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

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
1 
CLINICAL STUDY PROTOCOL 
ALN-TTR02-011 
DATED 30 JUNE 2021 
Protocol Title: 
APOLLO-B:  A Phase 3, Randomized, 
Double-blind, Placebo-controlled Multicenter 
Study to Evaluate the Efficacy and Safety of 
Patisiran in Patients with Transthyretin 
Amyloidosis with Cardiomyopathy (ATTR 
Amyloidosis with Cardiomyopathy)   
Short Title: 
APOLLO-B:  A Study to Evaluate Patisiran in 
Patients with Transthyretin Amyloidosis with 
Cardiomyopathy (ATTR Amyloidosis with 
Cardiomyopathy) 
Study Drug: 
Patisiran (ALN-TTR02)  
EudraCT Number: 
2019-001458-24 
IND Number: 
141240 
Protocol Date: 
Original protocol, 18 April 2019  
Amendment 1:  20 December 2019 
Amendment 2:  22 May 2020 
Amendment 3:  30 June 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-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-011 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-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
6 
population is anticipated to have hATTR and 80% wtATTR.  In addition, at baseline, patients are 
either: 
• Tafamidis naïve; or 
• Currently on tafamidis (for ≥6 months), with disease progression in the opinion of the 
Investigator.  This group will be capped at 30% of total enrollment in the study.   
The study consists of a screening period of up to 45 days, a 12-month, double-blind, placebo-
controlled period, a 36-month, open-label extension period (during which all patients will receive 
patisiran), and a 28-day follow-up period. 
After screening, during the 12-month double-blind period, eligible patients will be randomized to 
receive intravenous (IV) treatment every 3 weeks with either patisiran or placebo.  Prior to 
receiving randomized, double-blind study drug (patisiran or placebo), to reduce the potential for 
an infusion related reaction (IRR) with patisiran, all patients will receive premedications at least 
60 minutes before the start of their infusion.  Study drug will be administered as an 
approximately 80-minute IV infusion.  
During the open-label extension period, all patients will receive treatment with open-label 
patisiran.   
Study drug administration at a location other than the study center (eg, at home) may be 
administered as follows: 
• Double-blind period:  Patients who have received ≥2 doses of study drug at the study 
center with no evidence of IRRs or other drug-related adverse effects that impact safety 
and tolerability of the infusion may have study drug administered at a location other than 
the study center (eg, at home), where applicable country and local regulations allow.  
Study drug administration will be performed by a healthcare professional, trained on the 
protocol and on administration of premedications and study drug infusion, with oversight 
of the Investigator. 
• Open-label extension period:  Patients who have received ≥2 doses of open-label 
patisiran at the study center with no evidence of IRRs or other drug-related adverse 
effects that impact safety and tolerability of the infusion may have patisiran administered 
at a location other than the study center (eg, at home), where applicable country and local 
regulations allow.  Patisiran administration will be performed by a healthcare 
professional trained on the protocol and on administration of premedications and 
patisiran infusion, with oversight of the Investigator.  
To evaluate the efficacy of treatment with patisiran versus placebo in patients with ATTR 
amyloidosis with cardiomyopathy, the change from baseline in 6-MWT will be assessed at 
Month 12 (Weeks 52-53) as the primary endpoint; this assessment will also be performed at 
Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) in the double-blind period, and during the 
open-label extension period.  The first secondary endpoint will assess change from baseline at 
Month 12 in the KCCQ-OS score.  In situations where an efficacy study visit at Months 6, 9, 
and/or 12 is unable to be completed at the study center due to the coronavirus disease 2019 
(COVID-19) pandemic impacting activities at the study center or patient 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 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
7 
Month 6, 9, and/or 12 efficacy assessments.  After consultation with the Medical Monitor, 
efficacy assessments may be extended for that visit as follows:  Month 6 up to Day 214; Month 9 
up to Day 319; Month 12, up to Day 417, but prior to the first dose of open-label patisiran.  
Patients may continue to receive double-blind study drug until the Month 12 efficacy assessment 
is performed.    
Safety will be assessed throughout the double-blind and open-label extension periods of the 
study. 
Number of Planned Patients 
Approximately 300 patients are planned for enrollment in this study.   
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, inclusive, with ATTR amyloidosis with cardiomyopathy (hereditary or wild-type [wt]) who, 
at baseline, are either:  1) tafamidis naïve (on tafamidis for ≤30 days and none within 6 months 
prior to baseline); or 2) currently on tafamidis (for ≥6 months) with disease progression in the 
opinion of the Investigator. 
Study Drug, Dose, and Mode of Administration 
Patisiran is a ribonucleic acid (RNA) interference (RNAi) therapeutic consisting of a double-
stranded small interfering RNA (siRNA) targeting TTR mRNA formulated in a lipid 
nanoparticle (LNP).  The patisiran drug product is a sterile formulation of ALN-18328 (siRNA 
targeting TTR) formulated as LNPs with lipid excipients (1,2-Dilinoleyloxy-N,N-
dimethylpropylamine [DLin-MC3-DMA], 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.   
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs. 
An IV infusion of double-blind study drug (patisiran 0.3 mg/kg or placebo) will be administered 
under the supervision of the site personnel once every 3 weeks ±3 days.  Dosing is based on 
actual body weight.  For patients weighing ≥100 kg, the maximum recommended patisiran dose 
is 30 mg.  
The last dose of double-blind study drug will be at Week 51 and the first dose of open-label 
patisiran will be 3 weeks later (at Week 54) and thereafter every 3 weeks (±3 days) for the 
remainder of the study.  Open-label patisiran will be administered per the schedule and dose as is 
described above for double-blind patisiran. 
Reference Treatment, Dose, and Mode of Administration 
The control drug for this study will be a placebo (normal saline 0.9% for IV administration).  
Control drug will be provided by a central supplier (or, if necessary, by a local supplier, with 
prior Sponsor approval).    
Duration of Treatment and Study Participation 
The treatment duration in this study is up to 48 months, inclusive of a 12-month, double-blind, 
treatment period, and a 36-month, open-label, treatment period.  The estimated total time on 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
8 
study for each patient is up to 50.5 months, including up to 45 days of screening, up to 
48 months of treatment, and a 28-day safety follow-up period. 
Statistical Methods 
The planned enrollment for this study is 300 patients.  Randomization (1:1) will be stratified by:  
1) baseline tafamidis (yes vs no); 2) genotype (hATTR vs wtATTR); and 3) NYHA Class I or II 
and age < 75 years vs all other. 
For the change from baseline at Month 12 in the 6-MWT, assuming a treatment difference of 
33 meters between patisiran and placebo in the treatment-naïve group and 20 meters in patients 
with baseline tafamidis, the weighted average treatment difference between patisiran and placebo 
in the overall population is approximately 29 meters (standard deviation = 75 meters) assuming 
70% are in the treatment-naïve group and 30% are in the baseline tafamidis group.  A sample 
size of 300 patients provides >90% power for a 2-sided test to detect a treatment difference at a 
2-sided alpha = 0.05.  Additional patients may be enrolled based on a recommendation to 
increase the sample size in the interim assessment. 
The primary endpoint, change from baseline at Month 12 in the 6-MWT, will be analyzed using 
a mixed-effects model repeated measures (MMRM) approach.  The outcome variable is change 
from baseline in the 6-MWT.  The model will include the baseline value as a covariate, 
treatment, visit, baseline tafamidis (yes vs no), genotype (hATTR vs wtATTR), age (<75 vs ≥75 
years), the treatment-by-visit interaction, the treatment-by-baseline tafamidis interaction, the 
visit-by-baseline tafamidis interaction, and the treatment-by-visit-by-baseline tafamidis 
interaction as fixed factors.  The primary comparison is the contrast (difference in least squares 
[LS] means) between the patisiran and placebo groups at Month 12. 
To control the overall Type I error rate, secondary endpoints will be tested in a prespecified 
hierarchical order. 
For patients who are tafamidis treatment-naïve at baseline and start tafamidis during the double-
blind period, the primary analysis of the primary endpoint will censor data collected after the 
initiation of tafamidis treatment post-randomization.  
Safety data will be summarized descriptively. 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
9 
Figure 1: 
Study Design  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
10 
Table 1: 
Year 1 Schedule of Assessments:  Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NA 
Informed Consent 
6.1  
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion Criteria 
4.1, 
4.2  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / 
Medical History 
6.1  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PND Score 
6.2.7  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
6.5.2  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
X 
X 
 
 
 
 
 
 
 
 
 
X
d 
 
 
 
 
X
d 
 
 
 
 
 
X 
d 
X 
d 
X
d 
KCCQ 
6.2.2 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
mBMI 
6.2.4 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Cardiac Biomarker 
Samples 
6.2.5.1 
NT-
proBNP 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
ATTR amyloidosis 
disease stage 
6.2.5.2  
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
NYHA Class 
6.2.5.3 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Echocardiogram 
6.2.5.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CMR, technetium 
(select sites only) 
6.2.5.6,  
6.2.5.5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Norfolk QoL-DN 
6.2.6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
11 
Table 1: 
Year 1 Schedule of Assessments:  Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NA 
Pharmacodynamic Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
X 
X 
  
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Exploratory 
Biomarkers 
(plasma, serum) 
6.6 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
6.5.2 
X  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
(symptom-directed 
unless noted as full) 
6.5.3 
X  
Full 
X 
  
 
 
 
 
X 
 
 
 
  
X 
 
 
 
  
X 
 
 
 
 
 
X 
Full 
X 
Full 
X 
Single 12-lead ECG 
(unless otherwise 
indicated) 
6.5.4 
 
X (in 
triplicate, 
either visit) 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum Chemistry, 
Liver Function 
Tests 
6.5.5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Xe 
Xe 
X 
Hematology 
6.5.5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Coagulation 
6.5.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin A Levels 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA (on dosing 
days, prior to 
dosing) 
6.5.5.1 
 
 
X 
 
X 
  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
12 
Table 1: 
Year 1 Schedule of Assessments:  Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NA 
FSH (to confirm 
postmenopausal, if 
applicable) 
Table 5, 
6.5.5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
Table 5, 
6.5.5.2 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
  
  
Review/Record 
Hospitalization, 
Urgent HF Visits, 
Urgent Care Visits, 
and Procedures 
 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
 
Review/Record 
AEs, Con Meds 
6.5.7, 
5.3 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
6.4 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Drug Administration 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
3.5 
Window 
is 5D 
prior to 
Day 1 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication/ 
Study Drug 
5.2.1, 
5.2.3 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
13 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; COVID-19=coronavirus disease 2019; CMR=cardiac 
magnetic resonance; D=day; Disc=discontinuation; ECG=electrocardiogram; FSH=follicle-stimulating hormone; KCCQ=Kansas City Cardiomyopathy 
Questionnaire; HF=heart failure; M=month; mBMI=modified body mass index; 6-MWT=6-minute walk test; NA=not applicable; NT-proBNP=N-terminal 
prohormone B-type natriuretic peptide; NYHA=New York Heart Association; PK=pharmacokinetics; PND=Polyneuropathy Disability; QoL-DN=Quality of 
Life-Diabetic Neuropathy; TTR=transthyretin; V=visits. 
a  This efficacy visit is conducted 7 to 14 days after the prior visit.  In situations where a Month 6 (Day 176-183), Month 9 (Day 260-267), and/or Month 12 (Day 
365-372) study visit is unable to be completed at the study center due to the COVID-19 pandemic impacting activities at the study center or patient 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 Month 6, 9, and/or 12 efficacy assessments.  After consultation with the Medical Monitor, efficacy 
assessments may be extended as follows:  Month 6 up to Day 214; Month 9 up to Day 319; Month 12, up to Day 417, but prior to the first dose of open-label 
patisiran. Patients may continue to receive double-blind study drug until the Month 12 efficacy assessment is performed.   
b  This Modified Month 12 Efficacy Visit is to be performed at Month 12 for patients who discontinued treatment early (ie, prior to Month 12), and choose to 
remain in the study.  All patients who discontinue from study drug during the double-blind period will be encouraged to remain on the study and complete 
assessments through Month 12 (excluding PK assessments), including this Modified Month 12 Efficacy Visit.  Such patients will also receive assessments at 
the Early Treatment Discontinuation Visit (7 to 14 days after their last dose of study drug); and the safety follow-up visit (28 days after the last dose of study 
drug) (Table 4), as described in Section 4.3.1.  In situations where the Modified Month 12 Efficacy Visit is unable to be completed at the study center due to 
the COVID-19 pandemic impacting activities at the study center or patient 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 for these efficacy assessments.  
After consultation with the Medical Monitor, efficacy assessments may be extended, up to Day 417 (as is permitted for the regular Month 12 visit).    
c See Section 5.3.1; patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis drop-in”) during the double-blind period.  In 
all cases, the Pre-tafamidis Drop-in Visit should occur prior to starting concomitant tafamidis; where possible, this visit should occur between 1-2 weeks after 
the last dose of double-blind study drug (ie, 7 to 14 days post dose).  Thereafter, the patient will continue with all assessments per the Schedule of Assessments, 
including the Month 12 Efficacy Visit.  At the time of tafamidis drop-in, the reason for starting tafamidis will be recorded in the CRF. 
d As described in Section 6.2.1, to avoid a potential training effect resulting from repeated assessments of the 6-MWT within a short period of time, only one 6-
MWT assessment should be performed within each of the following time periods:  Day 2 to Day 214 (includes the scheduled Weeks 25-26 assessment); Day 
215 to Day 319 (includes the scheduled Weeks 37-38 assessment); and Day 320 to Day 417 (includes the scheduled Weeks 52-53 assessment).  Within a given 
time period, the 6-MWT assessment should be performed at whichever visit occurs first (scheduled assessment, Pre-tafamidis Drop-in Visit, or Early Treatment 
Discontinuation Visit [Table 4]); no additional 6-MWT assessments should be made in that time period.  In later time periods, the 6-MWT should be assessed 
as scheduled. 
e Serum creatinine only. 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
14 
Table 2: 
Year 2 Schedule of Assessments:  Open-label Extension Period (Through Month 24) 
Study Day  
±Visit Window 
  
Open-label Extension Period  
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
KCCQ 
6.2.2 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
mBMI 
6.2.4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Cardiac Biomarker Samples 
6.2.5.1 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
ATTR amyloidosis disease stage 
6.2.5.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NYHA Class 
6.2.5.3 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Echocardiogram 
6.2.5.4 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
CMR, technetium (select sites only)  
6.2.5.6, 
6.2.5.5 
 
 
 
 
 
 
 
 
 
X b 
 
 
 
 
 
 
 
 
 
 
X 
Norfolk QoL-DN 
6.2.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Exploratory Biomarkers (plasma, 
serum) 
6.6  
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Weight 
6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (symptom-directed) 
6.5.3 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Single 12-lead ECG 
6.5.4  
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum Chemistry, Liver Function Tests 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Xc 
Hematology 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pregnancy Test 
Table 5, 
6.5.5.2 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
Review/Record Hospitalization, Urgent 
HF Visits, Urgent Care Visits, and 
Procedures 
 
-------------------------------------------------------------------X------------------------------------------------------------------------- 
Review/Record AEs, Con Meds 
6.5.7, 5.3 
-------------------------------------------------------------------X------------------------------------------------------------------------- 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
15 
Table 2: 
Year 2 Schedule of Assessments:  Open-label Extension Period (Through Month 24) 
Study Day  
±Visit Window 
  
Open-label Extension Period  
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
 6.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication, Study Drug 
5.2.1, 
5.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; COVID-19=coronavirus disease 2019; CMR=cardiac 
magnetic resonance; D=day; ECG=electrocardiogram; HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire; mBMI=modified body mass 
index; 6-MWT=6-minute walk test; NT-proBNP=N-terminal prohormone B-type natriuretic peptide; NYHA=New York Heart Association; 
PK=pharmacokinetics; QoL-DN=Quality of Life-Diabetic Neuropathy; TTR=transthyretin; V=visits.  
a  This efficacy visit is conducted 7 to 14 days after the prior visit.  In situations where a Month 18 (Day 554-561), Month 21 (Day 638-645), and/or Month 24 
(Day 743-750) study visit is unable to be completed at the study center due to the COVID-19 pandemic impacting activities at the study center or patient ability 
or willingness to access 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 Month 18, 21, and/or 24 efficacy assessments.  After consultation with the Medical Monitor, efficacy assessments 
may be extended as follows:  Month 18 up to Day 592; Month 21 up to Day 697; Month 24, up to Day 791. 
b Consecutive CMR scans should not be performed within 5 months of each other.  Consecutive technetium scans should not be performed within 5 months of 
each other. 
c Serum creatinine only. 
 
  

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
16 
Table 3: 
Year 3 Schedule of Assessments:  Open-label Extension Period (Through Month 36)  
Study Day  
±Visit Window 
  
Open-label Extension Period  
For 
Details 
see 
Section 
D757±3 
D778±3 
D799±3 
D820±3 
D841±3 
D862±3 
D883±3 
D904±3 
D925±3 
D932-D938a 
D946±3 
D967±3 
D988±3 
D1009±3 
D1016-D1022a 
D1030±3 
D1051±3 
D1072±3 
D1093±3 
D1100-D1106a 
Study Week 
 
108 
111 
114 
117 
120 
123 
126 
129 
132 
133-134 
135 
138 
141 
144 
145-146 
147 
150 
153 
156 
157-158 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
KCCQ 
6.2.2 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
mBMI 
6.2.4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Cardiac Biomarker Samples 
6.2.5.1 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
ATTR amyloidosis disease stage 
6.2.5.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NYHA Class 
6.2.5.3 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Echocardiogram 
6.2.5.4 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
CMR, technetium (select sites only) 
6.2.5.6, 
6.2.5.5 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
X 
Norfolk QoL-DN 
6.2.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
 
 
 
  
 
 
 
 
X 
 
 
 
 
  
 
 
 
 
X 
Exploratory Biomarkers (plasma, 
serum) 
6.6  
 
 
 
 
  
 
 
 
 
X 
 
 
 
 
  
 
 
 
 
X 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Weight 
6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (symptom-directed) 
6.5.3 
 
 
 
 
  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Single 12-lead ECG 
6.5.4  
 
 
 
 
  
 
 
 
  
X 
 
 
 
 
X 
 
 
 
 
X 
Serum Chemistry, Liver Function 
Tests 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Xb 
Hematology 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pregnancy Test 
Table 5, 
6.5.5.2 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Review/Record Hospitalization, 
Urgent HF Visits, Urgent Care Visits, 
and Procedures 
 
-------------------------------------------------------------------X------------------------------------------------------------------------- 
Review/Record AEs, Con Meds 
6.5.7, 5.3 
-------------------------------------------------------------------X------------------------------------------------------------------------- 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
17 
Table 3: 
Year 3 Schedule of Assessments:  Open-label Extension Period (Through Month 36)  
Study Day  
±Visit Window 
  
Open-label Extension Period  
For 
Details 
see 
Section 
D757±3 
D778±3 
D799±3 
D820±3 
D841±3 
D862±3 
D883±3 
D904±3 
D925±3 
D932-D938a 
D946±3 
D967±3 
D988±3 
D1009±3 
D1016-D1022a 
D1030±3 
D1051±3 
D1072±3 
D1093±3 
D1100-D1106a 
Study Week 
 
108 
111 
114 
117 
120 
123 
126 
129 
132 
133-134 
135 
138 
141 
144 
145-146 
147 
150 
153 
156 
157-158 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
 6.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication, Study Drug 
5.2.1, 
5.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; COVID-19=coronavirus disease 2019; CMR=cardiac 
magnetic resonance; D=day; ECG=electrocardiogram; HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire; mBMI=modified body mass 
index; 6-MWT=6-minute walk test; NT-proBNP=N-terminal prohormone B-type natriuretic peptide; NYHA=New York Heart Association; 
PK=pharmacokinetics; QoL-DN=Quality of Life-Diabetic Neuropathy; TTR=transthyretin; V=visits.  
a  This efficacy visit is conducted 7 to 14 days after the prior visit.  In situations where a Week 133-134 (Day 932-938), Week 145-146 (Day 1016-1022), and/or 
Week 157-158 (Day 1100-1106) study visit is unable to be completed at the study center, the Medical Monitor should be consulted as soon as possible to 
determine the appropriate timing of the efficacy assessments for those visits.  After consultation with the Medical Monitor, efficacy assessments may be 
extended as follows:  Day 932-938 up to Day 977; Day 1016-1022 up to Day 1061; Day 1100-1106 up to Day 1148.   
b Serum creatinine only. 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
18 
Table 4: 
Year 4 Schedule of Assessments:  Open-label Extension Period (Through Month 48), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
EOSa 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D1114±3 
D1135±3 
D1156±3 
D1177±3 
D1198±3 
D1219±3 
D1240±3 
D1261±3 
D1282±3 
D1289-D1295a 
D1303±3 
D1324±3 
D1345±3 
D1366±3 
D1387±3 
D1408±3 
D1429±3 
D1450±3 
D1457-D1463a 
7- 14 Days 
after Last 
Dose 
D1478±10 
Study Week 
 
159 
162 
165 
168 
171 
174 
177 
180 
183 
184-185 
186  
189 
192 
195 
198 
201 
204 
207 
208-209 
NA 
211 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
KCCQ 
6.2.2 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
mBMI 
6.2.4 
 
 
 
 
 
 
  
 
 
X 
 
 
 
 
 
  
 
 
X 
X 
 
Cardiac Biomarker 
Samples 
6.2.5.1 
 
 
 
 
  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
ATTR amyloidosis 
disease stage 
6.2.5.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
NYHA Class 
6.2.5.3 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Echocardiogram 
6.2.5.4 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
CMR, technetium (select 
sites only) 
6.2.5.6, 
6.2.5.5 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
X 
 
 
Norfolk QoL-DN 
6.2.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacodynamic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
 
 
 
  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Exploratory Biomarkers 
(plasma, serum) 
6.6  
 
 
 
 
  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (symptom-
directed) 
6.5.3 
 
 
 
 
  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Single 12-lead ECG 
6.5.4  
 
 
 
 
  
 
 
 
  
X 
 
 
 
  
 
 
 
 
X 
X 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
19 
Table 4: 
Year 4 Schedule of Assessments:  Open-label Extension Period (Through Month 48), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
EOSa 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D1114±3 
D1135±3 
D1156±3 
D1177±3 
D1198±3 
D1219±3 
D1240±3 
D1261±3 
D1282±3 
D1289-D1295a 
D1303±3 
D1324±3 
D1345±3 
D1366±3 
D1387±3 
D1408±3 
D1429±3 
D1450±3 
D1457-D1463a 
7- 14 Days 
after Last 
Dose 
D1478±10 
Study Week 
 
159 
162 
165 
168 
171 
174 
177 
180 
183 
184-185 
186  
189 
192 
195 
198 
201 
204 
207 
208-209 
NA 
211 
Serum Chemistry, Liver 
Function Tests 
6.5.5 
 
 
 
 
 
 
  
 
 
X 
 
 
 
 
 
  
 
 
X 
X 
X 
Hematology 
6.5.5 
 
 
 
 
 
 
  
 
 
X 
 
 
 
 
 
  
 
 
X 
X 
X 
Pregnancy Test 
Table 5, 
6.5.5.2 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Review/Record 
Hospitalization, Urgent 
HF Visits, Urgent Care 
Visits, and Procedures 
 
-----------------------------------------------------------------------X----------------------------------------------------------------------------- 
Review/Record AEs,  
Con Meds 
6.5.7, 
5.3 
-----------------------------------------------------------------------X----------------------------------------------------------------------------- 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
 6.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication, Study 
Drug 
5.2.1, 
5.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; COVID-19=coronavirus disease 2019; CMR=cardiac 
magnetic resonance; D=day; Disc=discontinuation; ECG=electrocardiogram; EOS=End of Study (visit); HF=heart failure; KCCQ=Kansas City Cardiomyopathy 
Questionnaire; mBMI=modified body mass index; 6-MWT=6-minute walk test; NA=not applicable; NT-proBNP=N-terminal prohormone B-type natriuretic 
peptide; NYHA=New York Heart Association; PK=pharmacokinetics; QoL-DN=Quality of Life-Diabetic Neuropathy; TTR=transthyretin; V=visits.  
a  This efficacy visit is conducted 7 to 14 days after the prior visit.  This EOS visit will also be completed by patients who have completed Year 2 of the study and 
who transition to commercial patisiran (ie, patisiran is commercially available in the patient’s country of residence and patisiran is accessible to the patient); 
these patients do not need to complete efficacy assessments if those assessments were completed within the prior 3 months; consecutive CMR scans should not 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
20 
be performed within 5 months of each other; consecutive technetium scans should not be performed within 5 months of each other.  In situations where a 
Week 184-185 (Day 1289-1295) and/or Week 208-209 (Day 1457-1463) study visit is unable to be completed at the study center, the Medical Monitor should 
be consulted as soon as possible to determine the appropriate timing of the efficacy assessments for those visits.  After consultation with the Medical Monitor, 
efficacy assessments may be extended as follows:  Day 1289-1295 up to Day 1337; Day 1457-1463 up to Day 1488. 
b Patients who discontinue early from study drug will be asked to complete the Early Treatment Discontinuation Visit (7-14 days after their last dose) and the 
safety follow-up visit, 28 days after the last dose of study drug.  In addition, patients discontinuing early from study drug during the double-blind period will be 
encouraged to remain on the study and complete assessments through Month 12 and complete the Modified Month 12 Efficacy Visit (see Table 1); they will 
also be asked to complete an Early Treatment Discontinuation Visit (7-14 days after their last dose) and the safety follow-up visit, 28 days after the last dose of 
study drug as described in Section 4.3.1. 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
21 
TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................21 
LIST OF TABLES .........................................................................................................................25 
LIST OF FIGURES .......................................................................................................................25 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................26 
1. 
INTRODUCTION ......................................................................................................29 
1.1. 
Disease Overview .......................................................................................................29 
1.2. 
Current Treatments .....................................................................................................30 
1.3. 
Patisiran Clinical Development ..................................................................................31 
1.3.1. 
The Phase 3 APOLLO Study ......................................................................................32 
1.3.1.1. 
Cardiac Results and Cardiac Subpopulation Data from APOLLO ............................32 
1.3.2. 
Phase 3, Open-label Extension Study .........................................................................33 
1.4. 
Study Design Rationale ..............................................................................................33 
1.5. 
Dose Rationale ............................................................................................................34 
1.6. 
Benefit-risk Assessment .............................................................................................34 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................36 
3. 
INVESTIGATIONAL PLAN .....................................................................................37 
3.1. 
Summary of Study Design ..........................................................................................37 
3.2. 
Duration of Treatment ................................................................................................39 
3.3. 
Duration of Study Participation ..................................................................................39 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................39 
3.4. 
Number of Planned Patients .......................................................................................39 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................39 
3.6. 
Blinding ......................................................................................................................39 
3.6.1. 
Emergency Unblinding ...............................................................................................40 
3.7. 
Data Monitoring Committee .......................................................................................40 
3.8. 
Adjudication Committee .............................................................................................40 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................41 
4.1. 
Inclusion Criteria ........................................................................................................41 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
22 
4.2. 
Exclusion Criteria .......................................................................................................42 
4.3. 
Removal from Study Drug or Assessment .................................................................44 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................44 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................46 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................46 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................46 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................46 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................47 
4.3.3. 
Lost to Follow-up .......................................................................................................47 
4.3.4. 
Replacement of Study Patients ...................................................................................47 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................47 
5.1. 
Treatments Administered ............................................................................................47 
5.2. 
Study Drug ..................................................................................................................47 
5.2.1. 
Premedication .............................................................................................................48 
5.2.2. 
Study Drug Description ..............................................................................................49 
5.2.3. 
Dose and Administration ............................................................................................49 
5.2.3.1. 
Double-blind Study Drug (Patisiran or Placebo) ........................................................49 
5.2.3.2. 
Open-label Extension Period (Patisiran) ....................................................................50 
5.2.4. 
Suggested Guidelines for Management of Infusion-related Reactions ......................50 
5.2.5. 
Dose Modifications .....................................................................................................51 
5.2.6. 
Preparation, Handling, and Storage ............................................................................51 
5.2.7. 
Packaging and Labeling ..............................................................................................51 
5.2.8. 
Accountability .............................................................................................................52 
5.3. 
Concomitant Medications and Procedures .................................................................52 
5.3.1. 
Concomitant Tafamidis Use .......................................................................................52 
5.4. 
Treatment Compliance ................................................................................................53 
5.5. 
Other Requirements ....................................................................................................53 
5.5.1. 
Contraception ..............................................................................................................53 
6. 
STUDY ASSESSMENTS ..........................................................................................54 
6.1. 
Screening Assessments ...............................................................................................54 
6.1.1. 
Retesting .....................................................................................................................55 
6.1.2. 
Rescreening .................................................................................................................55 
6.2. 
Efficacy Assessments .................................................................................................56 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
23 
6.2.1. 
6-Minute Walk Test (6-MWT) ...................................................................................56 
6.2.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ...............................................57 
6.2.3. 
Deaths, Hospitalizations, and Urgent Heart Failure Visits .........................................57 
6.2.4. 
Modified Body Mass Index (mBMI) ..........................................................................57 
6.2.5. 
Cardiac Assessments ..................................................................................................58 
6.2.5.1. 
Cardiac Biomarkers ....................................................................................................58 
6.2.5.2. 
ATTR Amyloidosis Disease Stage .............................................................................58 
6.2.5.3. 
New York Heart Association (NYHA) Class .............................................................58 
6.2.5.4. 
Echocardiogram ..........................................................................................................58 
6.2.5.5. 
Technetium Scintigraphy Imaging .............................................................................59 
6.2.5.6. 
Cardiac Magnetic Resonance (CMR) .........................................................................59 
6.2.6. 
Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QoL-DN) .........................59 
6.2.7. 
Polyneuropathy Disability (PND)...............................................................................60 
6.3. 
Pharmacodynamic Assessments .................................................................................60 
6.4. 
Pharmacokinetic Assessments ....................................................................................60 
6.5. 
Safety Assessments .....................................................................................................61 
6.5.1. 
Vital Signs ..................................................................................................................61 
6.5.2. 
Weight and Height ......................................................................................................62 
6.5.3. 
Physical Examination .................................................................................................62 
6.5.4. 
Electrocardiogram .......................................................................................................62 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................62 
6.5.5.1. 
Immunogenicity ..........................................................................................................63 
6.5.5.2. 
Pregnancy Testing ......................................................................................................64 
6.5.6. 
Vital Status Check ......................................................................................................64 
6.5.7. 
Adverse Events ...........................................................................................................64 
6.5.7.1. 
Definitions ..................................................................................................................64 
6.5.7.2. 
Eliciting and Recording Adverse Events ....................................................................66 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................67 
6.5.7.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........67 
6.5.7.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................67 
6.5.7.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................67 
6.5.7.7. 
Pregnancy Reporting ..................................................................................................67 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
24 
6.5.7.8. 
Overdose Reporting ....................................................................................................68 
6.5.8. 
COVID-19 Data Collection ........................................................................................68 
6.6. 
Biomarkers and Biospecimen Repository ..................................................................68 
7. 
STATISTICS ..............................................................................................................69 
7.1. 
Determination of Sample Size ....................................................................................69 
7.2. 
Statistical Methodology ..............................................................................................69 
7.2.1. 
Populations to be Analyzed ........................................................................................69 
7.2.2. 
Examination of Subgroups .........................................................................................70 
7.2.3. 
Handling of Missing Data ...........................................................................................70 
7.2.4. 
Baseline Evaluations ...................................................................................................70 
7.2.5. 
Efficacy Analyses .......................................................................................................70 
7.2.5.1. 
Primary Endpoint ........................................................................................................70 
7.2.5.2. 
Secondary Endpoints ..................................................................................................71 
7.2.5.3. 
Exploratory Endpoints ................................................................................................71 
7.2.6. 
Pharmacodynamic Analysis........................................................................................71 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................71 
7.2.7.1. 
Pharmacokinetic Analysis ..........................................................................................71 
7.2.7.2. 
Exposure-Response Analysis......................................................................................72 
7.2.7.3. 
Population PK, PK/PD, and Disease Progression Modelling Analysis ......................72 
7.2.8. 
Safety Analyses ..........................................................................................................72 
7.2.9. 
Immunogenicity Analyses ..........................................................................................72 
7.2.10. 
Sample Size Re-assessment ........................................................................................73 
7.2.11. 
Optional Additional Research .....................................................................................73 
8. 
STUDY ADMINISTRATION ...................................................................................73 
8.1. 
Ethical and Regulatory Considerations ......................................................................73 
8.1.1. 
Informed Consent and Medical Records Release Form .............................................73 
8.1.2. 
Ethical Review ............................................................................................................74 
8.1.3. 
Serious Breach of Protocol .........................................................................................74 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................74 
8.1.5. 
End of Study ...............................................................................................................75 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................75 
8.2. 
Data Quality Control and Quality Assurance .............................................................75 
8.2.1. 
Data Handling .............................................................................................................75 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
25 
8.2.2. 
Study Monitoring ........................................................................................................76 
8.2.3. 
Audits and Inspections ................................................................................................76 
8.3. 
Publication Policy .......................................................................................................76 
9. 
LIST OF REFERENCES ............................................................................................77 
10. 
APPENDICES ............................................................................................................81 
10.1. 
Polyneuropathy Disability (PND) Scores ...................................................................81 
10.2. 
New York Heart Association Class (NYHA) .............................................................81 
10.3. 
Categorization of Infusion-Related Reactions ............................................................81 
 
