessments will be performed on separate 
days (1 assessment on each day); the 2 assessments should be performed approximately 24 hours 
apart from each other but not more than 7 days apart.  Each site should make every effort to have 
this assessment performed by the same assessor. 
6.2.3. 
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) 
The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes 
measure that assesses 5 domains:  physical function, large fiber neuropathy, activities of daily 
living, symptoms, small fiber neuropathy, and autonomic neuropathy. The total score ranges 
from -4 (best possible quality of life) to 136 points (worst possible quality of life) (Vinik, Hayes 
et al. 2005; Vinik, Vinik et al. 2014).  
The Norfolk QoL-DN questionnaire will be completed at the timepoints specified in the 
Schedule of Assessments (Table 1 to Table 3).  
6.2.4. 
Ten-meter Walk Test (10-MWT) 
The time it takes for a patient to walk 10 meters (gait speed) will be assessed at the timepoints 
specified in the Schedule of Assessments  (Table 1 to Table 3). The 10-MWT will be performed 
and recorded following procedures outlined in the Study Reference Manual. The test must be 
completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  
As per the Schedule of Assessments, 2 independent assessments are to be performed 
approximately 24 hours apart from each other but not more than 7 days apart. Each site should 
make every effort to have this assessment performed by the same assessor. 

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6.2.5. 
Modified Body Mass Index (mBMI) 
The nutritional status of patients is evaluated using the mBMI; calculated as the product of body 
mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum 
albumin (g/L).   
Weight, height, and serum albumin (collected as part of the serum chemistry panel) will be 
collected at the timepoints specified in the Schedule of Assessments (Table 1 to Table 3). The 
site will not perform the calculation for mBMI.   
6.2.6. 
Rasch-built Overall Disability Scale (R-ODS) 
An assessment of the disability each patient experiences will be assessed through the R-ODS 
questionnaire at the timepoints specified in the Schedule of Assessments (Table 1 to Table 3).  
The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity 
and social participation limitations in patients. 
6.2.7. 
Deaths and Hospitalizations 
All deaths and hospitalizations will be recorded at Day 1 post dose and throughout the study as 
specified as part of adverse events (AEs) monitoring (see Section 6.5.7) according to the 
Schedule of Assessments (Table 1 to Table 3).  
Reason for deaths and hospitalizations will be adjudicated by an Independent Clinical 
Adjudication Committee (see Section 3.8). 
6.2.8. 
European Quality of Life-5 Dimensions 5-Levels (EQ-5D-5L) and EQ-Visual 
Analog Scale (EQ-VAS) 
The EQ-5D index score is based on the response to questions evaluating 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression).  
Each dimension scored is based on 5 possible levels where level 1 reflects the best possible score 
for that dimension.  As an example, the 5 levels for the dimension of self-care include: level 1: 
no problems with washing or dressing self, level 2: slight problems, level 3: moderate problems, 
level 4: severe problems, level 5: unable.  The EQ-5D index score is derived based on scores 
from all 5 dimensions; score range is from 0 (worst QoL) to 1 (best QoL).   
The EQ-VAS is a single question evaluating the patient’s own global impression of their overall 
health and is evaluated on a scale of 0 (worst possible health) to 100 (best possible health). 
The EQ-5D-5L and EQ-VAS questionnaire will be completed at the timepoints specified in the 
Schedule of Assessments (Table 1 to Table 3).   
6.2.9. 
PND Score and FAP Stage 
Ambulation and changes in disease stage will be evaluated through physician assessment of PND 
score and FAP stage (Coutinho, DeSilva et al. 1980; Yamamoto, Wilczek et al. 2007).  
PND and FAP will be completed at the timepoints specified in the Schedule of Assessments 
(Table 1 to Table 3).  
PND scoring and FAP stages are described in Section 10.2. 

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6.2.10. 
Cardiac Assessments 
Manifestations of cardiac amyloid involvement will be assessed through echocardiogram, as well 
as measurement of serum levels of the cardiac biomarkers NT-proBNP and troponin T and 
troponin I.  The impact of heart failure on quality of life will also be assessed as described below.  
Certified technicians will be required to administer cardiac imaging assessments as specified in 
the Study Reference Manual. 
6.2.10.1. Echocardiogram  
Echocardiographic parameters will be used for assessment of cardiac structure and function.  
Echocardiograms will be performed at the timepoints specified in the Schedule of Assessments 
(Table 1 to Table 3), and analyzed at a central cardiac imaging core lab.   
Image acquisition, storage, and transfer guidelines will be provided in the Study Reference 
Manual. 
6.2.10.2. Cardiac Biomarkers 
Cardiac biomarkers, including NT-proBNP, troponin T and troponin I, will be used to assess 
cardiac stress and heart failure severity.  These biomarkers have also been shown to be 
prognostic of outcomes in heart failure including ATTR amyloidosis (Damy, Jaccard et al. 2016; 
Merlini, Lousada et al. 2016; Kristen, Maurer et al. 2017).  Blood samples will be drawn to 
measure levels of NT-proBNP, troponin T and troponin I at the timepoints specified in the 
Schedule of Assessments (Table 1 to Table 3).   
At Screening Visit 1, only NT-proBNP will be assessed for eligibility purposes. Baseline cardiac 
biomarkers (NT-proBNP, troponin T, and troponin I) will be assessed at Screening Visit 3.   
Details on cardiac biomarker sample collection, processing, and storage will be provided in a 
Study Laboratory Manual. 
6.2.10.3. Technetium Scintigraphy Imaging 
At select sites, technetium scintigraphy will be collected according to the Schedule of 
Assessments (Table 1 to Table 3), as an exploratory imaging parameter to assess cardiac amyloid 
involvement.  Based on local practice standards, either 99Tc-Pyrophosphate (99Tc-PYP), 99Tc-
3,3-diphosphono-1,2-propanodicarboxylic acid (99Tc-DPD) or 99Tc-hydroxymethylene 
diphosphonate (99Tc-HMDP) can be used as the tracer.  Technetium scintigraphy images will be 
interpreted at a central imaging core laboratory.  Image acquisition, storage, and transfer 
guidelines will be provided in the Study Reference Manual. 
At the select sites where technetium scintigraphy is being performed, patients may be exempt 
from baseline technetium scintigraphy assessment if a technetium scintigraphy has been 
performed prior to study entry as part of the patient clinical care within 6 months prior to the 
baseline assessment.  In such cases, where possible, the historical technetium scintigraphy exam 
performed prior to study entry as part of the patient’s clinical care should be collected and 
transferred to the central imaging core laboratory for interpretation. 

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6.2.10.4. New York Heart Association (NYHA) Class  
NYHA class is a clinical assessment of symptoms resulting from heart failure and is assessed 
according to the table in Section 10.3.  NYHA class will be evaluated at the timepoints specified 
in the Schedule of Assessments (Table 1 to Table 3).  The score collected at Screening will be 
used to determine eligibility and will also be collected on a regular basis during the study. 
6.2.11. 
Karnofsky Performance Status (KPS) 
The Karnofsky Performance Status (KPS) assessed according to Section 10.4 will be evaluated at 
the timepoints specified in the Schedule of Assessments (Table 1 to Table 3).  The score 
collected at Screening will be used to determine eligibility. 
6.3. 
Pharmacodynamic Assessments 
In this study serum TTR and vitamin A levels will be collected as measurements of PD effect.  
These measurements will be collected and analyzed centrally as specified in the Study 
Laboratory Manual.   
Blood samples will be collected prior to dosing for the assessment of TTR and vitamin A levels 
according to the timepoints specified in the Schedule of Assessments (Table 1 to Table 3).  TTR 
levels will be determined by a validated enzyme-linked immunoassay (ELISA) assay.   
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of plasma ALN-TTRSC02 and patisiran-LNP PK 
parameters and possible metabolite analysis at the time points in the Schedule of Assessments.  
A detailed schedule of time points for the collection of blood samples for PK analysis at the 
timepoints specified in the Schedule of Assessments (Table 4 for ALN-TTRSC02 and Table 5 
for patisiran-LNP). 
Plasma concentration of ALN-TTRSC02 and patisiran-LNP will be determined using a validated 
assay.  Details regarding sample volumes to be collected, and the processing, shipping, and 
analysis of the samples will be provided in the Study Laboratory Manual. 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of 
adverse events (AEs) including serious adverse events (SAEs), recording of concomitant 
medication and measurements of vital signs, weight and height, physical examination, ECG 
findings and laboratory tests. Clinically significant abnormalities observed during the physical 
examination are recorded. 
Safety will be monitored over the course of the study by the Sponsor’s Medical Monitors and 
Medical Monitors at the designated contract research organization in addition an independent 
DMC as described in Section 3.7. 
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, urgent care visits, procedures and concomitant medications.  Wherever possible, 

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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 Reference Manual. 
6.5.1. 
Vital Signs 
Vital signs will be measured as specified at the timepoints specified in the Schedule of 
Assessments (Table 1 to Table 3), and include blood pressure, heart rate, body temperature, and 
respiratory rate.  Vital signs will be measured predose, when applicable.  When vital signs and 
blood sample collection occur at the same time, vital signs should be performed before blood 
samples are drawn, where possible. Vital signs should be measured predose in the seated or 
supine position, after the patient has rested comfortably for 10 minutes.  Blood pressure should 
be taken using the same arm during a single visit.  Body temperature in degrees Celsius will be 
obtained via oral, tympanic, or axillary methods.  Heart rate will be counted for a full minute and 
recorded in beats per minute, and respiration rate will be counted for a full minute and recorded 
in breaths per minute. 
Additional vital sign assessments, as medially indicated, may be added at the discretion of the 
Investigator, or as per DMC advice (as applicable). 
Vital signs results will be recorded in the eCRF. 
6.5.2. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected at the timepoints specified in in the Schedule of 
Assessments (Table 1 to Table 3) and will be recorded in the eCRF.   
For patients on the patisiran-LNP arm, weight must be collected prior to each dose. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1 to Table 3); if a physical examination is scheduled for a dosing visit, it 
should be conducted prior to dosing.   
Full physical examinations will include the examination of the following: general appearance; 
head, eyes, ears, nose and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid; lymph nodes; and neurological status. 
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.5.4. 
Electrocardiogram 
A 12-lead ECG reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, and 
QT interval and Fridericia corrected QT interval (QTcF) will be obtained locally as specified in 
the Schedule of Assessments (Table 1 to Table 3).  Triplicate readings should be performed at 
Baseline and thereafter single readings can be performed.  If the ECG machine does not calculate 

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the heart rate corrected QT interval (QTc), either Bazett’s and/or Fridericia’s formula will be 
used to calculate the QTc. 
If the investigator performs an ECG over-read per standard of care, over-reads should be 
conducted on each individual ECG performed.    
Patients should be supine for at least 5 minutes before each ECG is obtained.   
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since baseline and to determine the clinical significance of the results.  Additional ECGs 
may be collected at the discretion of the Investigator, or as per DMC advice.   
ECG recordings will be archived according to the Study Reference Manual. 
6.5.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia–Suicide Severity Rating Scale (C-SSRS) will be used to assess patient’s mental 
status as it relates to suicidal ideation and behavior.   This questionnaire will be administered to 
the patient by trained and certified study personnel. The C-SSRS will be performed as specified 
in the Schedule of Assessments (Table 1 to Table 3).   
6.5.6. 
Clinical Laboratory Assessments 
Clinical laboratory assessments are listed in Table 7 will be collected as specified in the 
Schedule of Assessments (Table 1 to Table 3) and should be evaluated by a central laboratory.  
Clinical laboratory assessments may be collected at the clinical study center or outside the clinic 
(eg, home) by a trained healthcare professional. 
For the ALN-TTRSC02 arm, LFTs must be obtained within 28 days and reviewed by the 
investigator prior to each dose of ALN-TTRSC02. LFTs can be analyzed locally, but if a local 
assessment is drawn, a sample must also be drawn for analysis at the central laboratory. Specific 
instructions for transaminase elevations are provided in Section 5.2.3. 
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 7 which are performed 
at the clinic should also be sent in parallel to the central laboratory.  In the case of discrepant 
local and central laboratory results on samples drawn on the same day, central laboratory results 
will be relied upon for clinical and dosing decisions.   
For the patisiran-LNP arm, LFTs should be performed according to patisiran-LNP visit windows 
and do not need to be available prior to dosing.   
For any other unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator, 
or as per the Medical Monitor or DMC advice, until it has returned to the normal range or 
stabilized, and/or a diagnosis is made to adequately explain the abnormality.  Additional safety 
laboratories and assessments as indicated by the clinical situation may be requested.   

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For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 
 

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Table 7: 
Clinical Laboratory Assessments 
Hematology 
 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the MDRD formula) 
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
Glucose 
Chloride 
B12 vitamin (at Screening only) 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
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 
 
Immunogenicity (see Section 6.5.6.1) 
Antidrug Antibodies 
Pregnancy Testing/FSH Screening (see Section 6.5.6.2)  
β-human chorionic gonadotropin 
Follicle stimulating hormone (FSH) (Only if applicable, to confirm postmenopausal status prior to 
dosing) 
Hepatic Tests (only at Screening) 

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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 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; eGFR=estimated glomerular filtration rate; GGT=gamma glutamyl transferase; HBsAg=hepatitis B 
virus surface antigen; HBc=hepatitis B virus core; HCV=hepatitis C virus; IgG=immunoglobulin G antibody; 
IgM=immunoglobulin M antibody; PCR=polymerase chain reaction; RBC=red blood cell; RNA=ribonucleic acid 
MDRD=modification of diet in renal disease; WOCBP=women of child bearing potential. 
6.5.6.1. 
Immunogenicity 
Blood samples for anti-drug antibody (ADA) testing will be collected at the timepoints specified 
in Table 1 to Table 3.  On dosing days, ADA sample collection is within 1 hour before dosing. 
ADA will be assessed using a validated ELISA method.  For the patisiran-LNP arm, ADA 
defined as serum immunoglobulin (Ig) G (IgG)/IgM antibodies specific to the PEG2000-C-DMG 
component will be assessed.  
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Study Laboratory Manual. 
6.5.6.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential at the timepoints 
specified in Table 1 to Table 3. 
A serum pregnancy test will be performed at Screening and urine or serum pregnancy tests will 
be performed thereafter per the Schedule of Assessments (Table 1 to Table 3) and any time 
pregnancy is suspected.  The results of the pregnancy test must be known before study drug 
administration. More frequent pregnancy testing can be conducted according to country-specific 
regulations.  In Argentina and Brazil, pregnancy testing should be performed prior to each dose.  
Any woman with a positive 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 until the pregnancy outcome is known (see Section 6.5.7.7 for follow-up 
instructions).  
Follicle-stimulating hormone testing may be performed to confirm suspected post-menopausal 
status. 
6.5.6.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.3.  Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 8 will 
be performed one time, as well as hematology, serum chemistry, LFT, and coagulation 
assessments from Table 7, and other assessments or evaluations per Investigator discretion, as 
appropriate. 

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Monitoring and dose modification will also be performed as outlined in Section 5.2.3.  
Table 8: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBs Ag, 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; PT=prothrombin time; 
RNA=ribonucleic acid; SLA= soluble liver antigen 
Note: 
 
All assessments will be measured in central laboratory. The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
 
6.5.7. 
Adverse Events 
6.5.7.1. 
Definitions 
Adverse Event  
According to the International Council for 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 

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administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital 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:  
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3× upper limit 
of normal (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), 
recurrent ISRs that are increasing in severity, or ISRs that lead to temporary dose 
interruption or permanent discontinuation of ALN-TTRSC02 
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 6.5.7.2 and 
Section 6.5.7.3, 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?” 
6.5.7.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in his/her health since the last visit.  The patient should also be asked if he/she has been 
hospitalized, had any accidents, used any new medications, or changed concomitant medication 
routines (both prescription and OTC).  In addition to patient observations, AEs will be 
documented from any clinically relevant laboratory findings, physical examination findings, 
ECG changes, or other findings that are relevant to patient safety. 
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 

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as medical history (see Section 6.1.3), 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. 
For patients who discontinue study drug early and remain in the study, all AEs will be collected 
for 90 days after the last dose, thereafter, SAEs and AEs of clinical interest (see definition in 
Section 6.5.7.1) will be collected for the remainder of their participation in the study. 
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 6.5.7.1), the Sponsor or its designee 
should complete the supplemental AEs of Clinical Interest eCRF.  Additional clinical and 
laboratory information may be collected.  Refer to CRF 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 to 
determine if an ophthalmological assessment is needed.  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. 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.7.1), the Sponsor or its designee 
should be notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 
6.5.7.4. 
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 6.5.7.1 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 
Reference 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. 
6.5.7.5. 
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 Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.5.7.6. 
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. 
6.5.7.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 90 days following the last dose of 
study drug, 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. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 

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or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 6.5.7.4.   
6.5.7.8. 
Overdose Reporting 
An overdose is defined as any dose 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 considered an overdose, in 
consultation with the Sponsor.  In the event of an overdose, the actual dose administered must be 
recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with hATTR amyloidosis, as well as their responses to 
treatment. 
Where allowed per local regulations, ethics committee (IRB/EC) approval, and patient consent 
(and assent, where applicable), samples will be collected as part of this study to permit 
exploratory investigations and the application of novel approaches to bioanalyses that may 
further elucidate the outcomes of this study, or potentially advance understanding of the safety, 
mechanism of action, and/or efficacy of ALN-TTRSC02 and patisiran-LNP.   
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1 through Table 5). Potential exploratory investigations may include DNA, RNA, or 
biochemical metabolite assessments as they relate to disease progression, efficacy or safety.  
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 

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6.7. 
Pharmacoeconomic Assessments 
6.7.1. 
Patient and Caregiver Impact Survey 
To complement medical records, information about how hATTR amyloidosis impacts the lives 
of patients and their caregivers will be collected at the timepoints specified in the Schedule of 
Assessments (Table 1 to Table 3). The Patient and Caregiver Impact Survey includes questions 
related to how hATTR amyloidosis affects patients, including their symptoms at the time of 
diagnosis, utilization of various healthcare providers, employment status, and need for 
government compensation/assistance. Questions will also be asked about how hATTR 
amyloidosis impacts the employment status of the patient's caregiver and patients' need for both 
informal and professional caregivers. 
6.7.2. 
Hospitalization, Urgent Healthcare Visits, Surgeries, and Procedures  
Hospitalization, urgent healthcare visits, surgeries, and procedure information will be collected 
on a separate eCRF for pharmacoeconomic evaluations, as specified in the Schedule of 
Assessments (Table 1 to Table 3). 
Prior hospitalization, urgent healthcare visits, surgeries, and procedure information through 12 
months prior to first dose should be collected at Screening. 
6.7.3. 
Patient Experience Survey 
The Patient Experience Survey will be administered to understand patients' level of satisfaction 
with their current hATTR amyloidosis therapy and their level of comfort using this therapy. This 
survey will be administered at the timepoints specified in the Schedule of Assessments (Table 1 
to Table 3). 
6.7.4. 
Patient Preference Survey 
This Patient Preference Survey will only be administered to patients who were randomized to the 
patisiran-LNP arm and switched to treatment with ALN-TTRSC02 in the Treatment Extension 
Period. The survey will be administered to understand patients' preferred method of 
administration and the primary reasons for their preference. This survey will be administered at 
the timepoints specified in the Schedule of Assessments (Table 3). 
7. 
STATISTICS 
The principal features of the planned analysis are presented in this section.  A separate Statistical 
Analysis Plan (SAP) will be finalized prior to first patient dosed.  The SAP will detail the 
implementation of the statistical analyses in accordance with the principal features stated in the 
protocol.   
7.1. 
Determination of Sample Size 
Approximately 160 patients will be enrolled in this study, with a 3:1 randomization ratio to either 
ALN-TTRSC02 or patisiran-LNP.  

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The sample size was chosen to enable an adequate characterization of the long-term safety 
profile, as well as the efficacy of ALN-TTRSC02 in this patient population.  For the co-primary 
efficacy endpoints mNIS+7 and Norfolk QoL-DN total scores, the ALN-TTRSC02 arm in the 
Phase 3 study will be compared to the placebo arm from the APOLLO study.  For the mNIS+7 
change from baseline at 9 months, the observed mean (±standard deviation [SD]) was 15 ± 17 
points for the placebo arm from the APOLLO study.  Assuming a mean change of 0 points for 
the ALN-TTRSC02 arm, there is >90% power to establish the superiority over placebo using a 2-
sided t-test with a significance level of 0.05.  For the Norfolk-QoL DN total score change from 
baseline at 9 months, the observed mean (±SD) was 11.5 ± 19.2 points for the placebo arm from 
the APOLLO study.  Assuming a mean change of -4 points for the ALN-TTRSC02 arm, there is 
>90% power to establish the superiority over placebo using a 2-sided t-test with a significance 
level of 0.05.  
For safety, a sample size of >100 patients on ALN-TTRSC02 can provide reasonable assurance 
that the true cumulative one-year incidence of adverse drug events (ADE) is no greater than 3% 
when no ADE is observed.  
To match the cardiac disease severity with the APOLLO study population, the study plans to 
enroll no more than 15% of patients with NT-proBNP values greater than 3000 ng/L. 
7.2. 
Statistical Methodology 
7.2.1. 
Populations to be Analyzed 
The population analysis sets are defined as follows:  
 Modified ITT (mITT) population: All randomized patients who received any amount 
of study drug. Patients will be grouped by their randomized treatment group. 
 Safety Population: All randomized patients who received any amount of study drug, 
grouped according to the treatment actually received. 
 PK Population: All randomized patients who received any amount of study drug and 
have at least 1 post dose blood sample for PK parameters and have evaluable PK data. 
 Patients with cardiac involvement: All patients in the mITT population who had pre-
existing evidence of cardiac amyloid involvement. Specific details will be provided in 
the SAP. 
The primary population for efficacy analysis will be the mITT population.  Safety analysis will 
be conducted in the safety population.  PK analysis will be conducted in the PK population.  
Selected endpoints will be analyzed in the cardiac subpopulation.  
7.2.2. 
Examination of Subgroups 
Subgroup analyses will be conducted for selected endpoints. Detailed methodology will be 
provided in the SAP. 

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7.2.3. 
Handling of Missing Data 
For efficacy assessments, if the scheduled visits (eg, 9-month) are not performed, the 
unscheduled and/or discontinuation visits performed within a 3-month window will be grouped 
with the scheduled assessments.   
Sensitivity analyses for the co-primary endpoints, including different methods for handling of the 
missing data, will be conducted to assess the robustness of the primary analysis results. 
More details of missing data handling will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other baseline characteristics, including disease-specific information, will be 
summarized descriptively. 
7.2.5. 
Efficacy Analyses 
This Phase 3 study will use the placebo arm of the APOLLO study as an external control.  
Patient-level data from this study will be compared with patient-level data from APOLLO for 
efficacy analyses.  For the co-primary and secondary clinical efficacy endpoints, the ALN-
TTRSC02 arm in this study will be compared to the placebo arm from the APOLLO study.  For 
the secondary endpoint of TTR percent reduction, the ALN-TTRSC02 arm in this study will be 
compared to the patisiran-LNP arm in this study. The treatment comparison will be conducted at 
Month 9 and/or Month 18.  The efficacy endpoints beyond 18 months will be summarized 
descriptively. 
The patisiran-LNP arm in this study will mainly serve as a reference arm.  For the clinical 
efficacy endpoints at Month 9 and Month 18, the patisiran-LNP arm will be summarized 
descriptively and the treatment difference between ALN-TTRSC02 and patisiran-LNP arm in 
this study will not be tested.  In addition, the efficacy assessments over time for patients before 
and after the switch to ALN-TTRSC02 will be summarized.  
7.2.5.1. 
Co-Primary Endpoint 
The co-primary endpoints are change from baseline at Month 9 for mNIS+7 and Norfolk QoL- 
DN total scores. The co-primary endpoints will be each be tested at a significant level of 0.05 
and both must be significant to declare a positive trial. The primary comparison will be 
conducted at Month 9 and additional analyses will be performed at Month 18. 
The co-primary endpoint mNIS+7 will compare change in mNIS+7 from baseline at Month 9 
between the ALN-TTRSC02 group in this study and the placebo group in the APOLLO study. 
The treatment effect will be estimated based on the least-square (LS) means using an analysis of 
covariance (ANCOVA) model with baseline mNIS+7 score as a covariate and factors including 
treatment group (ALN-TTRSC02 vs placebo), genotype (V30M vs non-V30M) and age of 
disease onset (<50 vs ≥50 years old). 
The other co-primary endpoint Norfolk QoL-DN total score will compare change at Month 9 
between the ALN-TTRSC02 group in this study and the placebo group in the APOLLO study. 
The treatment effect will be estimated based on the least-square (LS) means using an analysis of 
covariance (ANCOVA) model with baseline score as a covariate and factors including treatment 

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group (ALN-TTRSC02 vs placebo), genotype (V30M vs non-V30M), age of disease onset (<50 
vs ≥50 years old), and baseline NIS score (<50 vs ≥50).  
Co-primary endpoint data that are missing will be multiply imputed separately for each treatment 
group using a regression procedure based on baseline covariates. The details will be specified in 
the SAP.  
The co-primary endpoints for the patisiran-LNP group in this study will be summarized 
descriptively. 
7.2.5.2. 
Secondary Endpoints 
For the secondary clinical efficacy endpoints, the treatment comparison will be made between 
the ALN-TTRSC02 group in this study and the placebo group in the APOLLO study. For the 
TTR percent reduction endpoint, the ALN-TTRSC02 group will be compared with the patisiran-
LNP group in this study. To control the overall type I error, the secondary endpoints will be 
tested in the following hierarchical order: 
 10-MWT gait speed change from baseline at Month 9 
 mBMI (BMI [kg/m2] multiplied by serum albumin level [g/L]) change from baseline 
at Month 9 
 R-ODS change from baseline at Month 9 
 TTR percent reduction through 9 months  
 All-cause hospitalization and death events over 18 months (overall population) 
 All-cause hospitalization and death events over 18 months (patients with cardiac 
involvement) 
For 10-MWT gait speed, mBMI, and R-ODS, the analysis will be based on an ANCOVA model 
similar to the model described for the analysis of Norfolk QoL-DN while adjusting for baseline 
value of the endpoint being modeled.  In the APOLLO study, mBMI was not assessed at Month 
9. The average values of Day 189 and Day 357 will be derived as Month 9. The primary 
comparison will be conducted at Month 9 and additional analyses will be performed at Month 
18. 
The TTR percent reduction through Month 9 will be derived as the average trough TTR percent 
reduction from Month 6 to 9 which is the steady state period for both ALN-TTRSC02 and 
patisiran-LNP. A Hodges-Lehmann method stratified by previous TTR stabilizer use (yes vs no) 
will be used to estimate the 95% CI for the median difference between the ALN-TTRSC02 and 
patisiran-LNP groups in this study. Non-inferiority will be declared if the lower limit of the 95% 
CI for the treatment difference is greater than –10%. A sensitivity analysis will be conducted to 
compare the TTR percent reduction between the ALN-TTRSC02 group from this study and the 
pooled patisiran-LNP groups from this Phase 3 study and the APOLLO study.   
The composite endpoint of all-cause hospitalization and death events over 18 months will be 
analyzed using recurrent event method Andersen-Gill model with treatment group (ALN-
TTRSC02 vs placebo) as an independent variable.  The endpoint will be analyzed for both the 
overall population and in patients with cardiac involvement.  

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7.2.5.3. 
Exploratory Endpoints 
Analysis of exploratory efficacy endpoints will be detailed in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
Summary tables and graphical displays of observed values, changes and percentage changes 
from baseline in PD biomarkers (TTR and vitamin A) will be presented. 
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted for ALN-TTRSC02 and patisiran-LNP using non-
compartmental method.  PK parameters will be calculated using a validated version of Phoenix® 
WinNonlin. 
Population pharmacokinetic analysis will be performed to describe the plasma pharmacokinetics 
using Phoenix NLME (Version 1.1 or later) or a similar software, such as NONMEM. The 
impact of relevant covariates, such as, weight, gender, race, age, renal function, and hepatic 
function on plasma PK will be evaluated. Summary tables and figures and inferential statistics 
will be generated. 
7.2.8. 
Safety Analyses 
A summary of study drug exposure, including the durations of exposure and the proportions of 
patients with dose modifications will be produced.  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary. Results will be tabulated by Anatomical Therapeutic Chemical Classification 
System (ATC) and Preferred Term. 
Adverse events will be summarized by MedDRA system organ class and preferred term.  The 
number and percentage of patients experiencing AEs after the first dose of the study drug will be 
summarized. Separate tabulations will be produced for treatment-related AEs, SAEs, and 
discontinuations due to AEs.  By-patient listings will be provided for deaths, SAEs, and events 
leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data, 12-lead ECG interval data and 
vital signs data, presented as both actual values and changes from baseline over time 
Laboratory shift tables from baseline to worst values will be presented.  Baseline will be defined 
as the last observation on or prior to Study Day 1. 
Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP.  
7.2.9. 
Immunogenicity Analyses 
Incidence of ADA and titers will be summarized descriptively.   
7.2.10. 
Other Analyses  
For all the efficacy endpoints defined for Month 9, additional analyses will also be conducted at 
Month 18. 

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7.2.11. 
Interim Analysis 
No interim analysis is planned. 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient/legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  
Patients/legal guardians must also be notified that they are free to discontinue from the study at 
any time.  The patient/legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.   
The patient’s/legal guardian’s signed and dated informed consent must be obtained before 
conducting any study tests or procedures that are not part of routine care.   
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient/legal guardian. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF (assent form, if applicable), 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.  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 6.5.7.  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. 

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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 enrolled or 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 serious 
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 
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 reserves the right to terminate the study for clinical or administrative reasons at any 
time.  If the site does not recruit at a reasonable rate, or if there is insufficient adherence to the 
protocol requirements, the study may be closed at that site.  Should the study be terminated 
and/or the site closed for whatever reason, all documentation and study drug pertaining to the 

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study must be returned to the Sponsor or its representative, and the Investigators, IEC/IRB and 
Regulatory Authorities will be promptly informed of the termination and the reason for the 
decision.  The Investigator should promptly inform the patients, and assure appropriate therapy 
and follow-up. 
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 
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 separate publication by 
Institution or Investigator may not be submitted for publication until after this primary 
manuscript is published, or following the period of 18 months after completion of the study at all 

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centers.  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 among the institution, 
Investigator, and Alnylam will detail the procedures for Alnylam’s review of 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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9. 
LIST OF REFERENCES 
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a multinational natural history study." Neurology 85(8): 675-682. 
Adams, D., A. Gonzalez-Duarte, et al. (2018). "Patisiran, an RNAi Therapeutic, for Hereditary 
Transthyretin Amyloidosis." N Engl J Med 379(1): 11-21. 
Adams, D., O. B. Suhr, et al. (2017). "Trial design and rationale for APOLLO, a Phase 3, 
placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with 
polyneuropathy." BMC Neurol 17(1): 181. 
Ando, Y., T. Coelho, et al. (2013). "Guideline of transthyretin-related hereditary amyloidosis for 
clinicians." Orphanet J of Rare Dis 8(31). 
Ashwell, G. and A. G. Morell (1974). "The role of surface carbohydrates in the hepatic 
recognition and transport of circulating glycoproteins." Adv Enzymol Relat Areas Mol 
Biol 41(0): 99-128. 
Baenziger, J. U. and D. Fiete (1980). "Galactose and N-acetylgalactosamine-specific endocytosis 
of glycopeptides by isolated rat hepatocytes." Cell 22(2 Pt 2): 611-620. 
Barroso, F. A., D. P. Judge, et al. (2017). "Long-term safety and efficacy of tafamidis for the 
treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years." 
Amyloid 24(3): 194-204. 
Benson, M. and J. Kincaid (2007). "The molecular biology and clinical features of amyloid 
neuropathy." Muscle Nerve 36(4): 411-423. 
Berk, J., O. Suhr, et al. (2013). "Repurposing diflunisal for familial amyloid polyneuropathy: a 
randomized clinical trial." JAMA 310(24): 2658-2667. 
Bumcrot, D., M. Manoharan, et al. (2006). "RNAi therapeutics: a potential new class of 
pharmaceutical drugs." Nat Chem Biol 2(12): 711-719. 
Carvalho, A., A. Rocha, et al. (2015). "Liver transplantation in transthyretin amyloidosis: issues 
and challenges." Liver Transpl 21(3): 282-292. 
Carvalho, M., M. Alves, et al. (1992). "Octreotide--a new treatment for diarrhoea in familial 
amyloidotic polyneuropathy." J Neurol Neurosurg Psychiatry 55(9): 860-861. 
Coelho, T., L. F. Maia, et al. (2012). "Tafamidis for transthyretin familial amyloid 
polyneuropathy: a randomized, controlled trial." Neurology 79(8): 785-792. 
Connors, L., T. Yamashita, et al. (2004). "A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy." Amyloid 11(1): 61-66. 
Connors, L. H., A. Lim, et al. (2003). "Tabulation of human transthyretin (TTR) variants, 2003." 
Amyloid 10(3): 160-184. 