LIST OF TABLES 
Table 1: 
Year 1 Schedule of Assessments:  Double-blind Period (Screening to Month 
12 Efficacy Assessments) ...........................................................................................10 
Table 2: 
Year 2 Schedule of Assessments:  Open-label Extension Period (Through 
Month 24) ...................................................................................................................14 
Table 3: 
Year 3 Schedule of Assessments:  Open-label Extension Period (Through 
Month 36) ...................................................................................................................16 
Table 4: 
Year 4 Schedule of Assessments:  Open-label Extension Period (Through 
Month 48), Early Treatment Discontinuation Visit, and Follow-up ..........................18 
Table 5: 
Clinical Laboratory Assessments ...............................................................................63 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
26 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALN-18328 
siRNA targeting TTR 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APOLLO 
Patisiran pivotal Phase 3 clinical study ALN-TTR02-004 
AST 
Aspartate aminotransferase 
ATTR 
Amyloid transthyretin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CHF 
Congestive heart failure 
Cmax 
Maximum plasma concentration at end of infusion 
Cmax,ss 
Steady-state Cmax   
Cmin 
Minimum pre-infusion concentration 
Cmin,ss 
Steady-state Cmin   
CMR 
Cardiac magnetic resonance 
Con Meds 
Concomitant medication 
COVID-19  
Coronavirus disease 2019 
Cp(30min) 
30-minute post-infusion concentration 
Cp,ss(30min) 
Steady-state Cp(30min) 
CRF 
Case report form 
CFR 
Code of Federal Regulations 
CV 
Cardiovascular 
DLin-MC3-DMA  
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DMC 
Data Monitoring Committee 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunoassay 
EOS 
End of study 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
27 
Abbreviation  
Definition 
EU 
European Union 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
H1 
Histamine 1 receptor 
H2 
Histamine 2 receptor 
hATTR 
Hereditary ATTR 
HF 
Heart failure 
ICF 
Informed consent form  
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IRS 
Interactive Response System 
IV 
Intravenous(ly) 
KCCQ 
Kansas City Cardiomyopathy Questionnaire  
KCCQ-OS 
Kansas City Cardiomyopathy Questionnaire– Overall Summary 
LNP 
Lipid nanoparticle 
LS 
Least squares 
mBMI 
Modified body mass index 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGUS 
Monoclonal gammopathy of undetermined significance 
MMRM 
Mixed-effects model repeated measures 
mNIS+7 
Modified neurological impairment score +7 
mRNA 
Messenger ribonucleic acid 
6-MWT 
6-minute walk test 
NA 
Not applicable 
Norfolk QoL-DN 
Norfolk Quality of Life - Diabetic Neuropathy 
NSAID 
Nonsteroidal anti-inflammatory drug 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
28 
Abbreviation  
Definition 
NT-proBNP 
N-terminal prohormone B-type natriuretic peptide 
NYHA 
New York Heart Association 
OLT 
Orthotopic liver transplantation 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PEG2000-C-DMG 
3-N-[(ω-methoxy poly(ethylene glycol)2000) carbamoyl]-1,2-
dimyristyloxy-propylamine 
PK 
Pharmacokinetic 
PND 
Polyneuropathy disability 
PT 
Preferred term 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RISC 
RNA-induced silencing complex 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
siRNA 
Small interfering RNA 
Tc 
Technetium 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
US 
United States 
V30M 
Valine to methionine mutation at position 30 
V122I 
Valine to isoleucine mutation at position 122 
wt 
Wild type 
wtTTR 
Wild type transthyretin 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
29 
1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) is a rare, serious, life-
threatening, multisystemic disease encompassing hereditary ATTR (hATTR) amyloidosis and 
wild-type ATTR (wtATTR) amyloidosis, which result from either hereditary (genetic mutation) 
or nonhereditary (ageing) causes, respectively.  In ATTR amyloidosis, deposition of TTR in 
various organs results in progressive, chronically debilitating morbidity and mortality.  The most 
common manifestations of ATTR amyloidosis are polyneuropathy and cardiomyopathy (ie, 
ATTR amyloidosis with cardiomyopathy). 
TTR, also known as prealbumin, is a tetrameric protein produced by hepatocytes, the choroid 
plexus, and retina.[Liz 2010]  More than 95% of TTR in the circulation is derived from the liver.  
The primary physiological role of TTR is to serve as a carrier of retinol (also known as vitamin 
A), which involves TTR binding to the retinol binding protein (RBP): vitamin A complex.  
However, there is evidence to suggest that vitamin A transport and tissue uptake can occur in the 
absence of circulating RBP.[Biesalski 1999; Episkopou 1993] 
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 amyloidosis, and 
almost all patients are heterozygous for the mutated TTR allele.[Ando 2013; Connors 2003]  The 
phenotypic expression varies depending on the predominant site of deposition of the amyloid 
fibrils with some mutations associated with predominantly polyneuropathy manifestations and 
others associated with predominantly cardiomyopathy manifestations.  However, most patients 
experience both over the course of their disease.   
The most common TTR mutation is the valine to methionine mutation at position 30 (V30M), 
accounting for approximately 50% of cases worldwide, and occurring primarily in families with 
heritage from Portugal, Sweden, Japan, and Brazil.[Parman 2016]  This genotype is most 
commonly associated with multisystemic polyneuropathy.  The valine to isoleucine at position 
122 (V122I) mutation is most commonly associated with cardiomyopathy and occurs primarily 
in African Americans.  In these individuals, the mean age at diagnosis is approximately 65 to 
70 years, with symptom onset typically occurring after the age of 65.[Jacobson 2011; Quarta 
2015]  While there appears to be an association between carrier status and the development of 
heart failure (HF) and echocardiographic features of cardiac amyloidosis, the exact penetrance of 
this particular allele is unknown, and estimates vary widely. 
Normal, nonmutant wtTTR alone can also be amyloidogenic; this is the basis for the 
nonhereditary, wtATTR amyloidosis.  This is a progressive disease typically seen in patients 
older than 70 years and is predominantly seen in men.[Westermark 2003]  Patients with this 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
30 
condition do not have a pathogenic mutation in the TTR gene and the amyloid fibrils consist only 
of wtTTR protein, which form amyloid deposits typically found in heart tissue.   
Cardiac infiltration of the extracellular matrix by TTR amyloid fibrils leads to a progressive 
increase of ventricular wall thickness and a marked increase in chamber stiffness, resulting in 
impaired diastolic function.  Systolic function is also impaired, typically reflected by abnormal 
longitudinal strain despite a normal ejection fraction, which is preserved until late stages of the 
disease.[Castano 2015; Dungu 2012; Mohty 2013; Ruberg 2012]  Cardiac infiltration by amyloid 
can also lead to conduction disturbances and arrhythmias.[Adams 2016; Ando 2013; Benson and 
Kincaid 2007; Connors 2004]  Patients with symptomatic HF experience rapid progression of 
their amyloidosis with cardiomyopathy, with substantial worsening of echocardiographic and 
biomarker measures of cardiac function, in addition to clinical measurements of ambulation, and 
quality of life.  Progression of disease in this population can be seen over a period of 12 months 
as demonstrated by differences in 6-minute walk test (6-MWT) and Kansas City 
Cardiomyopathy Questionnaire (KCCQ) – Overall Summary (KCCQ-OS) in the Phase 3 ATTR-
ACT study.[Maurer 2018]  Based on natural history data, patients typically experience 
progressive symptoms of HF resulting in hospitalization and with death typically occurring 2.5 to 
5 years after diagnosis.[Castano 2015; Damy 2015; Dungu 2012; Hawkins 2015] 
1.2. 
Current Treatments 
The treatment of ATTR amyloidosis requires a multidisciplinary approach primarily involving 
cardiology, neurology, and gastroenterology specialties.  While there are treatments for 
polyneuropathy that are available to hATTR amyloidosis patients, for most regions no treatments 
are currently available for the cardiomyopathy phenotype for either the hATTR or wtATTR 
forms.  Palliative/symptomatic therapies directed at specific symptoms, including volume control 
and treatment of cardiac arrhythmias and conduction system disturbances, including cardiac 
pacemakers where appropriate, have been the mainstay of treatment despite their limited 
effectiveness. 
Given that the liver is the primary source of TTR, orthotopic liver transplantation (OLT) has 
been used for hATTR amyloidosis patients since the early 1990s.  However, OLT is intended to 
eliminate mutant TTR from circulation, but has no effect on the hepatic production of wtTTR, 
which continues to be made by the transplanted liver and can continue to deposit in the heart.  
OLT has also only been shown to be effective in slowing the progression of disease in patients 
with an early age of onset (<50 years of age) [Okamoto 2009], and especially for those with the 
V30M mutation and short disease duration before transplant.  Consequently, almost two-thirds of 
patients with hATTR amyloidosis are not transplant-eligible.   
Tafamidis, a TTR tetramer stabilizer that acts by binding to the thyroxine-binding site on TTR to 
reduce its dissociation into misfolded amyloidogenic monomers, is currently approved in a 
number of markets, but not in the United States (US), for the treatment of patients with hATTR 
amyloidosis with polyneuropathy.[Coelho 2016]  In addition, tafamidis has been approved in 
some regions, including the European Union (EU) and US, for the treatment of patients with 
ATTR amyloidosis (hereditary and wt) with cardiomyopathy based on results from the Phase 3 
ATTR-ACT trial.[Maurer 2018]  In Japan, tafamidis was approved for use in transthyretin-type 
cardiac amyloidosis (wt and mutant), in addition to approval for transthyretin-type familial 
amyloid polyneuropathy.  The ATTR-ACT trial demonstrated that tafamidis treatment over 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
31 
30 months was associated with lower all-cause mortality and cardiovascular (CV)-related 
hospitalizations compared with placebo treatment.[Maurer 2018]  Additionally, tafamidis 
treatment resulted in a slowing of the decline in functional capacity (6-MWT) and quality of life 
(KCCQ-OS) compared to placebo.  However, consistent with the expected pharmacodynamic 
(PD) effect of TTR stabilization, the effects of tafamidis on mortality outcomes was not observed 
until late in treatment, with differentiation between treatment groups occurring only after 18 
months of treatment.  Furthermore, although improvements with tafamidis relative to placebo 
were observed in 6-MWT and KCCQ-OS, minimal changes in echocardiographic parameters 
were observed, and tafamidis-treated patients still progressed during the study.   
The results of the ATTR-ACT study support the general therapeutic hypothesis that modifying 
TTR has the potential to result in beneficial outcomes in patients with ATTR amyloidosis with 
cardiomyopathy.  However, the disease progression that was observed in both treatment arms in 
ATTR-ACT highlights an important unmet medical need and suggests that a more direct 
therapeutic mechanism of action, such as specifically targeting the production of the disease-
causing protein with a ribonucleic acid (RNA) interference (RNAi) therapeutic, may be required 
to halt or reverse the debilitating and ultimately fatal course of disease.    
1.3. 
Patisiran Clinical Development 
Patisiran is a small interfering RNA (siRNA) specific for TTR, which is formulated in a 
hepatotropic lipid nanoparticle (LNP) for intravenous (IV) administration.[Akinc 2010]  The 
patisiran drug product (ALN-TTR02; patisiran-LNP, hereafter referred to as “patisiran”) is 
designed to significantly suppress liver production of both wt and all mutant forms of TTR, 
thereby having the potential to reduce amyloid formation and provide clinical benefit to patients 
with ATTR amyloidosis.   
Patisiran utilizes the mechanism of RNAi to selectively degrade TTR messenger RNA (mRNA) 
and thereby reduce the expression of its corresponding protein.[Bumcrot 2006] Patisiran is 
formulated (via the 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 Pharmaceuticals, Inc. (the Sponsor) is developing patisiran for the treatment of patients 
with ATTR amyloidosis.  Based on results from the pivotal Phase 3 APOLLO study 
(Section 1.3.1), patisiran 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.  Ongoing development is intended to establish 
patisiran for the treatment of ATTR (hereditary and wt) amyloidosis with cardiomyopathy based 
on exploratory cardiac results from the APOLLO study (Section 1.3.1.1), which provides 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
32 
preliminary evidence in support of the use of patisiran for the treatment of the cardiomyopathy 
manifestations of the disease.  
The nonclinical pharmacology, pharmacokinetics (PK), and toxicology of patisiran were 
evaluated in a series of in vitro and in vivo studies that have enabled chronic dosing in clinical 
studies.   
1.3.1. 
The Phase 3 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 (modified neurological 
impairment score +7 [mNIS+7]) relative to placebo at 18 months (primary endpoint), as well as 
significant improvement in quality of life (Norfolk Quality of Life - Diabetic Neuropathy 
[Norfolk QoL-DN], key secondary endpoint) 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.    
In the patisiran group, serum TTR reduction was seen after the first dose and was stably 
maintained over the duration of the study; the mean TTR percent reduction from baseline was 
82.6% and 84.3% at Months 9 and 18, respectively.  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). 
1.3.1.1. 
Cardiac Results and Cardiac Subpopulation Data from APOLLO 
In APOLLO, evidence of potential cardiac amyloid involvement was seen in most patients in the 
study; 80% had left ventricular wall thickness >13 mm and 79% had abnormal levels of the 
cardiac biomarker N-terminal prohormone B-type natriuretic peptide (NT-proBNP).[Solomon 
2018]  As well, 56% of the population met the prespecified criteria for inclusion in a 
subpopulation of patients with evidence of cardiac amyloid involvement (ie, the cardiac 
subpopulation, with baseline left ventricular wall thickness ≥13 mm and no history of 
hypertension or aortic valve disease).  In these patients, treatment with patisiran for up to 
18 months resulted in improvement relative to placebo in important measures of cardiac structure 
and function.  These included reduction in ventricular wall thickness and decrease 
(improvement) in global longitudinal strain.[Solomon 2018]  In addition, patisiran treatment led 
to a reduction (improvement) in NT-proBNP and an improvement in functional capacity, as 
measured by 10-meter walk test assessment of gait speed, relative to the placebo group.   
Overall, patisiran had an acceptable safety profile, based on an in-depth analysis of cardiac 
events in both the overall (modified intent-to-treat) population and the cardiac subpopulation.  
Importantly, in a post hoc analysis of safety data in the modified intent-to-treat population, rates 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
33 
of any hospitalization and/or all-cause death were 71.8 and 34.7 per 100 patient-years in the 
placebo and patisiran groups respectively, while the rates of cardiac hospitalizations and/or 
all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups 
respectively.  This approximates a reduction in event rate of approximately 50% for all-cause 
hospitalization and mortality and approximately 45% for cardiac hospitalization and all-cause 
mortality for patients in the patisiran group compared to those in the placebo group.[Solomon 
2018]  Similar reductions in the event rates were observed in the cardiac subpopulation in 
APOLLO (approximately 55% for all-cause hospitalization and mortality and approximately 
45% for cardiac hospitalization and all-cause mortality; data on file). 
The observed cardiac data from the APOLLO study support the therapeutic hypothesis that 
patisiran may halt or reverse the progression of the cardiac manifestations of hATTR 
amyloidosis and warrant ongoing development for this indication. 
1.3.2. 
Phase 3, Open-label Extension Study 
Study ALN-TTR02-006 is an ongoing multicenter, open-label extension study designed to 
evaluate the long-term safety and efficacy of patisiran in patients with hATTR amyloidosis who 
have completed a prior Phase 2 or 3 parent study with patisiran (ALN-TTR02-003 or ALN-
TTR02-004 [APOLLO]).  The interim data from this open-label extension study were consistent 
with, and extended, the acceptable safety profile and clinical efficacy of patisiran observed in the 
Phase 3 APOLLO study.   
No new safety signals have emerged for patients with long-term patisiran treatment. 
1.4. 
Study Design Rationale 
This study is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study 
designed to evaluate the efficacy and safety of patisiran in adult patients with ATTR amyloidosis 
with cardiomyopathy.  The efficacy of patisiran on functional capacity will be evaluated via 
change at Month 12 in the 6-MWT (primary endpoint).  The study will include patients with 
wtATTR and hATTR amyloidosis with cardiomyopathy who, at baseline, are either tafamidis 
naïve or have been on tafamidis for ≥6 months with disease progression, in the opinion of the 
Investigator.   
Confidence in a beneficial treatment effect with patisiran in this patient population with ATTR 
amyloidosis with cardiomyopathy comes from the Phase 3 APOLLO study of patisiran in 
patients with hATTR amyloidosis with polyneuropathy.  As described in Section 1.3.1 and 
Section 1.3.1.1, TTR lowering with patisiran demonstrated multiple benefits in a broad range of 
disease manifestations, including a substantial improvement in neuropathy and quality of life, as 
well as autonomic symptoms, motor strength, ambulatory ability, disability, and nutritional 
status.[Adams 2018]  Furthermore, in a prespecified subgroup of patients with evidence of 
cardiac involvement, which was a majority (56%) of the overall study population, a beneficial 
treatment effect of patisiran compared to placebo was observed for assessments of cardiac 
structure and function as well as the cardiac biomarker NT-proBNP.[Solomon 2018]   
The 6-MWT (primary endpoint assessment) is a clinically relevant assessment of functional 
capacity that has been used as a primary endpoint in pivotal clinical trials in pulmonary arterial 
hypertension (Gabler 2012) and has been used in the evaluation of patients with HF.[Bittner 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
34 
1993; Flynn 2009; Flynn 2012; Mangla 2013; Masoudi 2004; Maurer 2014]  The KCCQ-OS 
(first secondary endpoint assessment) has been used as a common assessment in HF 
interventional studies and has been shown to be an independent predictor of prognosis in 
HF.(Heidenreich et al.  2006)  Both 6-MWT and KCCQ-OS were shown to rapidly and 
consistently decline over time in cardiac ATTR amyloidosis patients and, in the Phase 3 ATTR-
ACT study, these measures were used to demonstrate a reduction of decline with tafamidis 
treatment.[Maurer 2018]  These data support the use of 6-MWT and KCCQ-OS as clinically 
relevant primary and key secondary endpoints, respectively.   
Assessment of the primary endpoint at Month 12 is supported by placebo-arm data from the 
ATTR-ACT study showing substantial disease progression (via the 6-MWT) over an equivalent 
time; as well, data from APOLLO demonstrated a patisiran treatment effect as early as 9 months 
on multiple manifestations of hATTR amyloidosis (neuropathy, quality of life, NT-proBNP, and 
functional capacity [ie, gait speed]).[Maurer 2018] 
The inclusion of placebo as a control allows for a rigorous analysis of the treatment effect of 
patisiran.  If tafamidis becomes an approved therapy for ATTR amyloidosis with 
cardiomyopathy in a given region while this study is in progress, patients who are naïve to 
tafamidis treatment at baseline may commence concomitant on-label tafamidis during the study 
(ie, tafamidis drop-in) (Section 5.3.1).    
1.5. 
Dose Rationale 
The approved and recommended dosage of patisiran for the treatment of the polyneuropathy in 
patients with hATTR amyloidosis is 0.3 mg/kg administered IV every 3 weeks for patients 
weighing <100 kg and a fixed dose of 30 mg administered every 3 weeks for patients weighing 
100 kg or more.  This dosage was selected based on dose-response analyses from three Phase 1 
and 2 studies demonstrating dose-dependent TTR reduction, with the maximum reduction 
achieved at 0.3 mg/kg.  This regimen was further confirmed in the pivotal Phase 3 APOLLO 
study, where this dosage showed significant clinical activity and was well tolerated by patients 
with hATTR amyloidosis with polyneuropathy, including those in the cardiac subpopulation.  
The approved dosing regimen used in the treatment of polyneuropathy is being employed in this 
study since the mechanism of action of patisiran (ie, serum TTR lowering) for treatment of 
polyneuropathy and cardiomyopathy is the same.  
1.6. 
Benefit-risk Assessment 
ATTR amyloidosis with cardiomyopathy is a rare, serious, life-threatening, multisystemic 
disease characterized by deposition of TTR in various organs.  Without treatment, the disease 
progresses, resulting in chronically debilitating morbidity and mortality, with the most common 
manifestations being cardiomyopathy and polyneuropathy.  Patients with symptomatic HF 
experience rapid progression of their amyloidosis with 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]   
The benefit-risk profile of patisiran has been established in extensive clinical development; in 
Phase 1, 2, and 3 clinical studies, patisiran administered IV demonstrated a potent, 
dose-dependent inhibition of TTR.  In the Phase 3 APOLLO study of patisiran, the primary and 
all secondary endpoints were met.[Adams 2018]  Furthermore, exploratory cardiac results from 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
35 
the APOLLO study suggest that patisiran may halt or reverse the progression of the cardiac 
manifestations of hATTR amyloidosis [Solomon 2018] and provide preliminary evidence in 
support of the use of patisiran for the treatment of patients with ATTR amyloidosis with 
cardiomyopathy (Section 1.3.1.1). 
In APOLLO, as well as in the ongoing Phase 3, open-label extension study (ALN-TTR02-006), 
an acceptable safety profile with patisiran was demonstrated.  Most AEs were mild or moderate 
in severity.  Transient infusion-related reactions (IRRs) were observed, but all IRRs were mild or 
moderate in severity, none were reported as serious AEs (SAEs).  No clinically significant 
laboratory or hematologic changes were observed.  Furthermore, in APOLLO, an acceptable 
safety profile was also observed in a prespecified subgroup of patients with evidence of cardiac 
amyloid involvement. [Solomon 2018] 
For patisiran, important identified risks include IRRs.  To minimize this risk, all patients must 
receive premedication with a corticosteroid, paracetamol/acetaminophen, and H1 and H2 
blockers prior to patisiran administration (Section 5.2.1).  The infusion may be interrupted or 
slowed if an IRR occurs (Sections 5.2.3 and 5.2.4).  Important potential risks also include severe 
hypersensitivity (eg, anaphylaxis) to the active substance or any of the excipients.  Patisiran is 
contraindicated in patients with a history of severe hypersensitivity (eg, anaphylaxis or 
anaphylactoid reactions) to patisiran or any of the excipients. 
Vitamin A deficiency is also considered an important potential risk.  Nonclinical and clinical 
data with patisiran have shown that the lowering of circulating vitamin A associated with the 
reduction in TTR (a carrier of retinol) does not result in 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 (Section 5.3).  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 patisiran.  
Detailed information about the known and expected benefits and risks of patisiran may be found 
in the current edition of the Investigator’s Brochure.  
During the study, patients will be monitored, including evaluation of laboratory monitoring for 
liver function test abnormalities, renal function, and other standard hematology and blood 
chemistries.  As the risk of embryofetal toxicity is currently unknown, females of child-bearing 
potential participating in the study must have a negative pregnancy test, cannot be breast feeding, 
and must be willing to use a highly effective method of contraception as specified in the 
protocol. 
An external, independent Data Monitoring Committee (DMC) will monitor and ensure the safety 
of trial participants (see Section 3.7).   
In conclusion, exploratory cardiac results from the APOLLO study suggesting that patisiran may 
halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis [Solomon 
2018] (Section 1.3.1.1) together with the established benefit-risk profile of patisiran 
demonstrated in the Phase 3 APOLLO study (and supportive data from the ALN-TTR02-003 and 
ALN-TTR02-006 studies), support the evaluation of patisiran in a Phase 3 study in adult patients 
with ATTR amyloidosis (wtATTR and hATTR) cardiomyopathy.   

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
38 
During the open-label extension period, all patients will receive treatment with open-label 
patisiran.   
Study drug administration at a location other than the study center (eg, at home) may be 
administered as follows: 
• Double-blind period:  Patients who have received ≥2 doses of study drug at the study 
center with no evidence of IRRs or other drug-related adverse effects that impact safety 
and tolerability of the infusion may have study drug administered at a location other than 
the study center (eg, at home), where applicable country and local regulations allow.  
Study drug administration will be performed by a healthcare professional, trained on the 
protocol and on administration of premedications and study drug infusion, with oversight 
of the Investigator. 
• Open-label extension period:  Patients who have received ≥2 doses of open-label 
patisiran at the study center with no evidence of IRRs or other drug-related adverse 
effects that impact safety and tolerability of the infusion may have patisiran administered 
at a location other than the study center (eg, at home), where applicable country and local 
regulations allow.  Patisiran administration will be performed by a healthcare 
professional trained on the protocol and on administration of premedications and 
patisiran infusion, with oversight of the Investigator. 
Patients may receive patisiran on the study until the end of the open-label extension period or 
until the first of one of the following occurs:  1) they meet any of the study discontinuation 
criteria; 2) patisiran is commercially available in the patient’s country of residence, and patisiran 
is accessible to the patient, and the patient has completed Year 2 of the study, including the end 
of study visit; or 3) the patisiran development program is discontinued. 
To evaluate the efficacy of treatment with patisiran versus placebo in patients with ATTR 
amyloidosis with cardiomyopathy, the change from baseline in 6-MWT will be assessed at 
Month 12 (Weeks 52-53) as the primary endpoint (Section 2); this assessment will also be 
performed at Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) in the double-blind period, 
and during the open-label extension period at the time points noted in the Schedule of 
Assessments (Table 1, Table 2, Table 3, and Table 4).  The first secondary endpoint will assess 
change from baseline at Month 12 in the KCCQ-OS score.     
In situations where an efficacy study visit at Months 6, 9, and/or 12 is unable to be completed at 
the study center due to the coronavirus disease 2019 (COVID-19) pandemic impacting activities 
at the study center or patient 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 Month 6, 9, and/or 12 efficacy assessments.  
After consultation with the Medical Monitor, efficacy assessments may be extended for that visit 
as follows:  Month 6 up to Day 214; Month 9 up to Day 319; Month 12, up to Day 417, but prior 
to the first dose of open-label patisiran (Table 1).  Patients may continue to receive double-blind 
study drug until the Month 12 efficacy assessment is performed.  For the open-label extension 
period, the windows for study visits are also extended (Table 2, Table 3, and Table 4). 
Safety will be assessed throughout the study, as described in the Schedule of Assessments for the 
double-blind period (Table 1) and for the open-label extension period (Table 2, Table 3, and 
Table 4).   

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
39 
3.2. 
Duration of Treatment  
The treatment duration in this study is up to 48 months, inclusive of a 12-month, double-blind, 
treatment period, and a 36-month, open-label, treatment period. 
3.3. 
Duration of Study Participation  
The estimated total time on study for each patient is up to 50.5 months, including up to 45 days 
of screening, up to 48 months of treatment (see Section 3.2), and a 28-day safety follow-up 
period. 
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 end of study (EOS) visit, or 
• the patient has completed the follow-up visit 28 days after the last dose of patisiran.    
Patients who have transitioned to commercial patisiran (see Section 3.1 and Table 4) should have 
completed the end of study visit and are therefore considered to have reached the end of the 
study. 
3.4. 
Number of Planned Patients 
The planned enrollment for this study is 300 patients with wtATTR and hATTR amyloidosis 
with cardiomyopathy.  Approximately 20% of the study population is anticipated to have hATTR 
and 80% wtATTR. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the interactive response system (IRS), patients will be randomized 1:1 to the patisiran or 
placebo arm.  Randomization will be stratified by: 
1. Baseline tafamidis (yes vs no) 
2. Genotype (hATTR vs wtATTR amyloidosis with cardiomyopathy) 
3. NYHA Class I or II and age < 75 years vs all other     
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 
During the double-blind period of the study, all personnel will be blinded to the study treatment, 
except the pharmacist and designated pharmacy/healthcare personnel who will set-up, dispense, 
and prepare the infusion.  Patisiran confers a slightly opalescent color relative to the clear saline 
(placebo) infusate; therefore, all infusion bags and lines will be covered with amber bags and line 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
40 
covers by the unblinded personnel to prevent visualization by the blinded study personnel and 
patient, as described in detail in the Pharmacy Manual.   
After the pharmacist (or designated pharmacy/healthcare personnel) has prepared the infusion, 
separate blinded personnel will monitor the patient during and after the infusion.  All patients 
will be blinded to treatment and will receive an IV infusion once every 3 weeks using identical 
volumes for patisiran and placebo.    
Study personnel performing assessments related to the primary and secondary endpoints will be 
different from the Investigator and other personnel managing the patient, and all of these study 
personnel will be blinded to any clinical laboratory results that could potentially unblind them 
(eg, TTR levels).  In addition, the study personnel performing assessments related to the primary 
and secondary efficacy endpoints will not reference the results of any previous assessments. 
Study personnel involved in a patient’s medical care will also refrain from obtaining local 
laboratory results that could potentially unblind them to the patient’s treatment until after the 
study has been unblinded.  Such laboratory results would include TTR (ie, prealbumin), 
vitamin A, and RBP measurements. 
Furthermore, unblinded source documentation containing all descriptions of pharmacy 
preparations and infusions or distribution of study drug or randomization data will be stored 
separate from all other study data/records and from other pharmacy staff not participating on the 
study. 
Blinding will be maintained until the last patient completes their Month 12 visit. 
3.6.1. 
Emergency Unblinding 
During the double-blind period of the study, if the treating physician determines that the clinical 
management of the patient requires knowledge of the study drug assignment, the Investigator 
may break the blind, as necessary.  If time permits, clinical study center personnel should contact 
the Medical Monitor before unblinding to discuss the need to unblind the patient but must do so 
within 1 working day after the unblinding event.  Unblinding information should be limited to 
the fewest number of people on a need-to-know basis.  A record of when the blind was broken, 
who was unblinded, who broke the blind, and why it was broken, will be maintained in the trial 
master file. 
Refer to the IRS instructions for details on emergency unblinding. 
3.7. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study through the 
double-blind period (through Month 12), 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.  Details are provided in the DMC Charter. 
3.8. 
Adjudication Committee 
An independent Adjudication Committee will review deaths and non-elective hospitalizations 
and will attribute a cause (CV versus non-CV) according to the responsible underlying disease 
process rather than the immediate mechanism.  Urgent HF visits will also be adjudicated.  

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
41 
Deaths, hospitalizations, and urgent HF visits will be classified as specified in the Adjudication 
Committee Charter. 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive.  
Patient and Disease Characteristics 
2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either 
hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with 
cardiomyopathy: 
Hereditary ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of 
the following criteria: 
a. TTR pathogenic mutation consistent with hATTR.  
b. Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness >12 mm (based on central echocardiogram 
reading at screening).   
c. Amyloid deposits in cardiac or noncardiac tissue (eg, fat pad aspirate, salivary gland, 
median nerve connective sheath) confirmed by Congo Red (or equivalent) staining 
OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc], or 99mTc-
hydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if 
monoclonal gammopathy of undetermined significance (MGUS) has been excluded. 
d. If MGUS, confirm TTR protein in tissue with immunohistochemistry (IHC) or mass 
spectrometry. 
Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of 
the following criteria: 
a. Absence of pathogenic TTR mutation.  
b. Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness >12mm (based on central echocardiogram 
reading at screening).   
c. Amyloid deposits in cardiac tissue with TTR precursor identification by IHC, mass 
spectrometry, OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc] or 99mTc-
hydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if 
MGUS has been excluded. 
d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry.  
3. Medical history of HF with at least 1 prior hospitalization for HF (not due to arrhythmia 
or a conduction system disturbance treated with a permanent pacemaker) OR clinical 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
42 
evidence of HF (with or without hospitalization) manifested by signs and symptoms of 
volume overload or elevated intracardiac pressures (eg, elevated jugular venous pressure, 
shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral 
edema) that currently requires treatment with a diuretic. 
4. Patient meets one of the following criteria: 
a. Tafamidis naïve; in addition to patients who have never taken tafamidis, those who 
have been on tafamidis for ≤30 days total and have not received any tafamidis in the 
6 months prior to baseline will be considered tafamidis naïve and may qualify for the 
study. 
b. Currently on tafamidis (for ≥6 months) and has demonstrated disease progression, as 
determined by the Investigator.  (At the time of study entry, tafamidis treatment must 
be on-label use of commercial tafamidis for the treatment of ATTR amyloidosis with 
cardiomyopathy at the approved dose in the country of use.) 
5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to 
randomization, as assessed by the Investigator.   
6. Able to complete ≥150 m on the 6-MWT at screening. 
7. Screening NT-proBNP >300 ng/L and <8500 ng/L; in patients with permanent or 
persistent atrial fibrillation, screening NT-proBNP >600 ng/L and <8500 ng/L. 
Informed Consent 
8. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent; and patient agrees to sign the 
medical records release form for collection of vital status.   
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Has known primary amyloidosis (AL) or leptomeningeal amyloidosis.  
2. NYHA Class III AND ATTR amyloidosis disease Stage 3 (defined as both NT-proBNP 
>3000 ng/L and estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 
m2).[Gillmore 2018] 
3. NYHA Class IV at the Screening visit. 
4. Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to 
walk, or is wheelchair bound) at the Screening visit. 
Laboratory Assessments 
5. Has any of the following laboratory parameter assessments at screening:  
a. Aspartate transaminase (AST) or alanine transaminase (ALT) levels ˃2.0 × the upper 
limit of normal (ULN). 
b. Total bilirubin ˃2×ULN.    

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
43 
c. International normalized ratio (INR) ˃1.5 (unless patient is on anticoagulant therapy, 
in which case excluded if INR ˃3.5).  
6. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] 
formula). 
7. Has known human immunodeficiency virus infection; or evidence of current or chronic 
hepatitis C virus or hepatitis B virus infection.    
Prior/Concomitant Therapy 
8. Tafamidis naïve patients (at baseline) for whom the Investigator actively plans or 
anticipates commencing treatment with tafamidis during the 12-month double-blind 
period, taking into consideration clinical status, patient preference and/or commercial 
availability of tafamidis. 
9. Is currently taking diflunisal; if previously on this agent, must have at least a 30-day 
wash-out prior to dosing (Day 1). 
10. Is currently taking doxycycline, ursodeoxycholic acid, or tauroursodeoxycholic acid; if 
previously on any of these agents, must have completed a 30-day wash-out prior to 
dosing (Day 1).    
11. Received prior TTR-lowering treatment (including patisiran) or participated in a gene 
therapy trial for hATTR amyloidosis. 
12. Current or future participation in another investigational device or drug study, scheduled 
to occur during this study, or has received an investigational agent or device within 
30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing 
(Day 1).  In the case of investigational TTR stabilizer drugs, washout for 6 months prior 
to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at 
baseline (per inclusion Criterion 4). 
13. Requires chronic treatment with non-dihydropyridine calcium channel blockers (eg, 
verapamil, diltiazem).  
Medical Conditions 
14. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to 
valvular heart disease, or cardiomyopathy due to ischemic heart disease (eg, prior 
myocardial infarction with documented history of cardiac enzymes and 
electrocardiogram [ECG] changes). 
15. Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive 
pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation). 
16. Recent or planned orthopedic procedure during the double-blind period (eg, lower 
extremity or back surgery) that could impact 6-MWT. 
17. Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of 
screening required to achieve optimal treatment of CHF). 
18. Had acute coronary syndrome or unstable angina within the past 3 months. 
19. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.  

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
44 
20. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a 
pacemaker is indicated but will not be placed. 
21. Has persistent elevation of systolic (˃180 mmHg) and diastolic (˃100 mmHg) blood 
pressure that is considered uncontrolled by physician. 
22. Has untreated hypo- or hyperthyroidism. 
23. Prior or planned heart, liver, or other organ transplant. 
24. Had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix that has been successfully treated. 
25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation; or, in the opinion of the 
Investigator, taking part in the study would jeopardize the safety of the patient.   
26. Has a history of severe hypersensitivity (eg, anaphylaxis) to any of the excipients in 
patisiran.  Also see exclusion Criterion 11, which excludes all patients with prior 
TTR-lowering treatment including patisiran. 
Contraception, Pregnancy, and Breastfeeding 
27. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.5.1.   
28. Female patient is pregnant or breast-feeding.    
Alcohol Use 
29. Has a known history of alcohol abuse within the past 2 years or daily heavy alcohol 
consumption (for females, more than 14 units of alcohol per week; for males, more than 
21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ 
pint of beer]); 
30. History of illicit drug abuse within the past 5 years that in the opinion of the Investigator 
would interfere with compliance with study procedures or follow-up visits. 
4.3. 
Removal from Study Drug or Assessment 
Patients 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 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: 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
45 
• Significant violation of the protocol; which includes required treatment with 
prohibited medication (as defined in Section 5.3) per Investigator discretion 
• Adverse event  
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.7.7 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.   
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4), 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 AEs, and must document 
this decision in the patient’s medical records. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.5.7.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable. 
Patients who discontinue from study drug during the 12-month double-blind period, defined as 
the time the first dose of study drug is administered on Day 1 through completion of the 
Month 12 Efficacy Visit (primary endpoint assessment), will be encouraged to remain on the 
study and complete assessments through Month 12 (excluding PK assessments), including a 
Modified Month 12 Efficacy Visit (Table 1).  They will also be asked to complete an Early 
Treatment Discontinuation Visit (7-14 days after their last dose) and the safety follow-up visit, 
28 days after the last dose of study drug (Table 4); see Section 3.3.1. 
In situations where the Modified Month 12 Efficacy Visit is unable to be completed at the study 
center due to the COVID-19 pandemic impacting activities at the study center or patient 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 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
46 
timing of these efficacy assessments.  After consultation with the Medical Monitor, efficacy 
assessments may be extended up to Day 417 (as is permitted for the regular Month 12 visit).   
Patients who discontinue patisiran during the open-label extension period will be asked to 
complete an Early Treatment Discontinuation Visit (7-14 days after their last dose) and the safety 
follow-up visit, per the Schedule of Assessments (Table 4), 28 days after the last dose of 
patisiran; see Section 3.3.1. 
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 the patient's participation in the study at any time.  A 
patient or legal guardian considering stopping participation in the study should be informed that 
the patient can discontinue study drug and/or decline procedural assessments and remain in the 
study to complete their study assessments, through the Modified Month 12 Efficacy Visit, and 
the 28-day follow-up visit, or alternatively may complete any minimal assessments for which the 
patient or legal guardian consents as described in Section 4.3.1.  If a patient or legal guardian still 
chooses to discontinue study drug and stop participation in all follow-up prior to the completion 
of the Month 12 visit, every effort should be made to conduct the assessments scheduled to be 
performed at the Modified Efficacy Visit (Table 1). 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, 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, and 
use biological samples and, as applicable, other personal data, informing the study doctor at any 
time in writing or in any other form that may be locally required.  The Sponsor will continue to 
keep and use the patient’s study information (including any data resulting from the analysis of 
the patient’s biological samples until the time of withdrawal) according to applicable law.  The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements.   
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
47 
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 misses a required study visit: 
• The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes (for the patient) 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 or legal guardian (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 or legal guardian 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 and returned unused must not be re-dispensed. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of study drug 
(patisiran and placebo) is provided in the Pharmacy Manual. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
48 
All patients will be instructed to take the recommended daily allowance of vitamin A while on 
the study. 
5.2.1. 
Premedication 
All patients will receive premedication prior to study drug administration to reduce the risk of 
IRRs.  Each of the following medicinal products should be given on the day of study drug 
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; IV or oral 
nonsedating H1 blockers are acceptable.)  
• 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. Double-blind and open-label periods:  If a patient is having difficulty tolerating the 
steroid premedication regimen (eg, patient develops uncontrolled hyperglycemia, altered 
mental status, or other complication), then lowering of the steroid premedication may be 
allowed for that patient after consultation with the medical monitor at any time during the 
study.   
2. Double-blind period:  For patients who are tolerating their double-blind study drug 
infusions well with their current corticosteroid premedication regimen (ie, no IRRs 
during the past 3 or more infusions), corticosteroid dose may be reduced in 2.5 mg 
increments to a minimum dose of 5 mg of dexamethasone (IV) or equivalent.    
a. Open-label period:  At the start of the open-label period, patients must take 
dexamethasone 10 mg or the equivalent as their corticosteroid premedication.  
Patients taking more than 10 mg of dexamethasone at the end of the double-blind 
period should take the higher dose.  The corticosteroid dose may then be tapered as 
described above if the patient is tolerating infusions.  However, if a patient’s steroid 
premedication had been decreased in the double-blind period due to their inability to 
tolerate the premedication regimen as described above, continuation of the reduced 
dose regimen (as it had been in the double-blind period) may be permitted after 
consultation with the Medical Monitor. 
Infusions during corticosteroid tapering may be performed at the study center or at a location 
other than the study center (eg, at home), as described in detail in the Pharmacy Manual, at the 
discretion of the Investigator and after consultation with the Medical Monitor.   
Additional or higher doses of 1 or more of the premedications may be administered to reduce the 
risk of IRRs, if needed.  For suggested guidelines for management of IRRs, see Section 5.2.4; 
further details can be found in the Pharmacy Manual.   