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ALN-TTRSC02 
Original, 11 October 2018 
 
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Confidential 
84 
Coutinho, P., A. DeSilva, et al. (1980). Forty years of experience with type I amyloid 
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Glenner, P. Pinho, E. Costa and A. Falcao de Frietas. Amsterdam: 88-98. 
Damy, T., A. Jaccard, et al. (2016). "Identification of prognostic markers in transthyretin and AL 
cardiac amyloidosis." Amyloid 23(3): 194-202. 
Dyck PJ, K. J., Dyck PJ et al (2017). "Assessing mNIS+7Ionis and international neurologists' 
proficiency in a familial amyloidotic polyneuropathy trial." Muscle Nerve Jan 7. doi: 
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99(9): 1847-1854. 
Geffen, I. and M. Spiess (1992). "Asialoglycoprotein receptor." Int Rev Cytol 137B: 181-219. 
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Okamoto, S., J. Wixner, et al. (2009). "Liver transplantation for familial amyloidotic 
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ALN-TTRSC02 
Original, 11 October 2018 
 
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Yazaki, M., T. Tokuda, et al. (2000). "Cardiac amyloid in patients with familial amyloid 
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Clinical Study Protocol ALN-TTRSC02-002 
 
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10. 
APPENDICES 
10.1. 
mNIS+7 Components and Scoring 
Refer to the Study Reference Manual for additional details. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   

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Clinical Study Protocol ALN-TTRSC02-002 
 
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10.2. 
PND Scores and FAP Stages 
Polyneuropathy Disability (PND) Scores 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch 
Walking with the help of two sticks or crutches 
IV 
Confined to a wheelchair or bedridden 
 
Familial Amyloidotic Polyneuropathy (FAP) Stages 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs 
 

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ALN-TTRSC02 
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10.3. 
New York Heart Association (NYHA) Class 
 
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. 

Clinical Study Protocol ALN-TTRSC02-002 
 
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Alnylam Pharmaceuticals 
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90 
10.4. 
Karnofsky Performance Status (KPS) Scale 
 
Able to carry on normal activity and 
to work; no special care needed. 
100 
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able to 
care for most of his personal needs. 
50 
Requires considerable assistance and frequent 
medical care.  
Unable to care for self; requires 
equivalent of institutional or hospital 
care; disease may be progressing 
rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
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CLINICAL STUDY PROTOCOL 
ALN-TTRSC02-002 
DATED: 19 FEBRUARY 2021 
 
Protocol Title: 
HELIOS-A:  A Phase 3 Global, Randomized, 
Open-label Study to Evaluate the Efficacy and 
Safety of ALN-TTRSC02 in Patients with 
Hereditary Transthyretin Amyloidosis (hATTR 
Amyloidosis)  
Short Title: 
HELIOS-A:  A Phase 3 Study to Evaluate the 
Efficacy and Safety of ALN-TTRSC02 in Patients 
with hATTR Amyloidosis 
Study Drug: 
ALN-TTRSC02 (vutrisiran) 
EudraCT Number: 
2018-002098-23  
IND Number: 
139086   
Protocol Date: 
Original protocol:  11 October 2018 
Amendment 1:  10 October 2019 
Amendment 2: 06 May 2020 
Amendment 3: 17 July 2020 
Amendment 4: 19 February 2021 
 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone:  
 
Sponsor Contact:   
 
 
 
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. 
 

Clinical Study Protocol ALN-TIRSC02-002 
Amendment 4, 19 February 2021 
ALN-TIRSCOl (vutrisiran) 
SPONSOR PROTOCOL APPROVAL 
I have read this protocol and I approve the design of this study. 
rJJ F€A dOJ/ 
Date 
Alnylam Pharmaceuticals 
Confidential 
2 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
I have read the ALN-TTRSC02-002 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-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
Confidential 
4 
PROTOCOL SYNOPSIS 
Protocol Title 
HELIOS-A:  A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy and Safety of 
ALN-TTRSC02 in Patients with Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis) 
Short Title 
HELIOS-A:  A Phase 3 Study to Evaluate the Efficacy and Safety of ALN-TTRSC02 in Patients with 
hATTR Amyloidosis 
Study Drug 
ALN-TTRSC02 
Phase 
3 
Study Centers 
The study will be conducted at up to 80 clinical study centers worldwide. 
Objectives and Endpoints 
The primary and most secondary and exploratory efficacy endpoints are in comparison to the placebo arm 
of the Phase 3 pivotal patisiran study (ALN-TTR02-004, also referred to as the APOLLO study) as 
specified in the statistical analysis section of the HELIOS-A protocol.   
Objectives 
Endpoints 
Primary 
• 
To determine the efficacy of ALN-
TTRSC02 in patients with hATTR 
amyloidosis by evaluating the effect on 
neurologic impairment  
• 
Change from baseline in the Modified 
Neurologic Impairment Score +7 
(mNIS+7) compared to the placebo arm 
of the APOLLO study at Month 9 
Secondary 
• 
To determine the efficacy of ALN-
TTRSC02 on quality of life, gait speed, 
neurologic impairment, nutritional status, 
and disability 
• 
To demonstrate the noninferiority of 
ALN-TTRSC02 compared to patisiran 
with respect to serum TTR levels 
 
• 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study: 
− 
Norfolk Quality of Life-Diabetic 
Neuropathy (Norfolk QoL-DN) total 
score at Month 9;  
− 
Timed 10-meter walk test (10-MWT) 
at Month 9; 
− 
mNIS+7 at Month 18; 
− 
Norfolk QoL-DN total score at 
Month 18; 
− 
10-MWT at Month 18; 
− 
Modified body mass index (mBMI) 
at Month 18; 
− 
Rasch-built Overall Disability Scale 
(R-ODS) at Month 18 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
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Objectives 
Endpoints 
• 
Percent reduction in serum TTR levels in 
the ALN-TTRSC02 arm compared to the 
within-study patisiran arm through 
Month 18  
Exploratory 
 
• 
To determine the effect of ALN-
TTRSC02 on: 
− 
Disability and nutritional status; 
− 
Manifestations of cardiac amyloid 
involvement; 
− 
Other assessment of neurologic 
impairment; 
− 
Other assessments of quality of life; 
− 
Disease stage; 
− 
Performance of daily activities 
• 
To characterize the pharmacodynamic 
(PD) effect of ALN-TTRSC02 and 
patisiran on serum TTR and vitamin A 
levels 
• 
To characterize plasma pharmacokinetics 
(PK) of ALN-TTRSC02 and patisiran 
• 
To assess presence of antidrug antibodies 
(ADA) to ALN-TTRSC02 and patisiran 
• 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study at Month 9: 
− 
R-ODS; 
− 
mBMI 
• 
Change from baseline over time: 
− 
N-terminal prohormone B-type 
natriuretic peptide (NT-proBNP) 
levels, echocardiographic parameters, 
Troponin I and T levels, New York 
Heart Association (NYHA) class; 
− 
Neurologic Impairment Score (NIS); 
− 
EuroQoL-5 Dimensions-5 Levels 
(EQ-5D-5L) questionnaire and the 
EuroQoL-Visual Analog Scale (EQ-
VAS); 
− 
Familial Amyloidotic 
Polyneuropathy (FAP) stage and 
Polyneuropathy Disability (PND) 
score; 
− 
Karnofsky Performance Status (KPS) 
• 
Change from baseline in technetium 
scintigraphy cardiac parameters at Month 
18 
• 
Percent reduction in serum TTR and 
vitamin A levels over time 
• 
PK profile of ALN-TTRSC02 and 
patisiran 
• 
Incidence and titers of ADA to ALN-
TTRSC02 and patisiran 
Safety 
 
• 
To determine the safety and tolerability of 
ALN-TTRSC02 in patients with hATTR 
amyloidosis 
• 
Frequency of adverse events (AE) 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
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Study Design 
This is a global Phase 3 randomized, open-label study designed to evaluate efficacy, safety, and PK/PD of 
ALN-TTRSC02 in adult patients with hATTR amyloidosis.  Patients will be randomized 3:1 to ALN-
TTRSC02 or patisiran, a reference comparator.  Randomization will be stratified by TTR genotype 
(V30M vs. non-V30M) and baseline NIS score (<50 vs ≥50). 
The study will consist of a Screening Period of up to 42 days, an 18-month Treatment Period, and an 
18-month Randomized Treatment Extension Period (RTE) as of Amendment 4, in lieu of the 18-month 
Treatment Extension Period (hereafter referred to as the Legacy Treatment Extension Period).  A Follow-
up Period of up to 1 year will occur after the last dose of study drug. 
18-Month Treatment Period 
After the Screening period at the start of the Treatment Period, eligible patients will be randomized 3:1 on 
Day 1 to receive 25 mg of ALN-TTRSC02 administered as an SC injection q3M or patisiran administered 
as an IV infusion q3w.  During the 18-month Treatment Period, patients will undergo assessments for 
efficacy and/or safety (as outlined in the Schedule of Assessments), with key efficacy assessments being 
performed prior to first dose, at Month 9 (primary efficacy analysis timepoint), and at Month 18; samples 
for TTR assessment will be collected more frequently throughout the 18-month Treatment Period. 
All efficacy visits must be conducted at the clinic (Month 9, Month 18, and modified efficacy visits).  In 
situations in which a Month 9 or Month 18 efficacy visit is unable to be completed due to the Coronavirus 
disease 2019 (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, the Medical Monitor should be 
consulted as soon as possible to determine the appropriate timing of the Month 9 or Month 18 efficacy 
assessments as applicable.  After consultation with the Medical Monitor, the Month 9 or Month 18 
efficacy assessments may be completed within 6 months after the intended time point (ie, up to Month 15 
or Month 24, respectively). 
The placebo arm of the APOLLO study will be used as an external control for the primary, most 
secondary, and most exploratory efficacy analysis.  Primary and secondary efficacy evaluations will 
include mNIS+7, Norfolk QoL-DN questionnaire, 10-MWT, mBMI, R-ODS questionnaire, and percent 
TTR reduction.  Study personnel performing the mNIS+7 component assessments will not reference the 
results of any previous assessments. 
Randomized Treatment Extension (RTE) Period 
 
 
  
 
 
 
   
 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
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. 
Follow-up Period 
During the Follow-up Period, all patients on ALN-TTRSC02 will undergo safety assessments quarterly 
until serum TTR levels return to ≥80% of baseline (for up to 1 year after the last dose of study drug), or 
until the patient starts a TTR lowering regimen as a part of clinical care, whichever comes first; all 
patients will be followed for a minimum of 3 months.  Female patients of child-bearing potential who 
discontinue ALN-TTRSC02 will be followed until serum TTR levels return to ≥80% of baseline. 
Number of Planned Patients 
Approximately 160 patients are planned for enrollment in this study.   
To match the cardiac disease severity with the APOLLO study population, the study plans to enroll no 
more than 15% of patients with NT-proBNP values greater than 3000 ng/L at baseline.   

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
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Diagnosis and Main Eligibility Criteria 
This study will include adults age 18 (or age of legal consent, whichever is older) to 85 years of age, with 
a documented TTR mutation, and a confirmed diagnosis of symptomatic hATTR amyloidosis with a NIS 
of 5 to 130 (inclusive), a PND score of ≤3b, and KPS ≥60%. 
Study Drug, Dose, and Mode of Administration 
ALN-TTRSC02 drug product is a subcutaneously (SC) administered N-acetyl galactosamine ligand 
(GalNAc)-conjugated small interfering RNA (siRNA) targeting liver-expressed transthyretin (TTR) 
messenger RNA (mRNA).  
ALN-TTRSC02 will be administered as a 25 mg SC injection q3M (12 weeks).  
 
  
Reference Treatment, Dose, and Mode of Administration 
Patisiran drug product is an intravenously (IV) administered siRNA targeting liver-expressed TTR 
mRNA formulated with lipid excipients (DLin-MC3-DMA, DSPC, cholesterol, and PEG2000-C-DMG) in 
isotonic phosphate buffered saline. 
Patisiran will be administered as a 0.3 mg/kg IV infusion once every 3 weeks (q3w) ± 3 days.  All 
patients will receive premedication prior to patisiran infusions as described further in the protocol.   
Duration of Treatment and Study 
The estimated time on study for each patient is a maximum of 5 years, inclusive of 42 days of Screening, 
and up to 54 months of open-label treatment (including 18 months in the Treatment Period, 0 to 18 
months in the Legacy Treatment Extension Period and 18 months in the Randomized Treatment 
Extension Period), plus a Follow-Up Period up to 1 year.  
During the Follow-up Period, all patients on ALN-TTRSC02 will undergo safety assessments quarterly 
until serum TTR levels return to ≥80% of baseline (for up to 1 year after the last dose of study drug), or 
until the patient starts a TTR lowering regimen as a part of clinical care, whichever comes first; all 
patients will be followed for a minimum of 3 months.  Female patients of child-bearing potential who 
discontinue ALN-TTRSC02 will be followed until serum TTR levels return to ≥80% of baseline. 
Statistical Methods 
A full statistical analysis plan (SAP) will be finalized prior to first patient dosed. 
The primary endpoint mNIS+7 will compare change in mNIS+7 from baseline at Month 9 between the 
ALN-TTRSC02 group in this study and the placebo group in the APOLLO study. The treatment effect 
will be estimated based on the least squares (LS) means using an analysis of covariance (ANCOVA) 
model with baseline mNIS+7 score as a covariate and factors including treatment group (ALN-TTRSC02 
vs placebo), genotype (V30M vs non-V30M) and age of disease onset (<50 vs ≥50 years old). The 
primary endpoint will be tested at a significance level of 0.05 and must be significant to declare a positive 
trial.  
For the key secondary endpoints of change in Norfolk QoL-DN total score and 10-MWT gait speed from 
baseline at Month 9, the analysis will be based on an ANCOVA model similar to the model described for 
the analysis of change in mNIS+7 from baseline at Month 9, while adjusting for baseline value of the 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
Confidential 
9 
endpoint being modeled and including baseline NIS score (<50 vs ≥50) as an additional factor in the 
model. For these 2 endpoints, data that are missing will be multiply imputed separately for each treatment 
group using a regression procedure based on baseline covariates.  
For change from baseline at Month 18 analyses, the analysis will be based on a mixed-effects model for 
repeated measures (MMRM), adjusting for a covariate (baseline value for the endpoint being modeled), 
categorical factors (treatment group, visit [Month 9 vs Month 18], genotype, age of disease onset, 
baseline NIS score), and an interaction term (treatment group by visit). For mNIS+7, baseline NIS score 
will not be included in the model. 
The primary endpoint for the patisiran group in this study will be summarized descriptively. 
The TTR percent reduction through Month 18 will be derived as the average trough TTR percent 
reduction from Month 6 to 18 which is the steady state period for both ALN-TTRSC02 and patisiran. A 
Hodges-Lehmann method stratified by previous TTR stabilizer use (yes vs no) will be used to estimate 
the 95% confidence interval (CI) for the median difference between the ALN-TTRSC02 and patisiran 
groups in this study. Non-inferiority will be declared if the lower limit of the 95% CI for the treatment 
difference is greater than –10%. A sensitivity analysis will be conducted to compare the TTR percent 
reduction between the ALN-TTRSC02 group from this study and the pooled patisiran groups from this 
Phase 3 study and the APOLLO study.   
Overall type I error control for secondary endpoints will be achieved by a hierarchical testing procedure.    
The analysis of exploratory efficacy endpoints will be described in the SAP. 
Safety data will be summarized descriptively.   
 
 
 

Clinical Study Protocol ALN-TTRSC02-002
ALN-TTRSC02 (vutrisiran)
Amendment 4, 19 February 2021
Alnylam Pharmaceuticals
Confidential
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Figure 1:
Study Design
Screening and 
Baseline 
Period
ALN-TTRSC02 
25 mg 
every 3 months
N=120
Day -42 to Day -1
18-month Treatment Period
Legacy Treatment Extension Period*
Patisiran 
0.3 mg/kg 
every 3 weeks
N=40
d R
ALN-TTRSC02 
25 mg
every 3 months
Randomization
Day 1
Month 9
Primary Analysis
Month 18
Analysis
Switch patients on 
patisiran at Week 
84/Month 19
Month 36
Last Dose

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
Confidential 
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Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Scre
e-
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3
D 
±3D 
±3D 
±3D 
±3D ±3D 
±3D 
±3D 
NAa  
Informed Consent  Section 6.1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Records 
Release Form 
(optional) 
Section 6.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusio
n  
Section 4.1; 
Section 4.2  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical/Disease 
History 
Section 6.1.3  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
(PE) 
Symptom-
directed PE 
unless specified 
as Full see 
Section 6.5.3   
 
X 
PE 
Full 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PE 
Full 
 
Vital signs; 
Weight 
Section 6.5.1; 
Section 6.5.2 
X 
Vital 
signs 
only 
X 
X 
Vital 
signs 
only 
Xb 
Xb 
Xb 
X 
Xb 
Xb 
Xb 
X 
Xb 
Xb 
Xb 
X 
X 
Height 
Section 6.5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mBMI; NYHA 
Class; KPS  
Section 6.2.5;  
Section 6.2.11.4
Section 6.2.12  
X 
 
 
 
 
 
 
 
mBMI 
only 
 
 
 
mBMI 
only 
 
 
 
 
X 
PND Score 
Section 6.2.10 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FAP Stage 
Section 6.2.10 
 
X – Single 
assessment at any 
of these visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum Chemistry; 
Hematology; 
Urinalysis; 
Coagulation 
Section 6.5.6 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 

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Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Scre
e-
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3
D 
±3D 
±3D 
±3D 
±3D ±3D 
±3D 
±3D 
NAa  
Hepatitis Tests 
Section 6.5.6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 LFT 
See below Table 
1 notes. Results 
from both V1 
and V2 must 
meet eligibility 
criteria. 
Section 6.5.6;  
Section 6.5.6.3  
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
FSH (only to 
confirm 
postmenopausal 
status if 
applicable) 
Section 6.5.6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
At V1 serum 
pregnancy test; 
after V1, either 
urine or serum 
pregnancy test; 
Section 6.5.6.2 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Cardiac Biomarker 
Samples  
Section 6.2.11.2 
NT-
proB
NP 
only 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
TTR Protein; 
Vitamin A 
Section 6.3  
 
 
X 
X 
 
X  
X  
 
X 
 
 
 
X 
 
 
 
X 
X 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 4, 19 February 2021 
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Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Scre
e-
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3
D 
±3D 
±3D 
±3D 
±3D ±3D 
±3D 
±3D 
NAa  
ADA 
On dosing days, 
collect ADA 
within 1 hour 
before dosing; 
Section 6.5.6.1 
 
 
 
X 
 
X  
 
 
X 
 
 
 
X 
 
 
 
X 
 
ALN-TTRSC02 
Arm PK Sampling 
See Table 5 for 
detail timepoints 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Patisiran Arm PK 
Sampling 
See Table 6 for 
detail timepoints 
 
 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Sample for 
Exploratory 
Analysis  
Section 6.6 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Exploratory DNA 
sample (optional) 
Section 6.6 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Norfolk QoL-DN;  
R-ODS 
Section 6.2.3; 
Section 6.2.6 
 
X– single 
at any of 
these visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
EQ-5D-5L and 
EQ-VAS; C-
SSRS; Patient and 
Caregiver Impact 
Survey  
Section 6.2.9; 
Section 6.5.5; 
Section 6.7.1  
 
 
X– single 
at any of 
these visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Patient Experience 
Survey 
Section 6.7.3   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NIS; mNIS+7; 
HRdb  
See below Table 
1 Notes; and 
Section 6.2.1; 
Section 6.2.2  
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 

Clinical Study Protocol ALN-TTRSC02-002 
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Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Scre
e-
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3
D 
±3D 
±3D 
±3D 
±3D ±3D 
±3D 
±3D 
NAa  
10-MWT 
See below Table 
1 Notes; and 
Section 6.2.4 
 
X – Two 
assessments 
performed at any 
of these visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Single (unless 
indicated)  
12-Lead ECG 
Section 6.5.4 
 
X-Triplicate 
performed at any 
of these visits 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Echocardiogram 
Section 6.2.11.1 
 
X - Single 
performed at any 
of these visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Technetium 
scintigraphy 
imaging (select 
sites only) 
Section 6.2.11.3  
 
X - Single 
performed at any 
of these visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
Window:  -5D 
prior to Day 1 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALN-TTRSC02 
Study Drug 
Admin. 
Section 5.2.2.1  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 

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Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 
 
Note 
Scre
e-
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3
D 
±3D 
±3D 
±3D 
±3D ±3D 
±3D 
±3D 
NAa  
Patisiran Arm: 
Premedication 
Admin. 
Section 5.2.2.2  
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patisiran Study 
Drug Admin. 
Section 5.2.2.2 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital status check 
Section 6.2.8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review/Record 
Hospitalization; 
Urgent care visits; 
Procedures 
Section 6.7.2  
 
X - Collected 
through Day 1 
predose 
Continuous Monitoring 
Review/Record 
AEs, Con. Med. 
Section 6.5.7; 
Section 5.3 
 
 
Continuous Monitoring 
Abbreviations: AE=adverse event; ADA=antidrug antibodies; Admin.=administration; Con. Med.=concomitant medications; C-SSRS=Columbia-Suicide Severity Rating Scale; 
D=day; ECG=electrocardiogram; EQ-5D-5L= EuroQuality of Life 5-Dimensions 5-Levels; EQ-VAS=EuroQuality of Life-Visual Analog Scale; FAP=Familial Amyloidotic 
Polyneuropathy; FSH=follicle-stimulating hormone; HRdb=heart rate variability with deep breathing; KPS= Karnofsky Performance Status; LFT=liver function test; 
mBMI=modified body mass index; 10-MWT=10-meter walk test; mNIS+7=modified NIS+7; NIS=Neurologic Impairment Score; NT-proBNP= B-type natriuretic peptide; 
NYHA=New York Heart Association; PE=physical exam; PK=pharmacokinetics; PND=Polyneuropathy Disability; QoL-DN= Quality of Life-Diabetic Neuropathy; R-
ODS=Rasch-built Overall Disability Scale; TTR=transthyretin; V=visits 
Table 1 Notes: 
• 
The Screening and Baseline visits (V1, V2 and V3) will be performed on separate days and can each occur over multiple days.  V2 (first Baseline NIS, mNIS+7, HRdb 
assessment) must be performed within 21 days prior to the first dose of study drug (Day 1).  V3 (second Baseline NIS, mNIS+7, HRdb assessment) must be conducted 
within approximately 24 hours after Visit 2 but not more than 7 days after.  See Section 6.1 for retesting and re-screening instructions. 
• 
Pre-randomization 10-MWT:  Two independent assessments will be performed on separate days (1 assessment on each day); the 2 assessments should be performed 
approximately 24 hours apart from each other but not more than 7 days apart.  
• 
Dosing may be allowed outside of the study center (eg, the patient’s home) under certain circumstances as specified in Section 5.2.2.1 and Section 5.2.2.2. In addition, 
routine assessments and collection of relevant safety information may be collected outside the study center as specified in the beginning of Section 6. 
• 
LFT for screening:  Day 1 predose LFT does not need to be performed if there are available LFT results within 28 days of first dose.   
• 
LFT for after randomization: For the ALN-TTRSC02 cohort, dosing decisions may be made based on LFT results (Table 8) collected at the previous dosing visit (up to 
14 weeks prior to dosing); in all cases the most recently available LFTs should be used. LFT monitoring details are provided in Section 5.2.3. 
For the patisiran cohort, LFTs should be performed according to patisiran visit windows and do not need to be available prior to dosing. 

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• 
Unless otherwise specified, assessments on dosing days are predose. 
• 
For the Month 9, NIS, mNIS+7, HRdb and 10-MWT: Two independent assessments will be performed on separate days (1 assessment on each day); the 2 assessments 
should be performed approximately 24 hours apart from each other but not more than 7 days apart.  Components that are shared between the mNIS+7 and NIS will be 
performed once at each assessment (eg, the weakness component should not be performed more than once on any given day). 
a In situations in which a Month 9 efficacy visit is unable to be completed due to the Coronavirus disease 2019 (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, the Medical Monitor should be consulted as soon as possible to determine the 
appropriate timing of the Month 9 efficacy assessment.  After consultation with the Medical Monitor, Month 9 efficacy assessments may be completed within 6 months after the 
intended time point (ie, up to Study Month 15). 
b For the ALN-TTRSC02 cohort, collection of vital signs and weight may be deferred at this timepoint if issues related to the COVID-19 pandemic limit the patient’s ability or 
willingness to access the study site. 
 
 
 

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Table 2: 
Schedule of Assessments –Treatment Period from Month 9 through Month 18 
 
Note 
Treatment Period 
Month 18 
Efficacya 
Study Day  
D274 
D295 
D316 
D337 
D358 
D379 
D400 
D421 
D442 
D463 
D484 
D505 
D526 
D547 
D554- 
D561 
Study Week 
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
±Visit Window 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NAa 
Physical Exam (PE) Symptom-
directed PE 
Section 6.5.3 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs;  
Section 6.5.1;  
Xb 
Xb 
Xb 
X 
Xb 
Xb 
Xb 
X 
Xb 
Xb 
Xb 
X 
Xb 
Xb 
X - vitals 
only 
ALN-TTRSC02 
Arm: Weight 
Section 6.5.2 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Patisiran Arm: 
Weight 
Section 6.5.2. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NYHA class; KPS; 
PND and FAP; 
mBMI  
Section 6.2.11.4; 
Section 6.2.12; 
Section 6.2.10; 
Section 6.2.5 
 
 
 
mBMI 
only 
 
 
 
mBMI 
only 
 
 
 
mBMI 
only 
 
 
X 
Serum Chemistry; 
Hematology; 
Urinalysis; 
Coagulation 
Section 6.5.6 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X-Serum 
chemistry 
only 
LFT 
Section 6.5.6;  
Section 6.5.6.3 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Pregnancy Test 
Section 6.5.6.2 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Cardiac Biomarker 
Samples 
Section 6.2.11.2 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
TTR Protein; 
Vitamin A 
Section 6.3  
 
 
 
X 
 
  
 
X 
 
  
 
X 
 
X 
X 
ADA 
On dosing days, 
collect ADA 
within 1 hour 
before dosing, 
Section 6.5.6.1  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 4, 19 February 2021 
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Table 2: 
Schedule of Assessments –Treatment Period from Month 9 through Month 18 
 
Note 
Treatment Period 
Month 18 
Efficacya 
Study Day  
D274 
D295 
D316 
D337 
D358 
D379 
D400 
D421 
D442 
D463 
D484 
D505 
D526 
D547 
D554- 
D561 
Study Week 
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
±Visit Window 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NAa 
ALN-TTRSC02 
Arm PK  
See Table 5 for 
detail timepoints 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Patisiran Arm PK 
See Table 6 for 
detail timepoints 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Samples for 
Exploratory 
Analysis 
Plasma, serum, 
urine; 
Section 6.6 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
Norfolk QoL-DN; 
R-ODS; EQ-5D-5L 
and EQ-VAS; C-
SSRS; Patient and 
Caregiver Impact 
Survey  
Section 6.2.3; 
Section 6.2.6; 
Section 6.2.9; 
Section 6.5.5; 
Section 6.7.1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Patient Experience 
Survey 
Section 6.7.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NIS; mNIS+7; 
HRdb; 10-MWT 
See below Table 
2 Notes; 
Section 6.2.1; 
Section 6.2.2; 
Section 6.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Single 12-Lead 
ECG 
Section 6.5.4 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram 
Section 6.2.11.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Technetium 
scintigraphy 
imaging (select 
sites only)  
Section 6.2.11.3   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ALN-TTRSC02 
Study Drug 
Administration 
Section 5.2.2.1  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 

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Table 2: 
Schedule of Assessments –Treatment Period from Month 9 through Month 18 
 
Note 
Treatment Period 
Month 18 
Efficacya 
Study Day  
D274 
D295 
D316 
D337 
D358 
D379 
D400 
D421 
D442 
D463 
D484 
D505 
D526 
D547 
D554- 
D561 
Study Week 
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
±Visit Window 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NAa 
Patisiran: 
Premedication 
Administration 
Section 5.2.2.2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patisiran Study 
Drug 
Administration 
Section 5.2.2.2 
X – Dose 
after Month 
9 efficacy 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital status check 
Section 6.2.8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs; Con. Med.; 
Hospitalization; 
Urgent care visits; 
Procedures 
Section 6.5.7; 
Section 5.3; 
Section 6.7.2  
Continuous Monitoring 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con. Med.=concomitant medications; C-SSRS= Columbia-Suicide Severity Rating Scale; D=day; 
ECG=electrocardiogram; EQ-5D-5L=EuroQuality of Life 5-Dimensions 5-Levels; EQ-VAS=EuroQuality of Life-Visual Analog Scale; FAP=Familial Amyloidotic 
Polyneuropathy; HRdb=heart rate variability with deep breathing; KPS= Karnofsky Performance Status; LFT=liver function test; mBMI=modified body mass index; 10-
MWT=10-meter walk test; mNIS+7=modified NIS+7; NIS=Neurologic Impairment Score; NYHA=New York Heart Association; PE=physical exam; PK=pharmacokinetics; 
PND=Polyneuropathy Disability; QoL-DN=Quality of Life-Diabetic Neuropathy; R-ODS=Rasch-built Overall Disability Scale; TTR=transthyretin  
Table 2 Notes: 
• 
Unless otherwise specified, assessments on dosing days are predose. 
• 
For the Month 18 NIS; mNIS+7; HRdb and 10-MWT: Two independent assessments will be performed on separate days (1 assessment on each day); the 2 assessments 
should be performed approximately 24 hours apart from each other but not more than 7 days apart.  Components that are shared between the mNIS+7 and NIS will be 
performed once at each assessment (eg, the weakness component should not be performed more than once on any given day). 
• 
Dosing may be allowed outside of the study center (eg, the patient’s home) under certain circumstances as specified in Section 5.2.2.1 and Section 5.2.2.2. In addition, 
routine assessments and collection of relevant safety information may be collected outside the study center as specified in the beginning of Section 6. 
• 
For the ALN-TTRSC02 cohort, dosing decisions may be made based on LFT results (Table 8) collected at the previous dosing visit (up to 14 weeks prior to dosing); in 
all cases the most recently available LFTs should be used. LFT monitoring details are provided in Section 5.2.3. 
For the patisiran cohort, LFTs should be performed according to patisiran visit windows and do not need to be available prior to dosing. 
a 
In situations in which a Month 18 efficacy visit is unable to be completed due to the Coronavirus disease 2019 (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, the Medical Monitor should be consulted as soon as possible to 
determine the appropriate timing of the Month 18 efficacy assessment.  After consultation with the Medical Monitor, Month 18 efficacy assessments may be completed within 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 4, 19 February 2021 
Alnylam Pharmaceuticals 
Confidential 
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6 months after the intended time point (ie, up to Study Month 24). 
 
 
b   For the ALN-TTRSC02 cohort, collection of vital signs may be deferred at this timepoint if issues related to the COVID-19 pandemic limit the patient’s ability or willingness 
to access the study site. 
 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 4, 19 February 2021 
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Table 3: 
Schedule of Assessments:  Legacy Treatment Extension Period, Early Drug Discontinuation and Other Visits 
 
 
Note 
Legacy Treatment Extension Perioda,b,c 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy Visits for 
Patients Who Discontinue 
Treatment before Month 18 
 
Last Patisiran 
Dosing Visit 
(ALN-TTRSC02 
cohort exempt) 
ALN-TTRSC02 
Dosing Visits 
Every 12 Weeks 
4 (+1) Weeks 
from Last Dose* 
Month 9 
Month 18 
Study Week 
81 
84, 96, 108, 120, 
132, 144, and 156 
- 
36-39 
79-80 
±Visit Window 
 
±3D 
±7D 
- 
- 
- 
Medical Records Release 
Form (optional) 
Section 8.1.1  
Recheck 
 
 
X 
 
 
NYHA class; KPS; PND 
and FAP; mBMI  
Section 6.2.11.4; Section 6.2.12; 
Section 6.2.10; Section 6.2.5 
 
 
X 
X 
X 
Vital signs 
Section 6.5.1  
X 
X 
 
 
 
Physical Examination (PE); 
Weight  
Symptom-directed PE Section 6.5.3; 
Section 6.5.2  
X 
X 
X 
X 
X 
NIS; mNIS+7; HRdb 
See below Table 3 Notes; 
Section 6.2.1; Section 6.2.2  
 
 
X 
X 
X 
X 
X 
X 
10-MWT 
Section 6.2.4  
 
 
X 
X 
 
 
 
 
Questionnaires: Norfolk 
QoL-DN; R-ODS; EQ-5D-
5L and EQ-VAS; C-SSRS; 
Patient and Caregiver 
Impact Survey 
Section 6.2.3; Section 6.2.6; 
Section 6.2.9; Section 6.5.5; 
Section 6.7.1 
 
 
X 
X – No  
C-SSRS 
X – No  
C-SSRS 
Single 12-Lead ECG 
Section 6.5.4 
 
 
X 
 
 
Echocardiogram 
Section 6.2.11.1 
 
 
X 
 
 
Technetium scintigraphy 
imaging (select sites only) 
Section 6.2.11.3 
 
 
X 
 
 
Serum Chemistry, 
Hematology, Urinalysis, 
Coagulation and Liver 
Function Tests 
Section 6.5.6; Section 6.5.6.3 
LFT only 
X 
X 
Serum 
Chemistry 
and LFTs 
only 
Serum 
Chemistry 
and LFTs 
only 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 4, 19 February 2021 
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Table 3: 
Schedule of Assessments:  Legacy Treatment Extension Period, Early Drug Discontinuation and Other Visits 
 
 
Note 
Legacy Treatment Extension Perioda,b,c 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy Visits for 
Patients Who Discontinue 
Treatment before Month 18 
 
Last Patisiran 
Dosing Visit 
(ALN-TTRSC02 
cohort exempt) 
ALN-TTRSC02 
Dosing Visits 
Every 12 Weeks 
4 (+1) Weeks 
from Last Dose* 
Month 9 
Month 18 
Study Week 
81 
84, 96, 108, 120, 
132, 144, and 156 
- 
36-39 
79-80 
±Visit Window 
 
±3D 
±7D 
- 
- 
- 
Pregnancy Test  
Section 6.5.6.2 
 
X 
X 
X 
X 
Cardiac Biomarker Samples 
Section 6.2.11.2 
 
X -  
Week 96, Week 
120, Week 144 
X 
X 
X 
TTR Protein; Vitamin A 
Prior to each dose on dosing days; 
Section 6.3 
 
X 
X 
X 
X 
ADA 
On dosing days, collect within 1 hour 
before dosing; Section 6.5.6.1  
 
X – Week 96, Week 
120, Week 144 
X 
 
 
ALN-TTRSC02 PK  
Table 5 for PK collection timepoints 
 
 
X 
X 
X 
Samples for Exploratory 
Analysis 
Section 6.6 
 
 
X 
 
 
AEs; Con. Meds; 
Hospitalizations, Urgent 
care visits and Procedures 
Section 6.5.7; Section 5.4; 
Section 6.7.2 
Continuous monitoring 
ALN-TTRSC02 Study 
Drug Administration 
Section 5.2.2.1  
 
X – Every 12 weeks 
starting at Week 84 
to EOT Week 156 
 
 
 
Patisiran: Premedication 
Administration 
Section 5.2.2.2  
X 
 
 
 
 
Patisiran Study Drug 
Administration 
Section 5.2.2.2 
X 
 
 
 
 
Vital status check  
Section 6.2.8 
X 
X 
X 
X 
X 
Abbreviations:  ADA=antidrug antibodies; AE=adverse event; Con. Med.=concomitant medications; C-SSRS= Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
EOT=End of Treatment; EQ-5D-5L=EuroQuality of Life 5-Dimensions 5-Levels; EQ-VAS= EuroQuality of Life-Visual Analog Scale; FAP=Familial Amyloidotic 
Polyneuropathy; FU=Follow-up; HRdb=heart rate variability with deep breathing; KPS= Karnofsky Performance Status; LFT=liver function test; mBMI=modified body mass 

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index; 10-MWT=10-meter walk test; mNIS+7=modified NIS+7; NIS=Neurologic Impairment Score; NYHA=New York Heart Association; PE=physical exam; 
PK=pharmacokinetics; PND=Polyneuropathy Disability; QoL-DN=Quality of Life-Diabetic Neuropathy; R-ODS=Rasch-built Overall Disability Scale; TTR=transthyretin  
Table 3 Notes: 
• 
Dosing may be allowed outside of the study center (eg, the patient’s home) under certain circumstances as specified in Section 5.2.2.1 and Section 5.2.2.2. In addition, 
routine assessments and collection of relevant safety information may be collected outside the study center as specified in the beginning of Section 6. 
• 
For the NIS; mNIS+7; HRdb;10-MWT performed as part of the Early Drug Discontinuation Visit and the Modified Month 9 and 18 Efficacy Visit(s): Two independent 
assessments will be performed on separate days (1 assessment on each day); the 2 assessments should be performed approximately 24 hours apart from each other but not 
more than 7 days apart.   
• 
See Section 4.3 for instructions on early discontinuation of study drug procedures.  
• 
SAE, AECI will be collected throughout the Follow-up Period; AEs will be collected until 3 months after the last dose of study drug.   
• 
Dosing decisions may be made based on LFT results (Table 8) collected at the previous dosing visit (up to 14 weeks prior to dosing); in all cases, the most recently 
available LFTs should be used. LFT monitoring details are provided in Section 5.2.3. 
For the patisiran cohort, LFTs should be performed according to patisiran visit windows and do not need to be available prior to dosing. 
*  The Early Discontinuation Visit applies to all periods of the study.  
 