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
49 
5.2.2. 
Study Drug Description 
Patisiran is a RNAi therapeutic consisting of a double-stranded siRNA targeting TTR mRNA 
formulated in an LNP.  The patisiran drug product is a sterile formulation of ALN-18328 (siRNA 
targeting TTR) formulated as LNPs with lipid excipients (1,2-Dilinoleyloxy-N,N-
dimethylpropylamine [DLin-MC3-DMA], 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.  Patisiran Solution for 
IV infusion contains 2 mg/mL of patisiran. 
See the Pharmacy Manual for further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (normal saline 0.9% for IV administration).  
Control drug will be provided by a central supplier (or, if necessary, by a local supplier, with 
prior Sponsor approval).  
5.2.3. 
Dose and Administration 
Detailed instructions for study drug preparation and administration are found in the Pharmacy 
Manual.    
5.2.3.1. 
Double-blind Study Drug (Patisiran or Placebo) 
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs (Section 5.2.1).   
An IV infusion of double-blind study drug (patisiran 0.3 mg/kg or placebo) will be administered 
under the supervision of the site personnel once every 3 weeks ±3 days.   
The amount (in mg) of double-blind patisiran 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.  
Weight from the previous visit may be used for calculating dose.  Weight must be collected prior 
to dosing with study drug.  Study drug will be administered as an approximately 80-minute IV 
infusion (approximately 1 mL/minute for the first 15-minutes followed by approximately 
3 mL/minute for the remainder of the infusion).  The 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 be observed for 1 hour following completion of dosing for observation 
and completion of assessments. 
Patients who have received ≥2 doses of study drug at the study center with no evidence of IRRs 
or other drug-related adverse effects that impact safety and tolerability of the infusion may have 
study drug administered at a location other than the study center (eg, at home), where applicable 
country and local regulations allow.  Study drug administration will be performed by a 
healthcare professional, trained on the protocol and on administration of premedications and 
study drug infusion, with oversight of the Investigator.  
Missed doses of double-blind study drug   
If a patient does not receive a dose of study drug within the dosing window (±3 days), the 
delayed dose may be taken up to 7 days after the scheduled visit (ie, +4 days after the +3-day 
dosing window per the Schedule of Assessments [Table 1]), after consultation with the Medical 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
50 
Monitor.  If a dose is administered with a delay, the next dose will resume following the original 
schedule per the Schedule of Assessments.   
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. 
5.2.3.2. 
Open-label Extension Period (Patisiran) 
The last dose of double-blind study drug will be at Week 51 and the first dose of open-label 
patisiran will be 3 weeks later (at Week 54) and thereafter every 3 weeks (±3 days) for the 
remainder of the study.  Open-label patisiran will be administered per the schedule and dose as is 
described in Section 5.2.3.1 for double-blind patisiran.  As noted in Section 3.6, blinding will be 
maintained until the last patient completes their Month 12 visit. 
During the open-label extension period, patients who have received at least 2 doses of open-label 
patisiran at the study center with no evidence of IRRs or other drug-related adverse effects that 
impact safety and tolerability of the infusion may have patisiran administered at a location other 
than the study center (eg, at home), where applicable country and local regulations allow.  
Patisiran administration will be performed by a healthcare professional trained on the protocol 
and administration of premedications and patisiran infusion.    
All patients will receive premedications prior to open-label patisiran administration to reduce the 
risk of IRRs (Section 5.2.1).   
Missed doses of open-label patisiran   
If a patient does not receive a dose of open-label patisiran within the dosing window (±3 days), 
the delayed dose may be taken up to 7 days after the scheduled visit (ie, +4 days after the +3-day 
dosing window per the Schedule of Assessments [Table 2, Table 3, and Table 4]), after 
consultation with the Medical Monitor.  If a dose is administered with a delay, the next dose will 
resume following the original schedule per the Schedule of Assessments.   
5.2.4. 
Suggested Guidelines for Management of Infusion-related Reactions 
Criteria for categorizing IRRs are provided in Section 10.3. 
• In the event of an IRR, the infusion of study drug may be slowed or stopped and the patient 
closely monitored until resolution of the reaction.  Drugs that may be used to facilitate 
resolution and permit resumption of study drug administration include but are not limited to:  
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), nonsteroidal anti-inflammatory drugs (NSAIDs), adrenaline, supplemental 
oxygen, IV fluids, and/or corticosteroids. 
• Following resolution of a mild or moderate IRR that required interruption of the study drug 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate for that dose and for subsequent doses of study drug.  If the infusion is delayed, 
the administration of the infusion should be completed no more than 16 hours after study 
drug is first diluted in saline (including infusion time). 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
51 
• Study drug administration will not be resumed for any patient following a severe IRR until 
the case is discussed with the Medical Monitor. 
• If after consultation with the Medical Monitor it is agreed that an individual patient’s steroid 
premedication will be increased, then the following steps are recommended: 
1. If the IRR occurred while the patient received 10 mg IV dexamethasone or equivalent at 
least 60 minutes before the infusion and did not resolve with slowing of the infusion rate, 
then the patient should be increased by multiples of 5 mg IV dexamethasone or 
equivalent at least 60 minutes before the infusion.  
2. Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
IV dexamethasone or equivalent on the day of infusion.  
3. If the IRR occurred while the patient received less than 10 mg IV dexamethasone or 
equivalent, then the patient should return to the prior dose of IV dexamethasone or 
equivalent that did not result in an IRR. 
Patients will be instructed to call the Investigator if they experience symptoms such as fever, 
chills, myalgia, or nausea/vomiting after discharge from the site. 
5.2.5. 
Dose Modifications 
Dose modifications are not permitted.   
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
5.2.6. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of study drug (patisiran and placebo) 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. 
5.2.7. 
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. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
52 
5.2.8. 
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 and Procedures 
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs (Section 5.2.1).   
Use of the following medications/treatments are prohibited during study participation: 
• Any investigational agent other than study drug. 
• Inotersen, doxycycline, ursodeoxycholic acid, tauroursodeoxycholic acid, and 
diflunisal are also prohibited during the study (see exclusion Criterion 10 in 
Section 4.2).  Doxycycline is permitted if being taken for short-term treatment of 
infection.    
All patients will be asked to take the recommended daily allowance of vitamin A for the duration 
of their participation in the study while being administered study drug.  In countries where 
relevant, the clinical sites will provide patients with a prescription for vitamin A at a dose 
consistent with local guidelines.  
Standard vitamins and topical medications are permitted.  Any concomitant medication or 
treatment that is required for the patient’s welfare may be given by the Investigator.  However, it 
is the responsibility of the Investigator to ensure that details regarding the medication are 
recorded on the CRF, as specified in the Schedule of Assessments (Table 1, Table 2, Table 3, 
and Table 4).  Concomitant medications include 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 CRF.  Concomitant medication will be coded using 
an internationally recognized and accepted coding dictionary.  
5.3.1. 
Concomitant Tafamidis Use 
Per inclusion Criterion 4, at baseline patients are either: 1) tafamidis naïve or 2) currently on 
tafamidis for ≥6 months with demonstrated disease progression, as determined by the 
Investigator.  Patients who have been on tafamidis for ≤30 days total and have not received any 
tafamidis in the 6 months prior to baseline will be considered tafamidis naïve and may qualify 
for the study.   
For patients on tafamidis at baseline, the reasons for considering the patient to have 
demonstrated disease progression will be recorded in the eCRF.  Patients who are on tafamidis at 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
53 
baseline are encouraged, if it is medically appropriate in the opinion of the Investigator, to 
remain on tafamidis for the duration of the double-blind period. 
Per exclusion Criterion 8, patients who are tafamidis naïve at baseline, for whom the Investigator 
actively plans or anticipates commencing treatment with tafamidis during the 12-month 
double-blind period (taking into consideration clinical status, patient preference, and/or 
commercial availability of tafamidis), should not be enrolled in the trial. 
However, if tafamidis is granted approval by a Health Agency for treatment in patients with 
ATTR amyloidosis with cardiomyopathy in a given region, all enrolled patients in this region 
will be made aware of its potential benefits and risks at the time of regulatory approval and all 
patients will be reconsented.  In such circumstances, tafamidis is not considered prohibited and 
the Investigator may, using their medical judgement, commence concomitant on-label tafamidis 
during the study, if it is felt to be in the best interest of the patient and if it is commercially 
available in the country.   
Patients who are tafamidis naïve at baseline, but begin taking commercial tafamidis (ie, 
“tafamidis drop-in”), will remain in the study.  Prior to commencing concomitant tafamidis, the 
Investigator will perform assessments (including primary and select secondary efficacy 
assessments) at the Pre-tafamidis Drop-in Visit, as outlined in the Schedule of Assessments 
(Table 1).  In all cases, the Pre tafamidis Drop-in Visit should occur prior to starting concomitant 
tafamidis; where possible, this visit should occur between 1-2 weeks after the last dose of study 
drug (ie, 7 to 14 days post study drug dose).  Thereafter, the patient will continue with all 
assessments per the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4).  In 
addition, at the time of tafamidis drop-in, the reason for starting tafamidis will be recorded in the 
CRF. 
Initiation of TTR stabilizer therapies other than tafamidis (eg, diflunisal) is not allowed during 
the double-blind period of this study. 
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 a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 12 weeks 
after the last dose of study drug in this study.    
Birth control methods which are considered highly effective include:   
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system.   
• Bilateral tubal occlusion. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
54 
• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
• Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. 
• 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 12 weeks 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, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements as described in the corresponding patient informed consent forms.   
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.2).    
6. 
STUDY ASSESSMENTS 
The Schedule of Assessments is provided in Table 1 (double-blind period) and Table 2, Table 3, 
and Table 4 (open-label extension period).  Additional information on the collection of study 
assessments will be detailed in the respective reference manuals. 
6.1. 
Screening Assessments  
An ICF 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.  In addition, a medical records release form will be required of all patients for the 
purpose of obtaining vital status information from the patient’s physician or from death 
registries.    
See the Schedule of Assessments (Table 1) for a list of Screening visit assessments.   
To ensure patient safety and, to the extent possible, that study integrity is maintained amid travel 
and other restrictions related to the COVID-19 pandemic, the Investigator will notify the Sponsor 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
55 
before screening patients to allow an assessment of the ability of the study center or any new trial 
participant to comply with the protocol given COVID-19 limitations.  
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening (once) of patients is permitted with consultation of the Medical 
Monitor (see Section 6.1.2). 
Patient demographic data and medical history/disease history will be obtained, including 
completion of ophthalmologic history in the eCRF.  Any changes to medical history occurring 
between the screening assessment and Day 1 will be updated prior to study drug administration. 
If a genetic test result that shows the presence or absence of a TTR pathogenic mutation, which 
would be consistent with either wtATTR or hATTR, is not available at Screening for the 
assessment of eligibility (Section 4.1, inclusion Criterion 2a), genotyping may be conducted at a 
central laboratory.  Alternatively, a local laboratory may be selected by the study center in 
consultation with the Medical Monitor. 
The study eligibility biopsies and technetium scintigraphy noted in inclusion Criterion 2 are 
intended to be historical, as part of the patient’s clinical care and diagnosis, and are not 
performed as part of the study.    
If a diagnostic result that confirms ATTR amyloidosis is not available at Screening for the 
assessment of eligibility (inclusion Criterion 2c/d), testing may be conducted at a laboratory or 
diagnostic center selected by the study center, in consultation with the Medical Monitor, in 
countries in which this test is not standard of care. 
An echocardiogram will be performed at screening Visit 1 and results confirmed centrally to 
assess study eligibility, as indicated in the Schedule of Assessments (Table 1). 
6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then 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.  Any 
additional repeat testing may be considered after discussion with the Medical Monitor. 
6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening, or who fails to complete screening activities due to unforeseen or unavoidable 
circumstances, may be rescreened once after consultation with the Medical Monitor after a 
minimum of 5 days have elapsed from a patient’s last screening assessment.  A patient will be re-
consented if rescreening occurs outside of the 45-day screening window.  In this case, all 
screening procedures must be repeated.   
Patients who failed screening due to situations related to the COVID-19 pandemic may be 
allowed to rescreen after consultation with the Medical Monitor. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
56 
6.2. 
Efficacy Assessments 
As noted in Table 1, in situations where a Month 6 (Day 176-183), Month 9 (Day 260-267), 
and/or Month 12 (Day 365-372) study visit is unable to be completed at the study center due to 
the COVID-19 pandemic impacting activities at the study center or patient 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 Month 6, 9, and/or 12 efficacy assessments.  After consultation with the Medical Monitor, 
efficacy assessments may be extended as follows:  Month 6 up to Day 214; Month 9 up to 
Day 319; Month 12, up to Day 417, but prior to the first dose of open-label patisiran.  Patients 
may continue to receive double-blind study drug until the Month 12 efficacy assessment is 
performed.    
For the open-label extension period, as noted in Table 2, in situations where a Month 18 
(Day 554-561), Month 21 (Day 638-645), and/or Month 24 (Day 743-750) study visit is unable 
to be completed at the study center due to the COVID-19 pandemic impacting activities at the 
study center or patient 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 Month 18, 21, and/or 24 efficacy assessments.  After 
consultation with the Medical Monitor, efficacy assessments may be extended as follows:  
Month 18 up to Day 592; Month 21 up to Day 697; Month 24, up to Day 791.  
Similarly, for Years 3 and 4, in situations where a study visit at which efficacy assessments were 
to be performed is unable to be completed at the study center, the Medical Monitor should be 
consulted as soon as possible to determine the appropriate timing of the efficacy assessments for 
those visits.  After consultation with the Medical Monitor, efficacy assessments may be 
extended, as described in Table 3 and Table 4.   
6.2.1. 
6-Minute Walk Test (6-MWT) 
The 6-MWT, which will be assessed as the primary endpoint, is an assessment of functional 
exercise capacity.  The 6-MWT will be administered by staff trained in the procedure per the 
relevant study manual.  The staff administering the 6-MWT will be different from the 
Investigator or designee managing the care of the patient. 
The 6-MWT will be performed at each of the timepoints specified in the Schedule of 
Assessments (Table 1, Table 2, Table 3, and Table 4).  At screening Visit 1, the 6-MWT will be 
administered for study eligibility purposes (per inclusion Criterion 6 [Section 4.1]).  At screening 
Visit 1, prior to conducting the 6-MWT, the site staff will familiarize the patient with the purpose 
and conduct of the 6-MWT, as described in detail in the relevant study manual.  Familiarization 
can be repeated at other timepoints if deemed helpful. 
On Day 1 (baseline), which is a dosing day, the 6-MWT will be performed prior to study drug 
administration.  (No other dosing days have a 6-MWT assessment.)   
Patients who are hospitalized during the study should wait at least 2 weeks after hospitalization 
before completing a 6-MWT assessment; less time post-hospitalization may be permitted if, in 
the opinion of the Investigator, the patient is unencumbered due to the recent hospitalization.  In 
addition, if a patient is not feeling well due to an external factor (eg, flu, sprained ankle, pulled 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
57 
back muscle) at a visit when the 6-MWT will be performed, the test should not be done and 
should be rescheduled for another day within the permitted visit window. 
For each 6-MWT assessment, the site should make every effort to have this assessment 
performed by the same assessor and to perform the test at approximately the same time of day.  
If the test is interrupted or deemed unusable by the 6-MWT core laboratory, the 6-MWT should 
be repeated as soon as possible within the allowed visit window. 
Further details regarding the 6-MWT are provided in the relevant study manual. 
A 1.5-month window will be used to group 6-MWT assessments to the Month 6 (Weeks 25-26), 
Month 9 (Weeks 37-38), and Month 12 (Weeks 52-53) visits.  During the double-blind period, a 
patient may opt to begin tafamidis treatment or to discontinue study treatment, in which case 
they would complete a Pre-tafamidis Drop-in Visit (Table 1) or Early Treatment Discontinuation 
Visit (Table 4), respectively.  To avoid the potential training effect from repeated assessments of 
the 6-MWT within a short period of time, only one 6-MWT assessment should be collected for 
the following time periods:  Day 2 to Day 214 (for Month 6), Day 215 to Day 319 (for Month 9), 
and Day 320 to Day 417 (for Month 12).  
Within a given time period, the 6-MWT assessment should be performed at whichever visit 
occurs first (scheduled assessment, Pre-tafamidis Drop-in Visit, or Early Treatment 
Discontinuation Visit); no additional 6-MWT assessments should be made in that time period.  
In later time periods, the 6-MWT should be assessed per the Schedule of Assessments (Table 1).  
6.2.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ)   
The KCCQ [Green 2000] is a 23-item self-administered questionnaire developed to 
independently measure the patient’s perception of health status, which includes heart failure 
symptoms, impact on physical and social function, and how their heart failure impacts their 
quality of life within a 2-week recall period. 
The KCCQ quantifies 6 domains (symptoms, physical function, quality of life, social limitation, 
self-efficacy, and symptom stability) and 2 summary scores (clinical and overall summary [OS]).  
The KCCQ-OS will be assessed for the first secondary endpoint. 
The KCCQ questionnaire will be completed at the timepoints specified in the Schedule of 
Assessments (Table 1, Table 2, Table 3, and Table 4). 
6.2.3. 
Deaths, Hospitalizations, and Urgent Heart Failure Visits 
All deaths and hospitalizations will be recorded at Day 1 post dose and throughout the study as 
specified as part of AEs monitoring (see Section 6.5.7) and per the Schedule of Assessments 
(Table 1, Table 2, Table 3, and Table 4).  All urgent HF visits will also be recorded in the eCRF. 
Reasons for deaths and non-elective hospitalizations will be adjudicated by an independent 
Adjudication Committee (Section 3.8).  Urgent HF visits will also be adjudicated.   
6.2.4. 
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).   

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
58 
Weight, height, and serum albumin (collected as part of the serum chemistry panel) will be 
collected pre-dose at the timepoints specified in the Schedule of Assessments (Table 1, Table 2, 
Table 3, and Table 4).  The site will not perform the calculation for mBMI.   
6.2.5. 
Cardiac Assessments   
Manifestations of cardiac amyloid involvement will be assessed via cardiac biomarker, NYHA 
class, echocardiograms, CMR, and technetium scintigraphy imaging, as described. 
Qualified personnel will be required to administer cardiac imaging assessments as specified in 
the respective reference manuals. 
6.2.5.1. 
Cardiac Biomarkers   
The cardiac biomarkers NT-proBNP and troponin I will be used to assess cardiac stress and heart 
failure severity.  These biomarkers have been shown to be prognostic of outcomes in HF, 
including in ATTR amyloidosis.[Damy 2016; Kristen 2017; Merlini 2016]  Blood samples will 
be drawn to measure cardiac biomarker levels at the timepoints specified in the Schedule of 
Assessments (Table 1, Table 2, Table 3, and Table 4) and will be measured at a central 
laboratory.  At screening Visit 1, only NT-proBNP will be assessed for eligibility purposes.    
Details on cardiac biomarker sample collection, processing, and storage will be provided in a 
Study Laboratory Manual. 
6.2.5.2. 
ATTR Amyloidosis Disease Stage 
Based on published data from Gillmore et al, the ATTR amyloidosis disease staging used for this 
protocol stratifies patients with ATTR amyloidosis with cardiomyopathy (both hATTR and 
wtATTR) into prognostic categories using the serum biomarkers NT-proBNP and 
eGFR.[Gillmore 2018]  Patients are categorized as follows: 
• Stage 1 (lower risk):  NT-proBNP ≤3000 ng/L and eGFR ≥45 ml/min/1.73 m2 
• Stage 2 (intermediate risk):  all other patients not meeting criteria for Stages 1 or 3 
• Stage 3 (higher risk):  NT-proBNP >3000 ng/L and eGFR <45 ml/min/1.73 m2 
Based on published data, this staging system discriminates between patients with median 
survival of ~6 years, ~4 years, and ~2 years for Stage 1, Stage 2, and Stage 3, respectively. 
6.2.5.3. 
New York Heart Association (NYHA) Class 
NYHA class is a clinical assessment of symptoms resulting from HF and is assessed according to 
the table in Section 10.2.  NYHA class will be evaluated at the timepoints specified in the 
Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4).  The score collected at 
screening will be used to determine eligibility. 
6.2.5.4. 
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, Table 2, Table 3, and Table 4), and analyzed at a central cardiac imaging core lab.   

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
59 
Image acquisition, storage, and transfer guidelines will be provided in the relevant study manual. 
6.2.5.5. 
Technetium Scintigraphy Imaging  
At select sites, in a subset of approximately 100 patients, technetium scintigraphy will be 
collected according to the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4), as 
an optional exploratory imaging assessment, to assess cardiac amyloid involvement.  Based on 
local practice standards, either 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD-Tc], 
99mTc-pyrophosphate [PYP-Tc], or 99mTc-hydroxymethylene diphosphonate (99mTc-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 
relevant study manual.   
For patients in whom technetium scintigraphy is performed as a study efficacy parameter, the 
results of the baseline scan must be reviewed by the central reader and confirmed to be consistent 
with the diagnosis of ATTR amyloidosis prior to randomization. 
At select sites where technetium scintigraphy is being performed as an exploratory efficacy 
assessment, patients may be exempt from the baseline scan if technetium scintigraphy has been 
performed prior to study entry as part of the patient’s clinical care within 6 months prior to the 
baseline assessment.  In such cases, the historical technetium scintigraphy examination 
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; if the historical scan cannot 
be transferred to the central reader, or is deemed by the central reader to be of inadequate quality 
for interpretation, the patient should not participate in this optional efficacy assessment. 
6.2.5.6. 
Cardiac Magnetic Resonance (CMR)   
At select sites, in a subset of patients (≤60 patients), CMR will be collected according to the 
Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4), as an optional exploratory 
imaging assessment to assess cardiac amyloid involvement.  CMR imaging with late gadolinium 
enhancement will only be performed on patients without contraindications (ie, pacemakers, 
severe renal failure with eGFR <30 mL/min/1.73 m2, defibrillators, or allergy to gadolinium).  
Details for image acquisition and upload for central review can be found in the relevant study 
manual. 
6.2.6. 
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, Table 2, Table 3, and Table 4). 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
60 
6.2.7. 
Polyneuropathy Disability (PND)   
Physician assessment of ambulation via PND score [Coutinho 1980; Yamamoto 2007] will be 
evaluated only at screening to assess eligibility for the study as specified in the Schedule of 
Assessments (Table 1).  PND scoring is described in Section 10.1. 
6.3. 
Pharmacodynamic Assessments 
In this study, serum samples for measurement of TTR levels will be collected for the assessment 
of PD effects.  TTR levels will be determined by a validated enzyme-linked immunoassay 
(ELISA).  Details regarding sample volumes to be collected, and the processing, shipping, and 
analysis of the samples will be provided in the Laboratory Manual.   
For this assessment, blood samples will be collected prior to dosing according to the timepoints 
specified in the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4).  To ensure 
patient safety and, to the extent possible, that study integrity is maintained amid travel and other 
restrictions related to the COVID-19 pandemic, blood samples for assessment of TTR protein 
may be collected by a trained healthcare professional at a location other than the study center 
(eg, at home) at time points coinciding with the dosing visits closest to the intended sampling 
time points. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of plasma concentrations of ALN-18328 (siRNA 
component of patisiran) and 2 lipid excipients (DLin-MC3-DMA and PEG2000-C-DMG) during 
the double-blind period at the timepoints specified in the Schedule of Assessments (Table 1).  To 
ensure patient safety and, to the extent possible, that study integrity is maintained amid travel 
and other restrictions related to the COVID-19 pandemic, these blood samples may be collected 
at the study center, or by a trained healthcare professional at a location other than the study 
center (eg, at home) at time points coinciding with the dosing visits closest to the intended 
sampling time points.   
Plasma PK samples will be collected:  predose (within 1 hour of planned study drug dosing); at 
the end of the infusion (+5 minutes); and 30 minutes after the end of the infusion (+15 minutes) 
at the specified visits.   
For patients who discontinue treatment early during the double-blind period, a single PK sample 
will be taken at any time during the Early Treatment Discontinuation Visit, per the Schedule of 
Assessment (Table 4).   
Actual dates and times of sample collection will be recorded. 
Plasma concentrations of the 3 analytes will be determined using validated assay methods.  
Details regarding sample volumes to be collected, and the processing, shipping, and analysis of 
the samples will be provided in the Laboratory Manual. 
PK parameters will be analyzed, whenever possible, as outlined in Section 7.2.7.  

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
61 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight 
and height, 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. 
In situations where a study visit is not completed at the study center, offsite (eg, at home) 
assessments may be completed within the study visit window as follows: 
• Routine assessments (ie, vital signs and weight, blood collection, pregnancy testing, 
physical examinations, and ECGs) may be performed at a location other than the study 
center (eg, at home) by a trained healthcare professional at all timepoints, where 
applicable country and local regulations and infrastructure allow.  The Investigator or 
qualified designee will review all ECGs, including those collected by a healthcare 
professional outside of the study center. 
• Collection of relevant safety information:  The study physician (or delegate) must, at a 
minimum, verbally contact the patient within the expected study visit window to assess 
relevant safety information (including, but not limited to, AEs, concomitant medications, 
hospitalizations/procedures, vital status).  This information may also be collected by a 
home healthcare professional as part of an offsite study visit. 
• Blood samples for assessment of ADA may be collected by a trained healthcare 
professional at a location other than the study center (eg, at home) at time points 
coinciding with the dosing visits closest to the intended sampling time points.  
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1, Table 2, 
Table 3, and 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.  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 medically 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. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
62 
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 as specified in the Schedule of Assessments 
(Table 1, Table 2, Table 3, and Table 4) and will be recorded in the eCRF. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1, Table 2, Table 3, and 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. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.5.4. 
Electrocardiogram 
12-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, and QT 
interval will be obtained, as specified in the Schedule of Assessments (Table 1, Table 2, Table 3, 
and Table 4).  Patients should be supine for at least 5 minutes before each ECG is obtained.  The 
12-lead ECGs will be performed in triplicate at baseline, with readings approximately 1 minute 
apart.  At all other time points, a single 12-lead ECG will be performed. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn, when possible. 
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 the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded in the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator.  Recordings will be archived in the patient’s files.  
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  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, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality.  Additional safety laboratory tests and assessments as indicated by the 
clinical situation may be requested.  Clinical laboratory assessments are listed in Table 5 and will 
be assessed as specified in the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4).   
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 5, which are performed 
at the clinic should also be sent in parallel to the central laboratory.  In the case of discrepant 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
63 
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 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 5: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Carbon dioxide 
Creatinine and eGFR (using the MDRD formula) 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Coagulation (at Screening) 
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time   
 
Immunogenicity (see Section 6.5.5.1) 
Antidrug antibodies 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.2) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal women 
only) 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone; 
MDRD=modification of diet in renal disease; PCR=polymerase chain reaction; RBCs=red blood cells; 
RNA=ribonucleic acid. 
6.5.5.1. 
Immunogenicity 
Serum samples will be collected to evaluate the presence of antidrug antibodies (ADA) as 
outlined in the Schedule of Assessments (Table 1).  Details regarding the blood volume, 
processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
A validated ELISA will be used that specifically detects antibodies to PEG2000-C-DMG, which is 
a component of patisiran-LNP.  Serum samples will first be analyzed with a screening assay.  
Samples testing positive for ADA in the screening assay will be further evaluated in a 
confirmatory assay.  For the samples that tested positive for ADA in the confirmatory assay, the 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
64 
ADA titer will then be determined as the reciprocal of the highest dilution of the sample that 
yielded a positive ADA test result. 
6.5.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential at the timepoints 
specified in the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4).   
A serum pregnancy test will be performed at Screening and urine pregnancy tests will be 
performed thereafter at the timepoints specified in the Schedule of Assessments.  More frequent 
pregnancy testing may be performed where required per local requirements.  The results of the 
pregnancy test must be known before study drug administration.  Patients who are pregnant at 
Screening are not eligible for study participation.  Any woman with a positive urine pregnancy 
test, subsequently confirmed by a positive serum pregnancy test, during the study will be 
discontinued from study drug but will continue to be followed for safety.  Patients determined to 
be pregnant while on study will be followed at least until the pregnancy outcome is known (see 
Section 6.5.7.7 for follow-up instructions). 
In situations where a pregnancy test was missed as per the Schedule of Assessments because of 
the COVID-19 pandemic impacting activities at the study center or patient ability or willingness 
to access the study center, a pregnancy test must be performed prior to receiving the next dose of 
study drug.   
Follicle-stimulating hormone testing will be performed in all women suspected to be post-
menopausal to confirm post-menopausal status. 
6.5.6. 
Vital Status Check 
A vital status check will be performed at the timepoints specified in the Schedule of Assessments 
(Table 1, Table 2, Table 3, and Table 4).      
Due to the inclusion of all-cause mortality in the secondary endpoint analysis, a medical records 
release form will be required of all patients for the purpose of obtaining vital status information 
from the patient’s physician or from death registries.  The signing of this medical records release 
form is in addition to the ICF.  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.  
6.5.7. 
Adverse Events 
6.5.7.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an 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 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
65 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
No AEs of clinical interest are defined for this study.  
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 AE. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  AEs 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). 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
66 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?”  A “yes” response indicates that the event is considered as related to 
the study drug. 
6.5.7.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
study drug through the end of study.  Non-serious AEs will be followed until the end of study.  
Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1), while AEs that occur after study drug administration, and  
baseline events that worsen after study drug administration, must be recorded as AEs.    
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study drug 
through the end of study.  SAEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
All IRRs will be recorded as AEs.  All information on IRRs is to be recorded on the applicable 
eCRF per the CRF completion guidelines. 
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. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
67 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
Not applicable.  There were no AEs of Clinical Interest identified for this study. 
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. 
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 12 weeks following the last dose 
of study drug, the Investigator must report the pregnancy to the Sponsor or designee within 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
68 
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 12 weeks 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, 
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.  In the event of an overdose, the actual dose administered must be recorded as specified 
in the Pharmacy Manual. 
All reports of overdose (with or without an AE) must be reported within 24 hours following the 
instructions outlined in the Pharmacy Manual for reporting an overdose. 
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 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 ATTR amyloidosis with 
cardiomyopathy, as well as their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
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 patisiran.   
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1, Table 2, Table 3, and Table 4).  Potential exploratory investigations may include 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. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
69 
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. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principal features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
The planned enrollment for this study is 300 patients.  For the change from baseline at Month 12 
in the 6-MWT, assuming a treatment difference of 33 meters between patisiran and placebo in 
the treatment-naïve group and 20 meters in patients with baseline tafamidis, the weighted 
average treatment difference between patisiran and placebo in the overall population is 
approximately 29 meters (standard deviation = 75 meters) assuming 70% are in the treatment-
naïve group and 30% are in the baseline tafamidis group.  A sample size of 300 patients provides 
>90% power for a 2-sided test to detect a mean difference between treatment groups at a 2-sided 
alpha = 0.05.  Additional patients may be enrolled based on a recommendation to increase the 
sample size in the interim assessment (Section 7.2.10). 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses for 
the primary analysis, conducted at the completion of the 12-month, double-blind period.  More 
complete plans, including planned analyses for the open-label extension period, will be detailed 
in the SAP.  Changes to the methods described in the final SAP will be described and justified as 
needed in the clinical study report.  For information on study endpoints, see Section 2. 
Additional data summaries to help understand any impact of COVID-19 on efficacy and safety 
assessments will be outlined in the SAP. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
• Full Analysis Set (FAS):  All randomized patients who received any amount of study 
drug, grouped according to the randomized treatment arm.   
• Safety Analysis Set:  All patients who received any amount of study drug, grouped 
according to the treatment actually received.  

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
70 
• PK Analysis Set:  All patients who received at least 1 complete dose of study drug 
and have at least 1 postdose blood sample for PK parameters and have evaluable PK 
data.  
• PD Analysis Set:  All patients who received at least 1 complete dose of study drug 
and who have an evaluable baseline and at least 1 evaluable post-baseline serum TTR 
measurement will be included in the PD analyses. 
Note that a complete dose of study drug is defined as ≥80% (≥160 mL) of the planned infusion 
volume (200 mL). 
Efficacy endpoints will be analyzed using the Full Analysis Set.  Safety will be analyzed using 
the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct PK and PD 
analyses, respectively. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized by 
treatment arm and overall for the FAS and Safety Analysis Set. 
7.2.5. 
Efficacy Analyses 
The overall Type I error rate will be strongly controlled at a 2-sided 0.05 significance level for 
the primary and secondary endpoints using a fixed sequential testing procedure at the final 
analysis.  The primary endpoint will be compared between treatment arms at the 0.05 
significance level.  If the test of the primary endpoint is statistically significant, then the 
secondary endpoints will each be tested in the order specified in the Secondary Endpoints section 
(see Section 2).  If a test of the primary or a secondary endpoint is not statistically significant, the 
testing of the remaining endpoints in the sequence will stop. 
For patients who were tafamidis treatment-naïve at baseline and start tafamidis during the 
double-blind period, the primary analysis of the primary endpoint will censor data collected after 
the initiation of tafamidis treatment post-randomization.   
7.2.5.1. 
Primary Endpoint  
The primary endpoint, change from baseline at Month 12 in the 6-MWT, will be analyzed using 
a mixed-effects model repeated measures (MMRM) approach.  The outcome variable is change 
from baseline in the 6-MWT.  The model will include the baseline value as a covariate, 
treatment, visit, baseline tafamidis (yes vs no), genotype (hATTR vs wtATTR), age (<75 vs 
≥75 years), the treatment-by-visit interaction, the treatment-by-baseline tafamidis interaction, the 
visit-by-baseline tafamidis interaction, and the treatment-by-visit-by-baseline tafamidis 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
71 
interaction as fixed factors.  The primary comparison is the contrast (difference in least squares 
[LS] means) between the patisiran and placebo groups at Month 12. 
Sensitivity analyses will be detailed in the SAP. 
7.2.5.2. 
Secondary Endpoints  
Secondary endpoints are described in Section 2.   
KCCQ-OS will be analyzed using a similar MMRM model as used for the primary endpoint. 
The composite endpoint of all-cause mortality, frequency of CV events (CV hospitalizations and 
urgent HF visits) and change from baseline in 6-MWT will be analyzed using a generalized rank-
based win ratio method, which makes pairwise comparisons (for all possible patisiran/placebo 
patient pairs) of the 3 components in the hierarchical order specified above.  The point estimate 
for the win ratio is defined as the total number of better outcomes divided by the total number of 
worse outcomes in the patisiran group.  The detailed algorithm for assessment of this endpoint 
will be provided in the SAP.     
The composite endpoint of all-cause mortality and frequency of all-cause hospitalizations and 
urgent HF visits will be analyzed using a modified Andersen-Gill model stratified by baseline 
tafamidis (yes vs no), including treatment, genotype (hATTR vs wtATTR), NYHA Class (I/II vs 
III), and age (<75 vs ≥75 years) as covariates. 
Patients who undergo a heart transplantation and/or ventricular assist device placement after 
randomization will be handled in the same manner as death in the primary analyses of mortality 
related endpoints. 
Deaths and hospitalizations due to COVID-19 will be excluded from the primary analyses of 
endpoints involving all-cause death and/or all-cause hospitalizations.  Analyses of the individual 
components of the composite endpoints will be detailed in the SAP. 
To control the overall Type I error rate, secondary endpoints will be tested in a prespecified 
hierarchical order. 
7.2.5.3. 
Exploratory Endpoints 
Descriptive summaries will be provided for the exploratory endpoints (Section 2), and additional 
analyses may be conducted.  Details will be described in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
The PD endpoint is serum TTR.  Summary tables will be provided for observed values, change 
and percentage change from baseline for each scheduled time point.  In addition, the maximum 
and mean percentage reduction over 12 months will be summarized.   
7.2.7. 
Pharmacokinetic Analysis 
7.2.7.1. 
Pharmacokinetic Analysis 
Plasma concentrations of ALN-18328, DLin-MC3-DMA, and PEG2000-C-DMG will be obtained 
using a model-independent method.  PK exposure parameters will include:  maximum plasma 
concentration at the end of infusion (Cmax), 30-minute post-infusion concentration (Cp(30min)), and 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
72 
pre-infusion concentration (Cmin).  In addition, the steady-state Cmax (Cmax,ss), steady-state 
Cp(30min) (Cp,ss(30min)), and steady-state Cmin (Cmin,ss) will be calculated as the average of the 
respective values at Week 24, Week 36, and Month 12. 
The PK exposure parameters will be summarized by visit, and the steady-state PK parameters 
will be summarized. 
7.2.7.2. 
Exposure-Response Analysis  
Mean and maximum percent TTR reduction from baseline will be summarized by quartiles of the 
steady state PK parameters for all 3 analytes.  Change from baseline at Month 12 in clinical 
efficacy parameters may also be summarized by quartiles of the steady-state PK parameters for 
all 3 analytes.  
PK exposure will be summarized by mortality status.  In addition, the incidence of AEs and 
SAEs will be summarized by quartiles of the steady-state PK parameters for all 3 analytes. 
7.2.7.3. 
Population PK, PK/PD, and Disease Progression Modelling Analysis 
Population PK, PK/PD, and disease progression modelling analyses may be performed, if 
appropriate.  If performed, the analyses would be conducted according to a pre-specified analysis 
plan and reported separately. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical examinations.  The extent of exposure will be summarized.   
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary.  Results will be tabulated by the Anatomical Therapeutic Chemical classification 
system and Preferred Term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term.  The frequency and percentage of patients 
experiencing AEs, SAEs, related AEs, and AEs leading to discontinuation will be summarized 
by System Organ Class (SOC) and PT.  By patient listings will be provided for deaths, SAEs, 
and AEs leading to discontinuation.   
Descriptive statistics will be provided for clinical laboratory data, ECG, and vital signs data, 
summarizing the observed values and change from baseline over time.  Laboratory shift tables 
from baseline at the worst post-baseline values will be presented.  Abnormal physical 
examination findings and 12-lead ECG data will be presented in by-patient listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP.  
7.2.9. 
Immunogenicity Analyses 
 The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized.  The titer results for patients with 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
73 
confirmed positive ADA results will be summarized.  The impact of ADA on PK, PD, efficacy 
and safety endpoints will be explored.  Details will be described in the SAP. 
7.2.10. 
Sample Size Re-assessment 
Patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis 
drop-in”) during the double-blind period, which could result in a loss of statistical power.  An 
interim assessment may be performed to assess the impact of tafamidis drop-in on the power and 
the potential need to increase the sample size.  The interim assessment, if conducted, would 
examine the overall tafamidis drop-in rate in a blinded manner (ie, a non-comparative assessment 
of the drop-in rate); therefore, no impact on the type I error is expected and no multiplicity 
adjustment will be made.  A detailed sample size re-estimation plan will be outlined in a separate 
document prior to implementation. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the informed consent form 
(see Section 4.3.2). 
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 is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient 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 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. 
A medical records release form will be required of all patients for the purpose of obtaining vital 
status information from the patient’s physician or from death registries.  The signing of this 
medical records release form is in addition to the ICF. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
74 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study (except those that support the need to remove an apparent immediate 
hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.5.7.  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 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 
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. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
75 
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.  CRFs 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. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
76 
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). 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
77 
9. 
LIST OF REFERENCES 
Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, 
an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 
5;379(1):11-21. 
Adams D, Suhr OB, Hund E, Obici L, Tournev I, Campistol JM, et al. First European consensus 
for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr 
Opin Neurol. 2016 Feb;29 Suppl 1:S14-26. 
Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, et al. Targeted 
delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol 
Ther. 2010 Jul;18(7):1357-64. 
Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, et al. Guideline of transthyretin-
related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013 Feb 20;8:31. 
Benson MD,Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. 
Muscle Nerve. 2007 Oct;36(4):411-23. 
Biesalski HK, Frank J, Beck SC, Heinrich F, Illek B, Reifen R, et al. Biochemical but not clinical 
vitamin A deficiency results from mutations in the gene for retinol binding protein. Am J Clin 
Nutr. 1999 May;69(5):931-6. 
Bittner V, Weiner DH, Yusuf S, Rogers WJ, McIntyre KM, Bangdiwala SI, et al. Prediction of 
mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. 
SOLVD Investigators. JAMA. 1993 Oct 13;270(14):1702-7. 
Bumcrot D, Manoharan M, Koteliansky V,Sah DW. RNAi therapeutics: a potential new class of 
pharmaceutical drugs. Nat Chem Biol. 2006 Dec;2(12):711-9. 
Castano A, Drachman BM, Judge D,Maurer MS. Natural history and therapy of TTR-cardiac 
amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and 
silencer drugs. Heart Fail Rev. 2015 Mar;20(2):163-78. 
Coelho T, Merlini G, Bulawa CE, Fleming JA, Judge DP, Kelly JW, et al. Mechanism of Action 
and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis. Neurol Ther. 
2016 Jun;5(1):1-25. 
Connors LH, Lim A, Prokaeva T, Roskens VA,Costello CE. Tabulation of human transthyretin 
(TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. 
Connors LH, Yamashita T, Yazaki M, Skinner M,Benson MD. A rare transthyretin mutation 
(Asp18Glu) associated with cardiomyopathy. Amyloid. 2004 Mar;11(1):61-6. 
Coutinho P, DeSilva A, Lima J,Barbosa A. Forty years of experience with type I amyloid 
neuropathy: review of 483 cases. In: Glenner G,Pinho P,Costa E,Falcao de Frietas A, editors. 
Amyloid and Amyloidosis: Excerpta Medica. Amsterdam1980. p. 88-98. 
Damy T, Jaccard A, Guellich A, Lavergne D, Galat A, Deux JF, et al. Identification of 
prognostic markers in transthyretin and AL cardiac amyloidosis. Amyloid. 2016 Sep;23(3):194-
202. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
78 
Damy T, Judge DP, Kristen AV, Berthet K, Li H,Aarts J. Cardiac findings and events observed 
in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile 
hereditary transthyretin amyloidosis. J Cardiovasc Transl Res. 2015 Mar;8(2):117-27. 
Dungu JN, Anderson LJ, Whelan CJ,Hawkins PN. Cardiac transthyretin amyloidosis. Heart. 
2012 Nov;98(21):1546-54. 
Episkopou V, Maeda S, Nishiguchi S, Shimada K, Gaitanaris GA, Gottesman ME, et al. 
Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and 
thyroid hormone. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2375-9. 
Flynn KE, Lin L, Ellis SJ, Russell SD, Spertus JA, Whellan DJ, et al. Outcomes, health policy, 
and managed care: relationships between patient-reported outcome measures and clinical 
measures in outpatients with heart failure. Am Heart J. 2009 Oct;158(4 Suppl):S64-71. 
Flynn KE, Lin L, Moe GW, Howlett JG, Fine LJ, Spertus JA, et al. Relationships between 
changes in patient-reported health status and functional capacity in outpatients with heart failure. 
Am Heart J. 2012 Jan;163(1):88-94 e3. 
Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A 
new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018 Aug 7;39(30):2799-
806. 
Green CP, Porter CB, Bresnahan DR,Spertus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll 
Cardiol. 2000 Apr;35(5):1245-55. 
Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D,Suhr OB. Evolving 
landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38. 
Hou X, Aguilar MI,Small DH. Transthyretin and familial amyloidotic polyneuropathy. Recent 
progress in understanding the molecular mechanism of neurodegeneration. FEBS J. 2007 
Apr;274(7):1637-50. 
Jacobson D, Tagoe C, Schwartzbard A, Shah A, Koziol J,Buxbaum J. Relation of clinical, 
echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of 
the transthyretin V122I allele in older African-American men. Am J Cardiol. 2011 Aug 
1;108(3):440-4. 
Kristen AV, Maurer MS, Rapezzi C, Mundayat R, Suhr OB,Damy T. Impact of genotype and 
phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the 
Transthyretin Amyloidosis Outcome Survey (THAOS). PLoS One. 2017;12(4):e0173086. 
Liz MA, Mar FM, Franquinho F,Sousa MM. Aboard transthyretin: From transport to cleavage. 
IUBMB Life. 2010 Jun;62(6):429-35. 
Mangla A, Kane J, Beaty E, Richardson D, Powell LH,Calvin JE, Jr. Comparison of predictors 
of heart failure-related hospitalization or death in patients with versus without preserved left 
ventricular ejection fraction. Am J Cardiol. 2013 Dec 15;112(12):1907-12. 
Masoudi FA, Rumsfeld JS, Havranek EP, House JA, Peterson ED, Krumholz HM, et al. Age, 
functional capacity, and health-related quality of life in patients with heart failure. J Card Fail. 
2004 Oct;10(5):368-73. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
79 
Maurer M, Judge D, Rosas G, Mandel F,Aarts J. Interim analysis of long-term, open-label 
tafamidis treatment in transthyretin amyloid cardiomyopathy after up to 5 years of treatment.  
XIVth International Symposium on Amyloidosis; Indianapolis, Indiana2014. 
Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. 
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 
2018 Sep 13;379(11):1007-16. 
Merlini G, Lousada I, Ando Y, Dispenzieri A, Gertz MA, Grogan M, et al. Rationale, application 
and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in 
patients with AL amyloidosis. Leukemia. 2016 Oct;30(10):1979-86. 
Mohty D, Damy T, Cosnay P, Echahidi N, Casset-Senon D, Virot P, et al. Cardiac amyloidosis: 
updates in diagnosis and management. Arch Cardiovasc Dis. 2013 Oct;106(10):528-40. 
Okamoto S, Wixner J, Obayashi K, Ando Y, Ericzon BG, Friman S, et al. Liver transplantation 
for familial amyloidotic polyneuropathy: impact on Swedish patients' survival. Liver Transpl. 
2009 Oct;15(10):1229-35. 
Parman Y, Adams D, Obici L, Galan L, Guergueltcheva V, Suhr OB, et al. Sixty years of 
transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A 
European network approach to defining the epidemiology and management patterns for TTR-
FAP. Curr Opin Neurol. 2016 Feb;29 Suppl 1:S3-S13. 
Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, et al. The 
amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015 Jan 
1;372(1):21-9. 
Ruberg FL,Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012 Sep 
04;126(10):1286-300. 
Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective 
evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid 
cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012 
Aug;164(2):222-8 e1. 
Solomon SD, Adams D,Kristen A. Effects of Patisiran, an RNA Interference Therapeutic, on 
Cardiac Parameters in Patients with Hereditary Transthyretin-Mediated Amyloidosis: An 
Analysis of the APOLLO Study. Circulation. 2018;10.1161/CIRCULATIONAHA.118.035831. 
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. 
Westermark P, Bergstrom J, Solomon A, Murphy C,Sletten K. Transthyretin-derived senile 
systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 2003 Aug;10 
Suppl 1:48-54. 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
80 
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. 
 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
81 
10. 
APPENDICES 
10.1. 
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 
10.2. 
New York Heart Association Class (NYHA) 
  
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs does not 
cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, in cold weather, in wind or when under 
emotional stress causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to two blocks on the 
level and climbing more than one flight of stairs in normal conditions causes undue fatigue 
or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or dyspnea. 
10.3. 
Categorization of Infusion-Related Reactions 
Signs and symptoms of an IRR usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Signs/symptoms may 
include: allergic reaction/hypersensitivity (including drug fever), arthralgia (joint pain), 
bronchospasm, cough, dizziness, dyspnea (shortness of breath), fatigue (asthenia, lethargy, 
malaise), headache, hypertension, hypotension, myalgia (muscle pain), nausea, pruritus/itching, 

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 3, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
82 
rash/desquamation, rigors/chills, sweating (diaphoresis), tachycardia, urticaria (hives, welts, 
wheals), vomiting. 
Categorization of IRRs is as follows: 
Categorization 
Description 
Mild 
Mild reaction:  infusion may be continued; if intervention is indicated it is 
minimal and additional treatment (other than paracetamol for delayed 
reactions) is not required. 
Moderate 
Moderate reaction:  requires treatment including more intensive therapy 
(eg, IV fluids, NSAIDs) in addition to infusion interruption but responds 
promptly to medication.  Treatment is indicated for ≤24 hours. 
Severe 
More than moderate reaction:  not rapidly responsive to medication or to 
interruption of infusion; and/ or prolonged (treatment is indicated for 
>24 hours); recurrence of severe symptoms following initial improvement. 
 

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 3 Summary of Changes, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
1 
ALN-TTR02-011 PROTOCOL AMENDMENT 3  
SUMMARY OF CHANGES DATED 30 JUNE 2021 
APOLLO-B:  A Phase 3, Randomized, Double blind, Placebo-controlled Multicenter Study 
to Evaluate the Efficacy and Safety of Patisiran in Patients with Transthyretin Amyloidosis 
with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
The primary purpose for this protocol amendment is to extend the open-label extension period 
from 12 months to 36 months, for a total treatment period during the study of up to 48 months, to 
collect longer-term safety and efficacy data.  Key protocol modifications relating to this change 
include the following (as detailed in Section 2): 
• Addition of Schedule of Assessments for Years 3 and 4. 
In addition, other protocol modifications or clarifications include: 
• Update to the mixed-effects model repeated measures (MMRM) model specification 
to allow for potentially different treatment effects between the baseline tafamidis use 
(yes/no) subgroups. 
• Total number of study centers at which the study is being conducted was updated to 
85 centers (from 65). 
• Update to allow unblinded personnel to administer study drug, while monitoring of 
the patient during and after the infusion will be performed by blinded personnel. 
• Clarification that study personnel involved in a patient’s medical care will not obtain 
local laboratory results that could potentially unblind them to the patient’s treatment 
until after the study has been unblinded.   
• Clarification to note that the assessment of reasons for hospitalizations by the 
Adjudication Committee will be for non-elective hospitalizations.    
• Clarification in the definitions of the PK analysis set and PD analysis set to include 
all patients who received at least 1 complete dose of study drug. 
• Clarification of the dosing window for missed doses of study drug. 
• Clarification regarding allowable premedication equivalents to intravenous histamine 
1 receptor blockers. 
• Clarification that cardiac magnetic resonance (CMR) or technetium scans should not 
be performed within 5 months of another scan. 
Minor changes such as corrections to typographical errors, punctuation, grammar, abbreviations, 
and formatting are not detailed.
83

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 3 Summary of Changes, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
2 
2. 
PROTOCOL AMENDMENT 3 DETAILED SUMMARY OF CHANGES 
The primary sections 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:  Extended the open-label extension period from 12 months to 36 months, for a total treatment period during the study of up 
to 48 months, to collect longer term safety and efficacy data.  Schedule of Assessments for Years 3 and 4 were added. 
The primary change occurs in Table 2, Table 3, and Table 4, Schedules of Assessments  
Revised text: 
• Added Table 3, Year 3 Schedule of Assessments:  Open-label Extension Period (Through Month 36) 
• Added Table 4, Year 4 Schedule of Assessments:  Open-label Extension Period (Through Month 48), Early Treatment 
Discontinuation Visit, and Follow-up 
• Moved the Early Treatment Discontinuation Visit, End of Study Visit, and Follow-up from Table 2 to Table 4 
• Added the following text to Section 3.3.1:   Patients who have transitioned to commercial patisiran (see Section 3.1 and 
Table 4) should have completed the end of study visit and are therefore considered to have reached the end of the study. 
Sections also reflecting this change:    
• Synopsis 
• Figure 1, Study Design 
• Section 3.1, Summary of Study Design 
• Section 3.2, Duration of Treatment  
• Section 3.3, Duration of Study Participation  
• Section 6.2, Efficacy Assessments 
84

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 3 Summary of Changes, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
3 
Purpose:  Updated the mixed-effects model repeated measures (MMRM) model specification to allow for potentially different 
treatment effects between the baseline tafamidis use (yes/no) subgroups. 
The primary change occurs in Section 7.2.5.1, Primary Endpoint 
Revised text: 
The model will include the baseline value as a covariate, treatment, visit, the treatment by visit interaction, baseline tafamidis (yes vs no), 
genotype (hATTR vs wtATTR), and age (<75 vs ≥75 years), the treatment-by-visit interaction, the treatment-by-baseline tafamidis 
interaction, the visit-by-baseline tafamidis interaction, and the treatment-by-visit-by-baseline tafamidis interaction as fixed factors, and 
patient as a random effect.   
Section also reflecting this change:    
• Synopsis 
Purpose:  Total number of study centers at which the study is being conducted was updated to 85 centers (from 65). 
The primary change occurs in the Synopsis 
Revised text: 
The study will be conducted at approximately 65 85 clinical study centers worldwide. 
Purpose:  Allow unblinded personnel to administer study drug, while monitoring of the patient during and after the infusion will be 
performed by blinded personnel.  Clarification that study personnel involved in a patient’s medical care will not obtain local 
laboratory results that could potentially unblind them to the patient’s treatment until after the study has been unblinded.    
The primary change occurs in Section 3.6, Blinding 
Revised text: 
After the pharmacist (or designated pharmacy/healthcare personnel) has prepared the infusion, separate blinded personnel will 
administer study drug and monitor the patient during and after the infusion.  All patients will be blinded to treatment and will receive 
an IV infusion once every 3 weeks using identical volumes for patisiran and placebo.    
… 
Study personnel involved in a patient’s medical care will also refrain from obtaining local laboratory results that could 
potentially unblind them to the patient’s treatment until after the study has been unblinded.  Such laboratory results would 
include TTR (ie, prealbumin), vitamin A, and RBP measurements. 
85

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 3 Summary of Changes, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
4 
Purpose:  Clarification to note that the assessment of reasons for hospitalizations by the Adjudication Committee will be for 
non-elective hospitalizations.    
The primary change occurs in Section 3.8, Adjudication Committee and Section 6.2.3, Death, Hospitalizations, and Urgent Heart 
Failure Visits 
Revised text: 
An independent Adjudication Committee will review deaths and non-elective hospitalizations and will attribute a cause (CV versus 
non-CV) according to the responsible underlying disease process rather than the immediate mechanism.   
… 
Reasons for deaths and non-elective hospitalizations will be adjudicated by an independent Adjudication Committee (Section 3.8).   
Purpose:  Clarification in the definitions of the PK analysis set and PD analysis set to include all patients who received at least 1 
complete dose of study drug. 
The primary change occurs in Section 7.2.1, Populations to be Analyzed 
Revised text: 
• PK Analysis Set:  All patients who received any amount at least 1 complete dose of study drug and have at least 1 
postdose blood sample for PK parameters and have evaluable PK data.  
• PD Analysis Set:  All patients who received any amount at least 1 complete dose of study drug and who have an evaluable 
baseline and at least 1 evaluable post-baseline serum TTR measurement will be included in the PD analyses. 
Note that a complete dose of study drug is defined as ≥80% (≥160 mL) of the planned infusion volume (200 mL). 
Purpose:  Clarification of the dosing window for missed doses of study drug. 
The primary change occurs in Section 5.2.3.1, Double-blind Study Drug (Patisiran or Placebo) and Section 5.2.3.2, Open-label 
Extension Period (Patisiran) 
Revised text: 
If a patient does not receive a dose of study drug within the dosing window (±3 days), the delayed dose may be taken up to 7 days 
after the scheduled visit (ie, +4 days after the +3-day dosing window per the Schedule of Assessments [Table 1]), after 
consultation with the Medical Monitor.   
… 
86

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 3 Summary of Changes, 30 June 2021 
Alnylam Pharmaceuticals 
Confidential 
5 
If a patient does not receive a dose of open-label patisiran within the dosing window (±3 days), the delayed dose may be taken up to 7 
days after the scheduled visit (ie, +4 days after the +3-day dosing window per the Schedule of Assessments [Table 2, Table 3, and 
Table 4,]), after consultation with the Medical Monitor. 
Purpose:  Clarification regarding allowable premedication equivalents to intravenous histamine 1 receptor blockers. 
The primary change occurs in Section 5.2.1, Premedication 
Revised text: 
• Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent); IV or oral nonsedating H1 blockers are acceptable.)  
Purpose:  Clarification that cardiac magnetic resonance (CMR) or technetium scans should not be performed within 5 months of 
another scan. 
The primary change occurs in Footnote to Table 2, Year 2 Schedule of Assessments  
Added text: 
b Consecutive CMR scans should not be performed within 5 months of each other.  Consecutive technetium scans should not be 
performed within 5 months of each other. 
87

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
1 
 
CLINICAL STUDY PROTOCOL 
ALN-TTR02-011 
DATED 22 MAY 2020 
 
Protocol Title: 
APOLLO-B:  A Phase 3, Randomized, 
Double-blind, Placebo-controlled Multicenter 
Study to Evaluate the Efficacy and Safety of 
Patisiran in Patients with Transthyretin 
Amyloidosis with Cardiomyopathy (ATTR 
Amyloidosis with Cardiomyopathy)   
Short Title: 
APOLLO-B:  A Study to Evaluate Patisiran in 
Patients with Transthyretin Amyloidosis with 
Cardiomyopathy (ATTR Amyloidosis with 
Cardiomyopathy) 
Study Drug: 
Patisiran (ALN-TTR02)  
EudraCT Number: 
2019-001458-24 
IND Number: 
141240 
Protocol Date: 
Original protocol, 18 April 2019  
Amendment 1:  20 December 2019 
Amendment 2:  22 May 2020 
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. 
 
88

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-011 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 
90

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
6 
population is anticipated to have hATTR and 80% wtATTR.  In addition, at baseline, patients are 
either: 
• Tafamidis naïve; or 
• Currently on tafamidis (for ≥6 months), with disease progression in the opinion of the 
Investigator.  This group will be capped at 30% of total enrollment in the study.   
The study consists of a screening period of up to 45 days, a 12-month, double-blind, placebo-
controlled period, a 12-month, open-label extension period (during which all patients will receive 
patisiran), and a 28-day follow-up period. 
After screening, during the 12-month double-blind period, eligible patients will be randomized to 
receive intravenous (IV) treatment every 3 weeks with either patisiran or placebo.  Prior to 
receiving randomized, double-blind study drug (patisiran or placebo), to reduce the potential for 
an infusion related reaction (IRR) with patisiran, all patients will receive premedications at least 
60 minutes before the start of their infusion.  Study drug will be administered as an 
approximately 80-minute IV infusion.  
During the 12-month open-label extension period, all patients will receive treatment with 
open-label patisiran.   
Study drug administration at a location other than the study center (eg, at home) may be 
administered as follows: 
• Double-blind period:  Patients who have received ≥2 doses of study drug at the study 
center with no evidence of IRRs or other drug-related adverse effects that impact safety 
and tolerability of the infusion may have study drug administered at a location other than 
the study center (eg, at home), where applicable country and local regulations allow.  
Study drug administration will be performed by a healthcare professional, trained on the 
protocol and on administration of premedications and study drug infusion, with oversight 
of the Investigator. 
• 12-month open-label extension period:  Patients who have received ≥2 doses of 
open-label patisiran at the study center with no evidence of IRRs or other drug-related 
adverse effects that impact safety and tolerability of the infusion may have patisiran 
administered at a location other than the study center (eg, at home), where applicable 
country and local regulations allow.  Patisiran administration will be performed by a 
healthcare professional trained on the protocol and on administration of premedications 
and patisiran infusion, with oversight of the Investigator.  
To evaluate the efficacy of treatment with patisiran versus placebo in patients with ATTR 
amyloidosis with cardiomyopathy, the change from baseline in 6-MWT will be assessed at 
Month 12 (Weeks 52-53) as the primary endpoint; this assessment will also be performed at 
Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) in the double-blind period, and during the 
open-label extension period.  The first secondary endpoint will assess change from baseline at 
Month 12 in the KCCQ-OS score.  In situations where an efficacy study visit at Months 6, 9, 
and/or 12 is unable to be completed at the study center due to the Coronavirus disease 2019 
(COVID-19) pandemic impacting activities at the study center or patient 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 
93

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
7 
Month 6, 9, and/or 12 efficacy assessments.  After consultation with the Medical Monitor, 
efficacy assessments may be extended for that visit as follows:  Month 6 up to Day 214; Month 9 
up to Day 319; Month 12, up to Day 417, but prior to the first dose of open-label patisiran.  
Patients may continue to receive double-blind study drug until the Month 12 efficacy assessment 
is performed.    
Safety will be assessed throughout the double-blind and open-label extension periods of the 
study. 
Number of Planned Patients 
Approximately 300 patients are planned for enrollment in this study.   
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, inclusive, with ATTR amyloidosis with cardiomyopathy (hereditary or wild-type [wt]) who, 
at baseline, are either:  1) tafamidis naïve (on tafamidis for ≤30 days and none within 6 months 
prior to baseline); or 2) currently on tafamidis (for ≥6 months) with disease progression in the 
opinion of the Investigator. 
Study Drug, Dose, and Mode of Administration 
Patisiran is a ribonucleic acid (RNA) interference (RNAi) therapeutic consisting of a double-
stranded small interfering RNA (siRNA) targeting TTR mRNA formulated in a lipid 
nanoparticle (LNP).  The patisiran drug product is a sterile formulation of ALN-18328 (siRNA 
targeting TTR) formulated as LNPs with lipid excipients (1,2-Dilinoleyloxy-N,N-
dimethylpropylamine [DLin-MC3-DMA], 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.   
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs. 
An IV infusion of double-blind study drug (patisiran 0.3 mg/kg or placebo) will be administered 
under the supervision of the site personnel once every 3 weeks ±3 days.  Dosing is based on 
actual body weight.  For patients weighing ≥100 kg, the maximum recommended patisiran dose 
is 30 mg.  
The last dose of double-blind study drug will be at Week 51 and the first dose of open-label 
patisiran will be 3 weeks later (at Week 54) and thereafter every 3 weeks (±3 days) for the 
remainder of the study.  Open-label patisiran will be administered per the schedule and dose as is 
described above for double-blind patisiran. 
Reference Treatment, Dose, and Mode of Administration 
The control drug for this study will be a placebo (normal saline 0.9% for IV administration).  
Control drug will be provided by a central supplier (or, if necessary, by a local supplier, with 
prior Sponsor approval).    
Duration of Treatment and Study Participation 
The treatment duration in this study is up to 24 months, inclusive of a 12-month, double-blind, 
treatment period, and a 12-month, open-label, treatment period.  The estimated total time on 
94

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
8 
study for each patient is up to 26.5 months, including up to 45 days of screening, up to 
24 months of treatment, and a 28-day safety follow-up period. 
Statistical Methods 
The planned enrollment for this study is 300 patients.  Randomization (1:1) will be stratified by:  
1) baseline tafamidis (yes vs no); 2) genotype (hATTR vs wtATTR); and 3) NYHA Class I or II 
and age < 75 years vs all other. 
For the change from baseline at Month 12 in the 6-MWT, assuming a treatment difference of 
33 meters between patisiran and placebo in the treatment-naïve group and 20 meters in patients 
with baseline tafamidis, the weighted average treatment difference between patisiran and placebo 
in the overall population is approximately 29 meters (standard deviation = 75 meters) assuming 
70% are in the treatment-naïve group and 30% are in the baseline tafamidis group.  A sample 
size of 300 patients provides >90% power for a 2-sided test to detect a treatment difference at a 
2-sided alpha = 0.05.  Additional patients may be enrolled based on a recommendation to 
increase the sample size in the interim assessment. 
The primary endpoint, change from baseline at Month 12 in the 6-MWT, will be analyzed using 
a mixed-effects model repeated measures (MMRM) approach.  The outcome variable is change 
from baseline in the 6-MWT.  The model will include the baseline value as a covariate, 
treatment, visit, the treatment-by-visit interaction, baseline tafamidis (yes vs no), genotype 
(hATTR vs wtATTR), and age (<75 vs ≥75 years) as fixed factors, and patient as a random 
effect.  The primary comparison is the contrast (difference in least squares [LS] means) between 
the patisiran and placebo groups at Month 12. 
To control the overall Type I error rate, secondary endpoints will be tested in a prespecified 
hierarchical order. 
For patients who are tafamidis treatment-naïve at baseline and start tafamidis during the double-
blind period, the primary analysis of the primary endpoint will censor data collected after the 
initiation of tafamidis treatment post-randomization.  
Safety data will be summarized descriptively. 
 
95

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
9 
Figure 1: 
Study Design 
  
 
 
96

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
10 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NA 
Informed Consent 
6.1  
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion Criteria 
4.1, 
4.2  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / 
Medical History 
6.1  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PND Score 
6.2.7  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
6.5.2  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
X 
X 
 
 
 
 
 
 
 
 
 
X
d 
 
 
 
 
X
d 
 
 
 
 
 
X 
d 
X 
d 
X
d 
KCCQ 
6.2.2 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
mBMI 
6.2.4 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Cardiac Biomarker 
Samples 
6.2.5.1 
NT-
proBNP 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
ATTR amyloidosis 
disease stage 
6.2.5.2  
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
NYHA Class 
6.2.5.3 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Echocardiogram 
6.2.5.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CMR, technetium 
(select sites only) 
6.2.5.6,  
6.2.5.5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Norfolk QoL-DN 
6.2.6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
97

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
11 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NA 
Pharmacodynamic Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
X 
X 
  
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Exploratory 
Biomarkers 
(plasma, serum) 
6.6 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
6.5.2 
X  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
(symptom-directed 
unless noted as full) 
6.5.3 
X  
Full 
X 
  
 
 
 
 
X 
 
 
 
  
X 
 
 
 
  
X 
 
 
 
 
 
X 
Full 
X 
Full 
X 
Single 12-lead ECG 
(unless otherwise 
indicated) 
6.5.4 
 
X (in 
triplicate, 
either visit) 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum Chemistry, 
Liver Function 
Tests 
6.5.5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Xe 
Xe 
X 
Hematology 
6.5.5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Coagulation 
6.5.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin A Levels 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA (on dosing 
days, prior to 
dosing) 
6.5.5.1 
 
 
X 
 
X 
  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
98

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
12 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NA 
FSH (to confirm 
postmenopausal, if 
applicable) 
Table 3, 
6.5.5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
Table 3, 
6.5.5.2 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
  
  
Review/Record 
Hospitalization, 
Urgent HF Visits, 
Urgent Care Visits, 
and Procedures 
 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
 
Review/Record 
AEs, Con Meds 
6.5.7, 
5.3 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
6.4 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Drug Administration 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
3.5 
Window 
is 5D 
prior to 
Day 1 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication/ 
Study Drug 
5.2.1, 
5.2.3 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
99

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
13 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; COVID-19=Coronavirus disease 2019; CMR=cardiac 
magnetic resonance; D=day; Disc=discontinuation; ECG=electrocardiogram; FSH=follicle-stimulating hormone; KCCQ=Kansas City Cardiomyopathy 
Questionnaire; HF=heart failure; M=month; mBMI=modified body mass index; 6-MWT=6-minute walk test; NA=not applicable; NT-proBNP=N-terminal 
prohormone B-type natriuretic peptide; NYHA=New York Heart Association; PK=pharmacokinetics; PND=Polyneuropathy Disability; QoL-DN=Quality of 
Life-Diabetic Neuropathy; TTR=transthyretin; V=visits. 
a  This efficacy visit is conducted 7 to 14 days after the prior visit.  In situations where a Month 6 (Day 176-183), Month 9 (Day 260-267), and/or Month 12 (Day 
365-372) study visit is unable to be completed at the study center due to the COVID-19 pandemic impacting activities at the study center or patient 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 Month 6, 9, and/or 12 efficacy assessments.  After consultation with the Medical Monitor, efficacy 
assessments may be extended as follows:  Month 6 up to Day 214; Month 9 up to Day 319; Month 12, up to Day 417, but prior to the first dose of open-label 
patisiran. Patients may continue to receive double-blind study drug until the Month 12 efficacy assessment is performed.   
b  This Modified Month 12 Efficacy Visit is to be performed at Month 12 for patients who discontinued treatment early (ie, prior to Month 12), and choose to 
remain in the study.  All patients who discontinue from study drug during the double-blind period will be encouraged to remain on the study and complete 
assessments through Month 12 (excluding PK assessments), including this Modified Month 12 Efficacy Visit.  Such patients will also receive assessments at 
the Early Treatment Discontinuation Visit (7 to 14 days after their last dose of study drug); and the safety follow-up visit (28 days after the last dose of study 
drug) (Table 2), as described in Section 4.3.1.  In situations where the Modified Month 12 Efficacy Visit is unable to be completed at the study center due to 
the COVID-19 pandemic impacting activities at the study center or patient 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 for these efficacy assessments.  
After consultation with the Medical Monitor, efficacy assessments may be extended, up to Day 417 (as is permitted for the regular Month 12 visit).    
c See Section 5.3.1; patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis drop-in”) during the double-blind period.  In 
all cases, the Pre-tafamidis Drop-in Visit should occur prior to starting concomitant tafamidis; where possible, this visit should occur between 1-2 weeks after 
the last dose of double-blind study drug (ie, 7 to 14 days post dose).  Thereafter, the patient will continue with all assessments per the Schedule of Assessments, 
including the Month 12 Efficacy Visit.  At the time of tafamidis drop-in, the reason for starting tafamidis will be recorded in the CRF. 
d As described in Section 6.2.1, to avoid a potential training effect resulting from repeated assessments of the 6-MWT within a short period of time, only one 6-
MWT assessment should be performed within each of the following time periods:  Day 2 to Day 214 (includes the scheduled Weeks 25-26 assessment); Day 
215 to Day 319 (includes the scheduled Weeks 37-38 assessment); and Day 320 to Day 417 (includes the scheduled Weeks 52-53 assessment).  Within a given 
time period, the 6-MWT assessment should be performed at whichever visit occurs first (scheduled assessment, Pre-tafamidis Drop-in Visit, or Early Treatment 
Discontinuation Visit [Table 2]); no additional 6-MWT assessments should be made in that time period.  In later time periods, the 6-MWT should be assessed 
as scheduled. 
e Serum creatinine only. 
100

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
14 
  
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 24), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
7- 14 Days 
after Last 
Dose 
D764±10 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
NA 
109 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
KCCQ 
6.2.2 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
mBMI 
6.2.4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Cardiac Biomarker 
Samples 
6.2.5.1 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
ATTR amyloidosis 
disease stage 
6.2.5.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
NYHA Class 
6.2.5.3 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Echocardiogram 
6.2.5.4 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CMR, technetium (select 
sites only) 
6.2.5.6, 
6.2.5.5 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Norfolk QoL-DN 
6.2.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacodynamic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Exploratory Biomarkers 
(plasma, serum) 
6.6  
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (symptom-
directed) 
6.5.3 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Single 12-lead ECG 
6.5.4  
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
101

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
15 
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 24), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
7- 14 Days 
after Last 
Dose 
D764±10 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
NA 
109 
Serum Chemistry, Liver 
Function Tests 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X
c 
X 
X 
Hematology 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Pregnancy Test 
Table 3, 
6.5.5.2 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
Review/Record 
Hospitalization, Urgent 
HF Visits, Urgent Care 
Visits, and Procedures 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
Review/Record AEs,  
Con Meds 
6.5.7, 
5.3 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
 6.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication, Study 
Drug 
5.2.1, 
5.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; COVID-19=Coronavirus disease 2019; CMR=cardiac 
magnetic resonance; D=day; Disc=discontinuation; ECG=electrocardiogram; EOS=End of Study (visit); HF=heart failure; KCCQ=Kansas City Cardiomyopathy 
Questionnaire; mBMI=modified body mass index; 6-MWT=6-minute walk test; NA=not applicable; NT-proBNP=N-terminal prohormone B-type natriuretic 
peptide; NYHA=New York Heart Association; PK=pharmacokinetics; QoL-DN=Quality of Life-Diabetic Neuropathy; TTR=transthyretin; V=visits.  
a  This efficacy visit is conducted 7 to 14 days after the prior visit.  In situations where a Month 18 (Day 554-561), Month 21 (Day 638-645), and/or Month 24 
(Day 743-750) study visit is unable to be completed at the study center due to the COVID-19 pandemic impacting activities at the study center or patient ability 
or willingness to access study center or their ability to receive their scheduled doses of study drug, the Medical Monitor should be consulted as soon as possible 
102

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
16 
to determine the appropriate timing of the Month 18, 21, and/or 24 efficacy assessments.  After consultation with the Medical Monitor, efficacy assessments 
may be extended as follows:  Month 18 up to Day 592; Month 21 up to Day 697; Month 24, up to Day 774. 
b Patients who discontinue early from study drug will be asked to complete the Early Treatment Discontinuation Visit (7-14 days after their last dose) and the 
safety follow-up visit, 28 days after the last dose of study drug.  In addition, patients discontinuing early from study drug during the double-blind period will be 
encouraged to remain on the study and complete assessments through Month 12 and complete the Modified Month 12 Efficacy Visit (see Table 1); they will 
also be asked to complete an Early Treatment Discontinuation Visit (7-14 days after their last dose) and the safety follow-up visit, 28 days after the last dose of 
study drug as described in Section 4.3.1. 
c Serum creatinine only. 
 
103

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
17 
TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................22 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Disease Overview .......................................................................................................25 
1.2. 
Current Treatments .....................................................................................................26 
1.3. 
Patisiran Clinical Development ..................................................................................27 
1.3.1. 
The Phase 3 APOLLO Study ......................................................................................28 
1.3.1.1. 
Cardiac Results and Cardiac Subpopulation Data from APOLLO ............................28 
1.3.2. 
Phase 3, Open-label Extension Study .........................................................................29 
1.4. 
Study Design Rationale ..............................................................................................29 
1.5. 
Dose Rationale ............................................................................................................30 
1.6. 
Benefit-risk Assessment .............................................................................................30 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................32 
3. 
INVESTIGATIONAL PLAN .....................................................................................33 
3.1. 
Summary of Study Design ..........................................................................................33 
3.2. 
Duration of Treatment ................................................................................................35 
3.3. 
Duration of Study Participation ..................................................................................35 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................35 
3.4. 
Number of Planned Patients .......................................................................................35 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................35 
3.6. 
Blinding ......................................................................................................................35 
3.6.1. 
Emergency Unblinding ...............................................................................................36 
3.7. 
Data Monitoring Committee .......................................................................................36 
3.8. 
Adjudication Committee .............................................................................................36 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................36 
4.1. 
Inclusion Criteria ........................................................................................................36 
104

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
18 
4.2. 
Exclusion Criteria .......................................................................................................38 
4.3. 
Removal from Study Drug or Assessment .................................................................40 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................40 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................42 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................42 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................42 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................42 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................42 
4.3.3. 
Lost to Follow-up .......................................................................................................43 
4.3.4. 
Replacement of Study Patients ...................................................................................43 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................43 
5.1. 
Treatments Administered ............................................................................................43 
5.2. 
Study Drug ..................................................................................................................43 
5.2.1. 
Premedication .............................................................................................................43 
5.2.2. 
Study Drug Description ..............................................................................................44 
5.2.3. 
Dose and Administration ............................................................................................45 
5.2.3.1. 
Double-bind Study Drug (Patisiran or Placebo) .........................................................45 
5.2.3.2. 
Open-label Extension Period (Patisiran) ....................................................................46 
5.2.4. 
Suggested Guidelines for Management of Infusion-related Reactions ......................46 
5.2.5. 
Dose Modifications .....................................................................................................47 
5.2.6. 
Preparation, Handling, and Storage ............................................................................47 
5.2.7. 
Packaging and Labeling ..............................................................................................47 
5.2.8. 
Accountability .............................................................................................................47 
5.3. 
Concomitant Medications and Procedures .................................................................48 
5.3.1. 
Concomitant Tafamidis Use .......................................................................................48 
5.4. 
Treatment Compliance ................................................................................................49 
5.5. 
Other Requirements ....................................................................................................49 
5.5.1. 
Contraception ..............................................................................................................49 
6. 
STUDY ASSESSMENTS ..........................................................................................50 
6.1. 
Screening Assessments ...............................................................................................50 
6.1.1. 
Retesting .....................................................................................................................51 
6.1.2. 
Rescreening .................................................................................................................51 
6.2. 
Efficacy Assessments .................................................................................................51 
105

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
19 
6.2.1. 
6-Minute Walk Test (6-MWT) ...................................................................................52 
6.2.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ...............................................53 
6.2.3. 
Deaths, Hospitalizations, and Urgent Heart Failure Visits .........................................53 
6.2.4. 
Modified Body Mass Index (mBMI) ..........................................................................53 
6.2.5. 
Cardiac Assessments ..................................................................................................53 
6.2.5.1. 
Cardiac Biomarkers ....................................................................................................53 
6.2.5.2. 
ATTR Amyloidosis Disease Stage .............................................................................54 
6.2.5.3. 
New York Heart Association (NYHA) Class .............................................................54 
6.2.5.4. 
Echocardiogram ..........................................................................................................54 
6.2.5.5. 
Technetium Scintigraphy Imaging .............................................................................54 
6.2.5.6. 
Cardiac Magnetic Resonance (CMR) .........................................................................55 
6.2.6. 
Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QoL-DN) .........................55 
6.2.7. 
Polyneuropathy Disability (PND)...............................................................................55 
6.3. 
Pharmacodynamic Assessments .................................................................................55 
6.4. 
Pharmacokinetic Assessments ....................................................................................55 
6.5. 
Safety Assessments .....................................................................................................56 
6.5.1. 
Vital Signs ..................................................................................................................57 
6.5.2. 
Weight and Height ......................................................................................................57 
6.5.3. 
Physical Examination .................................................................................................57 
6.5.4. 
Electrocardiogram .......................................................................................................57 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................58 
6.5.5.1. 
Immunogenicity ..........................................................................................................59 
6.5.5.2. 
Pregnancy Testing ......................................................................................................59 
6.5.6. 
Vital Status Check ......................................................................................................59 
6.5.7. 
Adverse Events ...........................................................................................................60 
6.5.7.1. 
Definitions ..................................................................................................................60 
6.5.7.2. 
Eliciting and Recording Adverse Events ....................................................................61 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................62 
6.5.7.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........62 
6.5.7.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................63 
6.5.7.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................63 
6.5.7.7. 
Pregnancy Reporting ..................................................................................................63 
106

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
20 
6.5.7.8. 
Overdose Reporting ....................................................................................................63 
6.5.8. 
COVID-19 Data Collection ........................................................................................63 
6.6. 
Biomarkers and Biospecimen Repository ..................................................................63 
7. 
STATISTICS ..............................................................................................................64 
7.1. 
Determination of Sample Size ....................................................................................64 
7.2. 
Statistical Methodology ..............................................................................................65 
7.2.1. 
Populations to be Analyzed ........................................................................................65 
7.2.2. 
Examination of Subgroups .........................................................................................65 
7.2.3. 
Handling of Missing Data ...........................................................................................65 
7.2.4. 
Baseline Evaluations ...................................................................................................65 
7.2.5. 
Efficacy Analyses .......................................................................................................65 
7.2.5.1. 
Primary Endpoint ........................................................................................................66 
7.2.5.2. 
Secondary Endpoints ..................................................................................................66 
7.2.5.3. 
Exploratory Endpoints ................................................................................................66 
7.2.6. 
Pharmacodynamic Analysis........................................................................................67 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................67 
7.2.7.1. 
Pharmacokinetic Analysis ..........................................................................................67 
7.2.7.2. 
Exposure-Response Analysis......................................................................................67 
7.2.7.3. 
Population PK, PK/PD, and Disease Progression Modelling Analysis ......................67 
7.2.8. 
Safety Analyses ..........................................................................................................67 
7.2.9. 
Immunogenicity Analyses ..........................................................................................68 
7.2.10. 
Sample Size Re-assessment ........................................................................................68 
7.2.11. 
Optional Additional Research .....................................................................................68 
8. 
STUDY ADMINISTRATION ...................................................................................68 
8.1. 
Ethical and Regulatory Considerations ......................................................................68 
8.1.1. 
Informed Consent and Medical Records Release Form .............................................68 
8.1.2. 
Ethical Review ............................................................................................................69 
8.1.3. 
Serious Breach of Protocol .........................................................................................70 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................70 
8.1.5. 
End of Study ...............................................................................................................70 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................70 
8.2. 
Data Quality Control and Quality Assurance .............................................................71 
8.2.1. 
Data Handling .............................................................................................................71 
107

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
21 
8.2.2. 
Study Monitoring ........................................................................................................71 
8.2.3. 
Audits and Inspections ................................................................................................71 
8.3. 
Publication Policy .......................................................................................................71 
9. 
LIST OF REFERENCES ............................................................................................73 
10. 
APPENDICES ............................................................................................................77 
10.1. 
Polyneuropathy Disability (PND) Scores ...................................................................77 
10.2. 
New York Heart Association Class (NYHA) .............................................................77 
10.3. 
Categorization of Infusion-Related Reactions ............................................................77 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 
Efficacy Assessments) ................................................................................................10 
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 
24), Early Treatment Discontinuation Visit, and Follow-up ......................................14 
Table 3: 
Clinical Laboratory Assessments ...............................................................................58 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 
108

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALN-18328 
siRNA targeting TTR 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APOLLO 
Patisiran pivotal Phase 3 clinical study ALN-TTR02-004 
AST 
Aspartate aminotransferase 
ATTR 
Amyloid transthyretin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CHF 
Congestive heart failure 
Cmax 
Maximum plasma concentration at end of infusion 
Cmax,ss 
Steady-state Cmax   
Cmin 
Minimum pre-infusion concentration 
Cmin,ss 
Steady-state Cmin   
CMR 
Cardiac magnetic resonance 
Con Meds 
Concomitant medication 
COVID-19  
Coronavirus disease 2019 
Cp(30min) 
30-minute post-infusion concentration 
Cp,ss(30min) 
Steady-state Cp(30min) 
CRF 
Case report form 
CFR 
Code of Federal Regulations 
CV 
Cardiovascular 
DLin-MC3-DMA  
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DMC 
Data Monitoring Committee 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunoassay 
EOS 
End of study 
109

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
23 
Abbreviation  
Definition 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
H1 
Histamine 1 receptor 
H2 
Histamine 2 receptor 
hATTR 
Hereditary ATTR 
HF 
Heart failure 
ICF 
Informed consent form  
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IRS 
Interactive Response System 
IV 
Intravenous(ly) 
KCCQ 
Kansas City Cardiomyopathy Questionnaire  
KCCQ-OS 
Kansas City Cardiomyopathy Questionnaire– Overall Summary 
LNP 
Lipid nanoparticle 
LS 
Least squares 
mBMI 
Modified body mass index 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGUS 
Monoclonal gammopathy of undetermined significance 
MMRM 
Mixed-effects model repeated measures 
mNIS+7 
Modified neurological impairment score +7 
mRNA 
Messenger ribonucleic acid 
6-MWT 
6-minute walk test 
NA 
Not applicable 
Norfolk QoL-DN 
Norfolk Quality of Life - Diabetic Neuropathy 
NSAID 
Nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone B-type natriuretic peptide 
110

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
24 
Abbreviation  
Definition 
NYHA 
New York Heart Association 
OLT 
Orthotopic liver transplantation 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PEG2000-C-DMG 
3-N-[(ω-methoxy poly(ethylene glycol)2000) carbamoyl]-1,2-
dimyristyloxy-propylamine 
PK 
Pharmacokinetic 
PND 
Polyneuropathy disability 
PT 
Preferred term 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RISC 
RNA-induced silencing complex 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
siRNA 
Small interfering RNA 
Tc 
Technetium 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
US 
United States 
V30M 
Valine to methionine mutation at position 30 
V122I 
Valine to isoleucine mutation at position 122 
wt 
Wild type 
wtTTR 
Wild type transthyretin 
 
111

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
25 
1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) is a rare, serious, life-
threatening, multisystemic disease encompassing hereditary ATTR (hATTR) amyloidosis and 
wild-type ATTR (wtATTR) amyloidosis, which result from either hereditary (genetic mutation) 
or nonhereditary (ageing) causes, respectively.  In ATTR amyloidosis, deposition of TTR in 
various organs results in progressive, chronically debilitating morbidity and mortality.  The most 
common manifestations of ATTR amyloidosis are polyneuropathy and cardiomyopathy (ie, 
ATTR amyloidosis with cardiomyopathy). 
TTR, also known as prealbumin, is a tetrameric protein produced by hepatocytes, the choroid 
plexus, and retina.[Liz 2010]  More than 95% of TTR in the circulation is derived from the liver.  
The primary physiological role of TTR is to serve as a carrier of retinol (also known as vitamin 
A), which involves TTR binding to the retinol binding protein (RBP): vitamin A complex.  
However, there is evidence to suggest that vitamin A transport and tissue uptake can occur in the 
absence of circulating RBP.[Biesalski 1999; Episkopou 1993] 
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 amyloidosis, and 
almost all patients are heterozygous for the mutated TTR allele.[Ando 2013; Connors 2003]  The 
phenotypic expression varies depending on the predominant site of deposition of the amyloid 
fibrils with some mutations associated with predominantly polyneuropathy manifestations and 
others associated with predominantly cardiomyopathy manifestations.  However, most patients 
experience both over the course of their disease.   
The most common TTR mutation is the valine to methionine mutation at position 30 (V30M), 
accounting for approximately 50% of cases worldwide, and occurring primarily in families with 
heritage from Portugal, Sweden, Japan, and Brazil.[Parman 2016]  This genotype is most 
commonly associated with multisystemic polyneuropathy.  The valine to isoleucine at position 
122 (V122I) mutation is most commonly associated with cardiomyopathy and occurs primarily 
in African Americans.  In these individuals, the mean age at diagnosis is approximately 65 to 
70 years, with symptom onset typically occurring after the age of 65.[Jacobson 2011; Quarta 
2015]  While there appears to be an association between carrier status and the development of 
heart failure (HF) and echocardiographic features of cardiac amyloidosis, the exact penetrance of 
this particular allele is unknown, and estimates vary widely. 
Normal, nonmutant wtTTR alone can also be amyloidogenic; this is the basis for the 
nonhereditary, wtATTR amyloidosis.  This is a progressive disease typically seen in patients 
older than 70 years and is predominantly seen in men.[Westermark 2003]  Patients with this 
112