.  
a Previously referred to as the 18-month Treatment Extension Period (per Amendment 3 and earlier); 
 
 
 
 
  
 
 
   

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Table 5: 
Pharmacokinetic Time Points: ALN-TTRSC02 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood (Plasma) 
Day 1 and Day 253±3 days  
Predose (within 60 minutes before dosing) 
X 
03:00 (±1 hr) after dosing 
X 
06:00 (±1 hr) after dosing 
X 
24:00 (±2 hr) after dosing 
X 
Day 85 and Day 169 (±3 days) 
Predose (within 60 minutes before dosing) 
X 
03:00 (±1 hr) after dosing 
X 
Day 337, Day 421, and Day 505 (±3 days) 
Predose (within 60 minutes before dosing) 
X 
03:00 (±1 hr) after dosing 
X 
  
 
 
 
 
Early Drug Discontinuation Visit 
Collect any time within the visit window 
X 
Modified Efficacy Visits for Patients Who Discontinue 
Treatment before Month 18 
Collect any time within the visit window 
X 
Abbreviations: 
 
PK sample collection timepoints at 6 and 24 hours after dosing are optional when samples are being collected outside the clinic (eg, the patient’s home).  
 
Table 6: 
Pharmacokinetic Time Points: Patisiran 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood (Plasma) 
Day 1 and Day 253±3 days  
Predose (within 60 minutes before the start of infusion) 
X 
00:30 (±5 min) from the end of infusion 
X 
06:00 (±1 hr) from the end of infusion 
X 
24:00 (±2 hr) from the end of infusion 
X 
Day 22, Day 127, Day 274, Day 379, and Day 547 
(±3 days) 
Predose (within 60 minutes before the start of infusion) 
X 
03:00 (±1 hr) from the end of infusion 
X 
PK sample collection timepoints at 6 and 24 hours after dosing are optional when samples are being collected outside the clinic (eg, the patient’s home).  
 
 

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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................29 
LIST OF TABLES .........................................................................................................................33 
LIST OF FIGURES .......................................................................................................................34 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................35 
1. 
INTRODUCTION ......................................................................................................39 
1.1. 
Disease Overview .......................................................................................................39 
1.2. 
Current Treatments .....................................................................................................40 
1.3. 
RNAi Therapeutics to Reduce TTR Levels ................................................................41 
1.4. 
Clinical Experience with Patisiran and ALN-TTRSC02 ............................................42 
1.4.1. 
The APOLLO Study ...................................................................................................42 
1.4.2. 
ALN-TTRSC02-001 Phase 1 Clinical Study ..............................................................42 
1.5. 
Study Design Rationale ..............................................................................................43 
1.6. 
Dose Rationale ............................................................................................................44 
1.7. 
Benefit-Risk Assessment ............................................................................................45 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................46 
3. 
INVESTIGATIONAL PLAN .....................................................................................47 
3.1. 
Summary of Study Design ..........................................................................................47 
3.2. 
Duration of Treatment ................................................................................................50 
3.3. 
Duration of Study .......................................................................................................50 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................50 
3.4. 
Number of Planned Patients .......................................................................................50 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................51 
3.6. 
Blinding ......................................................................................................................51 
3.7. 
Data Monitoring Committee .......................................................................................51 
3.8. 
Adjudication Committee .............................................................................................51 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................51 
4.1. 
Inclusion Criteria ........................................................................................................52 
4.2. 
Exclusion Criteria .......................................................................................................52 

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4.3. 
Removal from Therapy or Assessment.......................................................................54 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................54 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................56 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................56 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................56 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................56 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................56 
4.3.3. 
Lost to Follow-Up.......................................................................................................57 
4.3.4. 
Replacement of Study Patients ...................................................................................57 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................57 
5.1. 
Treatments Administered ............................................................................................57 
5.2. 
Study Drug ..................................................................................................................57 
5.2.1. 
Description ..................................................................................................................58 
5.2.2. 
Dose and Administration ............................................................................................58 
5.2.2.1. 
ALN-TTRSC02 ..........................................................................................................58 
5.2.2.2. 
Patisiran ......................................................................................................................59 
5.2.2.3. 
Switching from Patisiran to ALN-TTRSC02 After Month 18 ...................................61 
5.2.3. 
LFT Criteria for Withholding, Monitoring and Stopping ALN-TTRSC02 
Dosing .........................................................................................................................61 
5.2.4. 
Preparation, Handling, and Storage ............................................................................62 
5.2.5. 
Packaging and Labeling ..............................................................................................63 
5.2.6. 
Accountability .............................................................................................................63 
5.3. 
Product Complaints ....................................................................................................63 
5.3.1. 
Definition ....................................................................................................................63 
5.3.2. 
Reporting ....................................................................................................................63 
5.4. 
Concomitant Medications ...........................................................................................64 
5.5. 
Treatment Compliance ................................................................................................64 
5.6. 
Other Requirements ....................................................................................................64 
5.6.1. 
Contraception ..............................................................................................................64 
5.6.2. 
Alcohol Restrictions ...................................................................................................65 
6. 
STUDY ASSESSMENTS ..........................................................................................66 
6.1. 
Screening Assessments ...............................................................................................67 
6.1.1. 
Retesting .....................................................................................................................67 

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6.1.2. 
Rescreening .................................................................................................................68 
6.1.3. 
Demographic and Medical History/Disease History ..................................................68 
6.2. 
Efficacy Assessments .................................................................................................68 
6.2.1. 
Neurologic Impairment Assessments .........................................................................68 
6.2.1.1. 
Modified Neurological Impairment Score +7 (mNIS+7) ...........................................68 
6.2.1.2. 
Neurologic Impairment Score (NIS) ..........................................................................69 
6.2.1.3. 
Personnel and Procedures to Ensure Quality and Consistency of NIS and 
mNIS+7 Scoring .........................................................................................................69 
6.2.2. 
Heart Rate Response to Deep Breathing (HRdb) .......................................................70 
6.2.3. 
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) ............................70 
6.2.4. 
Ten-meter Walk Test (10-MWT) ...............................................................................70 
6.2.5. 
Modified Body Mass Index (mBMI) ..........................................................................70 
6.2.6. 
Rasch-built Overall Disability Scale (R-ODS) ...........................................................70 
6.2.7. 
Deaths and Hospitalizations .......................................................................................71 
6.2.8. 
Vital Status Check ......................................................................................................71 
6.2.9. 
European Quality of Life-5 Dimensions 5-Levels (EQ-5D-5L) and EQ-
Visual Analog Scale (EQ-VAS) .................................................................................71 
6.2.10. 
PND Score and FAP Stage .........................................................................................71 
6.2.11. 
Cardiac Assessments ..................................................................................................72 
6.2.11.1. 
Echocardiogram ..........................................................................................................72 
6.2.11.2. 
Cardiac Biomarkers ....................................................................................................72 
6.2.11.3. 
Technetium Scintigraphy Imaging .............................................................................72 
6.2.11.4. 
New York Heart Association (NYHA) Class .............................................................73 
6.2.12. 
Karnofsky Performance Status (KPS) ........................................................................73 
6.3. 
Pharmacodynamic Assessments .................................................................................73 
6.4. 
Pharmacokinetic Assessments ....................................................................................73 
6.5. 
Safety Assessments .....................................................................................................73 
6.5.1. 
Vital Signs ..................................................................................................................74 
6.5.2. 
Weight and Height ......................................................................................................74 
6.5.3. 
Physical Examination .................................................................................................74 
6.5.4. 
Electrocardiogram .......................................................................................................74 
6.5.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................75 
6.5.6. 
Clinical Laboratory Assessments ...............................................................................75 

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6.5.6.1. 
Immunogenicity ..........................................................................................................77 
6.5.6.2. 
Pregnancy Testing ......................................................................................................77 
6.5.6.3. 
Additional Liver Function Assessments .....................................................................78 
6.5.7. 
Adverse Events ...........................................................................................................79 
6.5.7.1. 
Definitions ..................................................................................................................79 
6.5.7.2. 
Eliciting and Recording Adverse Events ....................................................................80 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................81 
6.5.7.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........81 
6.5.7.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................82 
6.5.7.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................82 
6.5.7.7. 
Pregnancy Reporting ..................................................................................................82 
6.5.7.8. 
Overdose Reporting ....................................................................................................83 
6.5.8. 
COVID-19 Data Collection ........................................................................................83 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................83 
6.7. 
Pharmacoeconomic Assessments ...............................................................................84 
6.7.1. 
Patient and Caregiver Impact Survey .........................................................................84 
6.7.2. 
Hospitalization, Urgent Healthcare Visits, Surgeries, and Procedures ......................84 
6.7.3. 
Patient Experience Survey ..........................................................................................84 
6.7.4. 
Patient Preference Survey ...........................................................................................84 
7. 
STATISTICS ..............................................................................................................84 
7.1. 
Determination of Sample Size ....................................................................................85 
7.2. 
Statistical Methodology ..............................................................................................85 
7.2.1. 
Populations to be Analyzed ........................................................................................85 
7.2.2. 
Examination of Subgroups .........................................................................................86 
7.2.3. 
Handling of Missing Data ...........................................................................................86 
7.2.4. 
Baseline Evaluations ...................................................................................................86 
7.2.5. 
Efficacy Analyses .......................................................................................................86 
7.2.5.1. 
Primary Endpoint ........................................................................................................86 
7.2.5.2. 
Secondary Endpoints ..................................................................................................87 
7.2.5.3. 
Exploratory Endpoints ................................................................................................88 
7.2.6. 
Pharmacodynamic Analysis........................................................................................88 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................88 

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7.2.8. 
Safety Analyses ..........................................................................................................88 
7.2.9. 
Immunogenicity Analyses ..........................................................................................89 
7.2.10. 
Other Analyses ............................................................................................................89 
7.2.11. 
Interim Analysis ..........................................................................................................89 
8. 
STUDY ADMINISTRATION ...................................................................................89 
8.1. 
Ethical and Regulatory Considerations ......................................................................89 
8.1.1. 
Informed Consent and Medical Records Release Form .............................................89 
8.1.2. 
Ethical Review ............................................................................................................90 
8.1.3. 
Serious Breach of Protocol .........................................................................................90 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................90 
8.1.5. 
End of Study ...............................................................................................................91 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................91 
8.2. 
Data Quality Control and Quality Assurance .............................................................91 
8.2.1. 
Data Handling .............................................................................................................91 
8.2.2. 
Study Monitoring ........................................................................................................92 
8.2.3. 
Audits and Inspections ................................................................................................92 
8.3. 
Publication Policy .......................................................................................................92 
9. 
LIST OF REFERENCES ............................................................................................93 
10. 
APPENDICES ............................................................................................................96 
10.1. 
mNIS+7 Components and Scoring .............................................................................96 
10.2. 
PND Scores and FAP Stages ......................................................................................97 
10.3. 
New York Heart Association (NYHA) Class .............................................................98 
10.4. 
Karnofsky Performance Status (KPS) Scale ...............................................................98 
LIST OF TABLES 
Table 1: 
Schedule of Assessments – Screening through Treatment Period Month 9 ...............11 
Table 2: 
Schedule of Assessments –Treatment Period from Month 9 through Month 
18 ................................................................................................................................17 
Table 3: 
Schedule of Assessments:  Legacy Treatment Extension Period, Early Drug 
Discontinuation and Other Visits ................................................................................21 
Table 4: 
 
 .................................................................................................24 
Table 5: 
Pharmacokinetic Time Points: ALN-TTRSC02 .........................................................28 
Table 6: 
Pharmacokinetic Time Points: Patisiran .....................................................................28 

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Table 7: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................62 
Table 8: 
Clinical Laboratory Assessments ...............................................................................76 
Table 9: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............78 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................10 
Figure 2: 
 – 
 .........................................10 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Antidrug antibodies  
AE 
Adverse event 
ALN-TTRSC02 
Name of study drug product 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
APOLLO 
Name of patisiran pivotal Phase 3 clinical study ALN-TTR02-004 
ASGPR 
Asialoglycoprotein receptor  
AST 
Aspartate transaminase 
ATTR 
Amyloid transthyretin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CAS 
Central Assessment Sites 
CASE 
Computer Aided Sensory Evaluator 
CI 
Confidence Interval 
CHMP 
Committee for Medicinal Products for Human Use 
CMAP 
Compound muscle action potential 
Cmax 
Observed peak concentration 
Con. Med 
Concomitant medication 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicine Agency 

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Abbreviation 
Definition 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQoL 5-Dimensions 5-Levels 
EQ-VAS 
EuroQoL visual analogue scale 
EU 
European Union 
FAC 
Familial amyloidotic cardiomyopathy, also known as hATTR amyloidosis 
with cardiomyopathy 
FAP 
Familial amyloidotic polyneuropathy, also known as hATTR amyloidosis 
with polyneuropathy 
GalNAc 
N-acetyl galactosamine ligand 
GCP 
Good Clinical Practice 
H1 
Histamine 1 receptor 
H2 
Histamine 2 receptor 
hATTR 
Hereditary ATTR 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency virus 
HRdb 
Heart rate variability with deep breathing 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRR 
Infusion related reaction 
IRS 
Interactive Response System 
ISR 
Injection site reaction 
IV 
Intravenous 
KPS 
Karnofsky Performance Status 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LS 
Least squares 
LV 
Left ventricle 

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Abbreviation 
Definition 
mBMI 
Modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of Diet in Renal Disease Study 
mITT 
Modified Intent-to-Treat 
10-MWT 
10-meter walk test 
mNIS+7 
Modified Neurologic Impairment Score +7 
mRNA 
Messenger RNA 
NCS 
Nerve conduction studies 
NCS Σ5 
NCS sum of 5 attributes 
NIS 
Neurologic Impairment Score 
NIS-R 
NIS reflexes 
NIS-S 
NIS sensation 
NIS-W 
NIS weakness 
Norfolk QoL-DN 
Norfolk Quality of Life-Diabetic Neuropathy 
NT-proBNP 
B-type natriuretic peptide 
NYHA 
New York Heart Association 
OLT 
Orthotopic Liver Transplantation 
Patisiran 
Name of patisiran drug product; patisiran-lipid nanoparticles 
PCS 
Patient Care Sites 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PND 
Polyneuropathy Disability 
PT 
Prothrombin time 
q3M 
Once every 3 months 
q3w 
Once every 3 weeks 
QoL or QOL 
Quality of life 
QST 
Quantitative sensory testing 
QST-BSAHP 
QST heat pain by body surface area 
QST-BSATP 
QST touch pressure by body surface area 
QTc 
Corrected QT interval 
QTcF 
QT obtained using Fridericia's formula  

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Abbreviation 
Definition 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RISC 
RNA-induced silencing complex 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
R-ODS 
Rasch-built Overall Disability Scale 
RTE 
Randomized Treatment Extension 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
siRNA 
Small interfering ribonucleic acid 
SNAP 
Sensory nerve action potential 
SOC 
System organ class 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T3 
Triiodothyronine 
T4 
Thyroxine 
tmax 
Time of observed maximum concentration 
TTR 
Transthyretin 
TUDCA 
Tauroursodeoxycholic acid 
ULN 
Upper limit of normal 
US 
United States 
USA 
United States of America 
V30M 
Valine to methionine mutation at position 30 
V122I 
Valine to isoleucine mutation at position 122 
WHO 
World Health Organization 
Wt 
Wild type 

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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Hereditary ATTR amyloidosis (hATTR amyloidosis) is a rare, life-threatening, autosomal 
dominant, multi-systemic disease caused by mutations in the transthyretin (TTR) gene that 
results in rapidly progressive, debilitating morbidity and high mortality.  The cardinal 
manifestations of hATTR amyloidosis are polyneuropathy and cardiomyopathy. 
TTR, also known as prealbumin, is a tetrameric protein predominantly produced by hepatocytes 
(>95% of circulating TTR is liver-derived), with a smaller fraction produced by the choroid 
plexus and retina [Liz 2010].  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. TTR also serves as a minor carrier for thyroxine (T4).  
In hATTR amyloidosis, 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.  These misfolded TTR monomers can 
then self-assemble into oligomers and form amyloid fibrils and plaques in the extracellular space 
of various tissues [Hou 2007], including the peripheral nervous system, heart, gastrointestinal 
tract, kidney, central nervous system and eye, leading to cellular injury and organ dysfunction 
with corresponding clinical manifestations. Since almost all patients are heterozygous for the 
mutated TTR allele, the amyloid fibrils typically consist of both mutant and wtTTR.  There are 
over 120 reported TTR genetic mutations associated with hATTR [Ando 2013; Brodsky 2008; 
Connors 2003]. The disease is most often caused by the valine to methionine mutation at position 
30 in the human TTR gene (V30M)primarily in families with heritage from Portugal, Sweden, 
Japan, and Brazil [Parman 2016]. Another common genotype is the isoleucine substitution for 
valine at position 122 (V122I).  This mutation occurs in up to 4% of African Americans and in 
over 5% of West African populations [Jacobson 1997]. 
Historically, due to incomplete understanding of etiology and pathogenesis, 2 clinical syndromes 
of hATTR amyloidosis have been described in the medical literature: hATTR amyloidosis with 
polyneuropathy (previously known as familial amyloidotic polyneuropathy, or FAP) and hATTR 
amyloidosis with cardiomyopathy (previously known as familial amyloidotic cardiomyopathy, or 
FAC), both of which are characterized by amyloid deposits comprised of both mutant and wt 
TTR [Yazaki 2000].  However, while patients with hATTR amyloidosis may present with 
predominantly polyneuropathy or cardiomyopathy, most patients with hATTR amyloidosis 
manifest signs and symptoms of both polyneuropathy and cardiomyopathy over the course of 
their disease.  Therefore, hATTR amyloidosis is increasingly viewed as a single hereditary 
disease with a spectrum of clinical manifestations rather than 2 distinct syndromes [Swiecicki 
2015]. 
The clinical manifestations of the length-dependent, symmetrical polyneuropathy are the result 
of amyloid-mediated injury to large and small peripheral nerve fibers [Ando 2013; Benson and 
Kincaid 2007; Plante-Bordeneuve and Said 2011].  Sensory abnormalities include painful 
dysesthesias in the feet and hands, as well as loss of sensation leading to thermal burns in these 
areas and to joint injury in the lower limbs.  Progressive muscle atrophy and motor weakness in 
both lower and upper limbs leads to impaired ambulation (progressing from the use of one stick 

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to two for ambulation, followed by needing to use a wheel chair and then becoming bed-ridden 
over just a few years), and inability to perform other activities of daily living.  Autonomic 
dysfunction results in debilitating orthostatic hypotension, severe gastrointestinal symptoms, and 
bladder dysfunction with recurrent urinary tract infections.   
Polyneuropathy stage or severity is classified by FAP stage or Polyneuropathy Disability (PND) 
score, both of which are based on ambulatory ability.  The degree of neurologic impairment has 
historically been measured using the Neurologic Impairment Score (NIS), which has been shown 
to be correlated with FAP stage and PND score; an increase from baseline in NIS score signifies 
worsening in neurologic impairment, which in turn correlates with a higher FAP stage 
designation and PND score [Adams 2015]. The maximum impairment score for the NIS is 244 
points, and a change from baseline of 10 to 14 points per year has been observed in untreated 
patients based on data from an hATTR amyloidosis clinical study and an observational natural 
history study [Adams 2015; Berk 2013]. This is in contrast to patients with diabetic 
polyneuropathy where NIS progression is <1 point/year [Ziegler 2011]. For clinical studies, the 
modified NIS+7 (mNIS+7) score, a more sensitive measure with a scale from 0 to 304 points, 
has been developed to provide a more comprehensive measure of polyneuropathy in patients 
with hATTR amyloidosis [Suanprasert 2014].  
Cardiac infiltration with amyloid leads to heart wall thickening and cardiomyopathy 
characterized by clinical heart failure due to both diastolic and systolic dysfunction, as well as 
cardiac conduction disturbances and arrhythmias [Ando 2013; Benson and Kincaid 2007; 
Carvalho 1992; Connors 2004; Soares 2005].  Patients with symptomatic heart failure experience 
rapid progression of their amyloid cardiomyopathy, with substantial worsening of 
echocardiographic and biomarker measures of cardiac function, ambulation, and quality of life 
seen over a period of 18 months or less [Ruberg and Berk 2012].   
1.2. 
Current Treatments 
The treatment of hATTR amyloidosis requires a multidisciplinary approach primarily involving 
neurology, gastroenterology, and cardiology specialties.  Palliative/symptomatic therapies 
directed at specific symptoms such as pain, nausea/vomiting and diarrhea have been the mainstay 
of treatment.   
Two treatment approaches that have historically been used for the treatment of hATTR 
amyloidosis are orthotopic liver transplantation (OLT), which serves to eliminate mutant TTR 
from the circulation, but does not affect the hepatic production of wt TTR [Carvalho 2015; 
Ericzon 2015; Okamoto 2009], and TTR tetramer stabilizers (including tafamidis and diflunisal), 
which have been shown in clinical studies to reduce neuropathy in patients with early stage 
polyneuropathy [Berk 2013; Coelho 2012]. However, these therapies are restricted to a small 
subset of patients with hATTR amyloidosis with early stage neuropathy. Furthermore, the 
majority of patients receiving tafamidis continue to experience neuropathy progression with a 
steady decline in quality of life, ability to walk, and to perform activities of daily living [Barroso 
2017].  
Recently, the antisense oligonucleotide inotersen and the short interfering ribonucleic acid 
(siRNA) patisiran were shown in randomized controlled studies to significantly reduce 
neurologic impairment and improve quality of life compared with placebo in patients with 
hATTR amyloidosis [Adams 2017; Dyck 2017; Wang et al. 2017].  Both novel therapies, albeit 

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through different mechanisms, aim at reducing the expression of TTR messenger RNA (mRNA), 
and the amount of circulating amyloidogenic protein in patients with hATTR amyloidosis.   
1.3. 
RNAi Therapeutics to Reduce TTR Levels  
Patisiran-LNP (ONPATTRO™; hereafter referred to as patisiran) developed by Alnylam, which 
targets the production of hepatic TTR, is approved in the US for the treatment of the 
polyneuropathy of hATTR amyloidosis in adults and in the EU for the treatment of hATTR 
amyloidosis in adult patients with stage 1 and stage 2 polyneuropathy.  The recommended dose 
of patisiran is 0.3 mg/kg administered via intravenous (IV) infusion once every 3 weeks (q3w).  
To minimize the risk of infusion related reactions (IRRs), all patients must receive pre-
medication including corticosteroids (10 mg dexamethasone IV), histamine 1 (H1) and histamine 
2 (H2) blockers, and paracetamol or equivalents 60 minutes prior to the infusion. 
Patisiran utilizes the mechanism of RNA interference to selectively degrade TTR mRNA and 
thereby reduce the expression of its corresponding protein [Bumcrot 2006]. Patisiran is an 
siRNA that is formulated as lipid nanoparticles (LNP) to target delivery to hepatocytes in the 
liver, the primary source of TTR protein in circulation.  Following IV infusion, opsonization of 
the LNP by apolipoprotein E facilitates binding to the low-density lipoprotein receptor on 
hepatocytes and subsequent endocytosis.  Fusion of the ionizable lipid component of the LNP 
with the endosomal membrane then leads to release of the siRNA into the cytoplasm where it can 
bind to and activate the RNA-induced silencing complex (RISC). Upon binding and activation of 
RISC in the cytoplasm within hepatocytes, the siRNA duplex unwinds and the antisense strand 
specifically binds to a genetically conserved sequence in the 3’ untranslated region of wt and 
mutant TTR mRNA.  The Argonaute-2 endonuclease within the RISC/siRNA enzyme complex 
catalytically degrades wt and mutant TTR mRNA, resulting in a reduction of wt and mutant TTR 
protein.   
Alnylam had also developed another siRNA-conjugate therapeutic, revusiran, primarily for the 
treatment of patients with hATTR amyloidosis with cardiomyopathy; however, this program was 
discontinued as described further in the ALN-TTRSC02 Investigator’s Brochure (IB).   
ALN-TTRSC02 (also known as vutrisiran) is in clinical development for the treatment of ATTR 
amyloidosis. This molecule is 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.  
ALN-TTRSC02 has the same nucleotide sequence as revusiran but employs a different ratio of 
chemical modifications to confer increased stability of the siRNA.   
ALN-TTRSC02 drug product comprises the drug substance ALN-65492, an siRNA targeting 
TTR mRNA that is conjugated to an N-acetyl galactosamine ligand (GalNAc) to facilitate 
delivery to the liver, formulated in 10 mM sodium phosphate, 110 mM sodium chloride at pH 7 
for subcutaneous (SC) injection.  Uptake of ALN-TTRSC02 occurs via the asialoglycoprotein 
receptor (ASGPR), a member of the C-type lectin family of receptors that recognizes and binds 
glycoproteins with terminal galactose (Gal) or GalNAc residues [Ashwell and Morell 1974; Nair 
2014]. It is expressed on the cell surface of hepatocytes at a high copy number (0.5-1 million per 
cell) [Baenziger and Fiete 1980; Schwartz 1980], and facilitates clearance of desialylated 
glycoproteins from the blood [Geffen and Spiess 1992]. Binding of the carbohydrate ligand to 
the ASGPR leads to receptor-mediated endocytosis of the ligand-receptor complex followed by 

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release of its cargo in the endocytic pathway, and subsequent recycling of the receptor to the cell 
surface for successive rounds of uptake. 
ALN-TTRSC02 has been shown to have increased potency and duration of TTR reduction in 
nonclinical species and in a clinical study in healthy volunteers described in Section 1.4.2, 
enabling a much lower dose, lower injection volume, and significantly less frequent dosing for 
patients compared to other TTR-lowering drugs. 
1.4. 
Clinical Experience with Patisiran and ALN-TTRSC02 
1.4.1. 
The APOLLO Study 
The safety and efficacy of patisiran was shown in a Phase 3 multicenter, multinational, 
randomized, double-blind, placebo-controlled study (ALN-TTR02-004, APOLLO) that met the 
primary and all secondary endpoints [Adams 2018].  This study demonstrated that in patients 
with hATTR amyloidosis, who exhibited a broad range of disease severity and TTR genotypes, 
treatment with patisiran leads to a significant improvement in neuropathy (mNIS+7) relative to 
placebo at 18 months (primary analysis), as well as significant improvement in quality of life 
(Norfolk QoL-DN, key secondary analysis) relative to placebo at 18 months.  Significant 
improvement in neuropathy and quality of life were also observed at Month 9.  This study 
furthermore demonstrated that treatment with patisiran is associated with an improvement in 
overall health (gait speed, nutritional status, and disability), with improvement in these endpoints 
seen as early as at Month 9.  Patisiran treatment was also associated with improvement compared 
to placebo in exploratory cardiac endpoints including key echocardiographic parameters and the 
biomarker NT-proBNP [Solomon 2018].  In post-hoc analyses, patisiran demonstrated a 
reduction in the composite event rate of hospitalization and mortality. 
In the patisiran group, the mean TTR percent reduction from baseline was 82.6% and 84.3% at 
Month 9 and Month 18, respectively.  TTR percent reduction was maintained over the duration 
of the study.  A correlation (Pearson’s r, 0.59; 95% CI, 0.49-0.68) was observed between the 
degree of TTR reduction from baseline and the change in the mNIS+7 at 18 months. 
Patisiran showed an acceptable safety profile in the APOLLO study.  Common adverse events 
(AEs) occurring more frequently with patisiran compared to placebo included peripheral edema 
(30% versus 22%) and infusion related reactions (IRRs) (19% versus 9%, respectively). 
1.4.2. ALN-TTRSC02-001 Phase 1 Clinical Study  
ALN-TTRSC02 has been evaluated in a recently completed Phase 1 study (study ALN-
TTRSC02-001).  ALN-TTRSC02-001 was a randomized, single-blind, placebo controlled single-
ascending dose study to evaluate the safety and tolerability, pharmacokinetics (PK) and 
pharmacodynamics (PD) of ALN-TTRSC02 in healthy subjects and in healthy subjects of 
Japanese descent.  Single doses of 5, 25, 50, 100, 200 or 300 mg ALN-TTRSC02 were 
administered by SC injection to cohorts of 8 subjects (6:2 ratio ALN-TTRSC02 to placebo). 
Subjects remained blinded to treatment assignment through Day 90. Eighty healthy volunteers 
were randomized in 10 cohorts and followed for up to 314 days.  
ALN-TTRSC02 reduced serum TTR in a dose dependent fashion with higher doses of ALN-
TTRSC02 achieving deeper and longer duration of serum TTR reduction.  At the proposed dose 
of 25 mg ALN-TTRSC02, a single dose resulted in maximum TTR reduction of 94% and mean 

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maximum TTR reduction of 83% that was maintained for 90 days (n=12). Consistent with the 
expected PD effect, vitamin A levels were also reduced following a single dose of ALN-
TTRSC02. Similar PD effects were observed in the subjects of Japanese descent, as compared to 
the subjects in the non-Japanese cohorts. 
AEs were reported in 77% and 50% of ALN-TTRSC02 and placebo treated subjects, 
respectively.  Among ALN-TTRSC02 treated patients, the majority of AEs were mild.  ALN-
TTRSC02 drug-related AEs included injection site reactions in 4 subjects that were mild and 
transient including bruising (50 mg), erythema (200 mg) and pain (200 mg and 300 mg); there 
were no drug-related AEs in patients receiving ALN-TTRSC02 doses ≤25 mg.  There were no 
severe or serious AEs; no subject discontinued from the study due to an AE. A dose-dependent 
pattern in transaminase elevations was observed across the ALN-TTRSC02 doses tested, in 
particular at doses ≥100 mg; the majority were mild, transient, and none were reported as AEs.  
Most alanine transaminase (ALT) and aspartate transaminase (AST) elevations were ≤3 x upper 
limit of normal (ULN); 1 subject receiving ALN-TTRSC02 50 mg had AST >3 x ULN and 1 
subject receiving ALN-TTRSC02 200 mg had ALT and AST >3 x ULN, which were 
asymptomatic and resolved to <ULN without intervention.  There were no concurrent elevations 
in bilirubin or alkaline phosphatase. There were no clinically significant changes in renal 
function or hematologic parameters, including platelets and no clinically significant changes in 
electrocardiogram (ECG), vital signs or physical exam. 
Further information on the chemistry, pharmacology, efficacy, and safety of ALN-TTRSC02 is 
provided in the current edition of the Investigator’s Brochure. 
1.5. 
Study Design Rationale 
This is a global Phase 3 open-label study designed to evaluate the efficacy, safety, and PK/PD 
profile of ALN-TTRSC02 in adult patients with hATTR amyloidosis.  Patients will be 
randomized 3:1 to ALN-TTRSC02 or patisiran.  Patisiran is the reference comparator arm.  All 
patients randomized to patisiran will be transitioned to ALN-TTRSC02 after completion of the 
18-month Treatment Period. 
The study will consist of a Screening Period of up to 42 days, an 18-month Treatment Period, 
and an 18-month Randomized Treatment Extension Period (RTE) as of Amendment 4, in lieu of 
the 18-month Treatment Extension Period (hereafter referred to as the Legacy Treatment 
Extension Period).  A Follow-up Period of up to 1 year will occur after the last dose of study 
drug. See also Section 3.1. 
The proposed development plan for ALN-TTRSC02 builds upon learnings from the previous 
development of another siRNA that targets TTR, patisiran (described in Section 1.4). The 
completed patisiran Phase 3 APOLLO study, which enrolled a similar patient population to the 
current study and incorporated similar endpoints to the current study, will be used as an external 
control for efficacy analysis.  The primary endpoint in this study, change from baseline in 
mNIS+7 score at Month 9, and the key secondary endpoint of Norfolk QoL-DN total score at 
Month 9, will be compared with the placebo group from the APOLLO study at Month 9 as the 
primary analysis.  The use of an external control for comparison is supported by the principles 
outlined in the EMA guideline on clinical trials in small populations (CHMP/EWP/83561/2005), 
ICH E10 guidance on control groups in clinical trials, as well as the USA's 21st Century Cures 
Act (Section 3012 Targeted Drugs for Rare Diseases).  Based on these guidelines, an external 

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comparison is an appropriate clinical study design for diseases occurring in small populations, 
with well understood natural history of disease course.  The natural history of hATTR 
amyloidosis has been well-characterized in several, large, randomized clinical trials, including 
the APOLLO study, as well as natural history studies.  Importantly, these studies all demonstrate 
similar rates of disease progression despite having been conducted at substantially different 
points in time and in patients with different disease characteristics across different geographies 
[Adams 2015; Adams 2018; Berk 2013; Maurer 2017].  The patisiran reference comparator arm 
will help to validate the use of the external control for the primary and secondary efficacy 
analyses both by allowing descriptive comparison of the clinical efficacy endpoints between 
treatment arms within this study and by establishing similar (non-inferior) level of TTR 
reduction is achieved for ALN-TTRSC02 and patisiran. 
Secondary and exploratory endpoints in this study assessing the clinical manifestations of 
hATTR amyloidosis are similar to those in the APOLLO study.  Additional cardiac assessments 
are included in this study as exploratory endpoints. These endpoints will all be assessed in 
comparison to the placebo group in the APOLLO study. 
Safety will be assessed by monitoring of AEs, laboratory data including liver function tests, 
changes in physical exam, vital signs, and ECG. 
 
1.6. 
Dose Rationale 
The proposed dose of ALN-TTRSC02 for this study is 25 mg SC given q3M.  This dose was 
well-tolerated in the Phase 1 study (see Section 1.4.2) and is expected to provide efficacy similar 
to patisiran based on the anticipated magnitude of TTR lowering.  
 
 
Modeling and simulation predicted that the proposed 25 mg dose of ALN-TTRSC02 
administered SC q3M will lead to substantial and persistent serum TTR reduction, comparable to 
TTR lowering observed with patisiran in the Phase 3 APOLLO study.  At steady state, which is 
achieved by approximately 6 months, 25 mg SC q3M regimen of ALN-TTRSC02 is predicted to 
achieve median trough TTR reductions of 86%, which is similar to patisiran.  This magnitude of 
TTR lowering is expected to lead to durable clinical benefit as evidenced by the statistically 
significant difference in mNIS+7 and all the secondary endpoints, including Norfolk QoL-DN, in 
the patisiran arm compared to placebo in the pivotal Phase 3 APOLLO study.  Furthermore, on 
the Phase 3 APOLLO study, this magnitude of TTR lowering was associated with an acceptable 
safety profile. 
 
 
 
 
 
 
 

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Overall, available nonclinical and clinical data suggest the selected dose will appropriately 
balance safety and efficacy in the broad hATTR patient population. 
1.7. 
Benefit-Risk Assessment 
Based on available nonclinical and clinical data, with evidence of TTR reduction in the healthy 
subject study, TTR reduction by ALN-TTRSC02 is anticipated to beneficially impact disease 
progression in patients with hATTR amyloidosis, as has been shown with other available TTR 
lowering agents including patisiran and inotersen.  The q3M and q6M SC regimens are 
infrequent, easy to administer, do not require premedication, and thus may maximize 
convenience and minimize overall burden of care.  In the Phase 1 clinical study in healthy 
subjects, single SC doses up to the highest tested dose (300 mg) of ALN-TTRSC02 were well 
tolerated. 
Patients with hATTR amyloidosis often suffer substantial loss in ambulation and mobility 
associated with other comorbidities that significantly impact activities of daily living and can 
make healthcare visits challenging.  
 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. 
Given the biological target of ALN-TTRSC02, the available nonclinical and clinical data, and 
the mode of administration, important potential risks for ALN-TTRSC02 are injection site 
reactions (ISRs), liver function test (LFT) abnormalities, and consequences of vitamin A 
deficiency.  During the study, patients will be closely monitored, including evaluation of 
injections sites.  As ALN-TTRSC02 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) 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 ALN-
TTRSC02 dosing due to LFT abnormalities are provided in Section 5.2.3.  Detailed information 
about the known and expected benefits and risks of ALN-TTRSC02 and additional safety 
information may be found in the current edition of the ALN-TTRSC02 Investigator’s Brochure. 
For patisiran, important identified risks include infusion related reactions (IRRs).  All patients 
must receive premedication with a corticosteroid, paracetamol/acetaminophen, and H1 and H2 
blockers prior to patisiran administration to reduce the risk of IRRs (see Section 5.2.2.2).  
Potential risks include consequences of vitamin A deficiency and severe hypersensitivity (eg, 
anaphylaxis) to the active substance or any of the excipients. Detailed information about the 
known and expected benefits and risks of patisiran and additional safety information may be 
found in the current edition of the patisiran Investigator’s Brochure or, where approved, in the 
ONPATTRO prescribing/product information. 
Nonclinical and clinical data with ALN-TTRSC02 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 5.2).  Laboratory 

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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 ALN-TTRSC02 and patisiran. 
2. 
OBJECTIVES AND ENDPOINTS 
The primary and most secondary and exploratory efficacy endpoints are in comparison to the 
placebo arm of the Phase 3 pivotal patisiran study (ALN-TTR02-004, also referred to as the 
APOLLO study) as specified in the statistical analysis section of this protocol.   
Objectives 
Endpoints 
Primary 
• 
To determine the efficacy of ALN-
TTRSC02 in patients with hATTR 
amyloidosis by evaluating the effect on 
neurologic impairment  
• 
Change from baseline in the Modified 
Neurologic Impairment Score +7 
(mNIS+7) compared to the placebo arm 
of the APOLLO study at Month 9 
Secondary 
• 
To determine the efficacy of ALN-
TTRSC02 on quality of life, gait speed, 
neurologic impairment, nutritional status, 
and disability 
• 
To demonstrate the noninferiority of 
ALN-TTRSC02 compared to patisiran 
with respect to serum TTR levels 
 
• 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study: 
− 
Norfolk Quality of Life-Diabetic 
Neuropathy (Norfolk QoL-DN) total 
score at Month 9;  
− 
Timed 10-meter walk test (10-MWT) 
at Month 9; 
− 
mNIS+7 at Month 18; 
− 
Norfolk QoL-DN total score at 
Month 18; 
− 
10-MWT at Month 18; 
− 
Modified body mass index (mBMI) 
at Month 18; 
− 
Rasch-built Overall Disability Scale 
(R-ODS) at Month 18 
• 
Percent reduction in serum TTR levels in 
the ALN-TTRSC02 arm compared to the 
within-study patisiran arm through 
Month 18  
Exploratory 
 
• 
To determine the effect of ALN-
TTRSC02 on: 
− 
Disability and nutritional status; 
− 
Manifestations of cardiac amyloid 
involvement; 
− 
Other assessment of neurologic 
impairment; 
− 
Other assessments of quality of life; 
− 
Disease stage; 
− 
Performance of daily activities 
• 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study at Month 9: 
− 
R-ODS; 
− 
mBMI 
• 
Change from baseline over time: 
− 
N-terminal prohormone B-type 
natriuretic peptide (NT-proBNP) 
levels, echocardiographic parameters, 

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Objectives 
Endpoints 
• 
To characterize the pharmacodynamic 
(PD) effect of ALN-TTRSC02 and 
patisiran on serum TTR and vitamin A 
levels 
• 
To characterize plasma pharmacokinetics 
(PK) of ALN-TTRSC02 and patisiran 
• 
To assess presence of antidrug antibodies 
(ADA) to ALN-TTRSC02 and patisiran 
Troponin I and T levels, New York 
Heart Association (NYHA) class; 
− 
Neurologic Impairment Score (NIS); 
− 
EuroQoL-5 Dimensions-5 Levels 
(EQ-5D-5L) questionnaire and the 
EuroQoL-Visual Analog Scale (EQ-
VAS); 
− 
Familial Amyloidotic 
Polyneuropathy (FAP) stage and 
Polyneuropathy Disability (PND) 
score; 
− 
Karnofsky Performance Status (KPS) 
• 
Change from baseline in technetium 
scintigraphy cardiac parameters at Month 
18 
• 
Percent reduction in serum TTR and 
vitamin A levels over time 
• 
PK profile of ALN-TTRSC02 and 
patisiran 
• 
Incidence and titers of ADA to ALN-
TTRSC02 and patisiran 
Safety 
 
• 
To determine the safety and tolerability of 
ALN-TTRSC02 in patients with hATTR 
amyloidosis 
• 
Frequency of adverse events (AE) 
 
For submission of the marketing authorization to the European Union, formal hypothesis testing 
will be conducted at Month 18, with mNIS+7 compared to the placebo arm of the APOLLO 
study at Month 18 considered the primary endpoint.  Details will be specified in the statistical 
analysis plan (SAP). 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a global Phase 3 randomized, open-label study designed to evaluate efficacy, safety, and 
PK/PD of ALN-TTRSC02 in adult patients with hATTR amyloidosis.  Patients will be 
randomized 3:1 to ALN-TTRSC02 or patisiran, a reference comparator.  Randomization will be 
stratified by TTR genotype (V30M vs. non-V30M) and baseline NIS score (<50 vs ≥50). 
The study will consist of a Screening Period of up to 42 days, an 18-month Treatment Period, 
and an 18-month RTE Period in lieu of the 18-month Legacy Treatment Extension Period.  A 
Follow-up Period of up to 1 year will occur after the last dose of study drug (Figure 2). 

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18-Month Treatment Period 
After the Screening period at the start of the Treatment Period, eligible patients will be 
randomized 3:1 on Day 1 to receive 25 mg of ALN-TTRSC02 administered as a SC injection 
q3M or patisiran administered as an IV infusion q3w; patients in the patisiran arm will also 
receive premedications prior to each dose (see Section 5.2.2.2).  During the 18-month Treatment 
Period, patients will undergo assessments for efficacy and/or safety (as outlined in the Schedule 
of Assessments), with key efficacy assessments being performed prior to first dose, at Month 9 
(primary efficacy analysis timepoint) and at Month 18; samples for TTR assessment will be 
collected more frequently throughout the 18-month Treatment Period.  
All efficacy visits must be conducted at the clinic (Month 9, Month 18, and modified efficacy 
visits).  In situations in which a Month 9 or Month 18 efficacy visit is unable to be completed 
due to the Coronavirus disease 2019 (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, the Medical Monitor should be consulted as soon as possible to determine the 
appropriate timing of the Month 9 or Month 18 efficacy assessments as applicable. After 
consultation with the Medical Monitor, the Month 9 or Month 18 efficacy assessments may be 
completed within 6 months after the intended time point (ie, up to Month 15 or Month 24, 
respectively).  
Dosing may be allowed outside of the study center (eg, the patient’s home) under certain 
circumstances as specified in Section 5.2.2.1 and Section 5.2.2.2.  In addition, routine 
assessments and collection of relevant safety information may be collected outside the study 
center as specified at the beginning of Section 6. 
The placebo arm of the APOLLO study will be used as an external control for the primary, most 
secondary, and most exploratory efficacy analysis.  Primary and secondary efficacy evaluations 
will include mNIS+7, Norfolk QoL-DN questionnaire, 10-MWT, mBMI, R-ODS questionnaire, 
and percent TTR reduction. Study personnel performing the mNIS+7 component assessments 
will not reference the results of any previous assessments. 
In order to allow for a robust cross study comparison, attempts will be made to minimize 
differences between the HELIOS-A and APOLLO study populations. As such, baseline disease 
characteristics will be monitored and may result in enrollment limitations based on certain 
characteristics (eg, genotype) to ensure comparability.  Decisions around enrollment adjustments 
will be made by staff without access to primary efficacy results. 
Randomized Treatment Extension (RTE) Period 
 
 
 
 
 
 

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Follow-up Period 
During the Follow-up Period, all patients on ALN-TTRSC02 will undergo safety assessments 
quarterly until serum TTR levels return to ≥80% of baseline (for up to 1 year after the last dose 
of study drug), or until the patient starts a TTR lowering regimen as a part of clinical care, 
whichever comes first; all patients will be followed for a minimum of 3 months.  Female patients 
of child-bearing potential who discontinue ALN-TTRSC02 will be followed until serum TTR 
levels return to ≥80% of baseline.  
3.2. 
Duration of Treatment  
The treatment duration in this study is up to a maximum of 54 months inclusive of the 18-month 
Treatment Period, potential time on the Legacy Treatment Extension Period prior to transition to 
the RTE Period, and an 18-month RTE Period. 
Refer to Section 4.3.1 for information on early treatment discontinuation. 
3.3. 
Duration of Study 
The estimated time on study for each patient is a maximum of 5 years, inclusive of 42 days of 
Screening and up to 54 months of open-label treatment (including 18 months in the Treatment 
Period, 0 to 18 months as applicable in the Legacy Treatment Extension Period, and 18 months 
in the Randomized Treatment Extension Period), plus the Follow-up Period of up to 1 year.  
The Follow-up Period is until serum TTR levels return to ≥80% of baseline (for up to 1 year after 
the last dose of study drug), or until the patient starts a TTR lowering regimen as a part of 
clinical care, whichever comes first; all patients will be followed for a minimum of 3 months.  
Female patients of child-bearing potential who discontinue ALN-TTRSC02 will be followed 
until serum TTR levels return to ≥80% of baseline. 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if: 
 
  
• the patient has completed the ALN-TTRSC02 Follow-up Period, until serum TTR levels 
return to ≥80% of baseline (for a maximum of up to 1 year after the last dose of study 
drug), or until the patient starts a TTR lowering regimen as a part of clinical care, 
whichever comes first; all patients will be followed for a minimum of 3 months. Female 
patients of child-bearing potential who discontinue ALN-TTRSC02 will be followed until 
serum TTR levels return to ≥80% of baseline. 
3.4. 
Number of Planned Patients 
Approximately 160 patients are planned for enrollment in this study.   
To match the cardiac disease severity with the APOLLO study population, the study plans to 
enroll no more than 15% of patients with NT-proBNP values greater than 3000 ng/L at baseline.   

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3.5. 
Method of Assigning Patients to Treatment Groups 
Using the Interactive Response System (IRS), patients will be randomized 3:1 to the ALN-
TTRSC02 or patisiran arm.  Randomization will be stratified by TTR genotype (V30M vs. non-
V30M) and baseline NIS score (<50 vs ≥50). 
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 IRS.  The Investigator or his/her designee will 
contact the IRS to randomize the patient after confirming that the patient fulfills all the inclusion 
criteria and none of the exclusion criteria. 
 
 
 
 
 
3.6. 
Blinding 
Not applicable, this is an open-label, controlled study. 
3.7. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will oversee the safety and overall conduct 
of this study through the Treatment Period (through Month 18), providing input to the Sponsor.  
The DMC will operate under the rules of a charter that will be reviewed and approved at the 
organizational meeting of the DMC.  The DMC has the responsibility for reviewing safety data 
and analyses and making recommendations to the Sponsor.  The DMC will perform periodic 
reviews of data during the course of the clinical trial through the Treatment Period, and on an ad 
hoc basis for review of emergent safety data.  Details are provided in the DMC Charter. 
3.8. 
Adjudication Committee 
An independent Adjudication Committee will review deaths and will attribute a cause according 
to the responsible underlying disease process rather than the immediate mechanism.  Deaths will 
be classified as specified in the Adjudication Committee Charter. 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Each patient must meet all of the following eligibility criteria at Screening Visit 1 (except where 
specified) to be eligible for enrollment in the study. 

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4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all of the following criteria apply: 
Age and Sex 
1. Male or female age 18 (or age of legal consent, whichever is older) to 85 years of age  
Patient and Disease Characteristics 
2. Have a diagnosis of hATTR amyloidosis with documented TTR mutation  
3. Have a NIS of 5 to 130 (inclusive; this criterion must be met at the Screening Visit 2) 
4. Have a PND score of ≤3b (this criterion must be met at the Screening Visit 2) 
5. Have a Karnofsky Performance Status (KPS) of ≥60% 
Informed Consent 
6. Patient is willing and able to comply with the study requirements and to provide written 
informed consent   
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Has had a liver transplant or is likely, in the opinion of the Investigator, to undergo liver 
transplantation during the 18-month Treatment Period of the study 
2. Has known other (non-hATTR) forms of amyloidosis or clinical evidence of 
leptomeningeal amyloidosis 
3. Has a New York Heart Association heart failure classification >2 
Laboratory Assessments 
4. Has any of the following laboratory parameter assessments:  
a. ALT and/or AST >1.5× upper limit of normal reference range (ULN) 
b. Total bilirubin >ULN (>1.5 ULN in patients with Gilbert's Syndrome) 
c. International normalized ratio (INR) >1.2 (patients on anticoagulant therapy with an 
INR of ≤3.5 will be allowed) 
(Note: ALT, AST, and total bilirubin laboratory criteria must be met at both Screening 
Visit 1 and Screening Visit 2) 
5. Platelet count <50,000/μL  
6. Absolute neutrophil count (ANC) <1500 cells/mm³ 
7. Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73m2 (using the Modification 
of Diet in Renal Disease [MDRD] formula) 
8. Has vitamin B12 levels below the lower limit of normal (LLN) 

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9. Has known human immunodeficiency virus (HIV) infection; or evidence of acute or 
chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection 
Prior/Concomitant Therapy 
10. 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) 
11. Received prior TTR-lowering treatment or participated in a gene therapy trial for hATTR 
amyloidosis 
12. Is currently taking tafamidis, doxycycline, or tauroursodeoxycholic acid; if previously on 
any of these agents, must have completed a 14-day wash-out prior to dosing (Day 1) 
13. Is currently taking diflunisal; if previously on this agent, must have at least a 3-day wash-
out prior to dosing (Day 1) 
Medical Conditions 
14. Has other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune 
disease, monoclonal gammopathy) that the treating physician believes to be contributing 
to the neuropathy 
15. Had acute coronary syndrome within the past 3 months 
16. Has uncontrolled clinically significant cardiac arrhythmia or unstable angina 
17. Has known type 1 diabetes 
18. Has had type 2 diabetes mellitus for ≥5 years 
19. Has untreated hypo- or hyperthyroidism 
20. Has had a major surgery within the past 3 months or has a major surgery planned during 
the study through Month 18 
21. Has an active infection requiring systemic antiviral, antiparasitic or antimicrobial therapy 
that will not be completed prior dosing (Day 1) 
22. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix that has been successfully treated 
23. Anticipated survival is less than 2 years, in the opinion of the Investigator 
24. History of multiple drug allergies; or history of allergic reaction to an oligonucleotide or 
GalNAc; or had a prior severe reaction to a liposomal product or any component of 
patisiran (ALN-TTR02) 
25. Is unable to take the required premedications (see Section 5.2.2.2) 
26. History of intolerance to subcutaneous (SC) injection(s) or significant abdominal scarring 
that could potentially hinder study drug administration or evaluation of local tolerability 
27. Any condition (eg, medical concern), which in the opinion of the Investigator, would 
make the patient unsuitable for dosing or which could interfere with the study 

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compliance, the patient’s safety and/or the patient’s participation through the Month 18 
visit of the study.  This includes significant active and poorly controlled (unstable) 
cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric disorders 
unrelated to hATTR identified by key laboratory abnormalities or medical history 
Contraception, Pregnancy, and Breastfeeding 
28. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.6.1.  
29. Female patient is pregnant or breastfeeding 
Alcohol Use 
30. 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]) 
31. History of alcohol abuse, within the last 12 months before screening, in the opinion of the 
Investigator 
4.3. 
Removal from Therapy or Assessment 
Patients or their legal guardians 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 and recorded in the 
electronic case report form (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-adverse event) 
• Or, the study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing of the patient.  Patients who are pregnant will be discontinued from study 

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drug dosing immediately (see Section 6.5.7.7 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 
procedures, LVAD placement and hospitalizations for the duration of the study) is captured in 
the final analyses.    
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the subject the options for continuation of 
the Schedule of Assessments (Table 3), 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 endpoints and adverse events, and must document this decision in 
the patient’s medical records. 
If a patient discontinues dosing due to an AE, including serious adverse events (SAEs), the event 
should be followed as described in Section 6.5.7. When a patient discontinues study drug dosing, 
the primary reason must be recorded in the electronic case report form (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 study drug early for any reason during the Treatment Period (defined as 
the time the first dose of study drug is administered on Study Day 1 through completion of the 
Month 18 assessments) should complete the Early Drug Discontinuation visit and will be 
encouraged to remain on the study to complete the modified Month 9 and Month 18 efficacy 
assessments visits, prioritizing the primary and secondary assessments, where possible so that 
their experience is captured in the final analyses.  If a patient discontinues study drug and 
completes the Early Drug Discontinuation visit within 3 months of Month 9 or Month 18 and 
remains on the study, they will not be required to complete the modified efficacy assessments at 
Month 9 and/or Month 18, as applicable depending on the time they discontinue study drug 
(Table 3). 
Patients who discontinue study drug during the Legacy Treatment Extension Period or the RTE 
Period will be asked to return to complete the Early Drug Discontinuation visit (Table 3). 
Patients who discontinue study drug, but who remain on study, may receive treatment consistent 
with local standard practice for their disease per Investigator judgment, as applicable.  For 
patients who discontinue study drug and remain in the study, all AEs will be collected for 
90 days after the last dose, thereafter, SAEs and AEs of clinical interest (see definition in 
Section 6.5.7.1) will be collected for the remainder of their participation in the study. 
All patients who discontinue study drug will also be asked to complete safety follow-up visits, 
per the Follow-up Period schedule (see Table 4) until serum TTR levels return to ≥80% of 
baseline (for up to 1 year after the last dose of study drug), or until the patient starts a TTR 
lowering regimen as a part of clinical care, whichever comes first; all patients will be followed 

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for a minimum of 3 months. Female patients of child-bearing potential who discontinue ALN-
TTRSC02 will be followed until serum TTR levels return to ≥80% of baseline. 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  Patients 
considering stopping their participation in the study should be informed that they can discontinue 
study drug and/or decline procedural assessments and remain in the study for the collection of 
important study data as described in Section 4.3.1. If a patient still chooses to discontinue study 
drug and stop participation in all follow-up, every effort should be made to conduct the Early 
Drug Discontinuation Visit assessments in Table 3 within 4 weeks of the last dose during the 
Treatment Period, and at any time during the Legacy Treatment Extension Period or the RTE 
Period. 
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’s 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, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and 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, 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. 
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 

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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 6.5.7. 
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 to continue in the study and/or should 
continue in the study. 
• Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, 
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable, the patient will be considered to have 
stopped participation in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status.  
Attempts should also be made to collect information related to cardiac transplant 
procedures, left-ventricular assist device placement and hospitalizations from other 
sources for the duration of the study.  This ensures that the outcome of the study is as 
comprehensive as possible. 
4.3.4. 
Replacement of Study Patients  
Patients who discontinue the study drug or stop participation in the study will not be replaced. 
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of ALN-TTRSC02 
and patisiran is provided in the Pharmacy Manual. Detailed Instructions for Use for the ALN-
TTRSC02 pre-filled syringe will also be provided. 
All patients will be instructed to take the recommended daily allowance of vitamin A while on 
the study. 

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5.2.1. 
Description 
ALN-TTRSC02 will be supplied as a vial of sterile solution containing 50 mg/mL of siRNA 
ALN-65492 free acid (equivalent to 53 mg/mL sodium salt) in phosphate buffered saline for SC 
injection.  The drug product does not contain preservatives and is intended for single use.  See 
the Pharmacy Manual for further details of solution concentration and fill volume.  
ALN-TTRSC02 will also be supplied as a pre-filled syringe and a needle safety device.  The pre-
filled syringe will be filled with ALN-TTRSC02 (25 mg dose) with a volume of 0.5 mL. 
 
 The pre-filled syringe is a single-
use injection device, and after injection the needle safety device will engage to cover the exposed 
needle. 
ALN-TTRSC02 will initially be administered using injections prepared from vials. Patients may 
be transitioned from vial-based injections to the pre-filled syringe-based injections at any study 
time point as this presentation becomes available. 
The comparator drug for this study will be patisiran that contains 2 mg/mL of drug substance 
ALN-18328 (siRNA) and lipid excipients DLin-MC3-DMA, DSPC, cholesterol, and PEG2000-C-
DMG formulated as lipid nanoparticles (LNPs) in isotonic phosphate buffered saline for IV 
administration.  Patisiran will be provided by the Sponsor.   
5.2.2. 
Dose and Administration 
5.2.2.1. 
ALN-TTRSC02 
ALN-TTRSC02 25 mg SC injection will be administered q3M (12 weeks ±3 days during the 
Treatment Period
 
 
.  Study drug SC injections in the clinic will 
be administered under the supervision of the Investigator or a trained healthcare professional.  
ALN-TTRSC02 may be administered at a location other than the study center (eg, the patient’s 
home) as specified below. 
If a patient has tolerated at least 1 dose of ALN-TTRSC02 in the clinic, subsequent dosing may 
be administered outside the study site (eg, the patient’s home) at all time points 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 center, and a visit by a home healthcare professional is not possible due to 
circumstances related to the COVID-19 pandemic, ALN-TTRSC02 25 mg SC q3M 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 ALN-
TTRSC02 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.  
 
 

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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 ALN-
TTRSC02 (25 mg q3M only) by a patient or caregiver will be provided in the Patient/Caregiver 
Storage and Administration Instructions. 
Method of Administration of ALN-TTRSC02 
ALN-TTRSC02 is for SC use. 
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. Detailed Instructions for Use for the pre-filled syringe will also be 
provided. 
Missed Doses of ALN-TTRSC02 
If a patient does not receive a dose of ALN-TTRSC02 within the specified dosing window, the 
Investigator should contact the Medical Monitor.  After such consultation, the dose 
 
 may be administered with up to an 8-week delay or as determined by the Medical 
Monitor (to be considered a delayed dose).  If a dose 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 unless the dose cannot be administered within 
the 8-week delay, then the Medical Monitor must be consulted.  In all cases, the dose should be 
administered as close as possible to the scheduled timepoint. If a dose is delayed, all assessments 
associated with the originally scheduled dose may also be delayed to coincide with the delayed 
dose. 
During the Treatment Period, every effort should be made to avoid missed doses of 
ALN-TTRSC02.  During the Treatment Period, 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 in the study (see also Section 4.3). 
5.2.2.2. 
Patisiran 
Patisiran 0.3 mg/kg IV infusion will be administered once every 3 weeks (q3w) ±3 days.  The 
amount (in mg) of study drug to be administered should be determined based on the patient's 
weight (kg).  Dosing is based on actual body weight. For patients weighing ≥ 100 kg, the 
maximum recommended dose is 30 mg. 
If a patient has tolerated at least 2 doses of patisiran administered in the clinic, 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. 

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Required premedication for patients in the patisiran arm 
All patients should receive premedication prior to patisiran administration to reduce the risk of 
infusion-related reactions (IRRs). Each of the following medicinal products should be given on 
the day of patisiran infusion at least 60 minutes prior to the start of infusion: 
• Intravenous corticosteroid (dexamethasone 10 mg, or equivalent) 
• Oral paracetamol (500 mg) 
• Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent)  
• Intravenous H2 blocker (ranitidine 50 mg, or equivalent) 
Oral premedication equivalents are permitted, but must be administered in the presence of a 
healthcare professional.   
Modifications to lower the corticosteroid dose may be made to the premedication regimen for 
either of the following 2 reasons: 
1. If a patient is having difficulty tolerating the corticosteroid premedication regimen (eg, 
patient develops uncontrolled hyperglycemia, altered mental status, or other 
complication), then lowering of the corticosteroid premedication may be allowed for that 
patient after consultation with the medical monitor.   
2. If a patient has tolerated 3 or more infusions of patisiran with their current corticosteroid 
premedication regimen (ie, patient has not had IRRs during the past 3 or more infusions), 
then lowering of the corticosteroid premedication is recommended.   
Steps to lower corticosteroid dosing are provided in the Study Manual.  Corticosteroid tapering 
may be performed in the clinic or, at the discretion of the investigator, may be performed outside 
of the clinic (eg, in the patient’s home) after consultation with the Medical Monitor. 
Additional or higher doses of one or more of the premedications may be administered to reduce 
the risk of IRRs, if needed.  Guidelines for management of IRRs can be found in the Pharmacy 
Manual.   
Method of Administration of patisiran 
Patisiran is for IV use and should be administered by a healthcare professional.  
Weight from previous visit may be used for calculating dose.  Weight must be collected predose. 
The patient’s infusion site should be assessed for signs of any localized reaction during the 
infusion and for 30 minutes after the end of the infusion. The patient should be observed for 1 
hour following completion of dosing for observation and completion of assessments. 
Detailed instructions for study drug preparation and administration can be found in the Pharmacy 
Manual. 
Missed Doses of patisiran 
If a patient does not receive a dose of patisiran within the dosing window (±3 days) due to the 
COVID-19 pandemic, the dose may be administered with up to 7 days delay after the scheduled 
visit, after consultation with the Medical Monitor (to be considered a delayed dose).  If a dose is 
administered with a delay, the next dose will resume following the original schedule per the 

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Schedule of Assessments. In all cases, the dose should be administered as close as possible to the 
scheduled time point. If a dose is delayed, all assessments associated with the originally 
scheduled dose may also be delayed to coincide with the delayed dose. 
A dose will be considered completed if 80% or more of the total volume of the IV solution has 
been administered to the patient.  Patients will be permitted to miss an occasional dose of study 
drug.  However, if a patient misses 2 consecutive doses 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 in the study.  
5.2.2.3. 
Switching from Patisiran to ALN-TTRSC02 After Month 18 
After the Treatment Period, patients in the patisiran arm will switch to ALN-TTRSC02 treatment 
 
 
 
 
Patients who enter the Legacy Treatment Extension Period 
 
 
 (as of Amendment 4) will receive the 25 mg q3M dose and complete visits in the 
Legacy Treatment Extension Period. 
 
 If a patient receiving patisiran is unable to complete 
the Month 18 efficacy visit at the study center due to the COVID-19 pandemic before Week 84 
 they may transition to treatment with ALN-TTRSC02 at Week 84 
 
; the patient should still complete the Month 18 efficacy assessment as 
soon as possible (see also Section 3.1). 
5.2.3. 
LFT Criteria for Withholding, Monitoring and Stopping ALN-TTRSC02 Dosing  
1. For the ALN-TTRSC02 cohort, dosing decisions may be made based on LFT results 
(Table 8) collected at the previous dosing 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 7.  
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 the COVID-19 
pandemic, 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 7 and Table 9. 