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
26 
condition do not have a pathogenic mutation in the TTR gene and the amyloid fibrils consist only 
of wtTTR protein, which form amyloid deposits typically found in heart tissue.   
Cardiac infiltration of the extracellular matrix by TTR amyloid fibrils leads to a progressive 
increase of ventricular wall thickness and a marked increase in chamber stiffness, resulting in 
impaired diastolic function.  Systolic function is also impaired, typically reflected by abnormal 
longitudinal strain despite a normal ejection fraction, which is preserved until late stages of the 
disease.[Castano 2015; Dungu 2012; Mohty 2013; Ruberg 2012]  Cardiac infiltration by amyloid 
can also lead to conduction disturbances and arrhythmias.[Adams 2016; Ando 2013; Benson and 
Kincaid 2007; Connors 2004]  Patients with symptomatic HF experience rapid progression of 
their amyloidosis with cardiomyopathy, with substantial worsening of echocardiographic and 
biomarker measures of cardiac function, in addition to clinical measurements of ambulation, and 
quality of life.  Progression of disease in this population can be seen over a period of 12 months 
as demonstrated by differences in 6-minute walk test (6-MWT) and Kansas City 
Cardiomyopathy Questionnaire (KCCQ) – Overall Summary (KCCQ-OS) in the Phase 3 ATTR-
ACT study.[Maurer 2018]  Based on natural history data, patients typically experience 
progressive symptoms of HF resulting in hospitalization and with death typically occurring 2.5 to 
5 years after diagnosis.[Castano 2015; Damy 2015; Dungu 2012; Hawkins 2015] 
1.2. 
Current Treatments 
The treatment of ATTR amyloidosis requires a multidisciplinary approach primarily involving 
cardiology, neurology, and gastroenterology specialties.  While there are treatments for 
polyneuropathy that are available to hATTR amyloidosis patients, for most regions no treatments 
are currently available for the cardiomyopathy phenotype for either the hATTR or wtATTR 
forms.  Palliative/symptomatic therapies directed at specific symptoms, including volume control 
and treatment of cardiac arrhythmias and conduction system disturbances, including cardiac 
pacemakers where appropriate, have been the mainstay of treatment despite their limited 
effectiveness. 
Given that the liver is the primary source of TTR, orthotopic liver transplantation (OLT) has 
been used for hATTR amyloidosis patients since the early 1990s.  However, OLT is intended to 
eliminate mutant TTR from circulation, but has no effect on the hepatic production of wtTTR, 
which continues to be made by the transplanted liver and can continue to deposit in the heart.  
OLT has also only been shown to be effective in slowing the progression of disease in patients 
with an early age of onset (<50 years of age) [Okamoto 2009], and especially for those with the 
V30M mutation and short disease duration before transplant.  Consequently, almost two-thirds of 
patients with hATTR amyloidosis are not transplant-eligible.   
Tafamidis, a TTR tetramer stabilizer that acts by binding to the thyroxine-binding site on TTR to 
reduce its dissociation into misfolded amyloidogenic monomers, is currently approved in 
Europe, Japan, Mexico, and select countries in South America, but not in the United States (US), 
for the treatment of patients with hATTR amyloidosis with polyneuropathy.[Coelho 2016]  
Recently, tafamidis was evaluated in the Phase 3 ATTR-ACT trial in patients with ATTR 
amyloidosis with cardiomyopathy (including hereditary and wt).[Maurer 2018]  This study 
demonstrated that tafamidis treatment over 30 months was associated with lower all-cause 
mortality and cardiovascular (CV)-related hospitalizations compared with placebo treatment.  
Additionally, tafamidis treatment resulted in a slowing of the decline in functional capacity 
113

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
27 
(6-MWT) and quality of life (KCCQ-OS) compared to placebo.  However, consistent with the 
expected pharmacodynamic (PD) effect of TTR stabilization, the effects of tafamidis on 
mortality outcomes was not observed until late in treatment, with differentiation between 
treatment groups occurring only after 18 months of treatment.  Furthermore, although 
improvements with tafamidis relative to placebo were observed in 6-MWT and KCCQ-OS, 
minimal changes in echocardiographic parameters were observed, and tafamidis-treated patients 
still progressed during the study.   
As of early 2019, tafamidis was not approved in the US for patients with ATTR amyloidosis 
(neither polyneuropathy nor cardiomyopathy phenotypes); however, it is anticipated that 
tafamidis may become available for patients with the cardiomyopathy phenotype in the US and 
in other regions, based on the ATTR-ACT study results.  In Japan, tafamidis was approved in 
2019 for use in transthyretin-type cardiac amyloidosis (wt and mutant), in addition to approval 
for transthyretin-type familial amyloid polyneuropathy. 
The results of the ATTR-ACT study support the general therapeutic hypothesis that modifying 
TTR has the potential to result in beneficial outcomes in patients with ATTR amyloidosis with 
cardiomyopathy.  However, the disease progression that was observed in both treatment arms in 
ATTR-ACT highlights an important unmet medical need and suggests that a more direct 
therapeutic mechanism of action, such as specifically targeting the production of the disease-
causing protein with a ribonucleic acid (RNA) interference (RNAi) therapeutic, may be required 
to halt or reverse the debilitating and ultimately fatal course of disease.    
1.3. 
Patisiran Clinical Development 
Patisiran is a small interfering RNA (siRNA) specific for TTR, which is formulated in a 
hepatotropic lipid nanoparticle (LNP) for intravenous (IV) administration.[Akinc 2010]  The 
patisiran drug product (ALN-TTR02; patisiran-LNP, hereafter referred to as “patisiran”) is 
designed to significantly suppress liver production of both wt and all mutant forms of TTR, 
thereby having the potential to reduce amyloid formation and provide clinical benefit to patients 
with ATTR amyloidosis.   
Patisiran utilizes the mechanism of RNAi to selectively degrade TTR messenger RNA (mRNA) 
and thereby reduce the expression of its corresponding protein.[Bumcrot 2006] Patisiran is 
formulated (via the 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 Pharmaceuticals, Inc. (the Sponsor) is developing patisiran for the treatment of patients 
with ATTR amyloidosis.  Based on results from the pivotal Phase 3 APOLLO study 
(Section 1.3.1), patisiran is approved in the US for the treatment of the polyneuropathy of 
hATTR amyloidosis in adults and in the European Union for the treatment of hATTR 
114

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
28 
amyloidosis in adult patients with stage 1 and stage 2 polyneuropathy.  Ongoing development is 
intended to establish patisiran for the treatment of ATTR (hereditary and wt) amyloidosis with 
cardiomyopathy based on exploratory cardiac results from the APOLLO study (Section 1.3.1.1), 
which provides preliminary evidence in support of the use of patisiran for the treatment of the 
cardiomyopathy manifestations of the disease.  
The nonclinical pharmacology, pharmacokinetics (PK), and toxicology of patisiran were 
evaluated in a series of in vitro and in vivo studies that have enabled chronic dosing in clinical 
studies.   
1.3.1. 
The Phase 3 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 (modified neurological 
impairment score +7 [mNIS+7]) relative to placebo at 18 months (primary endpoint), as well as 
significant improvement in quality of life (Norfolk Quality of Life - Diabetic Neuropathy 
[Norfolk QoL-DN], key secondary endpoint) 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.    
In the patisiran group, serum TTR reduction was seen after the first dose and was stably 
maintained over the duration of the study; the mean TTR percent reduction from baseline was 
82.6% and 84.3% at Months 9 and 18, respectively.  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). 
1.3.1.1. 
Cardiac Results and Cardiac Subpopulation Data from APOLLO 
In APOLLO, evidence of potential cardiac amyloid involvement was seen in most patients in the 
study; 80% had left ventricular wall thickness >13 mm and 79% had abnormal levels of the 
cardiac biomarker N-terminal prohormone B-type natriuretic peptide (NT-proBNP).[Solomon 
2018]  As well, 56% of the population met the prespecified criteria for inclusion in a 
subpopulation of patients with evidence of cardiac amyloid involvement (ie, the cardiac 
subpopulation, with baseline left ventricular wall thickness ≥13 mm and no history of 
hypertension or aortic valve disease).  In these patients, treatment with patisiran for up to 
18 months resulted in improvement relative to placebo in important measures of cardiac structure 
and function.  These included reduction in ventricular wall thickness and decrease 
(improvement) in global longitudinal strain.[Solomon 2018]  In addition, patisiran treatment led 
to a reduction (improvement) in NT-proBNP and an improvement in functional capacity, as 
measured by 10-meter walk test assessment of gait speed, relative to the placebo group.   
115

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
29 
Overall, patisiran had an acceptable safety profile, based on an in-depth analysis of cardiac 
events in both the overall (modified intent-to-treat) population and the cardiac subpopulation.  
Importantly, in a post hoc analysis of safety data in the modified intent-to-treat population, rates 
of any hospitalization and/or all-cause death were 71.8 and 34.7 per 100 patient-years in the 
placebo and patisiran groups respectively, while the rates of cardiac hospitalizations and/or 
all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups 
respectively.  This approximates a reduction in event rate of approximately 50% for all-cause 
hospitalization and mortality and approximately 45% for cardiac hospitalization and all-cause 
mortality for patients in the patisiran group compared to those in the placebo group.[Solomon 
2018]  Similar reductions in the event rates were observed in the cardiac subpopulation in 
APOLLO (approximately 55% for all-cause hospitalization and mortality and approximately 
45% for cardiac hospitalization and all-cause mortality; data on file). 
The observed cardiac data from the APOLLO study support the therapeutic hypothesis that 
patisiran may halt or reverse the progression of the cardiac manifestations of hATTR 
amyloidosis and warrant ongoing development for this indication. 
1.3.2. 
Phase 3, Open-label Extension Study 
Study ALN-TTR02-006 is an ongoing multicenter, open-label extension study designed to 
evaluate the long-term safety and efficacy of patisiran in patients with hATTR amyloidosis who 
have completed a prior Phase 2 or 3 parent study with patisiran (ALN-TTR02-003 or ALN-
TTR02-004 [APOLLO]).  The interim data from this open-label extension study were consistent 
with, and extended, the acceptable safety profile and clinical efficacy of patisiran observed in the 
Phase 3 APOLLO study.   
No new safety signals have emerged for patients with long-term patisiran treatment. 
1.4. 
Study Design Rationale 
This study is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study 
designed to evaluate the efficacy and safety of patisiran in adult patients with ATTR amyloidosis 
with cardiomyopathy.  The efficacy of patisiran on functional capacity will be evaluated via 
change at Month 12 in the 6-MWT (primary endpoint).  The study will include patients with 
wtATTR and hATTR amyloidosis with cardiomyopathy who, at baseline, are either tafamidis 
naïve or have been on tafamidis for ≥6 months with disease progression, in the opinion of the 
Investigator.   
Confidence in a beneficial treatment effect with patisiran in this patient population with ATTR 
amyloidosis with cardiomyopathy comes from the Phase 3 APOLLO study of patisiran in 
patients with hATTR amyloidosis with polyneuropathy.  As described in Section 1.3.1 and 
Section 1.3.1.1, TTR lowering with patisiran demonstrated multiple benefits in a broad range of 
disease manifestations, including a substantial improvement in neuropathy and quality of life, as 
well as autonomic symptoms, motor strength, ambulatory ability, disability, and nutritional 
status.[Adams 2018]  Furthermore, in a prespecified subgroup of patients with evidence of 
cardiac involvement, which was a majority (56%) of the overall study population, a beneficial 
treatment effect of patisiran compared to placebo was observed for assessments of cardiac 
structure and function as well as the cardiac biomarker NT-proBNP.[Solomon 2018]   
116

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
30 
The 6-MWT (primary endpoint assessment) is a clinically relevant assessment of functional 
capacity that has been used as a primary endpoint in pivotal clinical trials in pulmonary arterial 
hypertension (Gabler 2012) and has been used in the evaluation of patients with HF.[Bittner 
1993; Flynn 2009; Flynn 2012; Mangla 2013; Masoudi 2004; Maurer 2014]  The KCCQ-OS 
(first secondary endpoint assessment) has been used as a common assessment in HF 
interventional studies and has been shown to be an independent predictor of prognosis in 
HF.(Heidenreich et al.  2006)  Both 6-MWT and KCCQ-OS were shown to rapidly and 
consistently decline over time in cardiac ATTR amyloidosis patients and, in the Phase 3 ATTR-
ACT study, these measures were used to demonstrate a reduction of decline with tafamidis 
treatment.[Maurer 2018]  These data support the use of 6-MWT and KCCQ-OS as clinically 
relevant primary and key secondary endpoints, respectively.   
Assessment of the primary endpoint at Month 12 is supported by placebo-arm data from the 
ATTR-ACT study showing substantial disease progression (via the 6-MWT) over an equivalent 
time; as well, data from APOLLO demonstrated a patisiran treatment effect as early as 9 months 
on multiple manifestations of hATTR amyloidosis (neuropathy, quality of life, NT-proBNP, and 
functional capacity [ie, gait speed]).[Maurer 2018] 
The inclusion of placebo as a control allows for a rigorous analysis of the treatment effect of 
patisiran.  If tafamidis becomes an approved therapy for ATTR amyloidosis with 
cardiomyopathy in a given region while this study is in progress, patients who are naïve to 
tafamidis treatment at baseline may commence concomitant on-label tafamidis during the study 
(ie, tafamidis drop-in) (Section 5.3.1).    
1.5. 
Dose Rationale 
The approved and recommended dosage of patisiran for the treatment of the polyneuropathy in 
patients with hATTR amyloidosis is 0.3 mg/kg administered IV every 3 weeks for patients 
weighing <100 kg and a fixed dose of 30 mg administered every 3 weeks for patients weighing 
100 kg or more.  This dosage was selected based on dose-response analyses from three Phase 1 
and 2 studies demonstrating dose-dependent TTR reduction, with the maximum reduction 
achieved at 0.3 mg/kg.  This regimen was further confirmed in the pivotal Phase 3 APOLLO 
study, where this dosage showed significant clinical activity and was well tolerated by patients 
with hATTR amyloidosis with polyneuropathy, including those in the cardiac subpopulation.  
The approved dosing regimen used in the treatment of polyneuropathy is being employed in this 
study since the mechanism of action of patisiran (ie, serum TTR lowering) for treatment of 
polyneuropathy and cardiomyopathy is the same.  
1.6. 
Benefit-risk Assessment 
ATTR amyloidosis with cardiomyopathy is a rare, serious, life-threatening, multisystemic 
disease characterized by deposition of TTR in various organs.  Without treatment, the disease 
progresses, resulting in chronically debilitating morbidity and mortality, with the most common 
manifestations being cardiomyopathy and polyneuropathy.  Patients with symptomatic HF 
experience rapid progression of their amyloidosis with 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]   
117

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
31 
The benefit-risk profile of patisiran has been established in extensive clinical development; in 
Phase 1, 2, and 3 clinical studies, patisiran administered IV demonstrated a potent, 
dose-dependent inhibition of TTR.  In the Phase 3 APOLLO study of patisiran, the primary and 
all secondary endpoints were met.[Adams 2018]  Furthermore, exploratory cardiac results from 
the APOLLO study suggest that patisiran may halt or reverse the progression of the cardiac 
manifestations of hATTR amyloidosis [Solomon 2018] and provide preliminary evidence in 
support of the use of patisiran for the treatment of patients with ATTR amyloidosis with 
cardiomyopathy (Section 1.3.1.1). 
In APOLLO, as well as in the ongoing Phase 3, open-label extension study (ALN-TTR02-006), 
an acceptable safety profile with patisiran was demonstrated.  Most AEs were mild or moderate 
in severity.  Transient infusion-related reactions (IRRs) were observed, but all IRRs were mild or 
moderate in severity, none were reported as serious AEs (SAEs).  No clinically significant 
laboratory or hematologic changes were observed.  Furthermore, in APOLLO, an acceptable 
safety profile was also observed in a prespecified subgroup of patients with evidence of cardiac 
amyloid involvement. [Solomon 2018] 
For patisiran, important identified risks include IRRs.  To minimize this risk, all patients must 
receive premedication with a corticosteroid, paracetamol/acetaminophen, and H1 and H2 
blockers prior to patisiran administration (Section 5.2.1).  The infusion may be interrupted or 
slowed if an IRR occurs (Sections 5.2.3 and 5.2.4).  Important potential risks also include severe 
hypersensitivity (eg, anaphylaxis) to the active substance or any of the excipients.  Patisiran is 
contraindicated in patients with a history of severe hypersensitivity (eg, anaphylaxis or 
anaphylactoid reactions) to patisiran or any of the excipients. 
Vitamin A deficiency is also considered an important potential risk.  Nonclinical and clinical 
data with patisiran have shown that the lowering of circulating vitamin A associated with the 
reduction in TTR (a carrier of retinol) does not result in 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 (Section 5.3).  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 patisiran.  
Detailed information about the known and expected benefits and risks of patisiran may be found 
in the current edition of the Investigator’s Brochure.  
During the study, patients will be monitored, including evaluation of laboratory monitoring for 
liver function test abnormalities, renal function, and other standard hematology and blood 
chemistries.  As the risk of embryofetal toxicity is currently unknown, females of child-bearing 
potential participating in the study must have a negative pregnancy test, cannot be breast feeding, 
and must be willing to use a highly effective method of contraception as specified in the 
protocol. 
An external, independent Data Monitoring Committee (DMC) will monitor and ensure the safety 
of trial participants (see Section 3.7).   
In conclusion, exploratory cardiac results from the APOLLO study suggesting that patisiran may 
halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis [Solomon 
118

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
34 
randomized, double-blind study drug (patisiran or placebo), to reduce the potential for an IRR 
with patisiran, all patients will receive premedications at least 60 minutes before the start of their 
infusion.  (Patients randomized to placebo will also receive premedications to maintain the 
blind.)  Study drug will be administered as an approximately 80-minute IV infusion.  
During the 12-month open-label extension period, all patients will receive treatment with 
open-label patisiran.   
Study drug administration at a location other than the study center (eg, at home) may be 
administered as follows: 
• Double-blind period:  Patients who have received ≥2 doses of study drug at the study 
center with no evidence of IRRs or other drug-related adverse effects that impact safety 
and tolerability of the infusion may have study drug administered at a location other than 
the study center (eg, at home), where applicable country and local regulations allow.  
Study drug administration will be performed by a healthcare professional, trained on the 
protocol and on administration of premedications and study drug infusion, with oversight 
of the Investigator. 
• 12-month open-label extension period:  Patients who have received ≥2 doses of 
open-label patisiran at the study center with no evidence of IRRs or other drug-related 
adverse effects that impact safety and tolerability of the infusion may have patisiran 
administered at a location other than the study center (eg, at home), where applicable 
country and local regulations allow.  Patisiran administration will be performed by a 
healthcare professional trained on the protocol and on administration of premedications 
and patisiran infusion, with oversight of the Investigator. 
To evaluate the efficacy of treatment with patisiran versus placebo in patients with ATTR 
amyloidosis with cardiomyopathy, the change from baseline in 6-MWT will be assessed at 
Month 12 (Weeks 52-53) as the primary endpoint (Section 2); this assessment will also be 
performed at Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) in the double-blind period, 
and during the open-label extension period at the time points noted in the Schedule of 
Assessments (Table 1 and Table 2).  The first secondary endpoint will assess change from 
baseline at Month 12 in the KCCQ-OS score.     
In situations where an efficacy study visit at Months 6, 9, and/or 12 is unable to be completed at 
the study center due to the Coronavirus disease 2019 (COVID-19) pandemic impacting activities 
at the study center or patient 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 Month 6, 9, and/or 12 efficacy assessments.  
After consultation with the Medical Monitor, efficacy assessments may be extended for that visit 
as follows:  Month 6 up to Day 214; Month 9 up to Day 319; Month 12, up to Day 417, but prior 
to the first dose of open-label patisiran (Table 1).  Patients may continue to receive double-blind 
study drug until the Month 12 efficacy assessment is performed.  For the open-label extension 
period, the windows for study visits are also extended (Table 2). 
Safety will be assessed throughout the study, as described in the Schedule of Assessments for the 
double-blind period (Table 1) and for the open-label extension period (Table 2).   
121

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
35 
3.2. 
Duration of Treatment  
The treatment duration in this study is up to 24 months, inclusive of a 12-month, double-blind, 
treatment period, and a 12-month, open-label, treatment period. 
3.3. 
Duration of Study Participation  
The estimated total time on study for each patient is up to 26.5 months, including up to 45 days 
of screening, up to 24 months of treatment (see Section 3.2), and a 28-day safety follow-up 
period. 
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 end of study (EOS; Month 24) visit, or 
• the patient has completed the follow-up visit 28 days after the last dose of patisiran.    
3.4. 
Number of Planned Patients 
The planned enrollment for this study is 300 patients with wtATTR and hATTR amyloidosis 
with cardiomyopathy.  Approximately 20% of the study population is anticipated to have hATTR 
and 80% wtATTR. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the interactive response system (IRS), patients will be randomized 1:1 to the patisiran or 
placebo arm.  Randomization will be stratified by: 
1. Baseline tafamidis (yes vs no) 
2. Genotype (hATTR vs wtATTR amyloidosis with cardiomyopathy) 
3. NYHA Class I or II and age < 75 years vs all other     
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 
During the double-blind period of the study, all personnel will be blinded to the study treatment, 
except the pharmacist and designated pharmacy/healthcare personnel who will set-up, dispense, 
and prepare the infusion.  Patisiran confers a slightly opalescent color relative to the clear saline 
(placebo) infusate; therefore, all infusion bags and lines will be covered with amber bags and line 
covers by the unblinded personnel to prevent visualization by the blinded study personnel and 
patient, as described in detail in the Pharmacy Manual.   
After the pharmacist (or designated pharmacy/healthcare personnel) has prepared the infusion, 
separate blinded personnel will administer study drug and monitor the patient during and after 
122

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
36 
the infusion.  All patients will be blinded to treatment and will receive an IV infusion once every 
3 weeks using identical volumes for patisiran and placebo.    
Study personnel performing assessments related to the primary and secondary endpoints will be 
different from the Investigator and other personnel managing the patient, and all of these study 
personnel will be blinded to any clinical laboratory results that could potentially unblind them 
(eg, TTR levels).  In addition, the study personnel performing assessments related to the primary 
and secondary efficacy endpoints will not reference the results of any previous assessments. 
Furthermore, unblinded source documentation containing all descriptions of pharmacy 
preparations and infusions or distribution of study drug or randomization data will be stored 
separate from all other study data/records and from other pharmacy staff not participating on the 
study. 
Blinding will be maintained until the last patient completes their Month 12 visit. 
3.6.1. 
Emergency Unblinding 
During the double-blind period of the study, if the treating physician determines that the clinical 
management of the patient requires knowledge of the study drug assignment, the Investigator 
may break the blind, as necessary.  If time permits, clinical study center personnel should contact 
the Medical Monitor before unblinding to discuss the need to unblind the patient but must do so 
within 1 working day after the unblinding event.  Unblinding information should be limited to 
the fewest number of people on a need-to-know basis.  A record of when the blind was broken, 
who was unblinded, who broke the blind, and why it was broken, will be maintained in the trial 
master file. 
Refer to the IRS instructions for details on emergency unblinding. 
3.7. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study through the 
double-blind period (through Month 12), 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.  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 (CV versus non-CV) according to the responsible underlying disease process 
rather than the immediate mechanism.  Urgent HF visits will also be adjudicated.  Deaths, 
hospitalizations, and urgent HF visits will be classified as specified in the Adjudication 
Committee Charter. 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
123

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
37 
Age and Sex 
1. Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive.  
Patient and Disease Characteristics 
2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either 
hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with 
cardiomyopathy: 
Hereditary ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of 
the following criteria: 
a. TTR pathogenic mutation consistent with hATTR.  
b. Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness >12 mm (based on central echocardiogram 
reading at screening).   
c. Amyloid deposits in cardiac or noncardiac tissue (eg, fat pad aspirate, salivary gland, 
median nerve connective sheath) confirmed by Congo Red (or equivalent) staining 
OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc], or 99mTc-
hydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if 
monoclonal gammopathy of undetermined significance (MGUS) has been excluded. 
d. If MGUS, confirm TTR protein in tissue with immunohistochemistry (IHC) or mass 
spectrometry. 
Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of 
the following criteria: 
a. Absence of pathogenic TTR mutation.  
b. Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness >12mm (based on central echocardiogram 
reading at screening).   
c. Amyloid deposits in cardiac tissue with TTR precursor identification by IHC, mass 
spectrometry, OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc] or 99mTc-
hydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if 
MGUS has been excluded. 
d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry.  
3. Medical history of HF with at least 1 prior hospitalization for HF (not due to arrhythmia 
or a conduction system disturbance treated with a permanent pacemaker) OR clinical 
evidence of HF (with or without hospitalization) manifested by signs and symptoms of 
volume overload or elevated intracardiac pressures (eg, elevated jugular venous pressure, 
shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral 
edema) that currently requires treatment with a diuretic. 
4. Patient meets one of the following criteria: 
a. Tafamidis naïve; in addition to patients who have never taken tafamidis, those who 
have been on tafamidis for ≤30 days total and have not received any tafamidis in the 
124

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
38 
6 months prior to baseline will be considered tafamidis naïve and may qualify for the 
study. 
b. Currently on tafamidis (for ≥6 months) and has demonstrated disease progression, as 
determined by the Investigator.  (At the time of study entry, tafamidis treatment must 
be on-label use of commercial tafamidis for the treatment of ATTR amyloidosis with 
cardiomyopathy at the approved dose in the country of use.) 
5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to 
randomization, as assessed by the Investigator.   
6. Able to complete ≥150 m on the 6-MWT at screening. 
7. Screening NT-proBNP >300 ng/L and <8500 ng/L; in patients with permanent or 
persistent atrial fibrillation, screening NT-proBNP >600 ng/L and <8500 ng/L. 
Informed Consent 
8. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent; and patient agrees to sign the 
medical records release form for collection of vital status.   
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Has known primary amyloidosis (AL) or leptomeningeal amyloidosis.  
2. NYHA Class III AND ATTR amyloidosis disease Stage 3 (defined as both NT-proBNP 
>3000 ng/L and estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 
m2).[Gillmore 2018] 
3. NYHA Class IV at the Screening visit. 
4. Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to 
walk, or is wheelchair bound) at the Screening visit. 
Laboratory Assessments 
5. Has any of the following laboratory parameter assessments at screening:  
a. Aspartate transaminase (AST) or alanine transaminase (ALT) levels ˃2.0 × the upper 
limit of normal (ULN). 
b. Total bilirubin ˃2×ULN.    
c. International normalized ratio (INR) ˃1.5 (unless patient is on anticoagulant therapy, 
in which case excluded if INR ˃3.5).  
6. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] 
formula). 
7. Has known human immunodeficiency virus infection; or evidence of current or chronic 
hepatitis C virus or hepatitis B virus infection.    
125

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
39 
Prior/Concomitant Therapy 
8. Tafamidis naïve patients (at baseline) for whom the Investigator actively plans or 
anticipates commencing treatment with tafamidis during the 12-month double-blind 
period, taking into consideration clinical status, patient preference and/or commercial 
availability of tafamidis. 
9. Is currently taking diflunisal; if previously on this agent, must have at least a 30-day 
wash-out prior to dosing (Day 1). 
10. Is currently taking doxycycline, ursodeoxycholic acid, or tauroursodeoxycholic acid; if 
previously on any of these agents, must have completed a 30-day wash-out prior to 
dosing (Day 1).    
11. Received prior TTR-lowering treatment (including patisiran) or participated in a gene 
therapy trial for hATTR amyloidosis. 
12. Current or future participation in another investigational device or drug study, scheduled 
to occur during this study, or has received an investigational agent or device within 
30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing 
(Day 1).  In the case of investigational TTR stabilizer drugs, washout for 6 months prior 
to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at 
baseline (per inclusion Criterion 4). 
13. Requires chronic treatment with non-dihydropyridine calcium channel blockers (eg, 
verapamil, diltiazem).  
Medical Conditions 
14. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to 
valvular heart disease, or cardiomyopathy due to ischemic heart disease (eg, prior 
myocardial infarction with documented history of cardiac enzymes and 
electrocardiogram [ECG] changes). 
15. Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive 
pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation). 
16. Recent or planned orthopedic procedure during the double-blind period (eg, lower 
extremity or back surgery) that could impact 6-MWT. 
17. Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of 
screening required to achieve optimal treatment of CHF). 
18. Had acute coronary syndrome or unstable angina within the past 3 months. 
19. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.  
20. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a 
pacemaker is indicated but will not be placed. 
21. Has persistent elevation of systolic (˃180 mmHg) and diastolic (˃100 mmHg) blood 
pressure that is considered uncontrolled by physician. 
22. Has untreated hypo- or hyperthyroidism. 
23. Prior or planned heart, liver, or other organ transplant. 
126

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
40 
24. Had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix that has been successfully treated. 
25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation; or, in the opinion of the 
Investigator, taking part in the study would jeopardize the safety of the patient.   
26. Has a history of severe hypersensitivity (eg, anaphylaxis) to any of the excipients in 
patisiran.  Also see exclusion Criterion 11, which excludes all patients with prior 
TTR-lowering treatment including patisiran. 
Contraception, Pregnancy, and Breastfeeding 
27. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.5.1.   
28. Female patient is pregnant or breast-feeding.    
Alcohol Use 
29. Has a known history of alcohol abuse within the past 2 years or daily heavy alcohol 
consumption (for females, more than 14 units of alcohol per week; for males, more than 
21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ 
pint of beer]); 
30. History of illicit drug abuse within the past 5 years that in the opinion of the Investigator 
would interfere with compliance with study procedures or follow-up visits. 
4.3. 
Removal from Study Drug or Assessment 
Patients 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 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; which includes required treatment with 
prohibited medication (as defined in Section 5.3) per Investigator discretion 
• Adverse event  
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
127

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
41 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.7.7 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.   
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1 and Table 2), 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 AEs, and must document this decision in the 
patient’s medical records. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.5.7.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable. 
Patients who discontinue from study drug during the 12-month double-blind period, defined as 
the time the first dose of study drug is administered on Day 1 through completion of the 
Month 12 Efficacy Visit (primary endpoint assessment), will be encouraged to remain on the 
study and complete assessments through Month 12 (excluding PK assessments), including a 
Modified Month 12 Efficacy Visit (Table 1).  They will also be asked to complete an Early 
Treatment Discontinuation Visit (7-14 days after their last dose) and the safety follow-up visit, 
28 days after the last dose of study drug (Table 2); see Section 3.3.1. 
In situations where the Modified Month 12 Efficacy Visit is unable to be completed at the study 
center due to the COVID-19 pandemic impacting activities at the study center or patient 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 these efficacy assessments.  After consultation with the Medical Monitor, efficacy 
assessments may be extended up to Day 417 (as is permitted for the regular Month 12 visit).   
Patients who discontinue patisiran during the open-label extension period will be asked to 
complete an Early Treatment Discontinuation Visit (7-14 days after their last dose) and the safety 
follow-up visit, per the Schedule of Assessments (Table 2), 28 days after the last dose of 
patisiran; see Section 3.3.1. 
128

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
42 
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 the patient's participation in the study at any time.  A 
patient or legal guardian considering stopping participation in the study should be informed that 
the patient can discontinue study drug and/or decline procedural assessments and remain in the 
study to complete their study assessments, through the Modified Month 12 Efficacy Visit, and 
the 28-day follow-up visit, or alternatively may complete any minimal assessments for which the 
patient or legal guardian consents as described in Section 4.3.1.  If a patient or legal guardian still 
chooses to discontinue study drug and stop participation in all follow-up prior to the completion 
of the Month 12 visit, every effort should be made to conduct the assessments scheduled to be 
performed at the Modified Efficacy Visit (Table 1). 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, 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, and 
use biological samples and, as applicable, other personal data, informing the study doctor at any 
time in writing or in any other form that may be locally required.  The Sponsor will continue to 
keep and use the patient’s study information (including any data resulting from the analysis of 
the patient’s biological samples until the time of withdrawal) according to applicable law.  The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements.   
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
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. 
129

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
43 
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 or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes (for the patient) 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 or legal guardian (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 or legal guardian 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 and returned unused must not be re-dispensed. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of study drug 
(patisiran and placebo) 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. 
Premedication 
All patients will receive premedication prior to study drug administration to reduce the risk of 
IRRs.  Each of the following medicinal products should be given on the day of study drug 
infusion at least 60 minutes prior to the start of infusion: 
130

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
44 
• 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. Double-blind and open-label periods:  If a patient is having difficulty tolerating the 
steroid premedication regimen (eg, patient develops uncontrolled hyperglycemia, altered 
mental status, or other complication), then lowering of the steroid premedication may be 
allowed for that patient after consultation with the medical monitor at any time during the 
study.   
2. Double-blind period:  For patients who are tolerating their double-blind study drug 
infusions well with their current corticosteroid premedication regimen (ie, no IRRs 
during the past 3 or more infusions), corticosteroid dose may be reduced in 2.5 mg 
increments to a minimum dose of 5 mg of dexamethasone (IV) or equivalent.    
a. Open-label period:  At the start of the open-label period, patients must take 
dexamethasone 10 mg or the equivalent as their corticosteroid premedication.  
Patients taking more than 10 mg of dexamethasone at the end of the double-blind 
period should take the higher dose.  The corticosteroid dose may then be tapered as 
described above if the patient is tolerating infusions.  However, if a patient’s steroid 
premedication had been decreased in the double-blind period due to their inability to 
tolerate the premedication regimen as described above, continuation of the reduced 
dose regimen (as it had been in the double-blind period) may be permitted after 
consultation with the Medical Monitor. 
Infusions during corticosteroid tapering may be performed at the study center or at a location 
other than the study center (eg, at home), as described in detail in the Pharmacy Manual, at the 
discretion of the Investigator and after consultation with the Medical Monitor.   
Additional or higher doses of 1 or more of the premedications may be administered to reduce the 
risk of IRRs, if needed.  For suggested guidelines for management of IRRs, see Section 5.2.4; 
further details can be found in the Pharmacy Manual.   
5.2.2. 
Study Drug Description 
Patisiran is a RNAi therapeutic consisting of a double-stranded siRNA targeting TTR mRNA 
formulated in an LNP.  The patisiran drug product is a sterile formulation of ALN-18328 (siRNA 
targeting TTR) formulated as LNPs with lipid excipients (1,2-Dilinoleyloxy-N,N-
dimethylpropylamine [DLin-MC3-DMA], 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.  Patisiran Solution for 
IV infusion contains 2 mg/mL of patisiran. 
See the Pharmacy Manual for further details of solution concentration and fill volume. 
131

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
45 
The control drug for this study will be a placebo (normal saline 0.9% for IV administration).  
Control drug will be provided by a central supplier (or, if necessary, by a local supplier, with 
prior Sponsor approval).  
5.2.3. 
Dose and Administration 
Detailed instructions for study drug preparation and administration are found in the Pharmacy 
Manual.    
5.2.3.1. 
Double-bind Study Drug (Patisiran or Placebo) 
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs (Section 5.2.1).   
An IV infusion of double-blind study drug (patisiran 0.3 mg/kg or placebo) will be administered 
under the supervision of the site personnel once every 3 weeks ±3 days.   
The amount (in mg) of double-blind patisiran 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.  
Weight from the previous visit may be used for calculating dose.  Weight must be collected prior 
to dosing with study drug.  Study drug will be administered as an approximately 80-minute IV 
infusion (approximately 1 mL/minute for the first 15-minutes followed by approximately 
3 mL/minute for the remainder of the infusion).  The 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 be observed for 1 hour following completion of dosing for observation 
and completion of assessments. 
Patients who have received ≥2 doses of study drug at the study center with no evidence of IRRs 
or other drug-related adverse effects that impact safety and tolerability of the infusion may have 
study drug administered at a location other than the study center (eg, at home), where applicable 
country and local regulations allow.  Study drug administration will be performed by a 
healthcare professional, trained on the protocol and on administration of premedications and 
study drug infusion, with oversight of the Investigator.  
Missed doses of double-blind study drug   
If a patient does not receive a dose of study drug within the dosing window (±3 days), the 
delayed dose may be taken up to 7 days after the scheduled visit, after consultation with the 
Medical Monitor.  If a dose is administered with a delay, the next dose will resume following the 
original schedule per the Schedule of Assessments.       
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. 
132

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
46 
5.2.3.2. 
Open-label Extension Period (Patisiran) 
The last dose of double-blind study drug will be at Week 51 and the first dose of open-label 
patisiran will be 3 weeks later (at Week 54) and thereafter every 3 weeks (±3 days) for the 
remainder of the study.  Open-label patisiran will be administered per the schedule and dose as is 
described in Section 5.2.3.1 for double-blind patisiran.  As noted in Section 3.6, blinding will be 
maintained until the last patient completes their Month 12 visit. 
During the open-label extension period, patients who have received at least 2 doses of open-label 
patisiran at the study center with no evidence of IRRs or other drug-related adverse effects that 
impact safety and tolerability of the infusion may have patisiran administered at a location other 
than the study center (eg, at home), where applicable country and local regulations allow.  
Patisiran administration will be performed by a healthcare professional trained on the protocol 
and administration of premedications and patisiran infusion.    
All patients will receive premedications prior to open-label patisiran administration to reduce the 
risk of IRRs (Section 5.2.1).   
Missed doses of open-label patisiran   
If a patient does not receive a dose of open-label patisiran within the dosing window (±3 days), 
the delayed dose may be taken up to 7 days after the scheduled visit, after consultation with the 
Medical Monitor.  If a dose is administered with a delay, the next dose will resume following the 
original schedule per the Schedule of Assessments.     
5.2.4. 
Suggested Guidelines for Management of Infusion-related Reactions 
Criteria for categorizing IRRs are provided in Section 10.3. 
• In the event of an IRR, the infusion of study drug may be slowed or stopped and the patient 
closely monitored until resolution of the reaction.  Drugs that may be used to facilitate 
resolution and permit resumption of study drug administration include but are not limited to:  
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), nonsteroidal anti-inflammatory drugs (NSAIDs), adrenaline, supplemental 
oxygen, IV fluids, and/or corticosteroids. 
• Following resolution of a mild or moderate IRR that required interruption of the study drug 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate for that dose and for subsequent doses of study drug.  If the infusion is delayed, 
the administration of the infusion should be completed no more than 16 hours after study 
drug is first diluted in saline (including infusion time). 
• Study drug administration will not be resumed for any patient following a severe IRR until 
the case is discussed with the Medical Monitor. 
• If after consultation with the Medical Monitor it is agreed that an individual patient’s steroid 
premedication will be increased, then the following steps are recommended: 
1. If the IRR occurred while the patient received 10 mg IV dexamethasone or equivalent at 
least 60 minutes before the infusion and did not resolve with slowing of the infusion rate, 
then the patient should be increased by multiples of 5 mg IV dexamethasone or 
equivalent at least 60 minutes before the infusion.  
133

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
47 
2. Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
IV dexamethasone or equivalent on the day of infusion.  
3. If the IRR occurred while the patient received less than 10 mg IV dexamethasone or 
equivalent, then the patient should return to the prior dose of IV dexamethasone or 
equivalent that did not result in an IRR. 
Patients will be instructed to call the Investigator if they experience symptoms such as fever, 
chills, myalgia, or nausea/vomiting after discharge from the site. 
5.2.5. 
Dose Modifications 
Dose modifications are not permitted.   
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
5.2.6. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of study drug (patisiran and placebo) 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. 
5.2.7. 
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. 
5.2.8. 
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. 
134

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
48 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications and Procedures 
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs (Section 5.2.1).   
Use of the following medications/treatments are prohibited during study participation: 
• Any investigational agent other than study drug. 
• Inotersen, doxycycline, ursodeoxycholic acid, tauroursodeoxycholic acid, and 
diflunisal are also prohibited during the study (see exclusion Criterion 10 in 
Section 4.2).  Doxycycline is permitted if being taken for short-term treatment of 
infection.    
All patients will be asked to take the recommended daily allowance of vitamin A for the duration 
of their participation in the study while being administered study drug.  In countries where 
relevant, the clinical sites will provide patients with a prescription for vitamin A at a dose 
consistent with local guidelines.  
Standard vitamins and topical medications are permitted.  Any concomitant medication or 
treatment that is required for the patient’s welfare may be given by the Investigator.  However, it 
is the responsibility of the Investigator to ensure that details regarding the medication are 
recorded on the CRF, as specified in the Schedule of Assessments (Table 1 and Table 2).  
Concomitant medications include 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 CRF.  Concomitant medication will be coded using an internationally 
recognized and accepted coding dictionary.  
5.3.1. 
Concomitant Tafamidis Use 
Per inclusion Criterion 4, at baseline patients are either: 1) tafamidis naïve or 2) currently on 
tafamidis for ≥6 months with demonstrated disease progression, as determined by the 
Investigator.  Patients who have been on tafamidis for ≤30 days total and have not received any 
tafamidis in the 6 months prior to baseline will be considered tafamidis naïve and may qualify 
for the study.   
For patients on tafamidis at baseline, the reasons for considering the patient to have 
demonstrated disease progression will be recorded in the eCRF.  Patients who are on tafamidis at 
baseline are encouraged, if it is medically appropriate in the opinion of the Investigator, to 
remain on tafamidis for the duration of the double-blind period. 
Per exclusion Criterion 8, patients who are tafamidis naïve at baseline, for whom the Investigator 
actively plans or anticipates commencing treatment with tafamidis during the 12-month 
double-blind period (taking into consideration clinical status, patient preference, and/or 
commercial availability of tafamidis), should not be enrolled in the trial. 
However, if tafamidis is granted approval by a Health Agency for treatment in patients with 
ATTR amyloidosis with cardiomyopathy in a given region, all enrolled patients in this region 
will be made aware of its potential benefits and risks at the time of regulatory approval and all 
patients will be reconsented.  In such circumstances, tafamidis is not considered prohibited and 
135