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c. If an alternative cause is found, provide appropriate care. 
4. For any ALT or AST elevation >3× ULN without alternative cause 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, 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 7 
(below). 
Table 7: 
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 9 (all assessments to be performed once) 
− 
Hematology, serum chemistry, LFT and coagulation per Table 8  
• 
Monitor at least every two weeks (LFT and coagulation per Table 8)  
• 
If elevation persists for ≥2 months, must discuss with the medical monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold ALN-TTRSC02 dosing until recovery to ≤1.5× ULN; may resume 
dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments: 
− 
Table 9 (all assessments to be performed once) 
− 
Hematology, serum chemistry, LFT, and coagulation per Table 8  
• 
Monitor at least weekly (LFT and coagulation per Table 8) until ALT 
and/or AST is declining on two 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 
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; INR=international normalized ratio; 
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. 
5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center, or the home healthcare professional, will be responsible for 
preparation of ALN-TTRSC02 and patisiran doses, according to procedures detailed in the 
Pharmacy Manual.  In cases where ALN-TTRSC02 is administered outside the study center, 
dosing may be prepared by the home healthcare professional or patient/caregiver 
(patient/caregiver is applicable to only the 25 mg q3M dose) according to procedures detailed in 

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the Patient/Caregiver Storage and Administration Instructions.  No special procedures for the 
safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately 5±3°C until dose preparation. 
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. 
5.2.5. 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. Additional details will be available in the Pharmacy Manual. 
5.2.6. 
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, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study center according to applicable regulations. 
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 
vial/syringe, empty vial/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 using the appropriate 
eCRF. PCs that may be associated with an AE must be evaluated and reported as indicated in 
Section 6.5.7. Detailed instructions on reporting PCs will also be detailed in the Pharmacy 
Manual.  

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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 (see Table 1 to Table 4).  This includes all prescription medications, 
herbal 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 NSAIDs 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.   
Prohibited medications during the study include inotersen, tafamidis, diflunisal, and 
doxycycline/TUDCA (see Section 4.2 for prior medication washout requirements before first 
dose of study drug).  Use of patisiran outside of the protocol specified administration is also 
prohibited.  Any investigational agent other than ALN-TTRSC02 is not permitted during the 
study. 
For other permitted concomitant medications administered subcutaneously, do not administer in 
same injection site area as the study drug, for 2 weeks after the last dose of study drug.  
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 CRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
If available, information from a cardiac technetium scan and/or any tissue biopsy used to support 
the diagnosis of hATTR amyloidosis performed prior to study enrollment or during the study (as 
part of standard of care) should be collected and recorded as part of concomitant procedure 
information. 
5.5. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals. 
5.6. 
Other Requirements 
5.6.1. 
Contraception 
Females of child-bearing potential must be willing to use acceptable methods of contraception 
from 14 days before first ALN-TTRSC02 dose, throughout study participation, and for 90 days 
after last dose administration.   

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Females of child-bearing potential taking patisiran must use acceptable methods of contraception 
prior to dosing and for 12 weeks after the last dose of patisiran in this study if they do not switch 
and continue treatment with ALN-TTRSC02 starting at Day 337 (Week 48). 
Birth control methods which are considered highly effective include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system.  
• Bilateral tubal occlusion. 
• 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 for 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 childbearing 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, contraception use by males should be 
consistent with local regulations 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 6.5.6.2). 
5.6.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 

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6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1 (Screening through Treatment Period 
Month 9), Table 2 (Treatment Period from Month 9 through Month 18), Table 3 (Legacy 
Treatment Extension Period, Early Drug Discontinuation, and Other Visits), Table 4 
(Randomized Treatment Extension Period), Table 5 (ALN-TTRSC02 PK Time Points) and 
Table 6 (Patisiran PK Time Points).  Additional information on the collection of study 
assessments will be detailed in the Study Reference Manual.  In this study there are 2 types of 
study centers:  
• Patient Care Sites (PCS) can screen, dose, and manage the well-being of patients and 
collect safety assessments, and can administer efficacy assessments that include, but 
are not limited to, completion of a questionnaire or collection of blood samples for 
assessment of TTR and other PD biomarkers, as well as cardiac biomarkers, but will 
not perform the following efficacy assessments: NIS, mNIS+7, HRdb, 10-MWT, 
FAP and PND, KPS, echocardiogram.  
• Central Assessment Sites (CAS) can perform all efficacy assessments and perform 
the same assessments as at a PCS (as stated above).  Efficacy assessments (NIS, 
mNIS+7, HRdb, 10-MWT, FAP and PND, KPS, echocardiogram) in this study may 
require special training as described further in Section 6.2; therefore, all patients must 
be sent to a CAS to collect these efficacy assessments during screening and predose 
baseline assessments, Month 9 and Month 18 of the Treatment Period and the RTE 
Period, and modified efficacy visits for patients who discontinue early during the 
Treatment Period. 
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, 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.  All laboratory samples should be sent to the central laboratory; an exception is for 
situations related to the COVID-19 pandemic if central laboratory assessments are not possible, 
then 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. 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 due to the COVID-19 pandemic 
limiting the patient’s ability or willingness to access the study center, at a minimum, patients 
must visit the site for scheduled dosing and assessments at the Treatment Period Week 12 and 
Week 60 visits within the study visit windows 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). 

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All efficacy visits must be conducted at the clinic (Month 9, Month 18, 
 
, and modified efficacy visits for those who discontinue early during the Treatment 
Period).  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 center or their ability to 
receive their scheduled doses of study drug, the Medical Monitor should be consulted as soon as 
possible to determine the appropriate timing of the efficacy assessment.  After consultation with 
the Medical Monitor, efficacy assessments may be completed within 6 months after the intended 
time point (ie, up to Month 15 or Month 24) during 
 the Treatment Period 
 
 as necessary. 
Further details regarding visits performed outside of the clinic are provided in the Study 
Reference Manual. 
6.1. 
Screening Assessments 
See Table 1 for a list of Screening visit assessments.   
An informed consent form (ICF) or assent form that has been approved by the appropriate 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) must be signed by the 
patient (or legal guardian) before the Screening procedures are initiated (Table 1) and before any 
procedures are performed in the RTE Period (Table 4).  All patients (or their legal guardians) 
will be given a copy of the signed and dated ICF and/or assent form. 
In addition of the ICF, patients will be asked to sign a Medical Records Release Form (where 
allowed by local regulations) at Screening for the purpose of obtaining information on vital 
status, cardiac transplant procedures, left-ventricular assist device placement (Section 6.2.8 ), and 
hospitalizations (Section 6.2.7 ) from patients for the duration of the study. This information will 
be obtained by the patient’s physician through contacting the patient or family or from death 
registries.  
Signing the Medical Records Release Form will be optional and will apply if the patient 
discontinues from the study early. Every effort should be made to collect the Medical Records 
Release Form from all patients enrolled in the study.  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. 
Patients will complete the following 3 visit types prior to randomization for the Treatment 
Period:  the ICF and Medical Records Release Form will be obtained at the Visit 1 (Screening), 
and all inclusion/exclusion criteria will be assessed except for the NIS and PND score criteria; 
see Section 4.1); the NIS and PND score inclusion criteria will be assessed at Visit 2 (Baseline 
first assessment); other baseline assessments will be completed at Visit 3 or at Day 1 prior to first 
dose.  Visits 1, 2 and 3 may each occur over multiple days.   
6.1.1. Retesting 
If screening laboratory abnormalities, in the Investigator’s judgement, are felt likely to be 
transient, then the laboratory tests may be repeated. The Investigator’s rationale should be 
documented.  Laboratory values can be retested once during screening provided that the patient 
can be evaluated for eligibility and randomized within the allowed Screening period. Qualifying 
LFTs (AST, ALT and bilirubin) are an exception to this rule and may not be repeated. 

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6.1.2. Rescreening 
For patients who do not meet all study eligibility requirements, due to a transient clinical 
condition during screening or who fail to complete screening activities due to unforeseen and 
unavoidable circumstances, rescreening once may be permitted after consultation with the 
Medical Monitor after a minimum of 5 days have elapsed from a patient’s last screening 
assessment. In this case, a patient will be re-consented and all screening procedures must be 
repeated.  
6.1.3. Demographic and Medical History/Disease History 
Medical history will be collected during screening Visit 1 (including any cardiac disorders, any 
eye disorders or previous ophthalmology test results, and prior medications).  Documented 
technetium scintigraphy and/or tissue biopsy testing for amyloidosis performed prior to study 
enrollment should be collected and recorded as part of medical history. Information on prior use 
of tetramer stabilizers at any time prior to first dose should be collected and recorded. 
Information on other prior medications, hospitalization, and procedures through 1 year prior to 
first dose should be collected and recorded. 
At screening Visit 2 and Visit 3, only additional medical history changes since Visit 1 will be 
collected. 
Also, technetium scintigraphy scans and/or tissue biopsy testing for amyloidosis performed as 
part of clinical care during the study should be collected and recorded as part of concomitant 
procedure information.   
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 center. 
6.2.1. 
Neurologic Impairment Assessments  
6.2.1.1. 
Modified Neurological Impairment Score +7 (mNIS+7)  
The mNIS+7 assessment tool is a 304-point composite measure of neurologic impairment which 
includes the following measures and components [Suanprasert 2014]:  
• Physical exam of lower limbs, upper limbs and cranial nerves to assess motor 
strength/weakness and determine the following component scores:  
− NIS-weakness (NIS-W)  
− NIS-reflexes (NIS-R) 
• Electrophysiologic measures of small and large nerve fiber function to determine the 
5 NCS component score that includes assessment of the ulnar CMAP, ulnar SNAP, 
sural SNAP, tibial CMAP, peroneal CMAP  
• Sensory testing to determine the quantitative sensory testing (QST) score included 
assessing touch pressure by body surface area (QST-BSATP) and heat pain by body 

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surface area (QST-BSAHP).  A Computer Aided Sensory Evaluator (CASE) IV 
device will be used for this assessment. 
• Postural blood pressure will be measured to assess autonomic function as described in 
the Study Manual.  Points are assigned based on the change in blood pressure with 
standing. 
A summary of the scoring of the components of the mNIS+7 is provided in Section 10.1. 
6.2.1.2. 
Neurologic Impairment Score (NIS) 
The NIS assessment is a 244-point composite measure of neurologic impairment which includes 
a physical exam of lower limbs, upper limbs and cranial nerves to assess motor 
strength/weakness and determine the following component scores: 
• NIS-W 
• NIS-R 
• NIS-sensation (NIS-S) 
6.2.1.3. 
Personnel and Procedures to Ensure Quality and Consistency of NIS and 
mNIS+7 Scoring 
The NIS and mNIS+7 will be evaluated at the timepoints specified in the Schedule of 
Assessments (Table 1 to Table 4).  The NIS-W and NIS-R assessments obtained for NIS 
calculation do not need to be repeated for the mNIS+7 calculation. 
As per the Schedule of Assessments for the 18-month Treatment Period, 2 independent 
assessments will be performed on separate days (1 assessment on each day); the 2 assessments 
should be performed approximately 24 hours apart from each other but not more than 7 days 
apart.  Each site should make every effort to have these assessments performed by the same 
assessor.  
 
 
NIS and QST assessments will be performed by certified staff trained on the use of the CASE IV 
device.  NCS studies will be performed by trained staff.   
Study personnel performing the mNIS+7 component assessments will not reference the results of 
any previous assessments. 
All site staff performing the mNIS+7 will be trained and certified by the peripheral neuropathy 
laboratory at the 
, USA.  The peripheral neuropathy laboratory at the 
 
also serves as the central laboratory that will assess the mNIS+7 score.  All data will be 
transmitted to the 
 where qualified personnel will assess the quality and acceptability 
of all test scores.  The peripheral neuropathy laboratory at the 
 can request a site to 
repeat testing of mNIS+7 components per the 
 Standard Operating Procedures (SOP) 
if the quality was not acceptable at any time point. 
Data acquisition, storage, and transfer guidelines will be provided in the Study Reference 
Manual.  

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6.2.2. 
Heart Rate Response to Deep Breathing (HRdb) 
The HRdb test evaluates small nerve fiber autonomic function by the cardio-vagal response.  
This assessment will be performed by a certified trained staff during the Treatment Period at the 
timepoints specified in the Schedule of Assessments (Table 1 to Table 3).  The average heart rate 
difference while taking eight deep breaths will be measured using a CASE IV device.   
As per the Schedule of Assessments, 2 independent assessments will be performed on separate 
days (1 assessment on each day); the 2 assessments should be performed approximately 24 hours 
apart from each other but not more than 7 days apart.  Each site should make every effort to have 
this assessment performed by the same assessor. 
6.2.3. 
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) 
The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes 
measure that assesses 5 domains:  physical function, large fiber neuropathy, activities of daily 
living, symptoms, small fiber neuropathy, and autonomic neuropathy. The total score ranges 
from -4 (best possible quality of life) to 136 points (worst possible quality of life) [Vinik 2005; 
Vinik 2014].  
The Norfolk QoL-DN questionnaire will be completed at the timepoints specified in the 
Schedule of Assessments (Table 1 to Table 4).  
6.2.4. 
Ten-meter Walk Test (10-MWT) 
The time it takes for a patient to walk 10 meters (gait speed) will be assessed at the timepoints 
specified in the Schedule of Assessments (Table 1 to Table 4). The 10-MWT will be performed 
and recorded following procedures outlined in the Study Reference Manual. The test must be 
completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  
As per the Schedule of Assessments for the 18-month Treatment Period, 2 independent 
assessments are to be performed approximately 24 hours apart from each other but not more than 
7 days apart. Each site should make every effort to have this assessment performed by the same 
assessor.  
 
 
6.2.5. 
Modified Body Mass Index (mBMI) 
The nutritional status of patients is evaluated using the mBMI; calculated as the product of body 
mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum 
albumin (g/L).   
Weight, height, and serum albumin (collected as part of the serum chemistry panel) will be 
collected at the timepoints specified in the Schedule of Assessments (Table 1 to Table 4). The 
site will not perform the calculation for mBMI.   
6.2.6. 
Rasch-built Overall Disability Scale (R-ODS) 
An assessment of the disability each patient experiences will be assessed through the R-ODS 
questionnaire at the timepoints specified in the Schedule of Assessments (Table 1 to Table 4).  

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The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity 
and social participation limitations in patients. 
6.2.7. 
Deaths and Hospitalizations 
All deaths and hospitalizations will be recorded at Day 1 post dose and throughout the study as 
specified as part of adverse events (AEs) monitoring (see Section 6.5.7) according to the 
Schedule of Assessments (Table 1 to Table 4).  
Reason for deaths will be adjudicated by an Independent Clinical Adjudication Committee (see 
Section 3.8). 
6.2.8. 
Vital Status Check 
Vital status checks will be performed at the timepoints specified in the Schedule of Assessments 
(Table 1 to Table 4). Vital status checks should include checking for the occurrence of heart 
transplantation or left-ventricular assist device implantation 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.   
6.2.9. 
European Quality of Life-5 Dimensions 5-Levels (EQ-5D-5L) and EQ-Visual 
Analog Scale (EQ-VAS) 
The EQ-5D index score is based on the response to questions evaluating 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression).  
Each dimension scored is based on 5 possible levels where level 1 reflects the best possible score 
for that dimension.  As an example, the 5 levels for the dimension of self-care include: level 1: 
no problems with washing or dressing self, level 2: slight problems, level 3: moderate problems, 
level 4: severe problems, level 5: unable.  The EQ-5D index score is derived based on scores 
from all 5 dimensions; score range is from 0 (worst QoL) to 1 (best QoL).   
The EQ-VAS is a single question evaluating the patient’s own global impression of their overall 
health and is evaluated on a scale of 0 (worst possible health) to 100 (best possible health). 
The EQ-5D-5L and EQ-VAS questionnaire will be completed at the timepoints specified in the 
Schedule of Assessments (Table 1 to Table 4).   
6.2.10. 
PND Score and FAP Stage 
Ambulation and changes in disease stage will be evaluated through physician assessment of PND 
score and FAP stage [Coutinho 1980; Yamamoto 2007].  
PND and FAP will be completed at the timepoints specified in the Schedule of Assessments 
(Table 1 to Table 4).  
PND scoring and FAP stages are described in Section 10.2. 

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6.2.11. 
Cardiac Assessments 
Manifestations of cardiac amyloid involvement will be assessed through echocardiogram, as well 
as measurement of serum levels of the cardiac biomarkers NT-proBNP and troponin T and 
troponin I.  The impact of heart failure on quality of life will also be assessed as described below.  
Certified technicians will be required to administer cardiac imaging assessments as specified in 
the Study Reference Manual. 
6.2.11.1. Echocardiogram  
Echocardiographic parameters will be used for assessment of cardiac structure and function.  
Echocardiograms will be performed at the timepoints specified in the Schedule of Assessments 
(Table 1 to Table 4), and analyzed at a central cardiac imaging core lab.   
Image acquisition, storage, and transfer guidelines will be provided in the Study Reference 
Manual. 
6.2.11.2. Cardiac Biomarkers 
Cardiac biomarkers, including NT-proBNP, troponin T and troponin I, will be used to assess 
cardiac stress and heart failure severity.  These biomarkers have also been shown to be 
prognostic of outcomes in heart failure including ATTR amyloidosis [Damy 2016; Kristen 2017; 
Merlini 2016].  Blood samples will be drawn to measure levels of NT-proBNP, troponin T and 
troponin I at the timepoints specified in the Schedule of Assessments (Table 1 to Table 4).   
At Screening Visit 1, only NT-proBNP will be assessed for eligibility purposes. Baseline cardiac 
biomarkers (NT-proBNP, troponin T, and troponin I) will be assessed at Screening Visit 3.   
Details on cardiac biomarker sample collection, processing, and storage will be provided in a 
Study Laboratory Manual. 
6.2.11.3. Technetium Scintigraphy Imaging 
At select sites, technetium scintigraphy will be collected according to the Schedule of 
Assessments (Table 1 to Table 4), as an exploratory imaging parameter to assess cardiac amyloid 
involvement.  Based on local practice standards, either 99Tc-Pyrophosphate (99Tc-PYP), 99Tc-
3,3-diphosphono-1,2-propanodicarboxylic acid (99Tc-DPD) or 99Tc-hydroxymethylene 
diphosphonate (99Tc-HMDP) can be used as the tracer.  Technetium scintigraphy images will be 
interpreted at a central imaging core laboratory.  Image acquisition, storage, and transfer 
guidelines will be provided in the Study Reference Manual. 
At the select sites where technetium scintigraphy is being performed, patients may be exempt 
from baseline technetium scintigraphy assessment if a technetium scintigraphy has been 
performed prior to study entry as part of the patient clinical care within 6 months prior to the 
baseline assessment.  In such cases, where possible, the historical technetium scintigraphy exam 
performed prior to study entry as part of the patient’s clinical care should be collected and 
transferred to the central imaging core laboratory for interpretation. 

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6.2.11.4. New York Heart Association (NYHA) Class  
NYHA class is a clinical assessment of symptoms resulting from heart failure and is assessed 
according to the table in Section 10.3.  NYHA class will be evaluated at the timepoints specified 
in the Schedule of Assessments (Table 1 to Table 4).  The score collected at Screening will be 
used to determine eligibility and will also be collected on a regular basis during the study. 
6.2.12. 
Karnofsky Performance Status (KPS) 
The Karnofsky Performance Status (KPS) assessed according to Section 10.4 will be evaluated at 
the timepoints specified in the Schedule of Assessments (Table 1 to Table 4).  The score 
collected at Screening will be used to determine eligibility. 
6.3. 
Pharmacodynamic Assessments 
In this study serum TTR and vitamin A levels will be collected as measurements of PD effect.  
These measurements will be collected and analyzed centrally as specified in the Study 
Laboratory Manual.   
Blood samples will be collected prior to dosing for the assessment of TTR and vitamin A levels 
according to the timepoints specified in the Schedule of Assessments (Table 1 to Table 4).  TTR 
levels will be determined by a validated enzyme-linked immunoassay (ELISA) assay.   
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of plasma ALN-TTRSC02 and patisiran PK 
parameters and possible metabolite analysis at the time points in the Schedule of Assessments.  
A detailed schedule of time points for the collection of blood samples for PK analysis at the 
timepoints specified in the Schedule of Assessments (Table 5 for ALN-TTRSC02 and Table 6 
for patisiran). 
Plasma concentration of ALN-TTRSC02 and patisiran will be determined using a validated 
assay.  Details regarding sample volumes to be collected, and the processing, shipping, and 
analysis of the samples will be provided in the Study Laboratory Manual. 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of 
adverse events (AEs) including serious adverse events (SAEs), recording of concomitant 
medication and measurements of vital signs, weight and height, physical examination, ECG 
findings and laboratory tests. Clinically significant abnormalities observed during the physical 
examination are recorded. 
Safety will be monitored over the course of the study by the Sponsor’s Medical Monitors and 
Medical Monitors at the designated contract research organization in addition to an independent 
DMC as described in Section 3.7. 
Routine safety assessments and collection of relevant safety information may be collected 
outside of the study center where applicable country and local regulations and infrastructure 
allow (as described at the beginning of Section 6). 

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6.5.1. 
Vital Signs 
Vital signs will be measured as specified at the timepoints specified in the Schedule of 
Assessments (Table 1 to Table 4), and include blood pressure, heart rate, body temperature, and 
respiratory rate.  Vital signs will be measured predose, when applicable.  When vital signs and 
blood sample collection occur at the same time, vital signs should be performed before blood 
samples are drawn, where possible. Vital signs should be measured predose in the seated or 
supine position, after the patient has rested comfortably for 10 minutes.  Blood pressure should 
be taken using the same arm during a single visit.  Body temperature in degrees Celsius will be 
obtained via oral, tympanic, or axillary methods.  Heart rate will be counted for a full minute and 
recorded in beats per minute, and respiration rate will be counted for a full minute and recorded 
in breaths per minute. 
Additional vital sign assessments, as medially indicated, may be added at the discretion of the 
Investigator, or as per DMC advice (as applicable). 
Vital signs results will be recorded in the eCRF. 
6.5.2. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected at the timepoints specified in in the Schedule of 
Assessments (Table 1 to Table 4) and will be recorded in the eCRF.   
For patients on the patisiran arm, weight must be collected prior to each dose. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1 to Table 4); if a physical examination is scheduled for a dosing visit, it 
should be conducted prior to dosing.   
Full physical examinations will include the examination of the following: general appearance; 
head, eyes, ears, nose and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid; lymph nodes; and neurological status. 
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit.  In situations where the patient has a home 
visit, symptom-directed physical examinations may be deferred until the next in-clinic visit. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.5.4. 
Electrocardiogram 
A 12-lead ECG reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, and 
QT interval will be obtained locally as specified in the Schedule of Assessments (Table 1 to 
Table 4).   
Triplicate readings should be performed at Baseline and thereafter single readings can be 
performed.   

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If the investigator performs an ECG over-read per standard of care, over-reads should be 
conducted on each individual ECG performed.    
Patients should be supine for at least 5 minutes before each ECG is obtained.   
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs, including those collected by a 
healthcare professional outside of the study center, to assess whether the results have changed 
since baseline and to determine the clinical significance of the results.  Additional ECGs may be 
collected at the discretion of the Investigator, or as per DMC advice.   
ECG recordings will be archived according to the Study Reference Manual. 
6.5.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia–Suicide Severity Rating Scale (C-SSRS) will be used to assess patient’s mental 
status as it relates to suicidal ideation and behavior.   This questionnaire will be administered to 
the patient by trained and certified study personnel. The C-SSRS will be performed as specified 
in the Schedule of Assessments (Table 1 to Table 4).   
6.5.6. 
Clinical Laboratory Assessments 
Clinical laboratory assessments are listed in Table 8 will be collected as specified in the 
Schedule of Assessments (Table 1 to Table 4) and should be evaluated by a central laboratory.  
Clinical laboratory assessments may be collected at the clinical study center or outside the clinic 
(eg, the patient’s home) by a trained healthcare professional within the study visit window as 
described at the beginning of Section 6. 
For the ALN-TTRSC02 arm, ALN-TTRSC02 dosing decisions may be made based on LFT 
results (Table 8) collected at the previous dosing visit (up to 14 weeks prior to dosing); in all 
cases the most recently available LFTs should be used. Specific instructions for transaminase 
elevations are provided in Section 5.2.3. 
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the assessments, all laboratory assessments specified in Table 8 which are performed at the clinic 
or outside the study center (eg, the patient’s home) should also be sent in parallel to the central 
laboratory.  In the case of discrepant local and central laboratory results on samples drawn on the 
same day, central laboratory results will be relied upon for clinical and dosing decisions.  The 
only exception for central laboratory testing is related to the COVID-19 pandemic as described 
in the beginning of Section 6. 
For the patisiran arm, LFTs should be performed according to patisiran visit windows and do not 
need to be available prior to dosing.   
For any other unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator, 
or as per the Medical Monitor or DMC advice, until it has returned to the normal range or 
stabilized, and/or a diagnosis is made to adequately explain the abnormality.  Additional safety 
laboratories and assessments as indicated by the clinical situation may be requested.   

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For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database.  
Table 8: 
Clinical Laboratory Assessments 
Hematology 
 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the MDRD formula) 
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
Glucose 
Chloride 
B12 vitamin (at Screening only) 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT  
 
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 
 
Immunogenicity (see Section 6.5.6.1) 
Antidrug Antibodies 
Pregnancy Testing/FSH Screening (see Section 6.5.6.2)  
β-human chorionic gonadotropin 

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Follicle stimulating hormone (FSH) (Only if applicable, to confirm postmenopausal status prior to 
dosing) 
Hepatitis 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 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; eGFR=estimated glomerular filtration rate; GGT=gamma glutamyl transferase; HBsAg=hepatitis B 
virus surface antigen; HBc=hepatitis B virus core; HCV=hepatitis C virus; IgG=immunoglobulin G antibody; 
IgM=immunoglobulin M antibody; PCR=polymerase chain reaction; RBC=red blood cell; RNA=ribonucleic acid 
MDRD=modification of diet in renal disease; WOCBP=women of child bearing potential. 
6.5.6.1. 
Immunogenicity 
Blood samples for anti-drug antibody (ADA) testing will be collected at the timepoints specified 
in Table 1 to Table 4.  On dosing days, ADA sample collection is within 1 hour before dosing.  
ADA will be assessed using a validated ELISA method.  For the patisiran arm, ADA defined as 
serum immunoglobulin (Ig) G (IgG)/IgM antibodies specific to the PEG2000-C-DMG component 
will be assessed.  
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Study Laboratory Manual. 
6.5.6.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential at the timepoints 
specified in Table 1 to Table 4.  
A serum pregnancy test will be performed at Screening and urine or serum pregnancy tests will 
be performed thereafter per the Schedule of Assessments (Table 1 to Table 4) and any time 
pregnancy is suspected.  The results of the pregnancy test must be known before study drug 
administration. More frequent pregnancy testing can be conducted according to country-specific 
regulations.  In Brazil, pregnancy testing should be performed prior to each dose.  
Any woman with a positive 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 until the pregnancy outcome is known (see Section 6.5.7.7 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 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. 
Follicle-stimulating hormone testing will be performed in all post-menopausal women to confirm 
suspected post-menopausal status. 

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6.5.6.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.3.  Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 9 will 
be performed one time, as well as hematology, serum chemistry, LFT, and coagulation 
assessments from Table 8, and other assessments or evaluations per Investigator discretion, as 
appropriate. 
Monitoring and dose modification will also be performed as outlined in Section 5.2.3.  
Table 9: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBs Ag, 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; PT=prothrombin time; 
RNA=ribonucleic acid; SLA= soluble liver antigen 
Note: 
• 
All assessments will be measured in central laboratory. The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
 

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6.5.7. 
Adverse Events 
6.5.7.1. 
Definitions 
Adverse Event  
According to the International Council for 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 
this treatment. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital 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:  
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3× upper limit 
of normal (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), 
recurrent ISRs that are increasing in severity, or ISRs that lead to temporary dose 
interruption or permanent discontinuation of ALN-TTRSC02 
• 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  

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For information on recording and reporting of AEs of clinical interest, see Section 6.5.7.2 and 
Section 6.5.7.3, respectively. 
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?” 
6.5.7.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in his/her health since the last visit.  The patient should also be asked if he/she has been 
hospitalized, had any accidents, used any new medications, or changed concomitant medication 
routines (both prescription and OTC).  In addition to patient observations, AEs will be 
documented from any clinically relevant laboratory findings, physical examination findings, 
ECG changes, or other findings that are relevant to patient safety. 
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. 

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Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1.3), 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. 
For patients who discontinue study drug early and remain in the study, all AEs will be collected 
for 90 days after the last dose, thereafter, SAEs and AEs of clinical interest (see definition in 
Section 6.5.7.1) will be collected for the remainder of their participation in the study. 
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 6.5.7.1), the Sponsor or its designee 
should complete the supplemental AEs of Clinical Interest eCRF.  Additional clinical and 
laboratory information may be collected.  Refer to CRF 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 to 
determine if an ophthalmological assessment is needed.  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. 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.7.1), the Sponsor or its designee 
should be notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 
6.5.7.4. 
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 6.5.7.1 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 
Reference 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. 
6.5.7.5. 
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 Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.5.7.6. 
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. 
6.5.7.7. 
Pregnancy Reporting 
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.  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. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 

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or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 6.5.7.4.   
6.5.7.8. 
Overdose Reporting 
An overdose is defined as any dose 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.  When an overdose is suspected, the Investigator should inform the Medical Monitor.  
6.5.8. 
COVID-19 Data Collection 
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. 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with hATTR amyloidosis, as well as their responses to 
treatment. 
Where allowed per local regulations, ethics committee (IRB/EC) approval, and patient consent 
(and assent, where applicable), samples will be collected as part of this study to permit 
exploratory investigations and the application of novel approaches to bioanalyses that may 
further elucidate the outcomes of this study, or potentially advance understanding of the safety, 
mechanism of action, and/or efficacy of ALN-TTRSC02 and patisiran.   
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1 through Table 6). Potential exploratory investigations may include DNA, RNA, or 
biochemical metabolite assessments as they relate to disease progression, efficacy or safety.  
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 

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6.7. 
Pharmacoeconomic Assessments 
6.7.1. 
Patient and Caregiver Impact Survey 
To complement medical records, information about how hATTR amyloidosis impacts the lives 
of patients and their caregivers will be collected at the timepoints specified in the Schedule of 
Assessments (Table 1 to Table 4). The Patient and Caregiver Impact Survey includes questions 
related to how hATTR amyloidosis affects patients, including their symptoms at the time of 
diagnosis, utilization of various healthcare providers, employment status, and need for 
government compensation/assistance. Questions will also be asked about how hATTR 
amyloidosis impacts the employment status of the patient's caregiver and patients' need for both 
informal and professional caregivers. 
6.7.2. 
Hospitalization, Urgent Healthcare Visits, Surgeries, and Procedures  
Hospitalization, urgent healthcare visits, surgeries, and procedure information will be collected 
on a separate eCRF for pharmacoeconomic evaluations, as specified in the Schedule of 
Assessments (Table 1 to Table 4). As described in the beginning Section 6, in situations where a 
study visit is unable to be completed at the study center, the study physician (or delegate) may 
verbally contact the patient within the expected study visit window to assess hospitalizations, 
urgent healthcare visits, surgeries, and procedures. 
Prior hospitalization, urgent healthcare visits, surgeries, and procedure information through 
12 months prior to first dose should be collected at Screening. 
6.7.3. 
Patient Experience Survey 
The Patient Experience Survey will be administered to understand patients' level of satisfaction 
with their current hATTR amyloidosis therapy and their level of comfort using this therapy. This 
survey will be administered at the timepoints specified in the Schedule of Assessments (Table 1, 
Table 2, and Table 4). 
6.7.4. 
Patient Preference Survey 
 
  The 
survey aims to understand patients' preferred method of treatment administration and the primary 
reasons for their preference.  This survey will be administered at the timepoints specified in the 
Schedule of Assessments (Table 4). 
7. 
STATISTICS 
The principal features of the planned analysis are presented in this section.  A separate SAP will 
be finalized prior to first patient dosed.  The SAP will detail the implementation of the statistical 
analyses in accordance with the principal features stated in the protocol.  

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7.1. 
Determination of Sample Size 
Approximately 160 patients will be enrolled in this study, with a 3:1 randomization ratio to either 
ALN-TTRSC02 or patisiran.  
The sample size was chosen to enable an adequate characterization of the long-term safety 
profile, as well as the efficacy of ALN-TTRSC02 in this patient population.  For the primary 
efficacy endpoint of mNIS+7 and the key secondary endpoint of Norfolk QoL-DN total scores, 
the ALN-TTRSC02 arm in the Phase 3 study will be compared to the placebo arm from the 
APOLLO study.  For the mNIS+7 change from baseline at 9 months, the observed mean 
(±standard deviation [SD]) was 15 ± 17 points for the placebo arm from the APOLLO study.  
Assuming a mean change of 0 points for the ALN-TTRSC02 arm, there is >90% power to 
establish the superiority over placebo using a 2-sided t-test with a significance level of 0.05.  For 
the Norfolk-QoL DN total score change from baseline at 9 months, the observed mean (±SD) 
was 11.5 ± 19.2 points for the placebo arm from the APOLLO study.  Assuming a mean change 
of -4 points for the ALN-TTRSC02 arm, there is >90% power to establish the superiority over 
placebo using a 2-sided t-test with a significance level of 0.05.  
For safety, a sample size of >100 patients on ALN-TTRSC02 can provide reasonable assurance 
that the true cumulative one-year incidence of adverse drug events (ADE) is no greater than 3% 
when no ADE is observed.  
To match the cardiac disease severity with the APOLLO study population, the study plans to 
enroll no more than 15% of patients with NT-proBNP values greater than 3000 ng/L. 
7.2. 
Statistical Methodology 
Additional data summaries to help understand any impact of the COVID-19 pandemic and any 
descriptive comparison of 
 
on efficacy, PD and safety assessments will be outlined in the SAP. 
7.2.1. 
Populations to be Analyzed 
The population analysis sets are defined as follows:  
• Modified ITT (mITT) population: All randomized patients who received any amount 
of study drug. Patients will be grouped by their randomized treatment group. 
• TTR Per-protocol (PP) Population: All mITT population patients with a nonmissing 
TTR assessment at baseline and ≥1 trough TTR assessment associated with adequate 
treatment compliance between Month 6 and Month 18. Specific details will be 
provided in the SAP. 
• Safety Population: All randomized patients who received any amount of study drug, 
grouped according to the treatment actually received. 
• PK Population: All randomized patients who received any amount of study drug and 
have at least 1 post dose blood sample for PK parameters and have evaluable PK data. 
• Patients with cardiac involvement: All patients in the mITT population who had pre-
existing evidence of cardiac amyloid involvement. Specific details will be provided in 
the SAP. 

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The primary population for efficacy analysis will be the mITT population, except TTR percent 
reduction analysis, which will be conducted in the TTR PP population.  Safety analysis will be 
conducted in the safety population.  PK analysis will be conducted in the PK population.  
Selected endpoints will be analyzed in the cardiac subpopulation.  
7.2.2. 
Examination of Subgroups 
Subgroup analyses will be conducted for selected endpoints. Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
For efficacy assessments, if the scheduled visits (eg, 9-month) are not performed, the 
unscheduled and/or discontinuation visits performed within a 3-month window will be grouped 
with the scheduled assessments. For patients impacted by the COVID-19 pandemic, efficacy 
visits delayed up to 6 months will be included in the analysis.    
Sensitivity analyses for the primary efficacy endpoint of mNIS+7 and the key secondary 
endpoint of Norfolk QoL-DN total scores, including different methods for handling of the 
missing data, will be conducted to assess the robustness of the primary analysis results. 
More details of missing data handling will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other baseline characteristics, including disease-specific information, will be 
summarized descriptively. 
7.2.5. 
Efficacy Analyses 
This Phase 3 study will use the placebo arm of the APOLLO study as an external control.  
Patient-level data from this study will be compared with patient-level data from APOLLO for 
efficacy analyses.  For the primary and secondary clinical efficacy endpoints, the ALN-
TTRSC02 arm in this study will be compared to the placebo arm from the APOLLO study.  For 
the secondary endpoint of TTR percent reduction, the ALN-TTRSC02 arm in this study will be 
compared to the patisiran arm in this study. The treatment comparison will be conducted at 
Month 9 and/or Month 18.  The efficacy endpoints beyond 18 months will be summarized 
descriptively. 
The patisiran arm in this study will mainly serve as a reference arm.  For the clinical efficacy 
endpoints at Month 9 and Month 18, the patisiran arm will be summarized descriptively and the 
treatment difference between ALN-TTRSC02 and patisiran arm in this study will not be tested.  
 
7.2.5.1. 
Primary Endpoint 
The primary endpoint mNIS+7 will compare change in mNIS+7 from baseline at Month 9 
between the ALN-TTRSC02 group in this study and the placebo group in the APOLLO study. 
The treatment effect will be estimated based on the least squares (LS) means using an analysis of 

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covariance (ANCOVA) model with baseline mNIS+7 score as a covariate and factors including 
treatment group (ALN-TTRSC02 vs placebo), genotype (V30M vs non-V30M) and age of 
disease onset (<50 vs ≥50 years old). The primary endpoint will be tested at a significance level 
of 0.05 and must be significant to declare a positive trial.  
Primary endpoint data that are missing will be multiply imputed separately for each treatment 
group using a regression procedure based on baseline covariates. The details will be specified in 
the SAP.  
The mNIS+7 score for the patisiran group in this study will be summarized descriptively. 
7.2.5.2. 
Secondary Endpoints 
For the secondary clinical efficacy endpoints, the treatment comparison will be made between 
the ALN-TTRSC02 group in this study and the placebo group in the APOLLO study at Month 9 
or Month 18 as specified. For the TTR percent reduction endpoint, the ALN-TTRSC02 group 
will be compared with the patisiran group in this study. To control the overall type I error, the 
secondary endpoints will be tested in the following hierarchical order: 
• Norfolk QoL-DN total score change from baseline at Month 9 
• 10-MWT gait speed change from baseline at Month 9 
• mNIS+7 change from baseline at Month 18 
• Norfolk QoL-DN total score change from baseline at Month 18 
• 10-MWT gait speed change from baseline at Month 18 
• mBMI (BMI [kg/m2] multiplied by serum albumin level [g/L]) change from baseline 
at Month 18 
• R-ODS change from baseline at Month 18 
• TTR percent reduction through 18 months  
For change in Norfolk QoL-DN total score and 10-MWT gait speed from baseline at Month 9, 
the analysis will be based on an ANCOVA model similar to the model described for the analysis 
of change in mNIS+7 from baseline at Month 9, while adjusting for baseline value of the 
endpoint being modeled and including baseline NIS score (<50 vs ≥50) as an additional factor in 
the model. For these 2 endpoints, data that are missing will be multiply imputed separately for 
each treatment group using a regression procedure based on baseline covariates. The details will 
be specified in the SAP.   
For change from baseline at Month 18 analyses, the analysis will be based on a mixed-effects 
model for repeated measures (MMRM), adjusting for a covariate (baseline value for the endpoint 
being modeled), categorical factors (treatment group, visit [Month 9 vs Month 18], genotype, age 
of disease onset, baseline NIS score), and an interaction term (treatment group by visit). For 
mNIS+7, baseline NIS score will not be included in the model. 
In the APOLLO study, mBMI was not assessed at Month 9 or Month 18. The average values of 
Day 189 and Day 357 will be derived as Month 9, and the Day 546 value will be substituted as 
Month 18. 

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The TTR percent reduction through Month 18 will be derived as the average trough TTR percent 
reduction from Month 6 to 18 which is the steady state period for both ALN-TTRSC02 and 
patisiran. A Hodges-Lehmann method stratified by previous TTR stabilizer use (yes vs no) will 
be used to estimate the 95% CI for the median difference between the ALN-TTRSC02 and 
patisiran groups in this study. Non-inferiority will be declared if the lower limit of the 95% CI 
for the treatment difference is greater than –10%. A sensitivity analysis will be conducted to 
compare the TTR percent reduction between the ALN-TTRSC02 group from this study and the 
pooled patisiran groups from this Phase 3 study and the APOLLO study.   
7.2.5.3. 
Exploratory Endpoints 
Analysis of exploratory efficacy endpoints will be detailed in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
Summary tables and graphical displays of observed values, changes and percentage changes 
from baseline in PD biomarkers (TTR and vitamin A) will be presented. 
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted for ALN-TTRSC02 and patisiran using non-
compartmental method.  PK parameters will be calculated using a validated version of Phoenix® 
WinNonlin. 
Population pharmacokinetic analysis will be performed to describe the plasma pharmacokinetics 
using Phoenix NLME (Version 1.1 or later) or a similar software, such as NONMEM. The 
impact of relevant covariates, such as, weight, sex, race, age, renal function, and hepatic function 
on plasma PK will be evaluated. Summary tables and figures and inferential statistics will be 
generated. 
7.2.8. 
Safety Analyses 
A summary of study drug exposure, including the durations of exposure and the proportions of 
patients with dose modifications will be produced.  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary. Results will be tabulated by Anatomical Therapeutic Chemical Classification 
System (ATC) and Preferred Term. 
Adverse events will be summarized by MedDRA system organ class and preferred term.  The 
number and percentage of patients experiencing AEs after the first dose of the study drug will be 
summarized. Separate tabulations will be produced for treatment-related AEs, SAEs, and 
discontinuations due to AEs.  By-patient listings will be provided for deaths, SAEs, and events 
leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data, 12-lead ECG interval data and 
vital signs data, presented as both actual values and changes from baseline over time 
Laboratory shift tables from baseline to worst values will be presented.  Baseline will be defined 
as the last observation on or prior to Study Day 1. 

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Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP.  
7.2.9. 
Immunogenicity Analyses 
Incidence of ADA and titers will be summarized descriptively.   
7.2.10. 
Other Analyses 
Not applicable. 
7.2.11. 
Interim Analysis 
No interim analysis is planned. 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent and Medical Records Release Form 
The Investigator will ensure that the patient/legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  
Patients/legal guardians must also be notified that they are free to discontinue from the study at 
any time.  The patient/legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.   
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. 
The patient’s/legal guardian’s signed and dated informed consent must be obtained before 
conducting any study tests or procedures that are not part of routine care.   
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient/legal guardian. 
In addition of the ICF, patients will be asked to sign a Medical Records Release Form (where 
allowed by local regulations) at Screening for the purpose of obtaining information on vital 
status, cardiac transplant procedures, left-ventricular assist device placement (Section 6.2.8), and 
hospitalizations (Section 6.2.7) from patients for the duration of the study. This information will 
be obtained by the patient’s physician through contacting the patient or family or from death 
registries.  
Signing the Medical Records Release Form will be optional and will apply if the patient 
discontinues from the study early. The form should be checked at the Early Treatment 

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Discontinuation Visit and a new form will be signed if the information needs updating. Every 
effort should be made to collect the Medical Records Release Form from all patients enrolled in 
the study.   
8.1.2. 
Ethical Review 
The study protocol, including the ICF (assent form, if applicable), 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 6.5.7.  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 enrolled or 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 
serious 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 
Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable regulatory authorities to 

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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 
designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 

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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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European network approach to defining the epidemiology and management patterns for TTR-
FAP. Curr Opin Neurol. 2016 Feb;29 Suppl 1:S3-S13. 
Plante-Bordeneuve V,Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011 
Dec;10(12):1086-97. 
Ruberg FL,Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012 Sep 
04;126(10):1286-300. 
Schwartz AL, Rup D,Lodish HF. Difficulties in the quantification of asialoglycoprotein receptors 
on the rat hepatocyte. J Biol Chem. 1980 Oct 10;255(19):9033-6. 
Soares ML, Coelho T, Sousa A, Batalov S, Conceicao I, Sales-Luis ML, et al. Susceptibility and 
modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a 
single-gene disease. Hum Mol Genet. 2005 Feb 15;14(4):543-53. 
Solomon S, Adams D, Coelho T, Karsten V, Sweetser M, Chen J, et al., editors. APOLLO, a 
phase 3 study of patisiran for the treatment of hereditary transthyretin-mediated amyloidosis: 18-
month safety and efficacy in subgroup of patients with cardiac involvement. 2018 XVIIth 
International Symposium of Amyloidosis; 2018; Kumamoto, Japan. 
Suanprasert N, Berk JL, Benson MD, Dyck PJ, Klein CJ, Gollob JA, et al. Retrospective study of 
a TTR FAP cohort to modify NIS+7 for therapeutic trials. J Neurol Sci. 2014 Sep 15;344(1-
2):121-8. 
Swiecicki PL, Zhen DB, Mauermann ML, Kyle RA, Zeldenrust SR, Grogan M, et al. Hereditary 
ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-
31. 
Vinik EJ, Hayes RP, Oglesby A, Bastyr E, Barlow P, Ford-Molvik SL, et al. The development 
and validation of the Norfolk QOL-DN, a new measure of patients' perception of the effects of 
diabetes and diabetic neuropathy. Diabetes Technol Ther. 2005 Jun;7(3):497-508. 
Vinik EJ, Vinik AI, Paulson JF, Merkies IS, Packman J, Grogan DR, et al. Norfolk QOL-DN: 
validation of a patient reported outcome measure in transthyretin familial amyloid 
polyneuropathy. J Peripher Nerv Syst. 2014 Jun;19(2):104-14. 
Wang et al. Safety and Efficacy of Inotersen in Patients with Hereditary Transthyretin 
Amyloidosis with Polyneuropathy (NEURO-TTR). ANA abstract. 2017. 
Yamamoto S, Wilczek H, Nowak G, Larsson M, Oksanen A, Iwata T, et al. Liver transplantation 
for familial amyloidotic polyneuropathy (FAP): a single-center experience over 16 years. Am J 
Transplant. 2007;7(11):2597-604. 
Yazaki M, Tokuda T, Nakamura A, Higashikata T, Koyama J, Higuchi K, et al. Cardiac amyloid 
in patients with familial amyloid polyneuropathy consists of abundant wild-type transthyretin. 
Biochem Biophys Res Commun. 2000 Aug 11;274(3):702-6. 
Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, et al. Efficacy and safety of 
antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the 
NATHAN 1 trial. Diabetes Care. 2011 Sep;34(9):2054-60. 
 

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10. 
APPENDICES 
10.1. 
mNIS+7 Components and Scoring 
Refer to the Study Reference Manual for additional details. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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10.2. 
PND Scores and FAP Stages 
Polyneuropathy Disability (PND) Scores 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch 
Walking with the help of two sticks or crutches 
IV 
Confined to a wheelchair or bedridden 
 
Familial Amyloidotic Polyneuropathy (FAP) Stages 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs 
 

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10.3. 
New York Heart Association (NYHA) Class 
 
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. 
10.4. 
Karnofsky Performance Status (KPS) Scale 
 
Able to carry on normal activity and 
to work; no special care needed. 
100 
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able to 
care for most of his personal needs. 
50 
Requires considerable assistance and frequent 
medical care.  
Unable to care for self; requires 
equivalent of institutional or hospital 
care; disease may be progressing 
rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 1, Summary of Changes, 10 October 2019 
 
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ALN-TTRSC02-002 PROTOCOL AMENDMENT 1  
SUMMARY OF CHANGES DATED 10 OCTOBER 2019 
HELIOS-A:  A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy 
and Safety of ALN-TTRSC02 in Patients with Hereditary Transthyretin Amyloidosis 
(hATTR Amyloidosis) 
Rationale for Protocol Amendment 
The primary purpose of this protocol amendment is to introduce the use of a vutrisiran (ALN-
TTRSC02) in single-use, pre-filled syringes after completion of a patient’s Month 9 efficacy 
assessments. After the Week 36 dose (last dose prior to the Month 9 efficacy assessments), 
patients will be transitioned from vial-based injections to the pre-filled syringes as this 
presentation becomes available. 
Several additional changes are being implemented as outlined below. 
The following secondary objective/endpoint has been added: 
 A new objective has been added to determine the efficacy of ALN-TTRSC02 on 
improvement in neurologic impairment and quality of life. This will be assessed by 
analyzing the change at Month 18 compared to baseline in mNIS+7 and Norfolk 
QoL-DN total score in ALN-TTRSC02-treated patients. 
A Medical Records Release form has been added: 
 All patients will be asked to sign an optional Medical Records Release Form (where 
allowed by local regulations) in addition to the informed consent form. This form will 
ensure collection of vital status data, cardiac transplant procedures, left-ventricular 
assist device placement, and hospitalizations from patients who discontinue early 
from the study.  
The following additional assessment timepoints or clarification have been made to the Schedule 
of Assessments: 
 Vital status assessments have been added to reflect collection of this information at 
every visit throughout the study. 
 Collection of Polyneuropathy Disability (PND) score and Familial Amyloid 
Polyneuropathy (FAP) stage assessments at the Month 9 efficacy visit to ensure 
consistency in the timing of the collection of disease stage information with the ALN-
TTR02-004 (APOLLO) study. 
 Clarified the timing of hepatitis tests, exploratory biomarkers (urine, plasma, serum), 
optional exploratory DNA sample, and pharmacoeconomic assessments (Patient and 
Caregiver Impact Survey; Patient Experience Survey; Patient Preference Survey) 
 Added an additional check of serum TTR and vitamin A at Week 42. 
 Clarified that treatment administration and efficacy visits during the Extension Period 
at Month 27 and Month 36 are expected to be distinct visits, consistent with the 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
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efficacy visits at Month 9 and Month 18. Also clarified the safety assessments to be 
conducted at the administration and efficacy visits. 
 Added a clarification to indicate the predose and postdose patisiran pharmacokinetic 
blood draws will be timed based on the start and end of patisiran infusion. 
 Clarified that that LFTs must be obtained with results available within 28 days before 
the clinic visit on which ALN-TTRSC02 dosing is scheduled during treatment from 
Month 9 to Month 18 and during the treatment extension period.  
Additional protocol modifications or clarifications have been added for the following: 
 The study design description was updated to clarify that the Sponsor will be making 
efforts to enroll a population in this study that is comparable to the APOLLO study 
population to enable robust cross-study comparisons. 
 Under female contraception requirements, clarified that use of oral, implantable, 
injectable, or transdermal hormonal methods of contraception must be associated with 
the inhibition of ovulation. 
 When recording medical history, clarified that information on prior tetramer stabilizer 
use anytime should be recorded and not only the use within the 1 year prior to the 
first dose of study drug. 
 Clarified that follicle-stimulating hormone testing will be performed in all post-
menopausal women to confirm suspected post-menopausal status. 
 Additional requirements for study termination were implemented in line with ICH E6 
(R2) Guideline, and the publication policy details were updated to match language in 
the Clinical Trial Agreement.  
 Added the international non-proprietary name (INN), vutrisiran, of the drug product 
ALN-TTRSC02; updated the comparator name “patisiran-LNP” to “patisiran” 
throughout the protocol. 
 Rescreening criteria limited previously to LFT and NIS eligibility requirements have 
broadened to allow more flexibility.  
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting (including administrative changes) are not 
detailed. 
 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
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Table 1: 
Protocol Amendment 1 Detailed Summary of Changes 
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:  Updated the version and date of the protocol. 
The primary change occurs in the Title Page 
The Title Page now reads: 
Original protocol:  11 October 2018 
Amendment 1:  10 October 2019 
Sections also containing this change:   
All headers at the top of all protocol pages 
 
Purpose:  All patients will be asked to sign an optional Medical Records Release Form (where allowed by local regulations) in 
addition to the informed consent form. This form will ensure collection of vital status data, cardiac transplant procedures, left-
ventricular assist device placement, and hospitalizations from patients who discontinue early from the study. 
The primary change occurs in Section 6.1, Screening Assessments 
Section 6.1 now reads: 
An informed consent form (ICF) or assent form that has been approved by the appropriate Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) must be signed by the patient (or legal guardian) before the Screening procedures are 
initiated.  All patients (or their legal guardians) will be given a copy of the signed and dated ICF and/or assent form. 
In addition of the ICF, patients will be asked to sign a Medical Records Release Form (where allowed by local regulations) at 
Screening for the purpose of obtaining information on vital status, cardiac transplant procedures, left-ventricular assist device 
placement (Section 6.2.8), and hospitalizations (Section 6.2.7) from patients for the duration of the study. This information will 
be obtained by the patient’s physician through contacting the patient or family or from death registries.  
Signing the Medical Records Release Form will be optional and will apply if the patient discontinues from the study early. 
Every effort should be made to collect the Medical Records Release Form from all patients enrolled in the study.  Also see 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
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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. 
Patients will complete the following 3 visit types prior to randomization:  the ICF and Medical Records Release Form will be 
obtained at the Visit 1 (Screening), and all inclusion/exclusion criteria will be assessed except for the NIS and PND score criteria; see 
Section 4.1); the NIS and PND score inclusion criteria will be assessed at Visit 2 (Baseline first assessment); other baseline 
assessments will be completed at Visit 3 or at Day 1 prior to first dose.  Visits 1, 2 and 3 may each occur over multiple days.   
Sections also containing this change:  
 Table 1 (Schedule of Assessments, Screening through Treatment Period Month 9) 
 Table 3 (Schedule of Assessments, Treatment Extension Period, Other Visits, and Follow-up Period) 
 Section 4.3.3. Lost to Follow-Up 
 Section 8.1.1.  Informed Consent and Medical Records Release Form 
 
Purpose: The collection of Vital Status information has been expanded. Vital status assessments have been added throughout the study 
rather than just at the Month 18 efficacy or discontinuation visits.  
The primary change occurs in newly added Section 6.2.8, Vital Status Check 
6.2.8. Vital Status Check 
Vital status checks will be performed at the timepoints specified in the Schedule of Assessments (Table 1 to Table 3). Vital 
status checks should include checking for the occurrence of heart transplantation or left-ventricular assist device implantation 
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.   
Sections also containing this change:  
 Table 1 (Schedule of Assessments, Screening through Treatment Period Month 9),  
 Table 2 (Schedule of Assessments, Treatment Period from Month 9 through Month 18),  
 Table 3 (Schedule of Assessments, Treatment Extension Period, Other Visits, and Follow-up Period), 

Clinical Study Protocol ALN-TTRSC02-002 
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 Section 4.3.1, Discontinuation of Study Drug or Declining Procedural Assessments 
 Section 4.3.3, Lost to Follow-Up 
 Section 8.1.1,  Informed Consent and Medical Records Release Form 
 
Purpose:  Added additional assessments of Polyneuropathy Disability (PND) score and Familial Amyloid Polyneuropathy (FAP) 
stage at the Month 9 efficacy visit to ensure consistency in the timing of the collection of disease stage information with the ALN-
TTR02-004 (APOLLO) study. 
The primary change occurs in Table 1, Schedule of Assessments (Screening through Treatment Period Month 9) 
The Table 1 now reads: 
 
Note 
Scree
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-dose 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 30 
33 
36 
36-39 
±Visit Window 
See 
Section/Table 
for details 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3
D 
±3D 
±3
D 
±3
D 
±3
D 
±3D 
NA 
PND Score 
Section 
6.2.10 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FAP Stage 
Section 
6.2.10 
 
X – Single assessment at 
any of these visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Purpose:  Row added for “hepatitis tests” with an assessment at Screening. This is mentioned in Section 6.5.6, but is not clearly 
indicated in Table 1. Also clarified in Section 6.5.6/Table 7, that these are hepatitis tests and not hepatic tests. 
The primary change occurs in Table 1, Schedule of Assessments (Screening through Treatment Period Month 9) 
The Table 1 now reads: 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 1, Summary of Changes, 10 October 2019 
 
Alnylam Pharmaceuticals 
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Note 
Scree
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-dose 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 30 
33 
36 
36-39 
±Visit Window 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3
D 
±3D 
±3
D 
±3
D 
±3
D 
±3D 
NA 
Hepatitis Tests 
Section 
6.5.6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This part of Table 7 now reads: 
Hepatic Hepatitis 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 
 
Purpose:  Row added for “Exploratory DNA sample (optional)” with an assessment at Baseline. This is to clarify this to be an 
optional single sample obtained during baseline visit 3 and distinguish this from the sample for exploratory analysis that will be 
assessed at Baseline and several post-baseline time points. 
The primary change occurs in Table 1, Schedule of Assessments (Screening through Treatment Period Month 9) 
The Table 1 now reads: 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
Alnylam Pharmaceuticals 
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Note 
Scree
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-
dose 
Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
36-39 
±Visit Window 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D ±3D 
±3D 
±3D 
±3D 
±3D 
NA 
Sample for 
Exploratory 
Analysis  
Section 6.6 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Exploratory DNA 
sample (optional) 
Section 6.6 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
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Purpose: Removed “Patient Experience Survey” from the rows in which it was combined with other assessments or surveys as it is 
administered using a different schedule. 
The primary changes occur in Schedule of Assessments Table 1 (Screening through Treatment Period Month 9) and Table 2 
(Treatment Period from Month 9 through Month 18) 
The Table 1 now reads: 
 
Note 
Scree
ning 
Baseline 
Treatment Period 
Month 9 
Efficacy 
 
V1 
V2 
V3 
Pre-dose 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day  
 
 
 
Day 1 
D22 
D43 
D64 
D85 
D106 
D127 
D148 
D169 
D190 
D211 
D232 
D253 
D254-
D273 
Study Week 
 
 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 30 
33 
36 
36-39 
±Visit Window 
 
 
 
 
0 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3
D 
±3D 
±3
D 
±3
D 
±3
D 
±3D 
NA 
EQ-5D-5L and EQ-
VAS; C-SSRS; 
Patient and 
Caregiver Impact 
Survey and Patient 
Experience Surveys 
Section 6.2.9; 
Section 6.5.5; 
Section 6.7.1 
 
 
X– single at any of 
these visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Patient Experience 
Survey 
Section 6.7.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Table 2 now reads: 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 1, Summary of Changes, 10 October 2019 
 
Alnylam Pharmaceuticals 
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Note 
Treatment Period 
Month 
18 
Efficacy 
Study Day  
D274 
D295 
D316 
D337 
D358 
D379 
 
D400 
D421 
D442 
D463 
D484 
D505 
D526 
D547 
D554-D561 
Study Week 
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
±Visit Window 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NA 
Norfolk QoL-DN; R-
ODS; EQ-5D-5L and 
EQ-VAS; C-SSRS; 
Patient and Caregiver 
Survey and Patient 
Experience Surveys 
Section 6.2.3; 
Section 6.2.6; 
Section 6.2.9; 
Section 6.5.5; 
Section 6.7.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Patient Experience 
Survey 
Section 6.7.3   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Purpose:  Additional assessment of serum TTR and vitamin A added at Week 42. To avoid a prolonged gap in PD assessment between 
the previous and subsequent visits. 
The primary change occurs in Table 2, Schedule of Assessments (Treatment Period from Month 9 through Month 189) 
The Table 2 now reads: 
 
Note 
Treatment Period 
Month 
18 
Efficacy 
Study Day  
D274 
D295 
D316 
D337 
D358 
D379 
 
D400 
D421 
D442 
D463 
D484 
D505 
D526 
D547 
D554-D561 
Study Week 
39 
42 
45 
48 
51 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
±Visit Window 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
±3D 
NA 
TTR Protein;  
Vitamin A 
Section 6.3 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
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Purpose: Modified the assessments under the Month 27 and Month 36 visit columns to clarify that treatment administration and 
efficacy visits are expected to be distinct visits, consistent with the efficacy visits at Month 9 and 18. Also clarified the windows for 
these visits. In addition to these changes, several additional minor changes are detailed in the following table: 
Several other additional edits are also summarized below: 
 Full physical examinations (PEs) changed to symptom-directed PEs. Additional symptom-directed PEs added as indicated 
 Replaced the reference to “all Pharmacoeconomic assessments” and each individual survey (Patient and Caregiver 
Impact Survey; Patient Experience Survey; Patient Preference Survey) to be consistent with how these were presented in 
Table 1 and Table 2. Clarified the schedules of each survey during the Early Discontinuation and modified efficacy visits 
for patients who discontinued treatment before Month 18. 
 Medical Records Release Form recheck added (as described earlier) 
Changes to column headers and relevant rows in Table 3 (Schedule of Assessments:  Treatment Extension Period, Other Visits, and 
Follow-up Period) are indicated below: 
 
Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy Visits 
for Patients Who 
Discontinue Treatment 
before Month 18 
FU 
Period 
 
Last 
Patisiran 
Dosing 
Visit 
ALN-TTRSC02 
Dosing Visits Every 
12 Weeks 
ALN-
TTRSC02 
Dosing Visits 
at  Months 
27 and 36 
Month 27 
Efficacy and 
Dosing Visit 
Month 27 and 36 
Efficacy Visits 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
81 
84, 96, 108, 120, 
132, and 144, and 
156 
120, 156 
160120, 156 
- 
36-39 
79-80 
- 
±Visit Window 
±3D 
±7D 
±2 weeks±7D 
+14D (≥1D after W120 
and W156 doses, 
respectively) 
±2 weeks 
- 
- 
- 
- 
Medical Records 
Release Form 
(optional) 
Section 
8.1.1 
Recheck 
 
 
 
 
X 
 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
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Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy Visits 
for Patients Who 
Discontinue Treatment 
before Month 18 
FU 
Period 
 
Last 
Patisiran 
Dosing 
Visit 
ALN-TTRSC02 
Dosing Visits Every 
12 Weeks 
ALN-
TTRSC02 
Dosing Visits 
at  Months 
27 and 36 
Month 27 
Efficacy and 
Dosing Visit 
Month 27 and 36 
Efficacy Visits 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
81 
84, 96, 108, 120, 
132, and 144, and 
156 
120, 156 
160120, 156 
- 
36-39 
79-80 
- 
±Visit Window 
±3D 
±7D 
±2 weeks±7D 
+14D (≥1D after W120 
and W156 doses, 
respectively) 
±2 weeks 
- 
- 
- 
- 
NYHA class; KPS; 
PND and FAP; 
mBMI  
Section 
6.2.11.4; 
Section 
6.2.12; 
Section 
6.2.10; 
Section 
6.2.5 
 
 
 
X 
X 
X 
X 
 
Vital Signs 
Section 
6.5.1 
X 
X 
X 
X 
 
 
 
 
Full Physical 
Examination (PE); 
Weight 
Symptom-
directed 
PE Section 
6.5.3; 
Section 
6.5.2 
X 
X 
X 
XWeight only 
X 
X 
X 
X 
NIS; mNIS+7; 
HRdb 
See below 
Table 3 
Notes; 
Section 
6.2.1; 
Section 
6.2.2  
 
 
X 
X 
X 
X 
X 
X 
X  
X 
X 
 

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Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy Visits 
for Patients Who 
Discontinue Treatment 
before Month 18 
FU 
Period 
 
Last 
Patisiran 
Dosing 
Visit 
ALN-TTRSC02 
Dosing Visits Every 
12 Weeks 
ALN-
TTRSC02 
Dosing Visits 
at  Months 
27 and 36 
Month 27 
Efficacy and 
Dosing Visit 
Month 27 and 36 
Efficacy Visits 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
81 
84, 96, 108, 120, 
132, and 144, and 
156 
120, 156 
160120, 156 
- 
36-39 
79-80 
- 
±Visit Window 
±3D 
±7D 
±2 weeks±7D 
+14D (≥1D after W120 
and W156 doses, 
respectively) 
±2 weeks 
- 
- 
- 
- 
10-MWT 
Section 
6.2.4 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Questionnaires: 
Norfolk QoL-DN; 
R-ODS; EQ-5D-5L 
and EQ-VAS; C-
SSRS; all 
Pharmacoeconomic 
assessments 
Patient and 
Caregiver Impact 
Survey; Patient 
Experience 
Survey; Patient 
Preference Survey 
Section 
6.7; 
Section 
6.2.3; 
Section 
6.2.6; 
Section 
6.2.9; 
Section 
6.5.5; 
Section 
6.7.1; 
Section 
6.7.3; 
Section 
6.7.4    
 
 
X 
X 
X - No Patient 
Experience 
Survey; No 
Patient 
Preference 
Survey 
X – No  
C-SSRS; 
No Patient 
Experience 
Survey; 
No Patient 
Preference 
Survey 
X – No  
C-SSRS; 
No Patient 
Experience 
Survey; 
No Patient 
Preference 
Survey 
 
Single 12-Lead 
ECG 
Section 
6.5.4 
 
 
 
 
X 
 
 
 
Echocardiogram 
Section 
6.2.11.1 
 
 
X 
X 
X 
 
 
 

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Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy Visits 
for Patients Who 
Discontinue Treatment 
before Month 18 
FU 
Period 
 
Last 
Patisiran 
Dosing 
Visit 
ALN-TTRSC02 
Dosing Visits Every 
12 Weeks 
ALN-
TTRSC02 
Dosing Visits 
at  Months 
27 and 36 
Month 27 
Efficacy and 
Dosing Visit 
Month 27 and 36 
Efficacy Visits 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
81 
84, 96, 108, 120, 
132, and 144, and 
156 
120, 156 
160120, 156 
- 
36-39 
79-80 
- 
±Visit Window 
±3D 
±7D 
±2 weeks±7D 
+14D (≥1D after W120 
and W156 doses, 
respectively) 
±2 weeks 
- 
- 
- 
- 
Technetium 
scintigraphy 
imaging (select 
sites only) 
Section 
6.2.11.3 
 
 
X 
X 
X 
 
 
 
Serum Chemistry, 
Hematology, 
Urinalysis, 
Coagulation and 
Liver Function 
Tests 
Section 
6.5.6; 
Section 
6.5.6.3 
LFT 
only; 
applies 
to both 
arms 
X 
XLFTs only 
X No LFTs 
X 
Serum 
Chemistry 
and LFTs 
only 
Serum 
Chemistry 
and LFTs 
only 
X 
Pregnancy Test  
Section 
6.5.6.2 
 
X 
X 
X 
X 
X 
X 
X 
Cardiac Biomarker 
Samples 
Section 
6.2.11.2 
 
X - Every 24 weeks starting at  
Week 96 
X - Week 96, Week 120, Week 144 
X 
X 
X 
X 
 
TTR Protein; 
Vitamin A 
Prior to 
each dose 
on dosing 
days; 6.3 
 
X 
X 
X 
X 
X 
X 
X 

Clinical Study Protocol ALN-TTRSC02-002 
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Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy Visits 
for Patients Who 
Discontinue Treatment 
before Month 18 
FU 
Period 
 
Last 
Patisiran 
Dosing 
Visit 
ALN-TTRSC02 
Dosing Visits Every 
12 Weeks 
ALN-
TTRSC02 
Dosing Visits 
at  Months 
27 and 36 
Month 27 
Efficacy and 
Dosing Visit 
Month 27 and 36 
Efficacy Visits 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
81 
84, 96, 108, 120, 
132, and 144, and 
156 
120, 156 
160120, 156 
- 
36-39 
79-80 
- 
±Visit Window 
±3D 
±7D 
±2 weeks±7D 
+14D (≥1D after W120 
and W156 doses, 
respectively) 
±2 weeks 
- 
- 
- 
- 
ADA 
On dosing 
days, 
collect 
within 1 
hour before 
dosing; 
Section 
6.5.6.1 
 
X - Week 96, Week 120, Week 144-
Every 24 weeks starting at Week 96 
X 
X 
 
 
 
ALN-TTRSC02 
PK 
See Table 4 
for PK 
collection 
timepoints 
 
 
 
X 
X 
X 
 
Samples for 
Exploratory 
Analysis 
Section 6.6 
 
 
X 
X 
X 
 
 
 
AEs; Con. Meds; 
Hospitalizations, 
Urgent care visits 
and Procedures 
Section 
6.5.7; 
Section 
5.3; 
Section 
6.7.2 
Continuous monitoring X 
X -
Through 
week 12 
after 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
Alnylam Pharmaceuticals 
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Note 
Treatment Extension Period 
Early Drug 
Discontinuation 
Visit 
Modified Efficacy Visits 
for Patients Who 
Discontinue Treatment 
before Month 18 
FU 
Period 
 
Last 
Patisiran 
Dosing 
Visit 
ALN-TTRSC02 
Dosing Visits Every 
12 Weeks 
ALN-
TTRSC02 
Dosing Visits 
at  Months 
27 and 36 
Month 27 
Efficacy and 
Dosing Visit 
Month 27 and 36 
Efficacy Visits 
4 (+1) Weeks 
from Last Dose 
Month 9 
Month 18 
See 
Notes 
below 
Table 3  
Study Week 
81 
84, 96, 108, 120, 
132, and 144, and 
156 
120, 156 
160120, 156 
- 
36-39 
79-80 
- 
±Visit Window 
±3D 
±7D 
±2 weeks±7D 
+14D (≥1D after W120 
and W156 doses, 
respectively) 
±2 weeks 
- 
- 
- 
- 
ALN-TTRSC02 
Study Drug 
Administration 
Section 
5.2.2.1 
 
X - Every 12 weeks starting at Week 
84 to EOT Week 156 
 
 
 
 
 
Patisiran: 
Premedication 
Administration 
Section 
5.2.2.2 
X 
 
 
 
 
 
 
 
Patisiran Study 
Drug 
Administration 
Section 
5.2.2.2 
X 
 
 
 
 
 
 
 
Vital status check  
See note 
below 
Table 3 
Section 
6.2.8 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
Alnylam Pharmaceuticals 
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Purpose:  Added footnotes to the schedules of assessments in Table 2 and Table 3 to clarify that LFT results must be available within 
28 days before the clinic visit at which ALN-TTRSC02 dosing is scheduled. This is consistent with the guidance already indicated in 
Table 1, Section 5.2.3, and Section 6.5.6. 
The primary changes occur in Table 2 (Treatment Period from Month 9 through Month 18) and Table 3 (Treatment Extension Period, 
Other Visits, and Follow-up Period) 
 
 
The following footnote was added to Table 2: 
For the ALN-TTRSC02 cohort, LFTs must be obtained with results available within 28 days before the clinic visit on which 
ALN-TTRSC02 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. For the patisiran-cohort, LFTs should be performed according to patisiran visit 
windows and do not need to be available prior to dosing. 
The following footnote was added to Table 3:  
LFTs must be obtained with results available within 28 days before the clinic visit on which ALN-TTRSC02 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.  
 