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
49 
the Investigator may, using their medical judgement, commence concomitant on-label tafamidis 
during the study, if it is felt to be in the best interest of the patient and if it is commercially 
available in the country.   
Patients who are tafamidis naïve at baseline, but begin taking commercial tafamidis (ie, 
“tafamidis drop-in”), will remain in the study.  Prior to commencing concomitant tafamidis, the 
Investigator will perform assessments (including primary and select secondary efficacy 
assessments) at the Pre-tafamidis Drop-in Visit, as outlined in the Schedule of Assessments 
(Table 1).  In all cases, the Pre tafamidis Drop-in Visit should occur prior to starting concomitant 
tafamidis; where possible, this visit should occur between 1-2 weeks after the last dose of study 
drug (ie, 7 to 14 days post study drug dose).  Thereafter, the patient will continue with all 
assessments per the Schedule of Assessments (Table 1 and Table 2).  In addition, at the time of 
tafamidis drop-in, the reason for starting tafamidis will be recorded in the CRF. 
Initiation of TTR stabilizer therapies other than tafamidis (eg, diflunisal) is not allowed during 
the double-blind period of this study. 
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 a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 12 weeks 
after the last dose of study drug in this study.    
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 low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. 
• 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 12 weeks after the last 
dose of study drug.  
136

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
50 
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, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements as described in the corresponding patient informed consent forms.   
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.2).    
6. 
STUDY ASSESSMENTS 
The Schedule of Assessments is provided in Table 1 (double-blind period) and Table 2 
(open-label extension period).  Additional information on the collection of study assessments 
will be detailed in the respective reference manuals. 
6.1. 
Screening Assessments  
An ICF 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.  In addition, a medical records release form will be required of all patients for the 
purpose of obtaining vital status information from the patient’s physician or from death 
registries.    
See the Schedule of Assessments (Table 1) for a list of Screening visit assessments.   
To ensure patient safety and, to the extent possible, that study integrity is maintained amid travel 
and other restrictions related to the COVID-19 pandemic, the Investigator will notify the Sponsor 
before screening patients to allow an assessment of the ability of the study center or any new trial 
participant to comply with the protocol given COVID-19 limitations.  
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening (once) of patients is permitted with consultation of the Medical 
Monitor (see Section 6.1.2). 
Patient demographic data and medical history/disease history will be obtained, including 
completion of ophthalmologic history in the eCRF.  Any changes to medical history occurring 
between the screening assessment and Day 1 will be updated prior to study drug administration. 
If a genetic test result that shows the presence or absence of a TTR pathogenic mutation, which 
would be consistent with either wtATTR or hATTR, is not available at Screening for the 
assessment of eligibility (Section 4.1, inclusion Criterion 2a), genotyping may be conducted at a 
137

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
51 
central laboratory.  Alternatively, a local laboratory may be selected by the study center in 
consultation with the Medical Monitor. 
The study eligibility biopsies and technetium scintigraphy noted in inclusion Criterion 2 are 
intended to be historical, as part of the patient’s clinical care and diagnosis, and are not 
performed as part of the study.    
If a diagnostic result that confirms ATTR amyloidosis is not available at Screening for the 
assessment of eligibility (inclusion Criterion 2c/d), testing may be conducted at a laboratory or 
diagnostic center selected by the study center, in consultation with the Medical Monitor, in 
countries in which this test is not standard of care. 
An echocardiogram will be performed at screening Visit 1 and results confirmed centrally to 
assess study eligibility, as indicated in the Schedule of Assessments (Table 1). 
6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then 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.  Any 
additional repeat testing may be considered after discussion with the Medical Monitor. 
6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening, or who fails to complete screening activities due to unforeseen or unavoidable 
circumstances, may be rescreened once after consultation with the Medical Monitor after a 
minimum of 5 days have elapsed from a patient’s last screening assessment.  A patient will be re-
consented if rescreening occurs outside of the 45-day screening window.  In this case, all 
screening procedures must be repeated.   
Patients who failed screening due to situations related to the COVID-19 pandemic may be 
allowed to rescreen after consultation with the Medical Monitor. 
6.2. 
Efficacy Assessments 
As noted in Table 1, in situations where a Month 6 (Day 176-183), Month 9 (Day 260-267), 
and/or Month 12 (Day 365-372) study visit is unable to be completed at the study center due to 
the COVID-19 pandemic impacting activities at the study center or patient 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 Month 6, 9, and/or 12 efficacy assessments.  After consultation with the Medical Monitor, 
efficacy assessments may be extended as follows:  Month 6 up to Day 214; Month 9 up to 
Day 319; Month 12, up to Day 417, but prior to the first dose of open-label patisiran.  Patients 
may continue to receive double-blind study drug until the Month 12 efficacy assessment is 
performed.    
For the open-label extension period, as noted in Table 2, in situations where a Month 18 
(Day 554-561), Month 21 (Day 638-645), and/or Month 24 (Day 743-750) study visit is unable 
to be completed at the study center due to the COVID-19 pandemic impacting activities at the 
138

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
52 
study center or patient 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 Month 18, 21, and/or 24 efficacy assessments.  After 
consultation with the Medical Monitor, efficacy assessments may be extended as follows:  
Month 18 up to Day 592; Month 21 up to Day 697; Month 24, up to Day 774.  
6.2.1. 
6-Minute Walk Test (6-MWT) 
The 6-MWT, which will be assessed as the primary endpoint, is an assessment of functional 
exercise capacity.  The 6-MWT will be administered by staff trained in the procedure per the 
relevant study manual.  The staff administering the 6-MWT will be different from the 
Investigator or designee managing the care of the patient. 
The 6-MWT will be performed at each of the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2).  At screening Visit 1, the 6-MWT will be administered for 
study eligibility purposes (per inclusion Criterion 6 [Section 4.1]).  At screening Visit 1, prior to 
conducting the 6-MWT, the site staff will familiarize the patient with the purpose and conduct of 
the 6-MWT, as described in detail in the relevant study manual.  Familiarization can be repeated 
at other timepoints if deemed helpful. 
On Day 1 (baseline), which is a dosing day, the 6-MWT will be performed prior to study drug 
administration.  (No other dosing days have a 6-MWT assessment.)   
Patients who are hospitalized during the study should wait at least 2 weeks after hospitalization 
before completing a 6-MWT assessment; less time post-hospitalization may be permitted if, in 
the opinion of the Investigator, the patient is unencumbered due to the recent hospitalization.  In 
addition, if a patient is not feeling well due to an external factor (eg, flu, sprained ankle, pulled 
back muscle) at a visit when the 6-MWT will be performed, the test should not be done and 
should be rescheduled for another day within the permitted visit window. 
For each 6-MWT assessment, the site should make every effort to have this assessment 
performed by the same assessor and to perform the test at approximately the same time of day.  
If the test is interrupted or deemed unusable by the 6-MWT core laboratory, the 6-MWT should 
be repeated as soon as possible within the allowed visit window. 
Further details regarding the 6-MWT are provided in the relevant study manual. 
A 1.5-month window will be used to group 6-MWT assessments to the Month 6 (Weeks 25-26), 
Month 9 (Weeks 37-38), and Month 12 (Weeks 52-53) visits.  During the double-blind period, a 
patient may opt to begin tafamidis treatment or to discontinue study treatment, in which case 
they would complete a Pre-tafamidis Drop-in Visit (Table 1) or Early Treatment Discontinuation 
Visit (Table 2), respectively.  To avoid the potential training effect from repeated assessments of 
the 6-MWT within a short period of time, only one 6-MWT assessment should be collected for 
the following time periods:  Day 2 to Day 214 (for Month 6), Day 215 to Day 319 (for Month 9), 
and Day 320 to Day 417 (for Month 12).  
Within a given time period, the 6-MWT assessment should be performed at whichever visit 
occurs first (scheduled assessment, Pre-tafamidis Drop-in Visit, or Early Treatment 
Discontinuation Visit); no additional 6-MWT assessments should be made in that time period.  
In later time periods, the 6-MWT should be assessed per the Schedule of Assessments (Table 1).  
139

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
53 
6.2.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ)   
The KCCQ [Green 2000] is a 23-item self-administered questionnaire developed to 
independently measure the patient’s perception of health status, which includes heart failure 
symptoms, impact on physical and social function, and how their heart failure impacts their 
quality of life within a 2-week recall period. 
The KCCQ quantifies 6 domains (symptoms, physical function, quality of life, social limitation, 
self-efficacy, and symptom stability) and 2 summary scores (clinical and overall summary [OS]).  
The KCCQ-OS will be assessed for the first secondary endpoint. 
The KCCQ questionnaire will be completed at the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2). 
6.2.3. 
Deaths, Hospitalizations, and Urgent Heart Failure Visits 
All deaths and hospitalizations will be recorded at Day 1 post dose and throughout the study as 
specified as part of AEs monitoring (see Section 6.5.7) and per the Schedule of Assessments 
(Table 1 and Table 2).  All urgent HF visits will also be recorded in the eCRF. 
Reasons for deaths and hospitalizations will be adjudicated by an independent Adjudication 
Committee (Section 3.8).  Urgent HF visits will also be adjudicated.   
6.2.4. 
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 pre-dose at the timepoints specified in the Schedule of Assessments (Table 1 and 
Table 2).  The site will not perform the calculation for mBMI.   
6.2.5. 
Cardiac Assessments   
Manifestations of cardiac amyloid involvement will be assessed via cardiac biomarker, NYHA 
class, echocardiograms, CMR, and technetium scintigraphy imaging, as described. 
Qualified personnel will be required to administer cardiac imaging assessments as specified in 
the respective reference manuals. 
6.2.5.1. 
Cardiac Biomarkers   
The cardiac biomarkers NT-proBNP and troponin I will be used to assess cardiac stress and heart 
failure severity.  These biomarkers have been shown to be prognostic of outcomes in HF, 
including in ATTR amyloidosis.[Damy 2016; Kristen 2017; Merlini 2016]  Blood samples will 
be drawn to measure cardiac biomarker levels at the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2) and will be measured at a central laboratory.  At screening 
Visit 1, only NT-proBNP will be assessed for eligibility purposes.    
Details on cardiac biomarker sample collection, processing, and storage will be provided in a 
Study Laboratory Manual. 
140

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
54 
6.2.5.2. 
ATTR Amyloidosis Disease Stage 
Based on published data from Gillmore et al, the ATTR amyloidosis disease staging used for this 
protocol stratifies patients with ATTR amyloidosis with cardiomyopathy (both hATTR and 
wtATTR) into prognostic categories using the serum biomarkers NT-proBNP and 
eGFR.[Gillmore 2018]  Patients are categorized as follows: 
• Stage 1 (lower risk):  NT-proBNP ≤3000 ng/L and eGFR ≥45 ml/min/1.73 m2 
• Stage 2 (intermediate risk):  all other patients not meeting criteria for Stages 1 or 3 
• Stage 3 (higher risk):  NT-proBNP >3000 ng/L and eGFR <45 ml/min/1.73 m2 
Based on published data, this staging system discriminates between patients with median 
survival of ~6 years, ~4 years, and ~2 years for Stage 1, Stage 2, and Stage 3, respectively. 
6.2.5.3. 
New York Heart Association (NYHA) Class 
NYHA class is a clinical assessment of symptoms resulting from HF and is assessed according to 
the table in Section 10.2.  NYHA class will be evaluated at the timepoints specified in the 
Schedule of Assessments (Table 1 and Table 2).  The score collected at screening will be used to 
determine eligibility. 
6.2.5.4. 
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 and Table 2), and analyzed at a central cardiac imaging core lab.   
Image acquisition, storage, and transfer guidelines will be provided in the relevant study manual. 
6.2.5.5. 
Technetium Scintigraphy Imaging  
At select sites, in a subset of approximately 100 patients, technetium scintigraphy will be 
collected according to the Schedule of Assessments (Table 1 and Table 2), as an optional 
exploratory imaging assessment, to assess cardiac amyloid involvement.  Based on local practice 
standards, either 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD-Tc], 99mTc-
pyrophosphate [PYP-Tc], or 99mTc-hydroxymethylene diphosphonate (99mTc-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 relevant 
study manual.   
For patients in whom technetium scintigraphy is performed as a study efficacy parameter, the 
results of the baseline scan must be reviewed by the central reader and confirmed to be consistent 
with the diagnosis of ATTR amyloidosis prior to randomization. 
At select sites where technetium scintigraphy is being performed as an exploratory efficacy 
assessment, patients may be exempt from the baseline scan if technetium scintigraphy has been 
performed prior to study entry as part of the patient’s clinical care within 6 months prior to the 
baseline assessment.  In such cases, the historical technetium scintigraphy examination 
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; if the historical scan cannot 
141

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
55 
be transferred to the central reader, or is deemed by the central reader to be of inadequate quality 
for interpretation, the patient should not participate in this optional efficacy assessment. 
6.2.5.6. 
Cardiac Magnetic Resonance (CMR)   
At select sites, in a subset of patients (≤60 patients), CMR will be collected according to the 
Schedule of Assessments (Table 1 and Table 2), as an optional exploratory imaging assessment 
to assess cardiac amyloid involvement.  CMR imaging with late gadolinium enhancement will 
only be performed on patients without contraindications (ie, pacemakers, severe renal failure 
with eGFR <30 mL/min/1.73 m2, defibrillators, or allergy to gadolinium).  
Details for image acquisition and upload for central review can be found in the relevant study 
manual. 
6.2.6. 
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 and Table 2). 
6.2.7. 
Polyneuropathy Disability (PND)   
Physician assessment of ambulation via PND score [Coutinho 1980; Yamamoto 2007] will be 
evaluated only at screening to assess eligibility for the study as specified in the Schedule of 
Assessments (Table 1).  PND scoring is described in Section 10.1. 
6.3. 
Pharmacodynamic Assessments 
In this study, serum samples for measurement of TTR levels will be collected for the assessment 
of PD effects.  TTR levels will be determined by a validated enzyme-linked immunoassay 
(ELISA).  Details regarding sample volumes to be collected, and the processing, shipping, and 
analysis of the samples will be provided in the Laboratory Manual.   
For this assessment, blood samples will be collected prior to dosing according to the timepoints 
specified in the Schedule of Assessments (Table 1 and Table 2).  To ensure patient safety and, to 
the extent possible, that study integrity is maintained amid travel and other restrictions related to 
the COVID-19 pandemic, blood samples for assessment of TTR protein may be collected by a 
trained healthcare professional at a location other than the study center (eg, at home) at time 
points coinciding with the dosing visits closest to the intended sampling time points. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of plasma concentrations of ALN-18328 (siRNA 
component of patisiran) and 2 lipid excipients (DLin-MC3-DMA and PEG2000-C-DMG) during 
the double-blind period at the timepoints specified in the Schedule of Assessments (Table 1).  To 
ensure patient safety and, to the extent possible, that study integrity is maintained amid travel 
142

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
56 
and other restrictions related to the COVID-19 pandemic, these blood samples may be collected 
at the study center, or by a trained healthcare professional at a location other than the study 
center (eg, at home) at time points coinciding with the dosing visits closest to the intended 
sampling time points.   
Plasma PK samples will be collected:  predose (within 1 hour of planned study drug dosing); at 
the end of the infusion (+5 minutes); and 30 minutes after the end of the infusion (+15 minutes) 
at the specified visits.   
For patients who discontinue treatment early during the double-blind period, a single PK sample 
will be taken at any time during the Early Treatment Discontinuation Visit, per the Schedule of 
Assessment (Table 2).   
Actual dates and times of sample collection will be recorded. 
Plasma concentrations of the 3 analytes will be determined using validated assay methods.  
Details regarding sample volumes to be collected, and the processing, shipping, and analysis of 
the samples will be provided in the Laboratory Manual. 
PK parameters will be analyzed, whenever possible, as outlined in Section 7.2.7.  
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight 
and height, 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. 
In situations where a study visit is not completed at the study center, offsite (eg, at home) 
assessments may be completed within the study visit window as follows: 
• Routine assessments (ie, vital signs and weight, blood collection, pregnancy testing, 
physical examinations, and ECGs) may be performed at a location other than the study 
center (eg, at home) by a trained healthcare professional at all timepoints, where 
applicable country and local regulations and infrastructure allow.  The Investigator or 
qualified designee will review all ECGs, including those collected by a healthcare 
professional outside of the study center. 
• Collection of relevant safety information:  The study physician (or delegate) must, at a 
minimum, verbally contact the patient within the expected study visit window to assess 
relevant safety information (including, but not limited to, AEs, concomitant medications, 
hospitalizations/procedures, vital status).  This information may also be collected by a 
home healthcare professional as part of an offsite study visit. 
• Blood samples for assessment of ADA may be collected by a trained healthcare 
professional at a location other than the study center (eg, at home) at time points 
coinciding with the dosing visits closest to the intended sampling time points.  
143

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
57 
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1 and Table 2) 
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.  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 medically 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 as specified in the Schedule of Assessments 
(Table 1 and Table 2) and will be recorded in the eCRF. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1 and Table 2); 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 
12-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, and QT 
interval will be obtained, as specified in the Schedule of Assessments (Table 1 and Table 2).  
Patients should be supine for at least 5 minutes before each ECG is obtained.  The 12-lead ECGs 
will be performed in triplicate at baseline, with readings approximately 1 minute apart.  At all 
other time points, a single 12-lead ECG will be performed. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn, when possible. 
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 the Baseline visit and to determine the clinical significance of the results.  These 
144

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
58 
assessments will be recorded in the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator.  Recordings will be archived in the patient’s files.  
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  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, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality.  Additional safety laboratory tests and assessments as indicated by the 
clinical situation may be requested.  Clinical laboratory assessments are listed in Table 3 and will 
be assessed as specified in the Schedule of Assessments (Table 1 and Table 2).   
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 3, 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 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 3: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Carbon dioxide 
Creatinine and eGFR (using the MDRD formula) 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Coagulation (at Screening) 
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time   
 
Immunogenicity (see Section 6.5.5.1) 
Antidrug antibodies 
 
145

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
59 
Pregnancy Testing/FSH Screening (see Section 6.5.5.2) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal women 
only) 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone; 
MDRD=modification of diet in renal disease; PCR=polymerase chain reaction; RBCs=red blood cells; 
RNA=ribonucleic acid. 
6.5.5.1. 
Immunogenicity 
Serum samples will be collected to evaluate the presence of antidrug antibodies (ADA) as 
outlined in the Schedule of Assessments (Table 1).  Details regarding the blood volume, 
processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
A validated ELISA will be used that specifically detects antibodies to PEG2000-C-DMG, which is 
a component of patisiran-LNP.  Serum samples will first be analyzed with a screening assay.  
Samples testing positive for ADA in the screening assay will be further evaluated in a 
confirmatory assay.  For the samples that tested positive for ADA in the confirmatory assay, the 
ADA titer will then be determined as the reciprocal of the highest dilution of the sample that 
yielded a positive ADA test result. 
6.5.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential at the timepoints 
specified in the Schedule of Assessments (Table 1 and Table 2).   
A serum pregnancy test will be performed at Screening and urine pregnancy tests will be 
performed thereafter at the timepoints specified in the Schedule of Assessments (Table 1 and 
Table 2).  More frequent pregnancy testing may be performed where required per local 
requirements.  The results of the pregnancy test must be known before study drug administration.  
Patients who are pregnant at Screening are not eligible for study participation.  Any woman with 
a positive urine pregnancy test, subsequently confirmed by a positive serum pregnancy test, 
during the study will be discontinued from study drug but will continue to be followed for safety.  
Patients determined to be pregnant while on study will be followed at least until the pregnancy 
outcome is known (see Section 6.5.7.7 for follow-up instructions). 
In situations where a pregnancy test was missed as per the Schedule of Assessments because of 
the COVID-19 pandemic impacting activities at the study center or patient ability or willingness 
to access the study center, a pregnancy test must be performed prior to receiving the next dose of 
study drug.   
Follicle-stimulating hormone testing will be performed in all women suspected to be post-
menopausal to confirm post-menopausal status. 
6.5.6. 
Vital Status Check 
A vital status check will be performed at the timepoints specified in the Schedule of Assessments 
(Table 1 and Table 2).      
Due to the inclusion of all-cause mortality in the secondary endpoint analysis, a medical records 
release form will be required of all patients for the purpose of obtaining vital status information 
146

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
60 
from the patient’s physician or from death registries.  The signing of this medical records release 
form is in addition to the ICF.  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.  
6.5.7. 
Adverse Events 
6.5.7.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an 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 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability 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 
No AEs of clinical interest are defined for this study.  
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). 
147

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
61 
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 AE. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  AEs characterized as intermittent require 
documentation of the start and stop of each incidence.  When changes in the severity of an AE 
occur more frequently than once a day, the maximum severity for the experience that day should 
be noted.  If the severity category changes over a number of days, then those changes should be 
recorded separately (with distinct onset dates). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?”  A “yes” response indicates that the event is considered as related to 
the study drug. 
6.5.7.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
study drug through the end of study.  Non-serious AEs will be followed until the end of study.  
Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1), while AEs that occur after study drug administration, and  
baseline events that worsen after study drug administration, must be recorded as AEs.    
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study drug 
through the end of study.  SAEs will be followed until satisfactory resolution, until baseline level 
148

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
62 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
All IRRs will be recorded as AEs.  All information on IRRs is to be recorded on the applicable 
eCRF per the CRF completion guidelines. 
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 
Not applicable.  There were no AEs of Clinical Interest identified for this study. 
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. 
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. 
149

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
63 
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 12 weeks 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 12 weeks 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, 
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.  In the event of an overdose, the actual dose administered must be recorded as specified 
in the Pharmacy Manual. 
All reports of overdose (with or without an AE) must be reported within 24 hours following the 
instructions outlined in the Pharmacy Manual for reporting an overdose. 
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 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 
150

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
64 
well-described heterogeneous manifestations of disease in patients with ATTR amyloidosis with 
cardiomyopathy, as well as their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
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 patisiran.   
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1 and Table 2).  Potential exploratory investigations may include 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. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principal features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
The planned enrollment for this study is 300 patients.  For the change from baseline at Month 12 
in the 6-MWT, assuming a treatment difference of 33 meters between patisiran and placebo in 
the treatment-naïve group and 20 meters in patients with baseline tafamidis, the weighted 
average treatment difference between patisiran and placebo in the overall population is 
approximately 29 meters (standard deviation = 75 meters) assuming 70% are in the treatment-
naïve group and 30% are in the baseline tafamidis group.  A sample size of 300 patients provides 
>90% power for a 2-sided test to detect a mean difference between treatment groups at a 2-sided 
alpha = 0.05.  Additional patients may be enrolled based on a recommendation to increase the 
sample size in the interim assessment (Section 7.2.10). 
151

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
65 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses for 
the primary analysis, conducted at the completion of the 12-month, double-blind period.  More 
complete plans, including planned analyses for the open-label extension period, will be detailed 
in the SAP.  Changes to the methods described in the final SAP will be described and justified as 
needed in the clinical study report.  For information on study endpoints, see Section 2. 
Additional data summaries to help understand any impact of COVID-19 on efficacy and safety 
assessments will be outlined in the SAP. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
• Full Analysis Set (FAS):  All randomized patients who received any amount of study 
drug, grouped according to the randomized treatment arm.   
• Safety Analysis Set:  All patients who received any amount of study drug, grouped 
according to the treatment actually received.  
• PK Analysis Set:  All patients who received any amount of study drug and have at 
least 1 postdose blood sample for PK parameters and have evaluable PK data. 
• PD Analysis Set:  All patients who received any amount of study drug and who have 
an evaluable baseline and at least 1 evaluable post-baseline serum TTR measurement 
will be included in the PD analyses. 
Efficacy endpoints will be analyzed using the Full Analysis Set.  Safety will be analyzed using 
the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct PK and PD 
analyses, respectively. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized by 
treatment arm and overall for the FAS and Safety Analysis Set. 
7.2.5. 
Efficacy Analyses 
The overall Type I error rate will be strongly controlled at a 2-sided 0.05 significance level for 
the primary and secondary endpoints using a fixed sequential testing procedure at the final 
analysis.  The primary endpoint will be compared between treatment arms at the 0.05 
significance level.  If the test of the primary endpoint is statistically significant, then the 
secondary endpoints will each be tested in the order specified in the Secondary Endpoints section 
152

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
66 
(see Section 2).  If a test of the primary or a secondary endpoint is not statistically significant, the 
testing of the remaining endpoints in the sequence will stop. 
For patients who were tafamidis treatment-naïve at baseline and start tafamidis during the 
double-blind period, the primary analysis of the primary endpoint will censor data collected after 
the initiation of tafamidis treatment post-randomization.   
7.2.5.1. 
Primary Endpoint  
The primary endpoint, change from baseline at Month 12 in the 6-MWT, will be analyzed using 
a mixed-effects model repeated measures (MMRM) approach.  The outcome variable is change 
from baseline in the 6-MWT.  The model will include the baseline value as a covariate, 
treatment, visit, the treatment-by-visit interaction, baseline tafamidis (yes vs no), genotype 
(hATTR vs wtATTR), and age (<75 vs ≥75 years) as fixed factors, and patient as a random 
effect.  The primary comparison is the contrast (difference in least squares [LS] means) between 
the patisiran and placebo groups at Month 12. 
Sensitivity analyses will be detailed in the SAP. 
7.2.5.2. 
Secondary Endpoints  
Secondary endpoints are described in Section 2.   
KCCQ-OS will be analyzed using a similar MMRM model as used for the primary endpoint. 
The composite endpoint of all-cause mortality, frequency of CV events (CV hospitalizations and 
urgent HF visits) and change from baseline in 6-MWT will be analyzed using a generalized rank-
based win ratio method, which makes pairwise comparisons (for all possible patisiran/placebo 
patient pairs) of the 3 components in the hierarchical order specified above.  The point estimate 
for the win ratio is defined as the total number of better outcomes divided by the total number of 
worse outcomes in the patisiran group.  The detailed algorithm for assessment of this endpoint 
will be provided in the SAP.     
The composite endpoint of all-cause mortality and frequency of all-cause hospitalizations and 
urgent HF visits will be analyzed using an Andersen-Gill model stratified by baseline tafamidis 
(yes vs no), including treatment, genotype (hATTR vs wtATTR), NYHA Class (I/II vs III), and 
age (<75 vs ≥75 years) as covariates. 
Patients who undergo a heart transplantation and/or ventricular assist device placement after 
randomization will be handled in the same manner as death in the primary analyses of mortality 
related endpoints. 
Deaths and hospitalizations due to COVID-19 will be excluded from the primary analyses of 
endpoints involving all-cause death and/or all-cause hospitalizations.  Analyses of the individual 
components of the composite endpoints will be detailed in the SAP. 
To control the overall Type I error rate, secondary endpoints will be tested in a prespecified 
hierarchical order. 
7.2.5.3. 
Exploratory Endpoints 
Descriptive summaries will be provided for the exploratory endpoints (Section 2), and additional 
analyses may be conducted.  Details will be described in the SAP. 
153

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
67 
7.2.6. 
Pharmacodynamic Analysis 
The PD endpoint is serum TTR.  Summary tables will be provided for observed values, change 
and percentage change from baseline for each scheduled time point.  In addition, the maximum 
and mean percentage reduction over 12 months will be summarized.   
7.2.7. 
Pharmacokinetic Analysis 
7.2.7.1. 
Pharmacokinetic Analysis 
Plasma concentrations of ALN-18328, DLin-MC3-DMA, and PEG2000-C-DMG will be obtained 
using a model-independent method.  PK exposure parameters will include:  maximum plasma 
concentration at the end of infusion (Cmax), 30-minute post-infusion concentration (Cp(30min)), and 
pre-infusion concentration (Cmin).  In addition, the steady-state Cmax (Cmax,ss), steady-state 
Cp(30min) (Cp,ss(30min)), and steady-state Cmin (Cmin,ss) will be calculated as the average of the 
respective values at Week 24, Week 36, and Month 12. 
The PK exposure parameters will be summarized by visit, and the steady-state PK parameters 
will be summarized. 
7.2.7.2. 
Exposure-Response Analysis  
Mean and maximum percent TTR reduction from baseline will be summarized by quartiles of the 
steady state PK parameters for all 3 analytes.  Change from baseline at Month 12 in clinical 
efficacy parameters may also be summarized by quartiles of the steady-state PK parameters for 
all 3 analytes.  
PK exposure will be summarized by mortality status.  In addition, the incidence of AEs and 
SAEs will be summarized by quartiles of the steady-state PK parameters for all 3 analytes. 
7.2.7.3. 
Population PK, PK/PD, and Disease Progression Modelling Analysis 
Population PK, PK/PD, and disease progression modelling analyses may be performed, if 
appropriate.  If performed, the analyses would be conducted according to a pre-specified analysis 
plan and reported separately. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical examinations.  The extent of exposure will be summarized.   
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary.  Results will be tabulated by the Anatomical Therapeutic Chemical classification 
system and Preferred Term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term.  The frequency and percentage of patients 
experiencing AEs, SAEs, related AEs, and AEs leading to discontinuation will be summarized 
by System Organ Class (SOC) and PT.  By patient listings will be provided for deaths, SAEs, 
and AEs leading to discontinuation.   
154

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
68 
Descriptive statistics will be provided for clinical laboratory data, ECG, and vital signs data, 
summarizing the observed values and change from baseline over time.  Laboratory shift tables 
from baseline at the worst post-baseline values will be presented.  Abnormal physical 
examination findings and 12-lead ECG data will be presented in by-patient listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP.  
7.2.9. 
Immunogenicity Analyses 
 The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized.  The titer results for patients with 
confirmed positive ADA results will be summarized.  The impact of ADA on PK, PD, efficacy 
and safety endpoints will be explored.  Details will be described in the SAP. 
7.2.10. 
Sample Size Re-assessment 
Patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis 
drop-in”) during the double-blind period, which could result in a loss of statistical power.  An 
interim assessment may be performed to assess the impact of tafamidis drop-in on the power and 
the potential need to increase the sample size.  The interim assessment, if conducted, would 
examine the overall tafamidis drop-in rate in a blinded manner (ie, a non-comparative assessment 
of the drop-in rate); therefore, no impact on the type I error is expected and no multiplicity 
adjustment will be made.  A detailed sample size re-estimation plan will be outlined in a separate 
document prior to implementation. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the informed consent form 
(see Section 4.3.2). 
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 is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
155

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
69 
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 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. 
A medical records release form will be required of all patients for the purpose of obtaining vital 
status information from the patient’s physician or from death registries.  The signing of this 
medical records release form is in addition to the ICF. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study (except those that support the need to remove an apparent immediate 
hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.5.7.  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 randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
156

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
70 
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 
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 
157

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
71 
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.  CRFs 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 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. 
158

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
72 
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). 
159

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
73 
9. 
LIST OF REFERENCES 
Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, 
an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 
5;379(1):11-21. 
Adams D, Suhr OB, Hund E, Obici L, Tournev I, Campistol JM, et al. First European consensus 
for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr 
Opin Neurol. 2016 Feb;29 Suppl 1:S14-26. 
Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, et al. Targeted 
delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol 
Ther. 2010 Jul;18(7):1357-64. 
Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, et al. Guideline of transthyretin-
related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013 Feb 20;8:31. 
Benson MD,Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. 
Muscle Nerve. 2007 Oct;36(4):411-23. 
Biesalski HK, Frank J, Beck SC, Heinrich F, Illek B, Reifen R, et al. Biochemical but not clinical 
vitamin A deficiency results from mutations in the gene for retinol binding protein. Am J Clin 
Nutr. 1999 May;69(5):931-6. 
Bittner V, Weiner DH, Yusuf S, Rogers WJ, McIntyre KM, Bangdiwala SI, et al. Prediction of 
mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. 
SOLVD Investigators. JAMA. 1993 Oct 13;270(14):1702-7. 
Bumcrot D, Manoharan M, Koteliansky V,Sah DW. RNAi therapeutics: a potential new class of 
pharmaceutical drugs. Nat Chem Biol. 2006 Dec;2(12):711-9. 
Castano A, Drachman BM, Judge D,Maurer MS. Natural history and therapy of TTR-cardiac 
amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and 
silencer drugs. Heart Fail Rev. 2015 Mar;20(2):163-78. 
Coelho T, Merlini G, Bulawa CE, Fleming JA, Judge DP, Kelly JW, et al. Mechanism of Action 
and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis. Neurol Ther. 
2016 Jun;5(1):1-25. 
Connors LH, Lim A, Prokaeva T, Roskens VA,Costello CE. Tabulation of human transthyretin 
(TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. 
Connors LH, Yamashita T, Yazaki M, Skinner M,Benson MD. A rare transthyretin mutation 
(Asp18Glu) associated with cardiomyopathy. Amyloid. 2004 Mar;11(1):61-6. 
Coutinho P, DeSilva A, Lima J,Barbosa A. Forty years of experience with type I amyloid 
neuropathy: review of 483 cases. In: Glenner G,Pinho P,Costa E,Falcao de Frietas A, editors. 
Amyloid and Amyloidosis: Excerpta Medica. Amsterdam1980. p. 88-98. 
Damy T, Jaccard A, Guellich A, Lavergne D, Galat A, Deux JF, et al. Identification of 
prognostic markers in transthyretin and AL cardiac amyloidosis. Amyloid. 2016 Sep;23(3):194-
202. 
160

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
74 
Damy T, Judge DP, Kristen AV, Berthet K, Li H,Aarts J. Cardiac findings and events observed 
in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile 
hereditary transthyretin amyloidosis. J Cardiovasc Transl Res. 2015 Mar;8(2):117-27. 
Dungu JN, Anderson LJ, Whelan CJ,Hawkins PN. Cardiac transthyretin amyloidosis. Heart. 
2012 Nov;98(21):1546-54. 
Episkopou V, Maeda S, Nishiguchi S, Shimada K, Gaitanaris GA, Gottesman ME, et al. 
Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and 
thyroid hormone. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2375-9. 
Flynn KE, Lin L, Ellis SJ, Russell SD, Spertus JA, Whellan DJ, et al. Outcomes, health policy, 
and managed care: relationships between patient-reported outcome measures and clinical 
measures in outpatients with heart failure. Am Heart J. 2009 Oct;158(4 Suppl):S64-71. 
Flynn KE, Lin L, Moe GW, Howlett JG, Fine LJ, Spertus JA, et al. Relationships between 
changes in patient-reported health status and functional capacity in outpatients with heart failure. 
Am Heart J. 2012 Jan;163(1):88-94 e3. 
Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A 
new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018 Aug 7;39(30):2799-
806. 
Green CP, Porter CB, Bresnahan DR,Spertus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll 
Cardiol. 2000 Apr;35(5):1245-55. 
Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D,Suhr OB. Evolving 
landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38. 
Hou X, Aguilar MI,Small DH. Transthyretin and familial amyloidotic polyneuropathy. Recent 
progress in understanding the molecular mechanism of neurodegeneration. FEBS J. 2007 
Apr;274(7):1637-50. 
Jacobson D, Tagoe C, Schwartzbard A, Shah A, Koziol J,Buxbaum J. Relation of clinical, 
echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of 
the transthyretin V122I allele in older African-American men. Am J Cardiol. 2011 Aug 
1;108(3):440-4. 
Kristen AV, Maurer MS, Rapezzi C, Mundayat R, Suhr OB,Damy T. Impact of genotype and 
phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the 
Transthyretin Amyloidosis Outcome Survey (THAOS). PLoS One. 2017;12(4):e0173086. 
Liz MA, Mar FM, Franquinho F,Sousa MM. Aboard transthyretin: From transport to cleavage. 
IUBMB Life. 2010 Jun;62(6):429-35. 
Mangla A, Kane J, Beaty E, Richardson D, Powell LH,Calvin JE, Jr. Comparison of predictors 
of heart failure-related hospitalization or death in patients with versus without preserved left 
ventricular ejection fraction. Am J Cardiol. 2013 Dec 15;112(12):1907-12. 
Masoudi FA, Rumsfeld JS, Havranek EP, House JA, Peterson ED, Krumholz HM, et al. Age, 
functional capacity, and health-related quality of life in patients with heart failure. J Card Fail. 
2004 Oct;10(5):368-73. 
161

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
75 
Maurer M, Judge D, Rosas G, Mandel F,Aarts J. Interim analysis of long-term, open-label 
tafamidis treatment in transthyretin amyloid cardiomyopathy after up to 5 years of treatment.  
XIVth International Symposium on Amyloidosis; Indianapolis, Indiana2014. 
Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. 
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 
2018 Sep 13;379(11):1007-16. 
Merlini G, Lousada I, Ando Y, Dispenzieri A, Gertz MA, Grogan M, et al. Rationale, application 
and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in 
patients with AL amyloidosis. Leukemia. 2016 Oct;30(10):1979-86. 
Mohty D, Damy T, Cosnay P, Echahidi N, Casset-Senon D, Virot P, et al. Cardiac amyloidosis: 
updates in diagnosis and management. Arch Cardiovasc Dis. 2013 Oct;106(10):528-40. 
Okamoto S, Wixner J, Obayashi K, Ando Y, Ericzon BG, Friman S, et al. Liver transplantation 
for familial amyloidotic polyneuropathy: impact on Swedish patients' survival. Liver Transpl. 
2009 Oct;15(10):1229-35. 
Parman Y, Adams D, Obici L, Galan L, Guergueltcheva V, Suhr OB, et al. Sixty years of 
transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A 
European network approach to defining the epidemiology and management patterns for TTR-
FAP. Curr Opin Neurol. 2016 Feb;29 Suppl 1:S3-S13. 
Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, et al. The 
amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015 Jan 
1;372(1):21-9. 
Ruberg FL,Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012 Sep 
04;126(10):1286-300. 
Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective 
evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid 
cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012 
Aug;164(2):222-8 e1. 
Solomon SD, Adams D,Kristen A. Effects of Patisiran, an RNA Interference Therapeutic, on 
Cardiac Parameters in Patients with Hereditary Transthyretin-Mediated Amyloidosis: An 
Analysis of the APOLLO Study. Circulation. 2018;10.1161/CIRCULATIONAHA.118.035831. 
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. 
Westermark P, Bergstrom J, Solomon A, Murphy C,Sletten K. Transthyretin-derived senile 
systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 2003 Aug;10 
Suppl 1:48-54. 
162

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
76 
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. 
 
163

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
77 
10. 
APPENDICES 
10.1. 
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 
10.2. 
New York Heart Association Class (NYHA) 
  
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs does not 
cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, in cold weather, in wind or when under 
emotional stress causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to two blocks on the 
level and climbing more than one flight of stairs in normal conditions causes undue fatigue 
or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or dyspnea. 
10.3. 
Categorization of Infusion-Related Reactions 
Signs and symptoms of an IRR usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Signs/symptoms may 
include: allergic reaction/hypersensitivity (including drug fever), arthralgia (joint pain), 
bronchospasm, cough, dizziness, dyspnea (shortness of breath), fatigue (asthenia, lethargy, 
malaise), headache, hypertension, hypotension, myalgia (muscle pain), nausea, pruritus/itching, 
164

Clinical Study Protocol ALN-TTR02-011 
patisiran 
Amendment 2, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
78 
rash/desquamation, rigors/chills, sweating (diaphoresis), tachycardia, urticaria (hives, welts, 
wheals), vomiting. 
Categorization of IRRs is as follows: 
Categorization 
Description 
Mild 
Mild reaction:  infusion may be continued; if intervention is indicated it is 
minimal and additional treatment (other than paracetamol for delayed 
reactions) is not required. 
Moderate 
Moderate reaction:  requires treatment including more intensive therapy 
(eg, IV fluids, NSAIDs) in addition to infusion interruption but responds 
promptly to medication.  Treatment is indicated for ≤24 hours. 
Severe 
More than moderate reaction:  not rapidly responsive to medication or to 
interruption of infusion; and/ or prolonged (treatment is indicated for 
>24 hours); recurrence of severe symptoms following initial improvement. 
 