Purpose:  Clarified that predose and postdose patisiran pharmacokinetic blood draws will be timed based on the start and end of 
patisiran infusion in Table 5. 
The primary change occurs in Table 5 (Pharmacokinetic Time Points: Patisiran) 
Table 5 now reads: 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood (Plasma) 
Day 1 and Day 253±3 days  
Predose (within 60 minutes before dosingthe start of 
infusion) 
X 
00:30 (±5 min) from the end of infusion 
X 
06:00 (±1 hr) from the end of infusion 
X 

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Study Day 
Protocol Time 
(hh:mm) 
PK Blood (Plasma) 
24:00 (±2 hr) from the end of infusion 
X 
Day 22, Day 127, Day 274, Day 379, and Day 547 
(±3 days) 
Predose (within 60 minutes before dosingthe start of 
infusion) 
X 
03:00 (±1 hr) from the end of infusion 
X 
 
Purpose:  “Patisrian -LNP” drug product was changed to “patisiran” throughout the protocol. 
These changes are not listed individually. 
 
Purpose:  “Vutrisiran” drug product has been added as the associated International Nonproprietary Name of ALN-TTRSC02. 
These changes are not listed individually. 
 
Purpose:  Added additional secondary endpoints to evaluate the efficacy of ALN-TTRSC02 on improvement in neurologic impairment 
and quality of life.  
The primary change occurs in Section 2, Objectives and Endpoint 
This section now reads: 
Objectives 
Endpoints 
Secondary 
 
To determine the efficacy of ALN-
TTRSC02 on gait speed, nutritional status, 
and disability 
 
To characterize the effect of ALN-
TTRSC02 on serum TTR levels 
 
To evaluate patient mortality and 
hospitalization 
 
To determine the efficacy of ALN-
TTRSC02 on improvement in 
neurologic impairment and on quality 
of life 
 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study: 
 
Timed 10-meter walk test (10-
MWT); 
 
Modified body mass index (mBMI) 
 
Rasch-built Overall Disability Scale 
(R-ODS) 
 Percent reduction in serum TTR levels in 
the ALN-TTRSC02 arm compared to the 
within-study patisiran arm  

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Objectives 
Endpoints 
 
Composite events of all-cause deaths 
and/or all-cause hospitalizations in the 
overall population (over 18 months) 
compared to the placebo arm of the 
APOLLO study 
 Composite events of all-cause deaths 
and/or all-cause hospitalizations in 
patients with cardiac involvement (over 
18 months) compared to patients with 
cardiac involvement in the placebo arm of 
the APOLLO study 
 
Change at Month 18 compared to 
baseline in mNIS+7 in ALN-TTRSC02-
treated patients 
 
Change at Month 18 compared to 
baseline in Norfolk QoL-DN total score 
in ALN-TTRSC02-treated patients 
 
Sections also containing this change:  
 Protocol Synopsis  
 Section 7.2.5.2, Secondary Endpoints 
 
Purpose:  Language was added to more explicitly indicate how the Sponsor will maintain comparable populations between this study 
and the ALN-TTR02-004 (APOLLO) study  to enable cross-study comparisons; consistent with our original intent based on the study 
design. 
The primary change occurs in Section 3.1, Summary of Study Design 
The following paragraph has been added: 
In order to allow for a robust cross study comparison, attempts will be made to minimize differences between the HELIOS-A 
and APOLLO study populations. As such, baseline disease characteristics will be monitored and may result in enrollment 

Clinical Study Protocol ALN-TTRSC02-002 
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Amendment 1, Summary of Changes, 10 October 2019 
 
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limitations based on certain characteristics (eg, genotype) to ensure comparability. Decisions around enrollment adjustments 
will be made by staff without access to primary efficacy results. 
 
Purpose:  As part of the introduction of ALN-TTRSC02 in pre-filled syringes, details of the addition of the pre-filled syringe and 
needle safety device have been added.  
The primary change occurs in Section 5.2.1, Description 
The relevant paragraphs in Section 5.2.1 now read: 
5.2.1. Description 
ALN-TTRSC02 will be supplied as a vial of sterile solution containing 50 mg/mL of siRNA ALN-65492 free acid (equivalent to 53 
mg/mL sodium salt) in phosphate buffered saline for SC injection.  The drug product does not contain preservatives and is intended 
for single use.  See the Pharmacy Manual for further details of solution concentration and fill volume.  
ALN-TTRSC02 will also be supplied as a pre-filled syringe and a needle safety device.  The pre-filled syringe will be filled with 
ALN-TTRSC02 (25 mg dose) with a volume of 0.5 mL. The pre-filled syringe is a single-use injection device, and after 
injection the needle safety device will engage to cover the exposed needle.  
ALN-TTRSC02 will be administered using injections prepared from vials up to and including at least the Week 36 dose (the 
last dose prior to the Month 9 efficacy assessments). After the Week 36 dose, patients will be transitioned from vial-based 
injections to the pre-filled syringes as this presentation becomes available. 
Sections also containing this change:  
 Section 5.2, Study Drug 
 Section 5.2.2.1, ALN-TTRSC02 
 
Purpose:  As part of the introduction of ALN-TTRSC02 in pre-filled syringes, a new section on product complaints has been added to 
facilitate communication about issues related to study drug products provided in the study 
The primary change occurs in newly added Section 5.3. Product Complaints 
5.3. 
Product Complaints 
5.3.1. Definition 

Clinical Study Protocol ALN-TTRSC02-002 
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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 vial/syringe, empty vial/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 using the appropriate eCRF. PCs that may be 
associated with an AE must be evaluated and reported as indicated in Section 6.5.7. Detailed instructions on reporting PCs 
will also be detailed in the Pharmacy Manual.   
Purpose:  Under female contraception requirements, clarified that use of oral, implantable, injectable, or transdermal hormonal 
methods of contraception must be associated with the inhibition of ovulation. 
In Section 5.6.1, the fifth bullet under birth control methods which are considered highly effective now reads: 
 Established use of oral (except for low dose gestagens), implantable, injectable, or transdermal hormonal methods of 
contraception associated with the inhibition of ovulation. Females of child-bearing potential who use hormonal 
contraceptives as a method of contraception must also use a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault cap] in conjunction with spermicide [eg, foam, gel, film, cream, or suppository]).   
 
Purpose:  Clarified that follicle-stimulating hormone testing will be performed in all post-menopausal women. 
The primary change occurs in Section 6.5.6.2, Pregnancy Testing 
The last paragraph in this section not reads: 
Follicle-stimulating hormone testing may will be performed in all post-menopausal women to confirm suspected post-menopausal 
status. 
 
Purpose:  Rescreening criteria for LFT and NIS eligibility requirements have been broadened to allow more flexibility. 

Clinical Study Protocol ALN-TTRSC02-002 
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The primary change occurs in Section 6.1.2, Rescreening 
This section now reads: 
For patients who do not meet all study eligibility requirements, due to a transient clinical condition during screening or who 
fail to complete screening activities due to unforeseen and unavoidable circumstances, rescreening once may be permitted 
after consultation with the Medical Monitor after a minimum of 5 days have elapsed from a patient’s last screening 
assessment. In this case, a patient will be re-consented and all screening procedures must be repeated.  For patients who do not 
meet LFT or NIS eligibility 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 screening assessment. 
 
Purpose:  Clarified that, when recording medical history, information on prior tetramer stabilizer use anytime should be recorded and 
not only the use within the 1 year prior to the first dose of study drug. 
The primary change occurs in Section 6.1.3, Demographic and Medical History/Disease History 
The first paragraph in this section now reads: 
Medical history will be collected during screening Visit 1 (including any cardiac disorders, any eye disorders or previous 
ophthalmology test results, and prior medications).  Documented technetium scintigraphy and/or tissue biopsy testing for amyloidosis 
performed prior to study enrollment should be collected and recorded as part of medical history. Information on prior use of 
tetramer stabilizers at any time prior to first dose should be collected and recorded. Information on other prior medications, 
hospitalization, and procedures through 1 year prior to first dose should be collected and recorded. 
 
Purpose:  Additional requirements for study termination were implemented in line with ICH E6 (R2) Guideline. 
The primary change occurs in Section 8.1.6, Termination of the Clinical Study or Site Closure 
This section now reads: 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site for clinical or administrative reasons at any time.  If the 
site does not recruit at a reasonable rate, or if there is insufficient adherence to the protocol requirements, the study may be closed at that site.  
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 

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 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, IEC/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. 
 
Purpose:   Publication policy details were updated to match details that are provided in the Clinical Trial Agreement. 
The primary change occurs in Section 8.3, Publication Policy 
This section now reads: 
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 separate publication by Institution or Investigator may not be submitted for publication until after this 
primary manuscript is published, or following the period of 18 months after completion of the study at all centers.  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 among the institution, 
Investigator, and Alnylam will detail the procedures for Alnylam’s review of 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). 

Clinical Study Protocol ALN-TTRSC02-002 
ALN-TTRSC02 (vutrisiran) 
Amendment 2, 06 May 2020 
 
Alnylam Pharmaceuticals 
Confidential 
1 
ALN-TTRSC02-002 PROTOCOL AMENDMENT 2  
SUMMARY OF CHANGES DATED 06 MAY 2020 
HELIOS-A:  A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy 
and Safety of ALN-TTRSC02 in Patients with Hereditary Transthyretin Amyloidosis 
(hATTR Amyloidosis) 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
The purpose of this protocol amendment is to incorporate Urgent Safety Measures (USMs) that 
were communicated to investigators in a Dear Investigator Letter dated 31 March 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 dated 31 March 2020 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]  The USM modifications 
and new procedures are summarized in Section 1.1 and a detailed summary of protocol changes 
is provided in Section 2.1. 
This protocol amendment also incorporates removal of the secondary endpoint all-cause 
hospitalization and death events over 18 months in patients with cardiac involvement. This 
change is summarized in Section 1.2 and a detailed summary of protocol changes is provided in 
Section 2.2. These changes will not be implemented until appropriate Health Authority and 
Ethics Committee (EC) and/or Institutional Review Board (IRB) approval. 
1.1. 
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, and a detailed summary of the USMs is 
provided in Section 2.1. 
 Expanded ALN-TTRSC02 Dosing Outside the Study Center 
Administration of ALN-TTRSC02 will be permitted outside the study center by a 
home healthcare professional (eg, the patient’s home) at all time points provided the 
patient has tolerated at least 1 dose of ALN-TTRSC02 administered in the study 
center (previously allowed after Month 18).  
 Expanded use of Pre-filled Syringes for ALN-TTRSC02 Administration 
ALN-TTRSC02 may be administered via pre-filled syringes at any time point during 
the study as this presentation becomes available (previously allowed after Week 36).   
 ALN-TTRSC02 Dosing Outside the Study Center by Patient or Caregiver 
Following appropriate training on ALN-TTRSC02, dosing will be permitted by the 
patient or caregiver at all timepoints under the oversight of the Investigator and 
following consultation with the Medical Monitor. This measure is intended to remain 

Clinical Study Protocol ALN-TTRSC02-002 
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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 Window After Which a ALN-TTRSC02 Dose Will be Considered 
Delayed 
If a patient does not receive a dose of ALN-TTRSC02 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. 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 time point. 
Given the long activity of the drug 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 original dosing schedule is 
expected to be tolerated based on the safety from Phase 1 study which evaluated 
doses as high as 300 mg (12× higher than the therapeutic dose of 25 mg administered 
quarterly).  Accordingly, 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. 
 Expanded Patisiran Dosing Outside the Study Center 
Administration of patisiran will be permitted outside the study center by a home 
healthcare professional (eg, the patient’s home) at all timepoints (previously allowed 
after Month 9), provided the patient has tolerated at least 2 doses of patisiran 
administered in the study center.  
These changes were implemented to reduce the frequency of patient visits to the 
study center, and therefore reduce potential exposure to COVID-19, while 
maintaining continuity of study drug dosing. Based on the overall safety profile of 
patisiran, the frequency of infusion-related reactions (IRRs) decreases over time and 
IRRs do not increase in severity. When IRRs have occurred, most have been mild or 
moderate in severity, have not required any treatment and have not resulted in 
interruption during the infusion or a change in administration. When infusions have 
been interrupted due to an IRR, these have primarily been reported in patients during 
the first 2 infusions.  Thus, for patients who tolerate infusions, these data support 
home administration following 2 doses administered at the study center.  Home 
dosing of study drug will be performed by a healthcare professional, with oversight of 
the Investigator, allowing for ongoing appropriate monitoring of the patient. 

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 Premedication Equivalents may be Administered Orally 
Clarified that oral premedication equivalents are permitted, but must be administered 
in the presence of a healthcare professional. There have been no increases in IRR 
frequency with oral steroids compared to IV steroids for pre-medication.  
 Corticosteroid Tapering Outside the Study Center 
Corticosteroid tapering may be performed in the clinic or, at the discretion of the 
Investigator, may be performed outside of the clinic (eg, in the patient’s home) after 
consultation with the Medical Monitor.  
This change was implemented to allow for reduction of steroids, where it is deemed 
in the best interest of the patient by the investigator, in the context of expanded home 
dosing necessitated by the COVID-19 pandemic as outlined above.  Patisiran dosing, 
and thus steroid tapering, will be performed by a healthcare professional, with 
oversight of the investigator, allowing for appropriate monitoring of the patient.  
Support for this approach comes from a review of data from the patisiran treated 
patients who have tapered steroids in the global-label extension studies (ALN-
TTR02-003, ALN-TTR02-004 and ALN-TTR02-006) where IRRs were infrequent, 
mild, and tapering of steroids was not associated with an increase in the rate of IRRs. 
 Expanded the Patisiran Administration Window  
Expanded the patisiran administration window. If a patient does not receive a dose of 
patisiran within the dosing window (±3 days) due to COVID-19, the dose may be 
administered with up to 7 days delay after the scheduled visit, after consultation with 
the Medical Monitor (to be considered a delayed dose). Previously the dose was to be 
considered missed if received outside the dosing window (±3 days).  
Based on Phase 1 data with patisiran (ALN-TTR02-001), an occasional 7-day delay 
in dosing for patisiran is expected to have a minimal impact on TTR suppression (ie, 
a decrease of ~10% in TTR suppression relative to patisiran original scheduled 
dosing). Resumption of dosing as per the original dosing schedule is expected to be 
tolerated based on the safety results from earlier patisiran studies.  Accordingly, 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.    
 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. 

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All laboratory samples should be sent to the central laboratory however, an exception 
has been 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. 
Added 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 
center, at a minimum, patients must visit the site for scheduled dosing and 
assessments at the Week 12 and Week 60 visits within the study visit windows 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). 
 Liver Function Tests (LFTs)  
The timing of LFT assessments was updated to coincide with ALN-TTRSC02 dosing 
visits (which are every 12 weeks).  Thus, starting at Week 12, patients on ALN-
TTRSC02 will have LFT results done every 12 weeks, instead of the current schedule 
of assessments, where LFT were assessed every 6 weeks until Month 9 and then 
every 12 weeks after Month 9.  Additionally, the requirement for additional LFT 
results within 28 days prior to each ALN-TTRSC02 dose has been removed.  Dosing 
decisions may will be based on the LFTs collected at the previous dosing visit (up to 
14 weeks prior to dosing). 
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 from this study (HELIOS-A), which 
have shown that ALN-TTRSCO2 continues to have an acceptable safety profile.   
In HELIOS-A, 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 >3xULN 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 5.2.3 Table 6 [Monitoring and Dosing Rules for Asymptomatic 
Patients with Confirmed Isolated Elevations of ALT and/or AST >3× ULN, with No 
Alternative Cause Identified]).  

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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. 
 Efficacy Assessments at Month 9 
Clarified that all efficacy visits must be conducted at the clinic (Month 9, Month 18, 
Month 27, Month 36, and modified efficacy visits).  Specified that for situations in 
which a Month 9 efficacy visit is unable to be completed 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, the Medical 
Monitor should be consulted as soon as possible to determine the appropriate timing 
of the Month 9 efficacy assessment. After consultation with the Medical Monitor, 
Month 9 efficacy assessments may be completed within 6 months after the intended 
time point (ie, up to Study Month 15). 
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. It is anticipated that the estimated treatment effects at 
Months 9 and 18 on vutrisiran treatment will be similar to the treatment effects 
observed on patisiran treatment in Study ALN-TTR02-004 (APOLLO). For these 
endpoints in the APOLLO study, treatment differences between patisiran and 
placebo-treated patients increased from Month 9 to Month 18. These increasing 
treatment differences were attributable largely to continued progression between 
Months 9 and 18 among placebo-treated patients. Based on these data, the delayed 
Month 9 efficacy assessments up to Month 15 would be similar to unobserved Month 
9 efficacy assessments that would have been missed without this delayed assessment 
allowance, if not slightly worse considering potentially missed doses. Therefore, it is 
expected that this missing data minimization strategy will yield similar if not 
conservative estimated treatment effects on vutrisiran compared to what may have 
been observed had the COVID-19 pandemic not occurred during the course of this 
study. 
 Transthyretin (TTR)/Vitamin A Assessments 
After Week 12, TTR/Vitamin A sample collections between ALN-TTRSC02 dosing 
visits have been removed for all patients.  
This change has been made as part of the overall strategy of reducing visits and 
assessments during the COVID-19 pandemic.  Removal of these assessments is not 
expected to have a meaningful impact on the TTR efficacy endpoint at Month 18 as 
our modeling data support that there are minimal fluctuations in TTR levels over the 
dosing interval following Week 12; ie, following 2nd dose of ALN-TTRSC02. 

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 Timing of other assessments 
Reduced the frequency of select assessments or combined assessments from different 
visits to align with dosing visits 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. 
 Secondary Endpoint of TTR percent reduction 
Changed the secondary endpoint related to comparison of TTR percent reduction in 
the ALN-TTRSC02 arm compared to patisiran through 9 months to 18 months.   
This change is being implemented to address concerns with regard to missed doses 
related to COVID-19 during critical time periods preceding the Month 9 assessment 
with potential impact to the integrity of this endpoint. TTR percent reduction through 
Month 9 was planned to be evaluated for noninferiority compared to the within-study 
randomized patisiran arm. This endpoint was specified in the SAP to be evaluated on 
the Per-protocol (PP) Population. With dosing flexibility adopted due to the COVID-
19 pandemic, it is expected that the number of patients qualifying for the PP 
Population will be substantially reduced, thus greatly reducing power for the 
originally planned Month 9 analysis of TTR percent reduction. Changing TTR 
percent reduction from Month 9 to Month 18 is anticipated to allow for a more viable 
noninferiority comparison with sufficient power.  
 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. 
1.2. 
Changes Not Related to Urgent Safety Measures 
Several additional changes are being implemented, which are outlined below and a detailed 
summary is provided in Section 2.2. 
 Secondary Endpoint of all-cause hospitalization and death events over 
18 months in Patients with Cardiac Involvement 
The secondary endpoint all-cause hospitalization and death events over 18 months in 
patients with cardiac involvement was removed.  This change was implemented based 
on review of baseline data which suggests that a minority of patients are likely to 
meet pre-specified criteria for the cardiac subpopulation thus limiting the value of this 
analysis.   
Initial projections of sample size was based upon the ALN-TTR02-004 Study 
(APOLLO), which enrolled 90/148 (60.8%) patisiran-treated patients into the Cardiac 
Subpopulation. In the current study, only 36/122 (29%) vutrisiran-treated patients 

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qualified for the Cardiac Subpopulation, which is anticipated to result in an under-
powered endpoint. 
The following changes are not detailed: administrative changes, corrections to typographical 
errors, punctuation, grammar, abbreviations, and formatting. 

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2. 
PROTOCOL AMENDMENT 2 DETAILED SUMMARY OF CHANGES 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 2 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
2.1. 
Urgent Safety Measure COVID-19-related Changes to be Adopted Immediately 
Purpose:  The following changes were made related to administration of ALN-TTRSC02: 
 Expanded ALN-TTRSC02 Dosing Outside the Study Center 
 Expanded use of Pre-filled Syringes for ALN-TTRSC02 Administration 
 ALN-TTRSC02 Dosing Outside the Study Center by Patient or Caregiver 
 Expanded 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 5.2.2.1 (ALN-TTRSC02) and Section 5.2.1 (Description) 
5.2.2.1. 
ALN-TTRSC02 
Revised text: 
ALN-TTRSC02 25 mg SC injection will be administered q3M (12 weeks ±3 days during the Treatment Period and ±7 days during the 
Treatment Extension Period).  Study drug SC injections in the clinic will be administered under the supervision of the Investigator or 
a trained healthcare professional.  ALN-TTRSC02 may be administered at a location other than the study center (eg, the 
patient’s home) as specified below. 
All ALN-TTRSC02 doses will be administered at the clinic during scheduled study assessment visits during the Treatment Period on 
Day 1 through Month 18.  During the Treatment Extension Period, starting at Week 84/Month 19, patients who are tolerating their 
ALN-TTRSC02 injections as determined by the Investigator and where applicable country and local regulations allow, may have 
ALN-TTRSC02 administered outside the clinic (eg, home) by a healthcare professional trained on study drug administration.   
If a patient has tolerated at least 1 dose of ALN-TTRSC02 in the clinic, subsequent dosing may be administered outside the 
study site (eg, the patient’s home) at all time points 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 center, and a visit by a home healthcare professional is not possible due to circumstances related to the 
COVID-19 pandemic, ALN-TTRSC02 may be administered by the patient or the caregiver under the oversight of the 

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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 ALN-TTRSC02 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. 
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 ALN-TTRSC02 by a patient or caregiver will be provided 
in the ALN-TTRSC02 Patient/Caregiver Storage and Administration Instructions. 
 
Method of Administration of ALN-TTRSC02 
ALN-TTRSC02 is for SC use and should be administered by a healthcare professional. 
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. Detailed 
Instructions for Use for the pre-filled syringe will also be provided. 
 
Missed Doses of ALN-TTRSC02 
If a patient does not receive a dose of ALN-TTRSC02 within the specified dosing window, the Investigator should contact the 
Medical Monitor.  After such consultation, the dose may be administered with up to a 6an 8-week delay (to be considered a delayed 
dose).  Thereafter, the dose will be considered missed and not administered.  If a dose 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. 
During the Treatment Period, every effort should be made to avoid missed doses of ALN-TTRSC02.  During the Treatment Period, 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 in the study (see also Section 4.3).   
5.2.1. Description (relevant text only) 
 

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Revised text: 
ALN-TTRSC02 will initially be administered using injections prepared from vials up to and including at least the Week 36 dose (the 
last dose prior to the Month 9 efficacy assessments). After the Week 36 dose, patients will. Patients may be transitioned from vial-
based injections to the pre-filled syringessyringe-based injections at any study time point as this presentation becomes available. 
Sections also reflecting this change:   
 Table 1, Table 2 Schedules of Assessments 
 Section 3.1 Summary of Study Design 
 Section 5.2.4, Preparation, Handling, and Storage 
 Section 5.3.2, Reporting 
 
Purpose:  The following changes were made related to administration of patisiran: 
 Expanded Patisiran Dosing Outside the Study Center 
 Premedication Equivalents may be Administered Orally 
 Corticosteroid Tapering Outside the Study Center 
 Expanded the Patisiran Administration Window  
 Modified other dose, administration, and product complaint sections to match new administration strategy 
The primary changes occur in Section 5.2.2.2 (Patisiran) 
5.2.2.2. 
Patisiran 
Revised text: 
All patisiran doses will be administered at the clinic during the scheduled study assessment visits through Month 9.  After Month 9, 
patisiran dosing may be performed at home by a trained healthcare professional where applicable country and local regulations and 
infrastructure allow, with the exception of the patisiran dosing visits at Weeks 48, 60, and 72, which must be performed in the clinic 
during scheduled study assessment visits through Month 18. If a patient has tolerated at least 2 doses of patisiran administered in 
the clinic, dosing may be administered outside the study site (eg, the patient’s home) at all timepoints where allowed by 

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applicable country and local regulations. In these cases, dosing should be administered by a trained healthcare professional, 
with oversight by the Investigator. 
Required premedication for patients in the patisiran arm 
All patients should receive premedication prior to patisiran administration to reduce the risk of infusion-related reactions (IRRs). Each 
of the following medicinal products should be given on the day of patisiran infusion at least 60 minutes prior to the start of infusion: 
 Intravenous corticosteroid (dexamethasone 10 mg, or equivalent) 
 Oral paracetamol (500 mg) 
 Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent)  
 Intravenous H2 blocker (ranitidine 50 mg, or equivalent) 
For premedications not available or not tolerated intravenously, equivalents may be administered orally.   Oral premedication 
equivalents are permitted, but must be administered in the presence of a healthcare professional.   
Modifications to lower the corticosteroid dose may be made to the premedication regimen for either of the following 2 reasons: 
1. If a patient is having difficulty tolerating the corticosteroid premedication regimen (eg, patient develops uncontrolled 
hyperglycemia, altered mental status, or other complication), then lowering of the corticosteroid premedication may be allowed 
for that patient after consultation with the medical monitor.   
2. If a patient has tolerated 3 or more infusions of patisiran with their current corticosteroid premedication regimen (ie, patient 
has not had IRRs during the past 3 or more infusions), then lowering of the corticosteroid premedication is recommended.   
Corticosteroid tapering should be performed in the clinic. Steps to lower corticosteroid dosing are provided in the Study Manual 
Pharmacy Manual.  Corticosteroid tapering may be performed in the clinic or, at the discretion of the investigator, may be 
performed outside of the clinic (eg, in the patients home) after consultation with the Medical Monitor. 
Additional or higher doses of one or more of the premedications may be administered to reduce the risk of IRRs, if needed.  
Guidelines for management of IRRs can be found in the Pharmacy Manual.   
Method of Administration of patisiran 
Patisiran is for IV use and should be administered by a healthcare professional.  
Weight from previous visit may be used for calculating dose.  Weight must be collected predose. The patient’s infusion site should be 
assessed for signs of any localized reaction during the infusion and for 30 minutes after the end of the infusion.  The patient will 

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remain at the study site should be observed for 1 hour following completion of dosing for observation and completion of 
assessments. 
Detailed instructions for study drug preparation and administration can be found in the Pharmacy Manual. 
Missed Doses of patisiran   
If a patient does not receive a dose of patisiran within the dosing window (±3 days) due to COVID-19 the dose will be considered 
missed and not administered the dose may be administered with up to 7 days delay after the scheduled visit, after consultation 
with the Medical Monitor (to be considered a delayed dose).  If a dose is administered with a delay, the next dose will resume 
following the original schedule per the Schedule of Assessments. In all cases, the dose should be administered as close as 
possible to the scheduled timepoint. 
A dose will be considered completed if 80% or more of the total volume of the IV solution has been administered to the patient.  
Patients will be permitted to miss an occasional dose of study drug.  However, if a patient misses 2 consecutive doses 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 in the study. 
Sections also reflecting this change:   
 Table 1, Table 2 Schedules of Assessments 
 Section 3.1 Summary of Study Design 
 Section 5.2.4, Preparation, Handling, and Storage 
 Section 5.3.2, Reporting 
 
Purpose:  The following changes have been made relating to expanding the ability to perform assessments outside of the study center: 
 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 include: 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. 
 Clarified that all laboratory samples should be sent to the central laboratory, however, an exception has been 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. 

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 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). 
 Clarified that in even if ECGs are conducted outside the clinic, the Investigator or qualified designee will review them. 
 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), Section 6.5.4 (Electrocardiogram), and Section 6.5.6.2 (Pregnancy 
Testing) 
6. STUDY ASSESSMENTS (applicable text only) 
Revised text: 
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, urgent care visits, 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. 
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 to 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.  All laboratory samples should be sent to the 
central laboratory; an exception is for situations related to the COVID-19 pandemic if central laboratory assessments are not 
possible, then 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. 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 due to the COVID-19 pandemic limiting the patient’s ability or 
willingness to access the study center, at a minimum, patients must visit the site for scheduled dosing and assessments at the 
Week 12 and Week 60 visits within the study visit windows 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 

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relevant safety information (including, but not limited to, AEs, concomitant medications, hospitalizations/procedures, and vital 
status). 
Further details with regard to visits performed outside of the clinic are provided in the Study Reference Manual. 
6.5.4. Electrocardiogram (applicable text only) 
Revised text: 
The Investigator or qualified designee will review all ECGs, including those collected by a healthcare professional outside of the 
study center, to assess whether the results have changed since baseline and to determine the clinical significance of the results.  
Additional ECGs may be collected at the discretion of the Investigator, or as per DMC advice.   
6.5.6.2. 
Pregnancy Testing (applicable text only) 
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:   
 Table 1, Table 2, Table 3 Schedules 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 6.5.6. Clinical Laboratory Assessments 
 
Purpose:  The following changes were made related to performance of liver function tests: 
 The timing of LFT assessments was updated to coincide with ALN-TTRSC02 dosing visits (which are every 12 weeks).   

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 The requirement for additional LFT results within 28 days prior to each ALN-TTRSC02 dose has been removed.  Dosing 
decisions may will be based on the LFTs collected at the previous dosing visit 
The primary changes occur in Table 1 and Section 5.2.3 (LFT Criteria for Withholding, Monitoring and Stopping ALN-TTRSC02 
Dosing) 
Table 1 (Schedule of Assessments – Screening through Treatment Period Month 9)   
The LFT assessments previously indicated on Week 15, Week 21, Week 27, and Week 33 have been removed for all patients and LFT 
assessments have been added for all patients at Week 12, Week 24, and Week 36. 
  
5.2.3. LFT Criteria for Withholding, Monitoring and Stopping ALN-TTRSC02 Dosing 
Revised text (relevant text only) 
1. For the ALN-TTRSC02 cohort, dosing decisions may be made based on LFT results (Table 7) are to be obtained within 28 
days prior to ALN-TTRSC02 dosing and results are to be reviewed prior to each dose of ALN-TTRSC02 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 6.  
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 the COVID-19 pandemic, a local laboratory may be used for monitoring in 
consultation with the Medical Monitor; all local laboratory results should be sent to the clinical site for entry into 
the clinical database. 
b. Perform assessments per Table 6 and Table 8. 
c. If an alternative cause is found, provide appropriate care. 