165

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
1 
ALN-TTR02-011 PROTOCOL AMENDMENT 2  
SUMMARY OF CHANGES DATED 22 MAY 2020 
APOLLO-B:  A Phase 3, Randomized, Double blind, Placebo-controlled Multicenter Study 
to Evaluate the Efficacy and Safety of Patisiran in Patients with Transthyretin Amyloidosis 
with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
The primary purpose of this protocol amendment is to incorporate Urgent Safety Measures 
(USMs) that were communicated to Investigators in a Dear Investigator Letter dated 07 April 
2020 to ensure the safety of study participants while minimizing risks to study integrity amid the 
Coronavirus disease 2019 (COVID-19) pandemic.  These changes, which were adopted 
immediately by the Investigator site,  are in line with guidances published by the European 
Medicines Agency and the US Food and Drug Administration on the conduct of clinical trials 
during the COVID-19 pandemic [EMA 2020; FDA 2020] and are outlined in Section 1.1 and a 
detailed summary of the protocol changes is provided in Section 2.1. 
This protocol amendment also incorporates changes to the study endpoints, inclusion and 
exclusion criteria, and clarifications regarding doxycycline use and efficacy assessment 
procedures.   These changes are summarized in Section 2.1 and a detailed summary of changes is 
provided in Section 2.2; the 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 Study Drug Dosing Outside the Study Center (eg, at Home) 
Administration of study drug outside the study center (eg, at home or offsite) by a 
health care professional is permitted at all timepoints (in both the double-blind and 
open-label periods) provided the patient has tolerated at least 2 doses of study drug 
administered at the study center.  Previously, dosing outside the study center was only 
permitted during the open-label extension period, and only after tolerating at least 
3 consecutive doses. 
This change was implemented to reduce the frequency of patient visits to the study 
center, and therefore reduce potential exposure to COVID-19, while maintaining 
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 change in administration.  When infusions have been interrupted due 
166

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
2 
to an IRR, these have primarily been reported in patients during the first 2 infusions.  
Thus, for patients who tolerate infusions, these data support offsite study drug 
administration (eg, at home) following 2 doses administered at the study center.  
Offsite dosing of study drug will be performed by a health care professional, with 
oversight of the Investigator, allowing for ongoing appropriate monitoring of the 
patient.   
• Corticosteroid Tapering 
Corticosteroid tapering may be performed at the study center or at a location other 
than the study center (eg, at home) (previously was only permitted at the study 
center), after consultation with the Medical Monitor.   In addition, corticosteroid 
tapering is now permitted during the double-blind period for patients who are 
tolerating their infusions well. (Previously, tapering for patients who are tolerating 
their study drug infusions well was only permitted during the open-label period.) 
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 offsite 
dosing (eg, at home) necessitated by the COVID-19 pandemic as outlined above.  
Patisiran dosing, and thus steroid tapering, will be performed by a health care 
professional, with oversight of the investigator, allowing for appropriate monitoring 
of the patient.  Support for this approach comes from a review of data from patisiran 
studies (ALN-TTR02-003, ALN-TTR02-004, and ALN-TTR02-006) where IRRs 
were infrequent and mild among patients who had tapered corticosteroids and that 
corticosteroid tapering was not associated with an increase in the rate of IRRs. 
• Premedication Equivalents may be Administered Orally 
Clarified that oral premedication equivalents are permitted, but must be administered 
in the presence of a healthcare professional.    
• Extended Efficacy Assessment Visits Window   
The window for efficacy assessment visits at the study center was extended in 
situations where those visits are unable to be completed due to the COVID-19 
pandemic impacting activities at the study center or patient ability or willingness to 
access the study center or their ability to receive their scheduled doses of study drug.  
This change allows 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.   
Thus, in the situations described above, where a Month 6 (Day 176-183), Month 9 
(Day 260-267), and/or Month 12 (Day 365-372) study visit is unable to be completed 
or patients are unable to receive their scheduled doses of study drug, after 
consultation with the Medical Monitor, efficacy assessments may be extended as 
follows:  Month 6 up to Day 214; Month 9 up to Day 319; Month 12, up to Day 417, 
but prior to the first dose of open-label patisiran.  Patients may continue to receive 
double-blind study drug until the Month 12 efficacy assessment is performed.  For the 
167

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
3 
open-label extension period, the windows for study visits are also extended (see 
Section 2.1). 
• Screening Patients 
The requirement that the Investigator notify the Sponsor before screening patients 
was added to allow an assessment of the ability of the study center or any new trial 
participant to comply with the protocol given the COVID-19 pandemic limitations. 
In addition, patients who failed screening due to situations related to the COVID-19 
pandemic may be allowed to rescreen after consultation with the Medical Monitor. 
• Eliciting Adverse Events 
Added that, in situations where a study visit is unable to be completed at the study 
center, the study physician (or delegate) must, at a minimum, verbally contact the 
patient within the expected study visit window to assess relevant safety information 
(eg, adverse events [AEs], concomitant medications, hospitalizations/procedures, 
vital status).  This information may also be collected by a home healthcare 
professional as part of an offsite study visit. 
• Routine Assessments   
Added that, in situations where a study visit is not completed at the study center, 
offsite (eg, at home) assessments may be completed within the study visit window as 
follows: 
− Routine assessments (ie, vital signs and weight, blood collection, pregnancy 
testing, physical examinations, and ECGs) may be performed at a location other 
than the study center (eg, at home) by a trained healthcare professional at all 
timepoints, where applicable country and local regulations and infrastructure 
allow.   
− Blood samples for assessment of transthyretin (TTR) protein, pharmacokinetics 
(PK), and anti-drug antibodies (ADA) may be collected by a trained healthcare 
professional at a location other than the study center (eg, at home). 
• Timing of Physical Examinations 
Reduced the frequency of physical examinations and aligned the timing with onsite 
efficacy assessment visits to reduce potential exposure to COVID-19.  
• 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.   
• Study Administration Text 
Text was updated to provide clarification of Investigator responsibilities regarding 
communication of new study information to patients and Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC). 
168

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
4 
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 2.1. 
• Composite Clinical Endpoints   
The adjudicated composite clinical endpoints (2 secondary endpoints and the first 
exploratory endpoint) were revised to include urgent heart failure (HF) visits.  The 
corresponding objectives were similarly revised. 
Specifically, the secondary and exploratory endpoints that include “all-cause 
mortality and frequency of CV-related hospitalizations” were changed to include 
“all-cause mortality and CV events”, where “CV events” are defined in Section 2 as 
CV hospitalizations plus urgent HF visits.  To be included, an urgent HF visit must 
satisfy 2017 criteria developed by the Standardized Data Collection for 
Cardiovascular Trials Initiative and the US Food and Drug Administration.[Hicks 
2018]  
Similarly, the composite endpoint that includes “all-cause mortality and frequency of 
all-cause hospitalizations” will be revised to include “all-cause mortality and 
frequency of all-cause hospitalizations and urgent HF visits”.  
The change is being made because the management of HF is likely to shift from the 
hospital to the outpatient setting due to the COVID-19 pandemic.  Inclusion of urgent 
HF visits will also account for regional variations in practice standards, which may be 
further exacerbated by the impact of COVID-19.  
In addition, deaths and hospitalizations due to COVID-19 will be excluded from these 
composite endpoints.  The effects of the COVID-19 pandemic on global health are 
unprecedented, and the pandemic is expected to have a confounding effect on deaths 
and hospitalization events in the study. 
The following inclusion and exclusion criteria were modified based on feedback from 
Investigators that some criteria are unnecessarily strict and exclude suitable patients in the target 
population of ATTR amyloidosis with cardiomyopathy.  In addition, clarification is provided for 
some criteria. 
• Inclusion Criterion 4b, Tafamidis Use at Study Entry 
Clarified that the use of on-label, commercial tafamidis treatment at study entry must 
be for the treatment of ATTR amyloidosis with cardiomyopathy, at the approved dose 
in the country of use.  This clarification of the inclusion criterion text is consistent 
with text elsewhere in the protocol (in Section 5.3.1) and reflects the original intent of 
the sponsor. 
• Inclusion Criterion 7, NT-proBNP 
The inclusion criterion for NT-proBNP was changed to a lower threshold of 
>300 ng/L (previously was >600 ng/L); the upper threshold (<8500 ng/L) remains 
unchanged.  In addition, the criterion added that patients with permanent or persistent 
atrial fibrillation must have a screening NT-proBNP of >600 ng/L and <8500 ng/L. 
169

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
5 
The lower limit for NT-proBNP was decreased from 600 to 300 ng/L to better 
represent the real-world population of patients with ATTR amyloidosis with 
cardiomyopathy and to include patients who are likely to benefit from treatment.  
There is no clinically meaningful difference between 300 and 600 ng/L as the lower 
limit for patients who are not in atrial fibrillation.  The threshold of >600 ng/L for 
patients with atrial fibrillation accounts for the known, additional secretion of 
NT-proBNP from the fibrillating atrial myocardium. 
• Exclusion Criterion 5b, Total Bilirubin   
Revised exclusion criterion for total bilirubin to ˃2×ULN for all patients (previously 
was >ULN, with patients with Gilbert’s syndrome being eligible if total bilirubin was 
<2×ULN). 
The target population of patients with ATTR amyloidosis with cardiomyopathy is 
prone to hepatic congestion from HF.  The change in the criterion is to avoid 
excluding patients in the target population who have mild elevations in bilirubin, and 
to better reflect the real-world population of patients with ATTR amyloidosis with 
cardiomyopathy.  Furthermore, raising the exclusion threshold for total bilirubin is 
not expected to affect the risk of hepatic adverse effects.  In the patisiran clinical 
development program, the frequency of hepatic adverse events has been low and 
consistent with that observed in the placebo-controlled experience.  No significant 
changes in liver function tests have been reported in patients treated for up to 5 years. 
Based on the overall safety profile to date, there have been no hepatic safety 
concerns.  Refer to the Investigator's Brochure, Section 5.4.6.2 (Hepatic Safety) for 
more information.   
• Exclusion Criterion 9, Diflunisal Use 
The required diflunisal wash-out period was reduced to at least 30-days prior to 
dosing (Day 1) (previously was at least 6 months), as this was determined to be a 
reasonable amount of time to avoid any confounding effects from diflunisal on the 
baseline assessments. 
In addition, the following changes have also been implemented for this study: 
• Doxycycline Use 
Added a clarification that doxycycline use is permitted if taken for short-term 
treatment of infection; use of doxycycline is otherwise excluded.  
• Clarification for efficacy assessments 
Added a clarification that the study personnel performing assessments related to the 
primary and secondary efficacy endpoints will not reference the results of any 
previous assessments (previously, the protocol indicated that the assessor would be 
blinded to the results). 
For the primary endpoint measure (6-minute walk test), the protocol specifies that the 
same assessor be used for all assessments, which is critical for consistency across 
visits for a given patient.  Since the assessor may remember a patient’s prior test, it is 
not possible for the assessor to be blinded to previous results.   However, the 
170

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
6 
clarification of instructing the assessor not to refer to the prior results when 
conducting an assessment will limit bias in the assessment. 
•  Screening Assessments 
Added a clarification that TTR genotyping may be conducted at a central laboratory; 
or a local laboratory may be selected by the study center in consultation with the 
Medical Monitor.  If a diagnostic result to confirm ATTR amyloidosis is not available 
at Screening for the assessment of eligibility per inclusion criterion 2c/d, testing may 
be conducted at a laboratory or diagnostic center selected by the site, in consultation 
with the Medical Monitor, in countries in which this test is not standard of care. 
 
171

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
7 
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:  Study drug administration at a location other than the study center (eg, at home) was expanded.  
The primary change occurs in newly added Section 3.1, Summary of Study Design 
Revised text:   
Study drug will be administered in the clinic as an approximately 80-minute IV infusion.  
During the 12-month open-label extension period, all patients will receive treatment with open-label patisiran.  Furthermore, patients 
who have received ≥3 consecutive doses of patisiran on this study at the clinical site with no evidence of IRRs or other drug related 
adverse effects impacting safety and tolerability of the infusion may have patisiran administered at home, where applicable country 
and local regulations allow.  Home administration of patisiran will be performed by a healthcare professional trained on the protocol 
and on administration of premedications and patisiran infusion. 
Study drug administration at a location other than the study center (eg, at home) may be administered as follows: 
• Double-blind period:  Patients who have received ≥2 doses of study drug at the study center with no evidence of IRRs 
or other drug-related adverse effects that impact safety and tolerability of the infusion may have study drug 
administered at a location other than the study center (eg, at home), where applicable country and local regulations 
allow.  Study drug administration will be performed by a healthcare professional, trained on the protocol and on 
administration of premedications and study drug infusion, with oversight of the Investigator. 
• 12-month open-label extension period:  Furthermore, Ppatients who have received ≥3 consecutive 2 doses of open-label 
patisiran on this study at the study center with no evidence of IRRs or other drug-related adverse effects impacting safety and 
tolerability of the infusion may have patisiran administered at a location other than the study center (eg, at home), where 
applicable country and local regulations allow.  Home administration of patisiran will be performed by a healthcare 
professional trained on the protocol and on administration of premedications and patisiran infusion. 
Sections also reflecting this change:   
• Synopsis 
172

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
8 
• Section 5.2.3.1 
• Section 5.2.3.2 
Purpose:  Added permitted tapering of corticosteroid dose outside of the clinic (ie, at home).  Also added corticosteroid tapering in 
the double-blind period for patients who are tolerating their double-blind study drug infusions well with their current corticosteroid 
premedication regimen. 
The primary change occurs in Section 5.2.1, Premedication   
Revised text: 
Modifications to lower the corticosteroid dose may be made to the premedication regimen for either of the following 2 reasons: 
1. Double-blind and open-label periods:  If a patient is having difficulty tolerating the steroid premedication regimen (eg, 
patient develops uncontrolled hyperglycemia, altered mental status, or other complication), then lowering of the steroid 
premedication may be allowed for that patient after consultation with the medical monitor at any time during the study 
(double blind and open label periods). 
2. Double-blind period:  In the open label extension period only, fFor patients who are tolerating their double-blind study drug 
infusions well with their current corticosteroid premedication regimen (ie, no IRRs during the past 3 or more infusions), 
corticosteroid dose may be reduced in 2.5 mg increments to a minimum dose of 5 mg of dexamethasone (IV) or equivalent.    
a. Open-label period:  At the start of the open-label period, patients must take dexamethasone 10 mg or the 
equivalent as their corticosteroid premedication.  Patients taking more than 10 mg of dexamethasone at the end 
of the double-blind period should take the higher dose.  The corticosteroid dose may then be tapered as 
described above if the patient is tolerating infusions.  However, if a patient’s steroid premedication had been 
decreased in the double-blind period due to their inability to tolerate the premedication regimen as described 
above, continuation of the reduced dose regimen (as it had been in the double-blind period) may be permitted 
after consultation with the Medical Monitor. 
Infusions during corticosteroid tapering (and the 2 infusions after the new and stable lower corticosteroid dose is established) should 
may be performed in the clinic at the study center or at a location other than the study center (eg, at home), as described in detail 
in the Pharmacy Manual, at the discretion of the Investigator and after consultation with the Medical Monitor. 
Purpose:  Clarified that oral premedication equivalents are permitted. 
The primary change occurs in Section 5.2.1, Premedication   
173

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
9 
Revised text: 
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.      
Purpose:  Widened the window for completion of efficacy assessments at study visits. 
The primary change occurs in Section 6.2, Efficacy Assessments 
Added text:  
As noted in Table 1, in situations where a Month 6 (Day 176-183), Month 9 (Day 260-267), and/or Month 12 (Day 365-372) 
study visit is unable to be completed at the study center due to the COVID-19 pandemic impacting activities at the study 
center or patient ability or willingness to access the study center, efficacy assessments should be completed as close as possible 
to the time point per the current Schedule of Assessments, but may be extended as follows:  Month 6 up to Day 214; Month 9 
up to Day 319; Month 12, up to Day 417, but prior to the first dose of open-label patisiran.  Patients may continue to receive 
double-blind study drug until the Month 12 efficacy assessment is performed.   
For the open-label extension period, as noted in Table 2, in situations where a Month 18 (Day 554-561), Month 21 (Day 638-
645), and/or Month 24 (Day 743-750) study visit is unable to be completed at the study center due to the COVID-19 pandemic 
impacting activities at the study center or patient ability or willingness to access the site, efficacy assessments should be 
completed as close as possible to the time point per the current Schedule of Assessments, but may be extended as follows:  
Month 18 up to Day 592; Month 21 up to Day 697; Month 24, up to Day 774. 
Sections also reflecting this change:   
• Synopsis 
• Table 1 (Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)) 
• Table 2 (Schedule of Assessments – Open-label Extension Period (Through Month 24), Early Treatment Discontinuation 
Visit, and Follow-up) 
• Section 3.1 
• Section 4.3.1 
• Section 6.2.1 
174

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
10 
Purpose:  Added that the Investigator will notify the Sponsor before screening patients. 
The primary change occurs in Section 6.1, Screening Assessments 
Added text:  
To ensure patient safety and, to the extent possible, that study integrity is maintained amid travel and other restrictions 
related to the COVID-19 pandemic, the Investigator will notify the Sponsor before screening patients to allow an assessment of 
the ability of the site or any new trial participant to comply with the protocol given COVID-19 limitations. 
 
Purpose:  Added that patients who failed screening due to situations related to the COVID-19 pandemic may be allowed to rescreen 
after consultation with the Medical Monitor. 
The primary change occurs in Section 6.1.2, Rescreening  
Added text:  
Patients who failed screening due to situations related to the COVID-19 pandemic may be allowed to rescreen after 
consultation with the Medical Monitor. 
Purpose:  In situations where a study visit is not completed at the study center, offsite (eg, at home) assessments may be completed 
within the study visit window as follows:  
• Routine assessments outside of the clinic (eg, at home) by a trained healthcare professional at all timepoints, where 
applicable country and local regulations and infrastructure allow.    
• Verbal contact with the patient by the Investigator or designee within the study visit window to assess relevant safety 
information (including, but not limited to, adverse events (AEs), concomitant medications, hospitalizations/procedures) if a 
study visit is not able to be completed at the site or offsite by an HCP. 
• Blood sample collection for assessment of ADA by a trained healthcare professional at a location other than the study 
center (eg, at home).  
The primary change occurs in Section 6.5, Safety Assessments 
175

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
11 
Added text:  
In situations where a study visit is not completed at the study center, offsite (eg, at home) assessments may be completed 
within the study visit window as follows: 
• Routine assessments (ie, vital signs and weight, blood collection, pregnancy testing, physical examinations, and ECGs) 
may be performed at a location other than the study center (eg, at home) by a trained healthcare professional at all 
timepoints, where applicable country and local regulations and infrastructure allow.  The Investigator or qualified 
designee will review all ECGs, including those collected by a healthcare professional outside of the study center. 
• Collection of relevant safety information:  The study physician (or delegate) must, at a minimum, verbally contact the 
patient within the expected study visit window to assess relevant safety information (including, but not limited to, AEs, 
concomitant medications, hospitalizations/procedures, vital status).  This information may also be collected by a home 
healthcare professional as part of an offsite study visit. 
• Blood samples for assessment of ADA may be collected by a trained healthcare professional at a location other than the 
study center (eg, at home) at time points coinciding with the dosing visits closest to the intended sampling time points.  
Sections also reflecting this change:   
• Section 4.3.3 
• Section 6.5.4 
• Section 6.5.5.2 
Purpose:  Reduced the frequency of physical examinations and changed the timing to align with efficacy assessment visits to reduce 
potential exposure to COVID-19.  
The primary change occurs in Table 1 and Table 2, Schedules of Assessments:  
Revised text:  
• Table 1:   
o Symptom-directed physical examinations were removed from Weeks 3, 6, 9, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 
48.  
o Symptom-directed physical examinations were added to Weeks 25/26, 37/38.  
o A full physical examination was moved from Week 51 to Week 52/53. 
176

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
12 
• Table 2:   
o Symptom-directed physical examinations were removed from Weeks 54, 57, 60, 63, 69, 72, 75, 78, 81, 84, 87, 90, 93, 
96, 99, 102, 105.  
o Symptom-directed physical examinations were added to Weeks 78/80, 91/92, 106/107.  
Purpose:  Blood sample collection for assessment of TTR protein and for assessment of PK are being allowed at a location other than 
the study center (eg, at home), by a trained healthcare professional. 
The primary changes occur in Section 6.3, Pharmacokinetic Assessments, and Section 6.4, Pharmacodynamic Assessments 
Revised text:  
For this assessment, blood samples will be collected prior to dosing according to the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2).  To ensure patient safety and, to the extent possible, that study integrity is maintained amid 
travel and other restrictions related to the COVID-19 pandemic, blood samples for assessment of TTR protein may be 
collected by a trained healthcare professional at a location other than the study center (eg, at home) at time points coinciding 
with the dosing visits closest to the intended sampling time points. 
…  
Blood samples will be collected for assessment of plasma concentrations of ALN-18328 (siRNA component of patisiran) and 2 lipid 
excipients (DLin-MC3-DMA and PEG2000-C-DMG) during the double-blind period at the timepoints specified in the Schedule of 
Assessments (Table 1).  To ensure patient safety and, to the extent possible, that study integrity is maintained amid travel and 
other restrictions related to the COVID-19 pandemic, these blood samples may be collected at the site, or by a trained 
healthcare professional at a location other than the site (eg, at home) at time points coinciding with the dosing visits closest to 
the intended sampling time points. 
177

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
13 
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 
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. 
… 
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).    
2.2. 
Changes Not Related to Urgent Safety Measures to be Implemented After Regulatory Authority 
and Ethics Committee Approval 
Purpose:  The composite clinical endpoints (2 secondary endpoints and the first exploratory endpoints) were revised to include urgent 
HF visits; the corresponding objectives were also revised. 
The primary change occurs in Section 2, Objectives and Endpoints 
Revised text: 
Objectives 
• 
Patient mortality and, hospitalizations, and urgent heart failure (HF) visits 
178

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
14 
• 
All-cause mortality and CV related hospitalizations events 
Endpoints 
• 
Composite endpoint of all-cause mortality, frequency of cardiovascular (CV) related hospitalizations events (CV 
hospitalizations and urgent HF visits) and change from baseline in 6-MWT over the 12-month double-blind period 
• 
Composite endpoint of all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure (HF) visits 
over the 12-month double-blind period 
• 
Composite endpoint of all-cause mortality and frequency of (CV) related hospitalizations events (CV hospitalizations and 
urgent HF visits) over the 12-month double-blind period  
Sections also reflecting this change:   
• Synopsis 
• Section 3.8, Adjudication Committee 
• Section 7.2.5.2, Secondary Endpoints  
Purpose:  Deaths and hospitalizations due to COVID-19 will be excluded from the primary analyses of endpoints involving all-cause 
death and/or all-cause hospitalizations.    
The primary change occurs in Section 7.2.5.2, Secondary Endpoints 
Added text: 
Deaths and hospitalizations due to COVID-19 will be excluded from the primary analyses of endpoints involving all-cause 
death and/or all-cause hospitalizations.  Analyses of the individual components of the composite endpoints will be detailed in 
the SAP. 
Purpose:  Eligibility requirements have been broadened for inclusion Criterion 7 and exclusion Criterion 5b, and exclusion Criterion 9. 
The primary change occurs in Section 4, Selection and Withdrawal of Patients 
Revised text:  
4.1 Inclusion Criteria 
… 
7. Screening NT-proBNP >600300 ng/L and <8500 ng/L; in patients with permanent or persistent atrial fibrillation, screening 
NT-proBNP >600 ng/L and <8500 ng/L. 
179

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
15 
… 
4.2. 
Exclusion Criteria 
5. Has any of the following laboratory parameter assessments at screening:  
a. Aspartate transaminase (AST) or alanine transaminase (ALT) levels ˃2.0 × the upper limit of normal (ULN). 
b. Total bilirubin >2×ULN.  Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if 
total bilirubin <2 × ULN. 
… 
9. Is currently taking diflunisal; if previously on this agent, must have at least a 6 month30-day wash-out prior to dosing (Day 1). 
Purpose:  Added clarification for inclusion Criterion 4b. 
The primary change occurs in Section 4.1, Inclusion Criteria 
Revised text: 
4. Patient meets one of the following criteria: 
a. Tafamidis naïve; in addition to patients who have never taken tafamidis, those who have been on tafamidis for ≤30 days total and 
have not received any tafamidis in the 6 months prior to baseline will be considered tafamidis naïve and may qualify for the study. 
b. Currently on tafamidis (for ≥6 months) and has demonstrated disease progression, as determined by the Investigator.  (At the time 
of study entry, tafamidis treatment must be on-label use of commercial tafamidis for the treatment of ATTR amyloidosis with 
cardiomyopathy at the approved dose in the country of use.) 
Purpose:  Added clarification that use of doxycycline is permitted for short-term treatment of infection. 
The primary change occurs in Section 5.3, Concomitant Medications and Procedures 
Revised text: 
Inotersen, doxycycline, ursodeoxycholic acid, tauroursodeoxycholic acid, and diflunisal are also prohibited during the study (see 
exclusion Criterion 10 in Section 4.2).  Doxycycline is permitted if being taken for short-term treatment of infection.     
Purpose:  Added clarification that study personnel performing assessments related to the primary and secondary efficacy endpoints 
will not reference the results of any previous assessments. 
The primary change occurs in Section 3.6, Blinding 
Revised text: 
180

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
16 
In addition, the study personnel performing assessments related to the primary and secondary efficacy endpoints will also be blinded 
to will not reference the results of any previous assessments. 
Purpose:  Added clarification that TTR genotyping may be conducted at a central laboratory; or a local laboratory selected in 
consultation with the Medical Monitor.  Added that diagnostic testing for inclusion criterion 2c/d may be conducted at a laboratory or 
diagnostic center selected by the site, in consultation with the Medical Monitor, in countries in which this test is not standard of care. 
The primary change occurs in Section 6.1, Screening Assessments 
Revised text: 
If a genetic test result that shows the presence or absence of a TTR pathogenic mutation, which would be consistent with either 
wtATTR or hATTR, is not available at Screening for the assessment of eligibility (Section 4.1, inclusion Ccriterion 2a), genotyping 
may be conducted at a central laboratory.  Alternatively, a local laboratory may be selected by the site study center in consultation 
with the Medical Monitor. 
The study eligibility biopsies and technetium scintigraphy noted in inclusion Criterion 2 are intended to be historical, as part of the 
patient’s clinical care and diagnosis, and are not performed as part of the study.    
If a diagnostic result that confirms ATTR amyloidosis is not available at Screening for the assessment of eligibility (inclusion 
Criterion 2c/d), testing may be conducted at a laboratory or diagnostic center selected by the site, in consultation with the 
Medical Monitor, in countries in which this test is not standard of care. 
 
 
 
181

Clinical Study Protocol ALN-TTR02-011 
ALN-TTR02 (patisiran) 
Amendment 2 Summary of Changes, 22 May 2020 
Alnylam Pharmaceuticals 
Confidential 
17 
3. 
REFERENCES 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic, 
Version 2 (27/03/2020; 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 on 
16/04/2020). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-
guidance-conduct-clinical-trials-medical-products-during-covid-19-pandemic  
Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, et al. 2017 
Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. Circulation. 
2018;137(9):961-72. 
 
 
182

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
1 
 
CLINICAL STUDY PROTOCOL 
ALN-TTR02-011 
 DATED 20 DECEMBER 2019 
 
Protocol Title: 
APOLLO-B:  A Phase 3, Randomized, 
Double-blind, Placebo-controlled Multicenter 
Study to Evaluate the Efficacy and Safety of 
Patisiran in Patients with Transthyretin 
Amyloidosis with Cardiomyopathy (ATTR 
Amyloidosis with Cardiomyopathy)   
Short Title: 
APOLLO-B:  A Study to Evaluate Patisiran in 
Patients with Transthyretin Amyloidosis with 
Cardiomyopathy (ATTR Amyloidosis with 
Cardiomyopathy) 
Study Drug: 
Patisiran (ALN-TTR02)  
EudraCT Number: 
2019-001458-24 
IND Number: 
141240 
Protocol Date: 
Original protocol, 18 April 2019  
Amendment 1:  20 December 2019 
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. 
 
183

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-011 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 
185

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
6 
population is anticipated to have hATTR and 80% wtATTR.  In addition, at baseline, patients are 
either: 
• Tafamidis naïve; or 
• Currently on tafamidis (for ≥6 months), with disease progression in the opinion of the 
investigator.  This group will be capped at 30% of total enrollment in the study.   
The study consists of a screening period of up to 45 days, a 12-month, double-blind, placebo-
controlled period, a 12-month, open-label extension period (during which all patients will receive 
patisiran), and a 28-day follow-up period. 
After screening, during the 12-month double-blind period, eligible patients will be randomized to 
receive intravenous (IV) treatment every 3 weeks with either patisiran or placebo.  Prior to 
receiving randomized, double-blind study drug (patisiran or placebo), to reduce the potential for 
an infusion related reaction (IRR) with patisiran, all patients will receive premedications at least 
60 minutes before the start of their infusion.  Study drug will be administered in the clinic as an 
approximately 80-minute IV infusion.  
During the 12-month open-label extension period, all patients will receive treatment with 
open-label patisiran.  Furthermore, patients who have received ≥3 consecutive doses of patisiran 
on this study at the clinical site with no evidence of IRRs or other drug-related adverse effects 
impacting safety and tolerability of the infusion may have patisiran administered at home during 
the open-label extension period, where applicable country and local regulations allow.  Home 
administration of patisiran will be performed by a healthcare professional trained on the protocol 
and on administration of premedications and patisiran infusion. 
To evaluate the efficacy of treatment with patisiran versus placebo in patients with ATTR 
amyloidosis with cardiomyopathy, the change from baseline in 6-MWT will be assessed at 
Month 12 (Weeks 52-53) as the primary endpoint; this assessment will also be performed at 
Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) in the double-blind period, and during the 
open-label extension period.  The first secondary endpoint will assess change from baseline at 
Month 12 in the KCCQ-OS score.    
Safety will be assessed throughout the double-blind and open-label extension periods of the 
study. 
Number of Planned Patients 
Approximately 300 patients are planned for enrollment in this study.   
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, inclusive, with ATTR amyloidosis with cardiomyopathy (hereditary or wild-type [wt]) who, 
at baseline, are either:  1) tafamidis naïve (on tafamidis for ≤30 days and none within 6 months 
prior to baseline); or 2) currently on tafamidis (for ≥6 months) with disease progression in the 
opinion of the investigator. 
Study Drug, Dose, and Mode of Administration 
Patisiran is a ribonucleic acid (RNA) interference (RNAi) therapeutic consisting of a double-
stranded small interfering RNA (siRNA) targeting TTR mRNA formulated in a lipid 
188

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
7 
nanoparticle (LNP).  The patisiran drug product is a sterile formulation of ALN-18328 (siRNA 
targeting TTR) formulated as LNPs with lipid excipients (1,2-Dilinoleyloxy-N,N-
dimethylpropylamine [DLin-MC3-DMA], 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.   
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs. 
An IV infusion of double-blind study drug (patisiran 0.3 mg/kg or placebo) will be administered 
under the supervision of the site personnel once every 3 weeks ±3 days.  Dosing is based on 
actual body weight.  For patients weighing ≥100 kg, the maximum recommended patisiran dose 
is 30 mg.  
The last dose of double-blind study drug will be at Week 51 and the first dose of open-label 
patisiran will be 3 weeks later (at Week 54) and thereafter every 3 weeks (±3 days) for the 
remainder of the study.  Open-label patisiran will be administered per the schedule and dose as is 
described above for double-blind patisiran. 
Reference Treatment, Dose, and Mode of Administration 
The control drug for this study will be a placebo (normal saline 0.9% for IV administration).  
Control drug will be provided by a central supplier (or, if necessary, by a local supplier, with 
prior Sponsor approval).    
Duration of Treatment and Study Participation 
The treatment duration in this study is up to 24 months, inclusive of a 12-month, double-blind, 
treatment period, and a 12-month, open-label, treatment period.  The estimated total time on 
study for each patient is up to 26.5 months, including up to 45 days of screening, up to 
24 months of treatment, and a 28-day safety follow-up period. 
Statistical Methods 
The planned enrollment for this study is 300 patients.  Randomization (1:1) will be stratified by:  
1) baseline tafamidis (yes vs no); 2) genotype (hATTR vs wtATTR); and 3) NYHA Class I or II 
and age < 75 years vs all other. 
For the change from baseline at Month 12 in the 6-MWT, assuming a treatment difference of 
33 meters between patisiran and placebo in the treatment-naïve group and 20 meters in patients 
with baseline tafamidis, the weighted average treatment difference between patisiran and placebo 
in the overall population is approximately 29 meters (standard deviation = 75 meters) assuming 
70% are in the treatment-naïve group and 30% are in the baseline tafamidis group.  A sample 
size of 300 patients provides >90% power for a 2-sided test to detect a treatment difference at a 
2-sided alpha = 0.05.  Additional patients may be enrolled based on a recommendation to 
increase the sample size in the interim assessment. 
The primary endpoint, change from baseline at Month 12 in the 6-MWT, will be analyzed using 
a mixed-effects model repeated measures (MMRM) approach.  The outcome variable is change 
from baseline in the 6-MWT.  The model will include the baseline value as a covariate, 
treatment, visit, the treatment-by-visit interaction, baseline tafamidis (yes vs no), genotype 
(hATTR vs wtATTR), and age (<75 vs ≥75 years) as fixed factors, and patient as a random 
189

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
8 
effect.  The primary comparison is the contrast (difference in least squares [LS] means) between 
the patisiran and placebo groups at Month 12. 
To control the overall Type I error rate, secondary endpoints will be tested in a prespecified 
hierarchical order. 
For patients who are tafamidis treatment-naïve at baseline and start tafamidis during the double-
blind period, the primary analysis of the primary endpoint will censor data collected after the 
initiation of tafamidis treatment post-randomization.  
Safety data will be summarized descriptively. 
 
190

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
9 
Figure 1: 
Study Design 
  
 
 
191

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
10 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NAb 
Informed Consent 
6.1  
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion Criteria 
4.1, 
4.2  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / 
Medical History 
6.1  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PND Score 
6.2.7  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
6.5.2  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
X 
X 
 
 
 
 
 
 
 
 
 
X
d 
 
 
 
 
X
d 
 
 
 
 
 
X 
d 
X 
d 
X
d 
KCCQ 
6.2.2 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
mBMI 
6.2.4 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Cardiac Biomarker 
Samples 
6.2.5.1 
NT-
proBNP 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
ATTR amyloidosis 
disease stage 
6.2.5.2  
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
NYHA Class 
6.2.5.3 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Echocardiogram 
6.2.5.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CMR, technetium 
(select sites only) 
6.2.5.6,  
6.2.5.5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Norfolk QoL-DN 
6.2.6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
192

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
11 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NAb 
Pharmacodynamic Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
X 
X 
  
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Exploratory 
Biomarkers 
(plasma, serum) 
6.6 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
6.5.2 
X  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
(symptom-directed 
unless noted as full) 
6.5.3 
X  
Full 
X 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Full 
 
X 
Full 
X 
Single 12-lead ECG 
(unless otherwise 
indicated) 
6.5.4 
 
X (in 
triplicate, 
either visit) 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum Chemistry, 
Liver Function 
Tests 
6.5.5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Xe 
Xe 
X 
Hematology 
6.5.5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Coagulation 
6.5.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin A Levels 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA (on dosing 
days, prior to 
dosing) 
6.5.5.1 
 
 
X 
 
X 
  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
193

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
12 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22±3 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NAb 
FSH (to confirm 
postmenopausal, if 
applicable) 
Table 3, 
6.5.5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
Table 3, 
6.5.5.2 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
  
  
Review/Record 
Hospitalization, 
Urgent Care Visits, 
and Procedures 
 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
 
Review/Record 
AEs, Con Meds 
6.5.7, 
5.3 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
6.4 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Drug Administration 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
3.5 
Window
: 5D 
prior to 
Day 1 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication/ 
Study Drug 
5.2.1, 
5.2.3 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; CMR=cardiac magnetic resonance; D=day; 
Disc=discontinuation; ECG=electrocardiogram; FSH=follicle-stimulating hormone; KCCQ=Kansas City Cardiomyopathy Questionnaire; M=month; 
194

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
13 
mBMI=modified body mass index; 6-MWT=6-minute walk test; NA=not applicable; NT-proBNP=N-terminal prohormone B-type natriuretic peptide; 
NYHA=New York Heart Association; PK=pharmacokinetics; PND=Polyneuropathy Disability; QoL-DN=Quality of Life-Diabetic Neuropathy; 
TTR=transthyretin; V=visits. 
a  This efficacy visit is conducted 7 to 14 days after the prior visit.   
b  This Modified Month 12 Efficacy Visit is to be performed at Month 12 for patients who discontinued treatment early (ie, prior to Month 12), and choose to remain in the study.  
All patients who discontinue from study drug during the double-blind period will be encouraged to remain on the study and complete assessments through Month 12 (excluding 
PK assessments), including this Modified Month 12 Efficacy Visit.  Such patients will also receive assessments at the Early Treatment Discontinuation Visit (7 to 14 days after 
their last dose of study drug); and the safety follow-up visit (28 days after the last dose of study drug) (Table 2), as described in Section 4.3.1.    
c See Section 5.3.1; patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis drop-in”) during the double-blind period.  In all cases, the 
Pre-tafamidis Drop-in Visit should occur prior to starting concomitant tafamidis; where possible, this visit should occur between 1-2 weeks after the last dose of double-blind 
study drug (ie, 7 to 14 days post dose).  Thereafter, the patient will continue with all assessments per the Schedule of Assessments, including the Month 12 Efficacy Visit.  At the 
time of tafamidis drop-in, the reason for starting tafamidis will be recorded in the CRF.    
d As described in Section 6.2.1, to avoid a potential training effect resulting from repeated assessments of the 6-MWT within a short period of time, only one 6-MWT assessment 
should be performed within each of the following time periods:  Day 2 to Day 214 (includes the scheduled Weeks 25-26 assessment); Day 215 to Day 319 (includes the 
scheduled Weeks 37-38 assessment); and Day 320 to Day 372 (includes the scheduled Weeks 52-53 assessment).  Within a given time period, the 6-MWT assessment should be 
performed at whichever visit occurs first (scheduled assessment, Pre-tafamidis Drop-in Visit, or Early Treatment Discontinuation Visit [Table 2]); no additional 6-MWT 
assessments should be made in that time period.  In later time periods, the 6-MWT should be assessed as scheduled. 
e Serum creatinine only. 
195

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
14 
  
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 24), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
7- 14 Days 
after Last 
Dose 
D764±10 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
NA 
109 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
KCCQ 
6.2.2 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
mBMI 
6.2.4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Cardiac Biomarker 
Samples 
6.2.5.1 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
ATTR amyloidosis 
disease stage 
6.2.5.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
NYHA Class 
6.2.5.3 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Echocardiogram 
6.2.5.4 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CMR, technetium (select 
sites only) 
6.2.5.6, 
6.2.5.5 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Norfolk QoL-DN 
6.2.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacodynamic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Exploratory Biomarkers 
(plasma, serum) 
6.6  
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (symptom-
directed) 
6.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Single 12-lead ECG 
6.5.4  
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
196

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
15 
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 24), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
7- 14 Days 
after Last 
Dose 
D764±10 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
NA 
109 
Serum Chemistry, Liver 
Function Tests 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X
c 
X 
X 
Hematology 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Pregnancy Test 
Table 3, 
6.5.5.2 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
Review/Record 
Hospitalization, Urgent 
Care Visits, and 
Procedures 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
Review/Record AEs,  
Con Meds 
6.5.7, 
5.3 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
 6.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication, Study 
Drug 
5.2.1, 
5.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; CMR=cardiac magnetic resonance; D=day; 
Disc=discontinuation; ECG=electrocardiogram; EOS=End of Study (visit); KCCQ=Kansas City Cardiomyopathy Questionnaire; mBMI=modified body mass 
index; 6-MWT=6-minute walk test; NA=not applicable; NT-proBNP=N-terminal prohormone B-type natriuretic peptide; NYHA=New York Heart Association; 
PK=pharmacokinetics; QoL-DN=Quality of Life-Diabetic Neuropathy; TTR=transthyretin; V=visits.  
a  This efficacy visit is conducted 7 to 14 days after the prior visit.   
b Patients who discontinue early from study drug will be asked to complete the Early Treatment Discontinuation Visit (7-14 days after their last dose) and the safety follow-up 
visit, 28 days after the last dose of study drug.  In addition, patients discontinuing early from study drug during the double-blind period will be encouraged to remain on the 
197