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Sections also reflecting this change:   
 Table 1, Table 2, Table 3 Schedules of Assessments 
 Section 6.5.6, Clinical Laboratory Assessments 
 
Purpose:  Made the following visit to performance of efficacy assessments at Month 9: 
 Confirmed that all efficacy visits must be conducted at the clinic (Month 9, Month 18, Month 27, Month 36, and modified 
efficacy visits).   
 Specified that on situations in which a Month 9 efficacy visit is unable to be completed 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, the medical monitor should be consulted as soon as possible to determine the appropriate timing of the 
Month 9 efficacy assessment. After consultation with the medical monitor, Month 9 efficacy assessments may be completed 
within 6 months after the intended time point (ie, up to Study Month 15). 
The primary change occurs in Section 6 (Study Assessments), 
Added text: 
All efficacy visits must be conducted at the clinic (Month 9, Month 18, Month 27, Month 36, and modified efficacy visits).  In 
situations in which a Month 9 efficacy visit is unable to be completed 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, the 
medical monitor should be consulted as soon as possible to determine the appropriate timing of the Month 9 efficacy 
assessment.  After consultation with the medical monitor, Month 9 efficacy assessments may be completed within 6 months 
after the intended time point (ie, up to Study Month 15). 
Sections also reflecting this change:   
 Synopsis 
 Table 1 Schedule of Assessments 
 Section 3.1 Summary of Study Design 
 
Purpose:  After Week 12, TTR/Vitamin A sample collections between ALN-TTRSC02 dosing visits have been removed for all patients. 

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The primary changes occur in Table 1 and Table 2 
The following TTR/Vitamin A assessments have been eliminated for all patients: 
 Table 1: No longer required at Week 18 and Week 30  
 Table 2: No longer required at Week 42, Week 54, and Week 66 
 
Purpose:  Reduced the frequency of select assessments or combined assessments from different visits to align with doing visits in order 
to limit the number of times a patient needs to visit the site/interact with home healthcare professionals. The following changes have 
been made in this regard: 
 Reduced the number of visits at which symptom-directed physical examinations are conducted to reduce patient burden 
and issues related to inability of home healthcare professionals to conduct these visits outside the clinic. 
 Eliminated the previous requirement that patients in the ALN-TTRSC02 cohort have assessments of vital signs and weight 
at visits that were originally included to correspond to timepoints necessary to support dosing in the patisiran cohort. 
 Moved selected time points for collection of exploratory analysis samples so they coincide with assessments done at ALN-
TTRSC02 dosing visits. 
 Added guidance that PK sample collection timepoints at 6 and 24 hours after dosing are optional when samples are being 
collected outside the clinic (eg, the patient’s home). 
 
The primary changes occur in the following sections: 
Table 1, Table 2, Table 3, schedules of assessments: 
 Split physical examination assessments from assessments of vital signs and weight as they will now have a separate 
schedule. The following changes in the schedules of symptom-directed physical examinations have been made for all 
patients: 
 Table 1: No longer required at Week 3, Week 6, Week 9, Week 15, Week 18, Week 21, Week 27, Week 30, Week 33  
 Table 2: No longer required at Week 39, Week 42, Week 45, Week 51, Week 54, Week 57, Week 63, Week 66, 
Week 69, Week 75, Week 78 

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 Vital signs and weight assessments are no longer being required for patients in the ALN-TTRSC02 cohort outside of their 
dosing visits: 
 Table 1: No longer required at Week 3, Week 6, Week 9, Week 15, Week 18, Week 21, Week 27, Week 30, Week 33; 
Still required at Visit 3, Week 12, and Week 24 
 Table 2: No longer required at Week 39, Week 42, Week 45, Week 51, Week 54, Week 57, Week 63, Week 66, Week 
69, Week 75, Week 78. 
 Selected samples for exploratory analysis for all patients shifted to coincide with assessments done at ALN-TTRSC02 
dosing visits: 
 Table 1: Shifted sample collection from Week 18 to Week 24. 
 Table 2: Shifted sample collection from Week 57 to Week 60. 
 
Pharmacokinetic Time Points (Table 4 [ALN-TTRSC02] and Table 5 [Patisiran]): 
 Added the following footnote: PK sample collection timepoints at 6 and 24 hours after dosing are optional when samples 
are being collected outside the clinic (eg, the patient’s home).   
 
Purpose:  Changed the secondary endpoint related to comparison of TTR percent reduction in the ALN-TTRSC02 arm compared to 
patisiran through 9 months to 18 months.   
The primary change occurs in Section 7.2.5.2 (Secondary Endpoints) 
Revised text (relevant text only): 
Revised bullet in hierarchical order: TTR percent reduction through 918 months  
The TTR percent reduction through Month 918 will be derived as the average trough TTR percent reduction from Month 6 to 
918which is the steady state period for both ALN-TTRSC02 and patisiran. A Hodges-Lehmann method stratified by previous TTR 
stabilizer use (yes vs no) will be used to estimate the 95% CI for the median difference between the ALN-TTRSC02 and patisiran 
groups in this study. Non-inferiority will be declared if the lower limit of the 95% CI for the treatment difference is greater than –10%. 
A sensitivity analysis will be conducted to compare the TTR percent reduction between the ALN-TTRSC02 group from this study and 
the pooled patisiran groups from this Phase 3 study and the APOLLO study.   

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Sections also reflecting this change:   
 Synopsis 
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 6.5.8, 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 
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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2.2. 
Changes Not Related to Urgent Safety Measures to be Implemented After Regulatory Authority 
and Ethics Committee Approval 
 
Purpose:  The secondary endpoint all-cause hospitalization and death events over 18 months in patients with cardiac involvement was 
removed.   
The primary change occurs in Section 2 (Objectives and Endpoints)  
Objectives 
Endpoints 
Secondary 
 
To determine the efficacy of ALN-
TTRSC02 on gait speed, nutritional status, 
and disability 
 
To characterize the effect of ALN-
TTRSC02 on serum TTR levels 
 
To evaluate patient mortality and 
hospitalization 
 
To determine the efficacy of ALN-
TTRSC02 on improvement in neurologic 
impairment and on quality of life 
 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study: 
 
Timed 10-meter walk test (10-
MWT); 
 
Modified body mass index (mBMI) 
 
Rasch-built Overall Disability Scale 
(R-ODS) 
 
Percent reduction in serum TTR 
levels in the ALN-TTRSC02 arm 
compared to the within-study 
patisiran arm  
 
Composite events of all-cause deaths 
and/or all-cause hospitalizations in the 
overall population (over 18 months) 
compared to the placebo arm of the 
APOLLO study 
 Composite events of all-cause deaths 
and/or all-cause hospitalizations in 
patients with cardiac involvement (over 
18 months) compared to patients with 
cardiac involvement in the placebo arm of 
the APOLLO study 

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Objectives 
Endpoints 
 
Change at Month 18 compared to baseline 
in mNIS+7 in ALN-TTRSC02-treated 
patients 
 
Change at Month 18 compared to baseline 
in Norfolk QoL-DN total score in ALN-
TTRSC02-treated patients 
 
Sections also reflecting this change:   
 Synopsis 
 Section 7.2.5.2 (Secondary Endpoints) 
 

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3. 
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 
 

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ALN-TTRSC02-002 PROTOCOL AMENDMENT 3 
SUMMARY OF CHANGES DATED 17 JULY 2020 
HELIOS-A:  A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy 
and Safety of ALN-TTRSC02 in Patients with Hereditary Transthyretin Amyloidosis 
(hATTR Amyloidosis) 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
The COVID-19 pandemic has led to a shift in healthcare from the clinic to home settings world-
wide and has required adjustments to ensure patient safety and study integrity which were 
implemented in a previous protocol amendment (Amendment 2 dated 06 May 2020). To date, the 
risk mitigation steps introduced with this prior amendment have allowed dosing to continue as 
scheduled for the majority of ALN-TTRSC02 patients, while maintaining appropriate safety 
monitoring and minimizing missed efficacy assessments.  However, the ongoing COVID-19 
pandemic presents risks in some regions for disruption of treatment, potentially impacting key 
efficacy assessments, until a vaccine or effective treatment is widely available. This amendment 
includes revisions to the study endpoints for the primary purpose of mitigating any potential 
impact from the pandemic on key efficacy assessments.  This amendment also includes analysis 
of efficacy endpoints at Month 18 as secondary endpoints in the statistical hierarchy to allow 
more complete characterization of the treatment effect of ALN-TTRSC02. Collectively, these 
changes will ensure the adequate evaluation of the effects of ALN-TTRSCO2 on neurological 
impairment, quality of life, gait speed, nutritional status and disability, while minimizing 
potential confounding effects of the COVID-19 pandemic.   
As the primary analysis will be conducted at Month 9, it should be noted that as of the time of 
this amendment, the majority (approximately 67%) of patients have not yet completed the 
Month 9 efficacy visit. The Sponsor has remained blinded to efficacy data in accordance with the 
data integrity plan and thus has made the changes without any knowledge of these data. 
Therefore, the changes to the co-primary endpoint and select secondary endpoints are not 
considered to impact study integrity.  
The changes to the endpoints are outlined below and a detailed summary of changes is provided 
in Section 2. 
Changes to the Primary Analysis at Month 9 to Mitigate Risks related to the Pandemic 
Quality of life (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QoL-DN]), nutritional 
status (modified body mass index [mBMI]), and disability (Rasch-built Overall Disability Scale 
[R-ODS]) are efficacy measures that are important for establishing the benefit of ALN-
TTRSC02 in patients with hereditary ATTR amyloidosis with polyneuropathy. The pandemic 
has the potential to affect components of these assessments in multiple ways, including changes 
in anxiety and stress from the pandemic, the potential for loss of employment, and disruptions in 
physical activity and social interactions due to social distancing and the closure of public 
gathering places related to the pandemic. 

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While it is difficult to predict the precise impact of the pandemic, changes to endpoints at 
Month 9 have been introduced to mitigate the potential risk of these external factors confounding 
interpretation of the true treatment effect of ALN-TTRSC02: 
 The co-primary endpoint of change from baseline in Norfolk QoL-DN total score at 
Month 9 has been changed to the first key secondary endpoint in the hierarchical 
testing order. Modified NIS+7 will now be the sole primary endpoint at Month 9. 
While Norfolk QoL-DN involves neuropathy-specific measures, it also includes 
questions about general physical and emotional health, both of which may be 
impacted by the COVID-19 pandemic in a manner that is difficult to precisely 
estimate. The change to key secondary endpoint has been made to mitigate the risk of 
any potential confounding impact of the pandemic. Establishing the efficacy of ALN-
TTRSC02 on the patient’s perception of neuropathy impairment with the Norfolk-
QoL remains a critical objective of the study; having this measure as a key secondary 
endpoint will support the clinical relevance of observed changes in the primary 
endpoint of modified NIS+7.  Modified NIS+7 is a well-established and reproducible 
measure of neuropathy progression that may be less susceptible to external factors 
associated with the pandemic and thus will remain as the primary endpoint at 
Month 9. 
 The secondary endpoints of mBMI and R-ODS at Month 9 have been changed from 
secondary to exploratory endpoints. 
R-ODS captures activity and social participation limitations and provides an overall 
picture of disability. Modified BMI provides an assessment of nutritional status. Both 
of these assessments may also be impacted by pandemic related stressors, missed 
doses and/or impact on lifestyle. Accordingly, these two endpoints have been 
changed from secondary to exploratory endpoints at Month 9.  With this amendment, 
these endpoints will be formally tested at Month 18, when we expect they will be less 
subject to impact from the pandemic, as described below. 
Expanded Analysis at Month 18 to Further Characterize Treatment Effect Over Time 
 The following efficacy endpoints have been added to the testing hierarchy at 
Month 18 for change from baseline parameters compared to the placebo arm of 
Study ALN-TTR02-004 (APOLLO; patisiran): mNIS+7, Norfolk QoL-DN total 
score, timed 10-meter walk test (10-MWT), mBMI, and R-ODS.  
The addition of these endpoints at Month 18 is consistent with the timepoint used for 
analysis of the primary endpoint in the APOLLO study. The expanded analysis at 
Month 18 will allow for more complete characterization of the treatment effect of 
ALN-TTRSC02 over time and the potential for sustained improvements in neurologic 
impairment, quality of life, gait speed, disability and nutrition. 
Additional Changes to Endpoints 
 Removed change at Month 18 compared to baseline in mNIS+7 and Norfolk 
QoL-DN total score in ALN-TTRSC02-treated patients. The additional endpoint 
analyses added at Month 18 have replaced the need for this analysis.  

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 Removed the secondary endpoint of composite events of all-cause deaths and/or all-
cause hospitalizations in the overall population (over 18 months) compared to the 
placebo arm of the APOLLO study; removed adjudication of the reasons for 
hospitalizations. Deaths due to COVID-19 and changes in health care utilization 
related to COVID-19 may confound interpretation of these data. Adjudication of the 
reasons for hospitalizations was considered no longer necessary.   
 Added percent reduction in serum TTR compared to baseline as an exploratory 
endpoint. 
Additional Changes and Clarifications 
 Added a clarification that for submission of the marketing authorization to the 
European Union, formal hypothesis testing will be conducted at Month 18, with 
mNIS+7 compared to the placebo arm of the APOLLO study at Month 18 considered 
the primary endpoint. Details will be specified in the statistical analysis plan (SAP). 
 Added a definition of the Per-Protocol Population. 
 Similar to the clarification at Month 9 for efficacy assessments in the previous 
amendment (Amendment 2 dated 06 May 2020), a specification was added that when 
a Month 18 efficacy visit is unable to be completed 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, the Medical Monitor should be 
consulted as soon as possible to determine the appropriate timing of the Month 18 
efficacy assessment. After consultation with the Medical Monitor, Month 18 efficacy 
assessments may be completed within 6 months after the intended time point (ie, up 
to Study Month 24).  
 Added clarification that if a dose is delayed (up to 8-weeks for ALN-TTRSC02 or 
7 days for patisiran), study assessments associated with the originally scheduled dose 
may also be delayed to coincide with the delayed dose.  
 Added clarification that the delay of Month 18 efficacy assessments will not affect 
the timepoint for patients on patisiran to switch to ALN-TTRSC02 at Week 84.  
 Removed the requirement that assessors who perform efficacy assessments at Central 
Assessment Sites will be different from site personnel who monitor administration of 
study drug and the well-being of the patient during the study. This change was made 
as involvement of site personnel in patient management is not expected to impact 
efficacy assessment evaluations and the requirement placed an undue burden on sites, 
especially amid COVID-19 restrictions at the sites. 
 Added a clarification that postural blood pressure will be measured as described in 
the Study Manual. 
The following changes are not detailed: administrative changes and corrections to typographical 
errors, punctuation, grammar, abbreviations, and formatting. 

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2. 
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:  The following changes were made to the endpoints for the study: 
 The co-primary endpoint of change from baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total 
score at Month 9 compared to the placebo arm of the APOLLO study has been changed to the first key secondary endpoint 
in the hierarchical testing order. 
 Added mNIS+7, Norfolk QoL-DN total score, timed 10-meter walk test (10 MWT) at Month 18 in addition to analyses 
already specified for Month 9 to ensure the treatment effect of vutrisiran is completely characterized at Month 18. 
 Rasch-built Overall Disability Scale (R-ODS) and modified body mass index (mBMI) changed from Month 9 to Month 18; 
the Month 9 assessments of these parameters were moved to exploratory endpoints. These changes have been made to 
mitigate the potential for missed doses due to COVID-19, as well as the physical and mental impact of the pandemic, to 
affect the analyses of these endpoints at Month 9. 
 Removed change at Month 18 compared to baseline in mNIS+7 and Norfolk QoL DN total score in ALN-TTRSC02-treated 
patients. 
 Removed the secondary endpoint of composite events of all-cause deaths and/or all-cause hospitalizations in the overall 
population (over 18 months) compared to the placebo arm of the APOLLO study; removed adjudication of the reasons for 
hospitalizations. 
 Added percent reduction in serum TTR compared to baseline as an exploratory endpoint. 
 Added a clarification that for submission of the marketing authorization to the European Union, formal hypothesis testing 
will be conducted at Month 18, with mNIS+7 compared to the placebo arm of the APOLLO study at Month 18 considered 
the primary endpoint.  
The primary change occurs in Section 2, Objectives and Endpoints 
Revised text: 
The co-primary, and most secondary and exploratory efficacy endpoints are in comparison to the placebo arm of the Phase 3 pivotal 
patisiran study (ALN-TTR02-004, also referred to as the APOLLO study) as specified in the statistical analysis section of this 

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protocol the HELIOS-A protocol.  The primary analysis will be conducted at Month 9.  An additional analysis of all efficacy 
endpoints will be conducted at Month 18.  
Objectives 
Endpoints 
Primary 
 
To determine the efficacy of ALN-
TTRSC02 in patients with hATTR 
amyloidosis by evaluating the effect on 
neurologic impairment and on quality of 
life  
Co-Primary: 
 
Change from baseline in the Modified 
Neurologic Impairment Score +7 
(mNIS+7) compared to the placebo arm 
of the APOLLO study at Month 9 
 
Change from baseline in Norfolk Quality 
of Life-Diabetic Neuropathy (Norfolk 
QoL-DN) total score compared to the 
placebo arm of the APOLLO study 
Secondary 
 
To determine the efficacy of ALN-
TTRSC02 on quality of life, gait speed, 
neurologic impairment, nutritional 
status, and disability 
 
To characterize demonstrate the effect 
noninferiority of ALN-TTRSC02 on 
compared to patisiran with respect to 
serum TTR levels 
 
To evaluate patient mortality and 
hospitalization 
 
To determine the efficacy of ALN-
TTRSC02 on improvement in neurologic 
impairment and on quality of life 
 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study: 
 Norfolk Quality of Life-
Diabetic Neuropathy 
(Norfolk QoL-DN) total 
score at Month 9;  
 Timed 10-meter walk test (10-
MWT) at Month 9; 
 mNIS+7 at Month 18; 
 Norfolk QoL-DN total score 
at Month 18; 
 10-MWT at Month 18; 
 Modified body mass index 
(mBMI) at Month 18; 

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Objectives 
Endpoints 
 Rasch-built Overall Disability 
Scale (R-ODS) at Month 18 
 
Percent reduction in serum TTR levels in 
the ALN-TTRSC02 arm compared to the 
within-study patisiran arm through 
Month 18 
 
Composite events of all-cause deaths 
and/or all-cause hospitalizations in the 
overall population (over 18 months) 
compared to the placebo arm of the 
APOLLO study 
 
Change at Month 18 compared to baseline 
in mNIS+7 in ALN-TTRSC02-treated 
patients 
 
Change at Month 18 compared to baseline 
in Norfolk QoL-DN total score in ALN-
TTRSC02-treated patients 
Exploratory  
 
To determine the effect of ALN-
TTRSC02 on: 
 Disability and nutritional status; 
 
Manifestations of cardiac amyloid 
involvement; 
 
Other assessment of neurologic 
impairment;  
 
Other assessments of quality of life; 
 
Disease stage; 
 
Performance of daily activities 
 
To characterize the pharmacodynamic 
(PD) effect of ALN-TTRSC02 and 
 
Change from baseline in the following 
parameters compared to the placebo arm 
of the APOLLO study at Month 9: 
 R-ODS; 
 mBMI 
 
Change from baseline over time: 
 
N-terminal prohormone B-type 
natriuretic peptide (NT-proBNP) 
levels, echocardiographic parameters, 
Troponin I and T levels, New York 
Heart Association (NYHA) class; 
 
Neurologic Impairment Score (NIS); 
 
EuroQoL-5 Dimensions-5 Levels 
(EQ-5D-5L) questionnaire and the 

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Objectives 
Endpoints 
patisiran on serum TTR and vitamin A 
levels  
 
To characterize plasma pharmacokinetics 
(PK) of ALN-TTRSC02 and patisiran 
 
To assess presence of antidrug antibodies 
(ADA) to ALN-TTRSC02 and patisiran 
EuroQoL-Visual Analog Scale (EQ-
VAS); 
 
Familial Amyloidotic 
Polyneuropathy (FAP) stage and 
Polyneuropathy Disability (PND) 
score; 
 
Karnofsky Performance Status (KPS) 
 
Change from baseline in technetium 
scintigraphy cardiac parameters at 
Month 18 
 
Percent reduction in serum TTR and 
vitamin A levels over time 
 
PK profile of ALN-TTRSC02 and 
patisiran 
 
Incidence and titers of ADA to ALN-
TTRSC02 and patisiran 
Safety 
 
To determine the safety and tolerability of 
ALN-TTRSC02 in patients with hATTR 
amyloidosis 
 
Frequency of adverse events (AE) 
For submission of the marketing authorization to the European Union, formal hypothesis testing will be conducted at Month 
18, with mNIS+7 compared to the placebo arm of the APOLLO study at Month 18 considered the primary endpoint.  Details 
will be specified in the statistical analysis plan (SAP). 
Section(s) also reflecting these changes:  
 Synopsis 
 Section 3.1, Summary of Study Design 
 Section 3.8, Adjudication Committee 
 Section 6.2.7, Deaths and Hospitalizations 

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 Section 7.1, Determination of Sample Size 
 Section 7.2.3, Handling of Missing Data 
 Section 7.2.5.1, Primary Endpoint 
 Section 7.2.5.2, Secondary Endpoints 
 
Purpose:  Added a definition of the Per-Protocol Population. 
The primary change occurs in Section 7.2.1, Populations to be Analyzed 
Added text: TTR Per-protocol (PP) Population: All mITT population patients with a nonmissing TTR assessment at baseline 
and ≥1 trough TTR assessment associated with adequate treatment compliance between Month 6 and Month 18. Specific 
details will be provided in the SAP. 
 
 
Purpose:  Added a specification that when a Month 18 efficacy visit is unable to be completed 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, the 
Medical Monitor should be consulted as soon as possible to determine the appropriate timing of the Month 18 efficacy assessment. 
The primary change occurs in Section 6, Study Assessments: 
Revised text: All efficacy visits must be conducted at the clinic (Month 9, Month 18, Month 27, Month 36, and modified efficacy visits).  In 
situations in which a Month 9 or Month 18 efficacy visit is unable to be completed 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, the Medical Monitor should be 
consulted as soon as possible to determine the appropriate timing of the Month 9 or Month 18 efficacy assessment.  After consultation with the 
Medical Monitor, Month 9 or Month 18 efficacy assessments may be completed within 6 months after the intended time point (ie, up to Study 
Month 15 or Study Month 24).  
Section(s) also reflecting this change:   
 Section 3.1, Summary of Study Design 
 

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Purpose:  Added clarification that if a dose is delayed (up to 8-weeks for ALN-TTRSC02 or 7 days for patisiran), study assessments 
associated with the originally scheduled dose may also be delayed to coincide with the delayed dose. 
The primary change occurs in Section 5.2.2.1, ALN-TTRSC02 
Revised text: Missed Doses of ALN-TTRSC02 
If a patient does not receive a dose of ALN-TTRSC02 within the specified dosing window, the Investigator should contact the 
Medical Monitor.  After such consultation, the dose may be administered with up to an 8-week delay (to be considered a delayed 
dose).  Thereafter, the dose will be considered missed and not administered.  If a dose 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. If a dose is delayed, all assessments associated with the 
originally scheduled dose may also be delayed to coincide with the delayed dose. 
Section(s) also reflecting this change: 
 Section 5.2.2.2, Patisiran 
 
Purpose:  Added clarification that the delay of Month 18 efficacy assessments will not affect the timepoint for patients on patisiran to 
switch to ALN-TTRSC02 at Week 84. 
The primary change occurs in Section 5.2.2.3, Switching from Patisiran to ALN-TTRSC02 After Month 18 
Added text: On Week 84, patients in the patisiran arm will be switched to ALN-TTRSC02 treatment and will receive the first ALN-
TTRSC02 dose.  The last dose of patisiran will be at Week 81, and patients should receive treatment with ALN-TTRSC02 3 weeks 
later on Week 84 and thereafter q3M (12 weeks ±7 days) for the remainder of the study. If a patient receiving patisiran is unable to 
complete the Month 18 efficacy visit at the study center due to COVID-19 (Section 3.1) before Week 84, they may transition to 
treatment with ALN-TTRSC02 at Week 84 or later. 
 
 

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Purpose:  Removed the requirement that assessors who perform efficacy assessments at Central Assessment Sites will be different 
from site personnel who monitor administration of study drug and the well-being of the patient during the study. 
The primary change occurs in Section 6, STUDY ASSESSMENTS 
Deleted text: Central Assessment Sites (CAS) can perform all efficacy assessments and perform the same assessments as at a PCS (as 
stated above).  Efficacy assessments (NIS, mNIS+7, HRdb, 10-MWT, FAP and PND, KPS, echocardiogram) in this study may require 
special training as described further in Section 6.2; therefore, all patients must be sent to a CAS to collect these efficacy assessments 
during screening and predose baseline assessments, Month 9, Month 18, and during the Treatment Extension period at Month 27 and 
Month 36.  Assessors who will perform efficacy assessments at a CAS will be different from site personnel who monitor the 
administration of study drug during the study and monitor the well-being of the patient during the study.  This is instituted to minimize 
the influence patient management and AEs may have on efficacy assessment evaluation(s). 
 
Purpose:  Added a clarification that postural blood pressure will be measured as described in the Study Manual. 
The primary change occurs in Section 6.2.1.1, Modified Neurological Impairment Score +7 (mNIS+7) 
Revised text: Postural blood pressure is will be measured to assess autonomic function as described in the Study Manual. Postural 
blood pressure is measured sitting down and standing up.  Points are assigned based on the change in blood pressure with standing. 
 
 
 

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ALN-TTRSC02-002 PROTOCOL AMENDMENT 4 
SUMMARY OF CHANGES DATED 19 FEBRUARY 2021 
HELIOS-A:  A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy 
and Safety of ALN-TTRSC02 in Patients with Hereditary Transthyretin Amyloidosis 
(hATTR Amyloidosis) 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

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Additional updates 
• Specified that for study visits done outside the clinic, such as at home, physical 
examinations may be deferred to the next in clinic visit 
• Revised overdose reporting instructions  
• Updated pregnancy reporting to be any time during study conduct 
The following changes are not detailed: administrative changes and corrections to typographical 
errors, punctuation, grammar, abbreviations, cross references, and formatting. 
 

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2. 
PROTOCOL AMENDMENT 4 DETAILED SUMMARY OF CHANGES 
The primary section(s) of the protocol affected by the changes in Protocol 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:  Addition of a Randomized Treatment Extension (RTE) Period 
 
 
 
The primary change occurs in Section: Section 3.1, Summary of Study Design 
Revised text: 
This is a global Phase 3 randomized, open-label study designed to evaluate efficacy, safety, and PK/PD of ALN-TTRSC02 in adult 
patients with hATTR amyloidosis.  Patients will be randomized 3:1 to ALN-TTRSC02 or patisiran, a reference comparator. 
Randomization will be stratified by TTR genotype (V30M vs. non-V30M) and baseline NIS score (<50 vs ≥50). 
The study will consist of a Screening Period of up to 42 days, an 18-month Treatment Period, and an 18-month RTE Period in lieu of 
the Legacy Treatment Extension Period.  A Follow-up Period of up to 1 year will occur after the last dose of study drug (Figure 2). 
18-Month Treatment Period 
After the Screening period at the start of the Treatment Period, eligible patients will be randomized 3:1 on Day 1 to receive 25 mg of 
ALN-TTRSC02 administered as a SC injection q3M or patisiran administered as an IV infusion q3w; patients in the patisiran arm will 
also receive premedications prior to each dose (see Section 5.2.2.2).  During the 18-month Treatment Period, patients will undergo 
assessments for efficacy and/or safety (as outlined in the Schedule of Assessments), with key efficacy assessments being performed 
prior to first dose, at Month 9 (primary efficacy analysis timepoint) and at Month 18; samples for TTR assessment will be collected 
more frequently throughout the 18-month Treatment Period. 
All efficacy visits must be conducted at the clinic (Month 9, Month 18, Month 27, Month 36, and modified efficacy visits).  In 
situations in which a Month 9 or Month 18 efficacy visit is unable to be completed due to the Coronavirus disease 2019 (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, the Medical Monitor should be consulted as soon as possible to determine the appropriate timing of the Month 9 or 
Month 18 efficacy assessments as applicable. After consultation with the Medical Monitor, the Month 9 or Month 18 efficacy 
assessments may be completed within 6 months after the intended time point (ie, up to Month 15 or Month 24, respectively).  
Dosing may be allowed outside of the study center (eg, the patient’s home) under certain circumstances as specified in Section 5.2.2.1 
and Section 5.2.2.2.  In addition, routine assessments and collection of relevant safety information may be collected outside the study 
center as specified at the beginning of Section 6. 

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The placebo arm of the APOLLO study will be used as an external control for the primary, most secondary, and most exploratory 
efficacy analysis.  Primary and secondary efficacy evaluations will include mNIS+7, Norfolk QoL-DN questionnaire, 10-MWT, 
mBMI, R-ODS questionnaire, and percent TTR reduction. Study personnel performing the mNIS+7 component assessments will not 
reference the results of any previous assessments. 
In order to allow for a robust cross study comparison, attempts will be made to minimize differences between the HELIOS-A and 
APOLLO study populations. As such, baseline disease characteristics will be monitored and may result in enrollment limitations 
based on certain characteristics (eg, genotype) to ensure comparability.  Decisions around enrollment adjustments will be made by 
staff without access to primary efficacy results. 
Randomized Treatment Extension (RTE) Period 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 

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Follow-up Period 
During the Follow-up Period, all patients on ALN-TTRSC02 will undergo safety assessments quarterly until serum TTR levels return to ≥80% of 
baseline (for up to 1 year after the last dose of study drug), or until the patient starts a TTR lowering regimen as a part of clinical care, whichever 
comes first; all patients will be followed for a minimum of 3 months.  Female patients of child-bearing potential who discontinue ALN-
TTRSC02 will be followed until serum TTR levels return to ≥80% of baseline. 
Section(s) also reflecting these changes:  
• Synopsis 
• Synopsis Footnote to Table 2, revisions to Table 3; and addition of Table 4 
• Study Design Figure 1 and added Figure 2 
• Section 1.5, Study Design Rationale 
• Section 1.6, Dose Rationale 
• Section 1.7, Benefit-Risk Assessment 

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• Section 3.1, Summary of Study Design 
• Section 3.2, Duration of Treatment 
• Section 3.3, Duration of Study 
• Section 3.3.1, Definition of End of Study for an Individual Patient 
• Section 3.5, Method of Assigning Patients to Treatment Groups 
• Section 4.3.1, Discontinuation of Study Drug or Declining Procedural Assessments 
• Section 4.3.2.1, Patient or Legal Guardian Stops Participation in the Study 
• Section 5.2.1, Description (Study Drug) 
• Section 5.2.2.1, ALN-TTRSC02 (Dose and Administration) 
• Section 5.2.2.3, Switching from Patisiran to ALN-TTRSC02 After Month 18 
• Section 5.2.4, Preparation, Handling, and Storage 
• Section 6 (and subsections within), Study Assessments 
• Section 7.2, Statistical Methodology 
• Section 7.2.5, Efficacy Analyses 
Purpose:  To define the collection times for PK blood samples during the Treatment Extension Period 
The primary change occurs in Section: Synopsis, Table 5 
Added text:  
Study Day 
Protocol Time 
(hh:mm) 
PK Blood (Plasma) 
Day 1 and Day 253±3 days  
Predose (within 60 minutes before dosing) 
X 
03:00 (±1 hr) after dosing 
X 
06:00 (±1 hr) after dosing 
X 
24:00 (±2 hr) after dosing 
X 
Day 85 and Day 169 (±3 days) 
Predose (within 60 minutes before dosing) 
X 
03:00 (±1 hr) after dosing 
X 
Day 337, Day 421, and Day 505 (±3 days) 
Predose (within 60 minutes before dosing) 
X 
03:00 (±1 hr) after dosing 
X 
 
 
 
 
 
Early Drug Discontinuation Visit 
Collect any time within the visit window 
X 
Modified Efficacy Visits for Patients Who Discontinue 
Treatment before Month 18 (Part A or Part B) 
Collect any time within the visit window 
X 
 
Purpose:  Vutrisiran does not have a drug-drug interaction with hormonal contraception. 

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The primary change occurs in Section 5.6.1: Contraception 
Revised text:  
• Established use of oral (except for low dose gestagens), implantable, injectable, or transdermal hormonal methods of 
contraception associated with the inhibition of ovulation. Females of child-bearing potential who use hormonal contraceptives 
as a method of contraception must also use a barrier method (condom or occlusive cap [diaphragm or cervical/vault cap] in 
conjunction with spermicide [eg, foam, gel, film, cream, or suppository]).   
Section(s) also reflecting this change: 
Not applicable 
Purpose:  To allow flexibility due to the COVID-19 pandemic. 
The primary change occurs in Section 6.5.3: Physical Examination 
Revised text:  
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, or the onset of new symptoms, since 
the last visit.  In situations where the patient has a home visit, symptom-directed physical examinations may be deferred until 
the next in-clinic visit. 
Section(s) also reflecting this change: 
Not applicable 
Purpose:  Clarifications to pregnancy reporting and overdose reporting instructions. 
The primary change occurs in Section 6.5.7.7 Pregnancy Reporting and Section 6.5.7.8: Overdose Reporting, respectively 
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.   
An overdose is defined as any dose 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.  When an overdose is suspected, the Investigator should inform the 
Medical Monitor. The investigator will decide whether a dose is to be considered an overdose, in consultation with the Sponsor.  In 
the event of an overdose, the actual dose administered must be recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor or designee. 
Section(s) also reflecting this change:  Not applicable