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
16 
study and complete assessments through Month 12 and complete the Modified Month 12 Efficacy Visit (see Table 1); they will also be asked to complete an Early Treatment 
Discontinuation Visit (7-14 days after their last dose) and the safety follow-up visit, 28 days after the last dose of study drug as described in Section 4.3.1.    
c Serum creatinine only. 
198

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
17 
TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................22 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Disease Overview .......................................................................................................25 
1.2. 
Current Treatments .....................................................................................................26 
1.3. 
Patisiran Clinical Development ..................................................................................27 
1.3.1. 
The Phase 3 APOLLO Study ......................................................................................28 
1.3.1.1. 
Cardiac Results and Cardiac Subpopulation Data from APOLLO ............................28 
1.3.2. 
Phase 3, Open-label Extension Study .........................................................................29 
1.4. 
Study Design Rationale ..............................................................................................29 
1.5. 
Dose Rationale ............................................................................................................30 
1.6. 
Benefit-risk Assessment .............................................................................................30 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................32 
3. 
INVESTIGATIONAL PLAN .....................................................................................33 
3.1. 
Summary of Study Design ..........................................................................................33 
3.2. 
Duration of Treatment ................................................................................................34 
3.3. 
Duration of Study Participation ..................................................................................34 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................34 
3.4. 
Number of Planned Patients .......................................................................................34 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................35 
3.6. 
Blinding ......................................................................................................................35 
3.6.1. 
Emergency Unblinding ...............................................................................................35 
3.7. 
Data Monitoring Committee .......................................................................................36 
3.8. 
Adjudication Committee .............................................................................................36 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................36 
4.1. 
Inclusion Criteria ........................................................................................................36 
199

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
18 
4.2. 
Exclusion Criteria .......................................................................................................37 
4.3. 
Removal from Study Drug or Assessment .................................................................40 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................40 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................41 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................41 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................41 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................42 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................42 
4.3.3. 
Lost to Follow-up .......................................................................................................42 
4.3.4. 
Replacement of Study Patients ...................................................................................42 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................43 
5.1. 
Treatments Administered ............................................................................................43 
5.2. 
Study Drug ..................................................................................................................43 
5.2.1. 
Premedication .............................................................................................................43 
5.2.2. 
Study Drug Description ..............................................................................................44 
5.2.3. 
Dose and Administration ............................................................................................44 
5.2.3.1. 
Double-bind Study Drug (Patisiran or Placebo) .........................................................44 
5.2.3.2. 
Open-label Extension Period (Patisiran) ....................................................................45 
5.2.4. 
Suggested Guidelines for Management of Infusion-related Reactions ......................45 
5.2.5. 
Dose Modifications .....................................................................................................46 
5.2.6. 
Preparation, Handling, and Storage ............................................................................46 
5.2.7. 
Packaging and Labeling ..............................................................................................46 
5.2.8. 
Accountability .............................................................................................................46 
5.3. 
Concomitant Medications and Procedures .................................................................47 
5.3.1. 
Concomitant Tafamidis Use .......................................................................................47 
5.4. 
Treatment Compliance ................................................................................................48 
5.5. 
Other Requirements ....................................................................................................48 
5.5.1. 
Contraception ..............................................................................................................48 
6. 
STUDY ASSESSMENTS ..........................................................................................49 
6.1. 
Screening Assessments ...............................................................................................49 
6.1.1. 
Retesting .....................................................................................................................50 
6.1.2. 
Rescreening .................................................................................................................50 
6.2. 
Efficacy Assessments .................................................................................................50 
200

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
19 
6.2.1. 
6-Minute Walk Test (6-MWT) ...................................................................................50 
6.2.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ...............................................51 
6.2.3. 
Deaths and Hospitalizations .......................................................................................51 
6.2.4. 
Modified Body Mass Index (mBMI) ..........................................................................51 
6.2.5. 
Cardiac Assessments ..................................................................................................52 
6.2.5.1. 
Cardiac Biomarkers ....................................................................................................52 
6.2.5.2. 
ATTR Amyloidosis Disease Stage .............................................................................52 
6.2.5.3. 
New York Heart Association (NYHA) Class .............................................................52 
6.2.5.4. 
Echocardiogram ..........................................................................................................52 
6.2.5.5. 
Technetium Scintigraphy Imaging .............................................................................53 
6.2.5.6. 
Cardiac Magnetic Resonance (CMR) .........................................................................53 
6.2.6. 
Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QoL-DN) .........................53 
6.2.7. 
Polyneuropathy Disability (PND)...............................................................................54 
6.3. 
Pharmacodynamic Assessments .................................................................................54 
6.4. 
Pharmacokinetic Assessments ....................................................................................54 
6.5. 
Safety Assessments .....................................................................................................54 
6.5.1. 
Vital Signs ..................................................................................................................54 
6.5.2. 
Weight and Height ......................................................................................................55 
6.5.3. 
Physical Examination .................................................................................................55 
6.5.4. 
Electrocardiogram .......................................................................................................55 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................56 
6.5.5.1. 
Immunogenicity ..........................................................................................................57 
6.5.5.2. 
Pregnancy Testing ......................................................................................................57 
6.5.6. 
Vital Status Check ......................................................................................................57 
6.5.7. 
Adverse Events ...........................................................................................................58 
6.5.7.1. 
Definitions ..................................................................................................................58 
6.5.7.2. 
Eliciting and Recording Adverse Events ....................................................................59 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................60 
6.5.7.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........60 
6.5.7.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................61 
6.5.7.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................61 
6.5.7.7. 
Pregnancy Reporting ..................................................................................................61 
201

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
20 
6.5.7.8. 
Overdose Reporting ....................................................................................................61 
6.6. 
Biomarkers and Biospecimen Repository ..................................................................61 
7. 
STATISTICS ..............................................................................................................62 
7.1. 
Determination of Sample Size ....................................................................................62 
7.2. 
Statistical Methodology ..............................................................................................62 
7.2.1. 
Populations to be Analyzed ........................................................................................63 
7.2.2. 
Examination of Subgroups .........................................................................................63 
7.2.3. 
Handling of Missing Data ...........................................................................................63 
7.2.4. 
Baseline Evaluations ...................................................................................................63 
7.2.5. 
Efficacy Analyses .......................................................................................................63 
7.2.5.1. 
Primary Endpoint ........................................................................................................63 
7.2.5.2. 
Secondary Endpoints ..................................................................................................64 
7.2.5.3. 
Exploratory Endpoints ................................................................................................64 
7.2.6. 
Pharmacodynamic Analysis........................................................................................64 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................64 
7.2.7.1. 
Pharmacokinetic Analysis ..........................................................................................64 
7.2.7.2. 
Exposure-Response Analysis......................................................................................65 
7.2.7.3. 
Population PK, PK/PD, and Disease Progression Modelling Analysis ......................65 
7.2.8. 
Safety Analyses ..........................................................................................................65 
7.2.9. 
Immunogenicity Analyses ..........................................................................................65 
7.2.10. 
Sample Size Re-assessment ........................................................................................66 
7.2.11. 
Optional Additional Research .....................................................................................66 
8. 
STUDY ADMINISTRATION ...................................................................................66 
8.1. 
Ethical and Regulatory Considerations ......................................................................66 
8.1.1. 
Informed Consent and Medical Records Release Form .............................................66 
8.1.2. 
Ethical Review ............................................................................................................67 
8.1.3. 
Serious Breach of Protocol .........................................................................................67 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................67 
8.1.5. 
End of Study ...............................................................................................................68 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................68 
8.2. 
Data Quality Control and Quality Assurance .............................................................68 
8.2.1. 
Data Handling .............................................................................................................68 
8.2.2. 
Study Monitoring ........................................................................................................69 
202

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
21 
8.2.3. 
Audits and Inspections ................................................................................................69 
8.3. 
Publication Policy .......................................................................................................69 
9. 
LIST OF REFERENCES ............................................................................................70 
10. 
APPENDICES ............................................................................................................74 
10.1. 
Polyneuropathy Disability (PND) Scores ...................................................................74 
10.2. 
New York Heart Association Class (NYHA) .............................................................74 
10.3. 
Categorization of Infusion-Related Reactions ............................................................74 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 
Efficacy Assessments) ................................................................................................10 
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 
24), Early Treatment Discontinuation Visit, and Follow-up ......................................14 
Table 3: 
Clinical Laboratory Assessments ...............................................................................56 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 
203

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALN-18328 
siRNA targeting TTR 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APOLLO 
Patisiran pivotal Phase 3 clinical study ALN-TTR02-004 
AST 
Aspartate aminotransferase 
ATTR 
Amyloid transthyretin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CHF 
Congestive heart failure 
Cmax 
Maximum plasma concentration at end of infusion 
Cmax,ss 
Steady-state Cmax   
Cmin 
Minimum pre-infusion concentration 
Cmin,ss 
Steady-state Cmin   
CMR 
Cardiac magnetic resonance 
Con Meds 
Concomitant medication 
Cp(30min) 
30-minute post-infusion concentration 
Cp,ss(30min) 
Steady-state Cp(30min) 
CRF 
Case report form 
CFR 
Code of Federal Regulations 
CV 
Cardiovascular 
DLin-MC3-DMA  
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DMC 
Data Monitoring Committee 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunoassay 
EOS 
End of study 
FAS 
Full analysis set 
204

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
23 
Abbreviation  
Definition 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
H1 
Histamine 1 receptor 
H2 
Histamine 2 receptor 
hATTR 
Hereditary ATTR 
HF 
Heart failure 
ICF 
Informed consent form  
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IRS 
Interactive Response System 
IV 
Intravenous(ly) 
KCCQ 
Kansas City Cardiomyopathy Questionnaire  
KCCQ-OS 
Kansas City Cardiomyopathy Questionnaire– Overall Summary 
LNP 
Lipid nanoparticle 
LS 
Least squares 
mBMI 
Modified body mass index 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGUS 
Monoclonal gammopathy of undetermined significance 
MMRM 
Mixed-effects model repeated measures 
mNIS+7 
Modified neurological impairment score +7 
mRNA 
Messenger ribonucleic acid 
6-MWT 
6-minute walk test 
NA 
Not applicable 
Norfolk QoL-DN 
Norfolk Quality of Life - Diabetic Neuropathy 
NSAID 
Nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone B-type natriuretic peptide 
NYHA 
New York Heart Association 
205

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
24 
Abbreviation  
Definition 
OLT 
Orthotopic liver transplantation 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PEG2000-C-DMG 
3-N-[(ω-methoxy poly(ethylene glycol)2000) carbamoyl]-1,2-
dimyristyloxy-propylamine 
PK 
Pharmacokinetic 
PND 
Polyneuropathy disability 
PT 
Preferred term 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RISC 
RNA-induced silencing complex 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
siRNA 
Small interfering RNA 
Tc 
Technetium 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
US 
United States 
V30M 
Valine to methionine mutation at position 30 
V122I 
Valine to isoleucine mutation at position 122 
wt 
Wild type 
wtTTR 
Wild type transthyretin 
 
206

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
25 
1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) is a rare, serious, life-
threatening, multisystemic disease encompassing hereditary ATTR (hATTR) amyloidosis and 
wild-type ATTR (wtATTR) amyloidosis, which result from either hereditary (genetic mutation) 
or nonhereditary (ageing) causes, respectively.  In ATTR amyloidosis, deposition of TTR in 
various organs results in progressive, chronically debilitating morbidity and mortality.  The most 
common manifestations of ATTR amyloidosis are polyneuropathy and cardiomyopathy (ie, 
ATTR amyloidosis with cardiomyopathy). 
TTR, also known as prealbumin, is a tetrameric protein produced by hepatocytes, the choroid 
plexus, and retina.[Liz 2010]  More than 95% of TTR in the circulation is derived from the liver.  
The primary physiological role of TTR is to serve as a carrier of retinol (also known as vitamin 
A), which involves TTR binding to the retinol binding protein (RBP): vitamin A complex.  
However, there is evidence to suggest that vitamin A transport and tissue uptake can occur in the 
absence of circulating RBP.[Biesalski 1999; Episkopou 1993] 
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 amyloidosis, and 
almost all patients are heterozygous for the mutated TTR allele.[Ando 2013; Connors 2003]  The 
phenotypic expression varies depending on the predominant site of deposition of the amyloid 
fibrils with some mutations associated with predominantly polyneuropathy manifestations and 
others associated with predominantly cardiomyopathy manifestations.  However, most patients 
experience both over the course of their disease.   
The most common TTR mutation is the valine to methionine mutation at position 30 (V30M), 
accounting for approximately 50% of cases worldwide, and occurring primarily in families with 
heritage from Portugal, Sweden, Japan, and Brazil.[Parman 2016]  This genotype is most 
commonly associated with multisystemic polyneuropathy.  The valine to isoleucine at position 
122 (V122I) mutation is most commonly associated with cardiomyopathy and occurs primarily 
in African Americans.  In these individuals, the mean age at diagnosis is approximately 65 to 
70 years, with symptom onset typically occurring after the age of 65.[Jacobson 2011; Quarta 
2015]  While there appears to be an association between carrier status and the development of 
heart failure (HF) and echocardiographic features of cardiac amyloidosis, the exact penetrance of 
this particular allele is unknown, and estimates vary widely. 
Normal, nonmutant wtTTR alone can also be amyloidogenic; this is the basis for the 
nonhereditary, wtATTR amyloidosis.  This is a progressive disease typically seen in patients 
older than 70 years and is predominantly seen in men.[Westermark 2003]  Patients with this 
207

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
26 
condition do not have a pathogenic mutation in the TTR gene and the amyloid fibrils consist only 
of wtTTR protein, which form amyloid deposits typically found in heart tissue.   
Cardiac infiltration of the extracellular matrix by TTR amyloid fibrils leads to a progressive 
increase of ventricular wall thickness and a marked increase in chamber stiffness, resulting in 
impaired diastolic function.  Systolic function is also impaired, typically reflected by abnormal 
longitudinal strain despite a normal ejection fraction, which is preserved until late stages of the 
disease.[Castano 2015; Dungu 2012; Mohty 2013; Ruberg 2012]  Cardiac infiltration by amyloid 
can also lead to conduction disturbances and arrhythmias.[Adams 2016; Ando 2013; Benson and 
Kincaid 2007; Connors 2004]  Patients with symptomatic HF experience rapid progression of 
their amyloidosis with cardiomyopathy, with substantial worsening of echocardiographic and 
biomarker measures of cardiac function, in addition to clinical measurements of ambulation, and 
quality of life.  Progression of disease in this population can be seen over a period of 12 months 
as demonstrated by differences in 6-minute walk test (6-MWT) and Kansas City 
Cardiomyopathy Questionnaire (KCCQ) – Overall Summary (KCCQ-OS) in the Phase 3 ATTR-
ACT study.[Maurer 2018]  Based on natural history data, patients typically experience 
progressive symptoms of HF resulting in hospitalization and with death typically occurring 2.5 to 
5 years after diagnosis.[Castano 2015; Damy 2015; Dungu 2012; Hawkins 2015] 
1.2. 
Current Treatments 
The treatment of ATTR amyloidosis requires a multidisciplinary approach primarily involving 
cardiology, neurology, and gastroenterology specialties.  While there are treatments for 
polyneuropathy that are available to hATTR amyloidosis patients, for most regions no treatments 
are currently available for the cardiomyopathy phenotype for either the hATTR or wtATTR 
forms.  Palliative/symptomatic therapies directed at specific symptoms, including volume control 
and treatment of cardiac arrhythmias and conduction system disturbances, including cardiac 
pacemakers where appropriate, have been the mainstay of treatment despite their limited 
effectiveness. 
Given that the liver is the primary source of TTR, orthotopic liver transplantation (OLT) has 
been used for hATTR amyloidosis patients since the early 1990s.  However, OLT is intended to 
eliminate mutant TTR from circulation, but has no effect on the hepatic production of wtTTR, 
which continues to be made by the transplanted liver and can continue to deposit in the heart.  
OLT has also only been shown to be effective in slowing the progression of disease in patients 
with an early age of onset (<50 years of age) [Okamoto 2009], and especially for those with the 
V30M mutation and short disease duration before transplant.  Consequently, almost two-thirds of 
patients with hATTR amyloidosis are not transplant-eligible.   
Tafamidis, a TTR tetramer stabilizer that acts by binding to the thyroxine-binding site on TTR to 
reduce its dissociation into misfolded amyloidogenic monomers, is currently approved in 
Europe, Japan, Mexico, and select countries in South America, but not in the United States (US), 
for the treatment of patients with hATTR amyloidosis with polyneuropathy.[Coelho 2016]  
Recently, tafamidis was evaluated in the Phase 3 ATTR-ACT trial in patients with ATTR 
amyloidosis with cardiomyopathy (including hereditary and wt).[Maurer 2018]  This study 
demonstrated that tafamidis treatment over 30 months was associated with lower all-cause 
mortality and cardiovascular (CV)-related hospitalizations compared with placebo treatment.  
Additionally, tafamidis treatment resulted in a slowing of the decline in functional capacity 
208

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
27 
(6-MWT) and quality of life (KCCQ-OS) compared to placebo.  However, consistent with the 
expected pharmacodynamic (PD) effect of TTR stabilization, the effects of tafamidis on 
mortality outcomes was not observed until late in treatment, with differentiation between 
treatment groups occurring only after 18 months of treatment.  Furthermore, although 
improvements with tafamidis relative to placebo were observed in 6-MWT and KCCQ-OS, 
minimal changes in echocardiographic parameters were observed, and tafamidis-treated patients 
still progressed during the study.   
As of early 2019, tafamidis was not approved in the US for patients with ATTR amyloidosis 
(neither polyneuropathy nor cardiomyopathy phenotypes); however, it is anticipated that 
tafamidis may become available for patients with the cardiomyopathy phenotype in the US and 
in other regions, based on the ATTR-ACT study results.  In Japan, tafamidis was approved in 
2019 for use in transthyretin-type cardiac amyloidosis (wt and mutant), in addition to approval 
for transthyretin-type familial amyloid polyneuropathy. 
The results of the ATTR-ACT study support the general therapeutic hypothesis that modifying 
TTR has the potential to result in beneficial outcomes in patients with ATTR amyloidosis with 
cardiomyopathy.  However, the disease progression that was observed in both treatment arms in 
ATTR-ACT highlights an important unmet medical need and suggests that a more direct 
therapeutic mechanism of action, such as specifically targeting the production of the disease-
causing protein with a ribonucleic acid (RNA) interference (RNAi) therapeutic, may be required 
to halt or reverse the debilitating and ultimately fatal course of disease.    
1.3. 
Patisiran Clinical Development 
Patisiran is a small interfering RNA (siRNA) specific for TTR, which is formulated in a 
hepatotropic lipid nanoparticle (LNP) for intravenous (IV) administration.[Akinc 2010]  The 
patisiran drug product (ALN-TTR02; patisiran-LNP, hereafter referred to as “patisiran”) is 
designed to significantly suppress liver production of both wt and all mutant forms of TTR, 
thereby having the potential to reduce amyloid formation and provide clinical benefit to patients 
with ATTR amyloidosis.   
Patisiran utilizes the mechanism of RNAi to selectively degrade TTR messenger RNA (mRNA) 
and thereby reduce the expression of its corresponding protein.[Bumcrot 2006] Patisiran is 
formulated (via the 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 Pharmaceuticals, Inc. (the Sponsor) is developing patisiran for the treatment of patients 
with ATTR amyloidosis.  Based on results from the pivotal Phase 3 APOLLO study 
(Section 1.3.1), patisiran is approved in the US for the treatment of the polyneuropathy of 
hATTR amyloidosis in adults and in the European Union for the treatment of hATTR 
209

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
28 
amyloidosis in adult patients with stage 1 and stage 2 polyneuropathy.  Ongoing development is 
intended to establish patisiran for the treatment of ATTR (hereditary and wt) amyloidosis with 
cardiomyopathy based on exploratory cardiac results from the APOLLO study (Section 1.3.1.1), 
which provides preliminary evidence in support of the use of patisiran for the treatment of the 
cardiomyopathy manifestations of the disease.  
The nonclinical pharmacology, pharmacokinetics (PK), and toxicology of patisiran were 
evaluated in a series of in vitro and in vivo studies that have enabled chronic dosing in clinical 
studies.   
1.3.1. 
The Phase 3 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 (modified neurological 
impairment score +7 [mNIS+7]) relative to placebo at 18 months (primary endpoint), as well as 
significant improvement in quality of life (Norfolk Quality of Life - Diabetic Neuropathy 
[Norfolk QoL-DN], key secondary endpoint) 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.    
In the patisiran group, serum TTR reduction was seen after the first dose and was stably 
maintained over the duration of the study; the mean TTR percent reduction from baseline was 
82.6% and 84.3% at Months 9 and 18, respectively.  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). 
1.3.1.1. 
Cardiac Results and Cardiac Subpopulation Data from APOLLO 
In APOLLO, evidence of potential cardiac amyloid involvement was seen in most patients in the 
study; 80% had left ventricular wall thickness >13 mm and 79% had abnormal levels of the 
cardiac biomarker N-terminal prohormone B-type natriuretic peptide (NT-proBNP).[Solomon 
2018]  As well, 56% of the population met the prespecified criteria for inclusion in a 
subpopulation of patients with evidence of cardiac amyloid involvement (ie, the cardiac 
subpopulation, with baseline left ventricular wall thickness ≥13 mm and no history of 
hypertension or aortic valve disease).  In these patients, treatment with patisiran for up to 
18 months resulted in improvement relative to placebo in important measures of cardiac structure 
and function.  These included reduction in ventricular wall thickness and decrease 
(improvement) in global longitudinal strain.[Solomon 2018]  In addition, patisiran treatment led 
to a reduction (improvement) in NT-proBNP and an improvement in functional capacity, as 
measured by 10-meter walk test assessment of gait speed, relative to the placebo group.   
210

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
29 
Overall, patisiran had an acceptable safety profile, based on an in-depth analysis of cardiac 
events in both the overall (modified intent-to-treat) population and the cardiac subpopulation.  
Importantly, in a post hoc analysis of safety data in the modified intent-to-treat population, rates 
of any hospitalization and/or all-cause death were 71.8 and 34.7 per 100 patient-years in the 
placebo and patisiran groups respectively, while the rates of cardiac hospitalizations and/or 
all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups 
respectively.  This approximates a reduction in event rate of approximately 50% for all-cause 
hospitalization and mortality and approximately 45% for cardiac hospitalization and all-cause 
mortality for patients in the patisiran group compared to those in the placebo group.[Solomon 
2018]  Similar reductions in the event rates were observed in the cardiac subpopulation in 
APOLLO (approximately 55% for all-cause hospitalization and mortality and approximately 
45% for cardiac hospitalization and all-cause mortality; data on file). 
The observed cardiac data from the APOLLO study support the therapeutic hypothesis that 
patisiran may halt or reverse the progression of the cardiac manifestations of hATTR 
amyloidosis and warrant ongoing development for this indication. 
1.3.2. 
Phase 3, Open-label Extension Study 
Study ALN-TTR02-006 is an ongoing multicenter, open-label extension study designed to 
evaluate the long-term safety and efficacy of patisiran in patients with hATTR amyloidosis who 
have completed a prior Phase 2 or 3 parent study with patisiran (ALN-TTR02-003 or ALN-
TTR02-004 [APOLLO]).  The interim data from this open-label extension study were consistent 
with, and extended, the acceptable safety profile and clinical efficacy of patisiran observed in the 
Phase 3 APOLLO study.   
No new safety signals have emerged for patients with long-term patisiran treatment. 
1.4. 
Study Design Rationale 
This study is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study 
designed to evaluate the efficacy and safety of patisiran in adult patients with ATTR amyloidosis 
with cardiomyopathy.  The efficacy of patisiran on functional capacity will be evaluated via 
change at Month 12 in the 6-MWT (primary endpoint).  The study will include patients with 
wtATTR and hATTR amyloidosis with cardiomyopathy who, at baseline, are either tafamidis 
naïve or have been on tafamidis for ≥6 months with disease progression, in the opinion of the 
investigator.   
Confidence in a beneficial treatment effect with patisiran in this patient population with ATTR 
amyloidosis with cardiomyopathy comes from the Phase 3 APOLLO study of patisiran in 
patients with hATTR amyloidosis with polyneuropathy.  As described in Section 1.3.1 and 
Section 1.3.1.1, TTR lowering with patisiran demonstrated multiple benefits in a broad range of 
disease manifestations, including a substantial improvement in neuropathy and quality of life, as 
well as autonomic symptoms, motor strength, ambulatory ability, disability, and nutritional 
status.[Adams 2018]  Furthermore, in a prespecified subgroup of patients with evidence of 
cardiac involvement, which was a majority (56%) of the overall study population, a beneficial 
treatment effect of patisiran compared to placebo was observed for assessments of cardiac 
structure and function as well as the cardiac biomarker NT-proBNP.[Solomon 2018]   
211

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
30 
The 6-MWT (primary endpoint assessment) is a clinically relevant assessment of functional 
capacity that has been used as a primary endpoint in pivotal clinical trials in pulmonary arterial 
hypertension (Gabler 2012) and has been used in the evaluation of patients with HF.[Bittner 
1993; Flynn 2009; Flynn 2012; Mangla 2013; Masoudi 2004; Maurer 2014]  The KCCQ-OS 
(first secondary endpoint assessment) has been used as a common assessment in HF 
interventional studies and has been shown to be an independent predictor of prognosis in 
HF.(Heidenreich et al.  2006)  Both 6-MWT and KCCQ-OS were shown to rapidly and 
consistently decline over time in cardiac ATTR amyloidosis patients and, in the Phase 3 ATTR-
ACT study, these measures were used to demonstrate a reduction of decline with tafamidis 
treatment.[Maurer 2018]  These data support the use of 6-MWT and KCCQ-OS as clinically 
relevant primary and key secondary endpoints, respectively.   
Assessment of the primary endpoint at Month 12 is supported by placebo-arm data from the 
ATTR-ACT study showing substantial disease progression (via the 6-MWT) over an equivalent 
time; as well, data from APOLLO demonstrated a patisiran treatment effect as early as 9 months 
on multiple manifestations of hATTR amyloidosis (neuropathy, quality of life, NT-proBNP, and 
functional capacity [ie, gait speed]).[Maurer 2018] 
The inclusion of placebo as a control allows for a rigorous analysis of the treatment effect of 
patisiran.  If tafamidis becomes an approved therapy for ATTR amyloidosis with 
cardiomyopathy in a given region while this study is in progress, patients who are naïve to 
tafamidis treatment at baseline may commence concomitant on-label tafamidis during the study 
(ie, tafamidis drop-in) (Section 5.3.1).    
1.5. 
Dose Rationale 
The approved and recommended dosage of patisiran for the treatment of the polyneuropathy in 
patients with hATTR amyloidosis is 0.3 mg/kg administered IV every 3 weeks for patients 
weighing <100 kg and a fixed dose of 30 mg administered every 3 weeks for patients weighing 
100 kg or more.  This dosage was selected based on dose-response analyses from three Phase 1 
and 2 studies demonstrating dose-dependent TTR reduction, with the maximum reduction 
achieved at 0.3 mg/kg.  This regimen was further confirmed in the pivotal Phase 3 APOLLO 
study, where this dosage showed significant clinical activity and was well tolerated by patients 
with hATTR amyloidosis with polyneuropathy, including those in the cardiac subpopulation.  
The approved dosing regimen used in the treatment of polyneuropathy is being employed in this 
study since the mechanism of action of patisiran (ie, serum TTR lowering) for treatment of 
polyneuropathy and cardiomyopathy is the same.  
1.6. 
Benefit-risk Assessment 
ATTR amyloidosis with cardiomyopathy is a rare, serious, life-threatening, multisystemic 
disease characterized by deposition of TTR in various organs.  Without treatment, the disease 
progresses, resulting in chronically debilitating morbidity and mortality, with the most common 
manifestations being cardiomyopathy and polyneuropathy.  Patients with symptomatic HF 
experience rapid progression of their amyloidosis with 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]   
212

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
31 
The benefit-risk profile of patisiran has been established in extensive clinical development; in 
Phase 1, 2, and 3 clinical studies, patisiran administered IV demonstrated a potent, 
dose-dependent inhibition of TTR.  In the Phase 3 APOLLO study of patisiran, the primary and 
all secondary endpoints were met.[Adams 2018]  Furthermore, exploratory cardiac results from 
the APOLLO study suggest that patisiran may halt or reverse the progression of the cardiac 
manifestations of hATTR amyloidosis [Solomon 2018] and provide preliminary evidence in 
support of the use of patisiran for the treatment of patients with ATTR amyloidosis with 
cardiomyopathy (Section 1.3.1.1). 
In APOLLO, as well as in the ongoing Phase 3, open-label extension study (ALN-TTR02-006), 
an acceptable safety profile with patisiran was demonstrated.  Most AEs were mild or moderate 
in severity.  Transient infusion-related reactions (IRRs) were observed, but all IRRs were mild or 
moderate in severity, none were reported as serious AEs (SAEs).  No clinically significant 
laboratory or hematologic changes were observed.  Furthermore, in APOLLO, an acceptable 
safety profile was also observed in a prespecified subgroup of patients with evidence of cardiac 
amyloid involvement. [Solomon 2018] 
For patisiran, important identified risks include IRRs.  To minimize this risk, all patients must 
receive premedication with a corticosteroid, paracetamol/acetaminophen, and H1 and H2 
blockers prior to patisiran administration (Section 5.2.1).  The infusion may be interrupted or 
slowed if an IRR occurs (Sections 5.2.3 and 5.2.4).  Important potential risks also include severe 
hypersensitivity (eg, anaphylaxis) to the active substance or any of the excipients.  Patisiran is 
contraindicated in patients with a history of severe hypersensitivity (eg, anaphylaxis or 
anaphylactoid reactions) to patisiran or any of the excipients. 
Vitamin A deficiency is also considered an important potential risk.  Nonclinical and clinical 
data with patisiran have shown that the lowering of circulating vitamin A associated with the 
reduction in TTR (a carrier of retinol) does not result in 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 (Section 5.3).  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 patisiran.  
Detailed information about the known and expected benefits and risks of patisiran may be found 
in the current edition of the Investigator’s Brochure.  
During the study, patients will be monitored, including evaluation of laboratory monitoring for 
liver function test abnormalities, renal function, and other standard hematology and blood 
chemistries.  As the risk of embryofetal toxicity is currently unknown, females of child-bearing 
potential participating in the study must have a negative pregnancy test, cannot be breast feeding, 
and must be willing to use a highly effective method of contraception as specified in the 
protocol. 
An external, independent Data Monitoring Committee (DMC) will monitor and ensure the safety 
of trial participants (see Section 3.7).   
In conclusion, exploratory cardiac results from the APOLLO study suggesting that patisiran may 
halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis [Solomon 
213

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
34 
randomized, double-blind study drug (patisiran or placebo), to reduce the potential for an IRR 
with patisiran, all patients will receive premedications at least 60 minutes before the start of their 
infusion.  (Patients randomized to placebo will also receive premedications to maintain the 
blind.)  Study drug will be administered in the clinic as an approximately 80-minute IV infusion.  
During the 12-month open-label extension period, all patients will receive treatment with 
open-label patisiran.  Furthermore, patients who have received ≥3 consecutive doses of patisiran 
on this study at the clinical site with no evidence of IRRs or other drug-related adverse effects 
impacting safety and tolerability of the infusion may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be 
performed by a healthcare professional trained on the protocol and on administration of 
premedications and patisiran infusion. 
To evaluate the efficacy of treatment with patisiran versus placebo in patients with ATTR 
amyloidosis with cardiomyopathy, the change from baseline in 6-MWT will be assessed at 
Month 12 (Weeks 52-53) as the primary endpoint (Section 2); this assessment will also be 
performed at Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) in the double-blind period, 
and during the open-label extension period at the time points noted in the Schedule of 
Assessments (Table 1 and Table 2).  The first secondary endpoint will assess change from 
baseline at Month 12 in the KCCQ-OS score.     
Safety will be assessed throughout the study, as described in the Schedule of Assessments for the 
double-blind period (Table 1) and for the open-label extension period (Table 2).   
3.2. 
Duration of Treatment  
The treatment duration in this study is up to 24 months, inclusive of a 12-month, double-blind, 
treatment period, and a 12-month, open-label, treatment period. 
3.3. 
Duration of Study Participation  
The estimated total time on study for each patient is up to 26.5 months, including up to 45 days 
of screening, up to 24 months of treatment (see Section 3.2), and a 28-day safety follow-up 
period. 
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 end of study (EOS; Month 24) visit, or 
• the patient has completed the follow-up visit 28 days after the last dose of patisiran.    
3.4. 
Number of Planned Patients 
The planned enrollment for this study is 300 patients with wtATTR and hATTR amyloidosis 
with cardiomyopathy.  Approximately 20% of the study population is anticipated to have hATTR 
and 80% wtATTR. 
216

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
35 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the interactive response system (IRS), patients will be randomized 1:1 to the patisiran or 
placebo arm.  Randomization will be stratified by: 
1. Baseline tafamidis (yes vs no) 
2. Genotype (hATTR vs wtATTR amyloidosis with cardiomyopathy) 
3. NYHA Class I or II and age < 75 years vs all other     
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 
During the double-blind period of the study, all site personnel will be blinded to the study 
treatment, except the pharmacist and designated pharmacy personnel who will set-up, dispense, 
and prepare the infusion.  Patisiran confers a slightly opalescent color relative to the clear saline 
(placebo) infusate; therefore, all infusion bags and lines will be covered with amber bags and line 
covers by the unblinded personnel to prevent visualization by the blinded study personnel and 
patient, as described in detail in the Pharmacy Manual.   
After the pharmacist (and designated pharmacy personnel) has prepared the infusion, separate 
blinded personnel will administer study drug and monitor the patient during and after the 
infusion.  All patients will be blinded to treatment and will receive an IV infusion once every 
3 weeks using identical volumes for patisiran and placebo.    
Study personnel performing assessments related to the primary and secondary endpoints will be 
different from the Investigator and other personnel managing the patient, and all of these study 
personnel will be blinded to any clinical laboratory results that could potentially unblind them 
(eg, TTR levels).  In addition, the study personnel performing assessments related to the primary 
and secondary efficacy endpoints will also be blinded to the results of any previous assessments. 
Furthermore, unblinded source documentation containing all descriptions of pharmacy 
preparations and infusions or distribution of study drug or randomization data will be stored 
separate from all other study data/records and from other pharmacy staff not participating on the 
study. 
Blinding will be maintained until the last patient completes their Month 12 visit. 
3.6.1. 
Emergency Unblinding 
During the double-blind period of the study, if the treating physician determines that the clinical 
management of the patient requires knowledge of the study drug assignment, the Investigator 
may break the blind, as necessary.  If time permits, clinical study center personnel should contact 
the Medical Monitor before unblinding to discuss the need to unblind the patient but must do so 
within 1 working day after the unblinding event.  Unblinding information should be limited to 
the fewest number of people on a need-to-know basis.  A record of when the blind was broken, 
217

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
36 
who was unblinded, who broke the blind, and why it was broken, will be maintained in the trial 
master file. 
Refer to the IRS instructions for details on emergency unblinding. 
3.7. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study through the 
double-blind period (through Month 12), 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.  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 (CV versus non-CV) 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 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive.  
Patient and Disease Characteristics 
2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either 
hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with 
cardiomyopathy: 
Hereditary ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of 
the following criteria: 
a. TTR pathogenic mutation consistent with hATTR.  
b. Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness >12 mm (based on central echocardiogram 
reading at screening).   
c. Amyloid deposits in cardiac or noncardiac tissue (eg, fat pad aspirate, salivary gland, 
median nerve connective sheath) confirmed by Congo Red (or equivalent) staining 
OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc], or 99mTc-
hydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if 
monoclonal gammopathy of undetermined significance (MGUS) has been excluded. 
d. If MGUS, confirm TTR protein in tissue with immunohistochemistry (IHC) or mass 
spectrometry. 
218

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
37 
Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of 
the following criteria: 
a. Absence of pathogenic TTR mutation.  
b. Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness >12mm (based on central echocardiogram 
reading at screening).   
c. Amyloid deposits in cardiac tissue with TTR precursor identification by IHC, mass 
spectrometry, OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc] or 99mTc-
hydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if 
MGUS has been excluded. 
d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry  
3. Medical history of HF with at least 1 prior hospitalization for HF (not due to arrhythmia 
or a conduction system disturbance treated with a permanent pacemaker) OR clinical 
evidence of HF (with or without hospitalization) manifested by signs and symptoms of 
volume overload or elevated intracardiac pressures (eg, elevated jugular venous pressure, 
shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral 
edema) that currently requires treatment with a diuretic. 
4. Patient meets one of the following criteria: 
a. Tafamidis naïve; in addition to patients who have never taken tafamidis, those who 
have been on tafamidis for ≤30 days total and have not received any tafamidis in the 
6 months prior to baseline will be considered tafamidis naïve and may qualify for the 
study. 
b. Currently on tafamidis (for ≥6 months) and has demonstrated disease progression, as 
determined by the Investigator.  (At the time of study entry, tafamidis treatment must 
be on-label use of commercial tafamidis.) 
5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to 
randomization, as assessed by the Investigator.   
6. Able to complete ≥150 m on the 6-MWT at screening. 
7. Screening NT-proBNP >600 ng/L and <8500 ng/L. 
Informed Consent 
8. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent; and patient agrees to sign the 
medical records release form for collection of vital status.   
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Has known primary amyloidosis (AL) or leptomeningeal amyloidosis.  
219

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
38 
2. NYHA Class III AND ATTR amyloidosis disease Stage 3 (defined as both NT-proBNP 
>3000 ng/L and estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 
m2).[Gillmore 2018] 
3. NYHA Class IV at the Screening visit. 
4. Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to 
walk, or is wheelchair bound) at the Screening visit. 
Laboratory Assessments 
5. Has any of the following laboratory parameter assessments at screening:  
a. Aspartate transaminase (AST) or alanine transaminase (ALT) levels ˃2.0 × the upper 
limit of normal (ULN). 
b. Total bilirubin ˃ULN.  Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if total bilirubin <2 × ULN. 
c. International normalized ratio (INR) ˃1.5 (unless patient is on anticoagulant therapy, 
in which case excluded if INR ˃3.5).  
6. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] 
formula). 
7. Has known human immunodeficiency virus infection; or evidence of current or chronic 
hepatitis C virus or hepatitis B virus infection.    
Prior/Concomitant Therapy 
8. Tafamidis naïve patients (at baseline) for whom the Investigator actively plans or 
anticipates commencing treatment with tafamidis during the 12-month double-blind 
period, taking into consideration clinical status, patient preference and/or commercial 
availability of tafamidis. 
9. Is currently taking diflunisal; if previously on this agent, must have at least a 6-month 
wash-out prior to dosing (Day 1). 
10. Is currently taking doxycycline, ursodeoxycholic acid, or tauroursodeoxycholic acid; if 
previously on any of these agents, must have completed a 30-day wash-out prior to 
dosing (Day 1). 
11. Received prior TTR-lowering treatment (including patisiran) or participated in a gene 
therapy trial for hATTR amyloidosis. 
12. Current or future participation in another investigational device or drug study, scheduled 
to occur during this study, or has received an investigational agent or device within 
30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing 
(Day 1).  In the case of investigational TTR stabilizer drugs, washout for 6 months prior 
to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at 
baseline (per inclusion Criterion 4). 
13. Requires chronic treatment with non-dihydropyridine calcium channel blockers (eg, 
verapamil, diltiazem).  
Medical Conditions 
220

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
39 
14. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to 
valvular heart disease, or cardiomyopathy due to ischemic heart disease (eg, prior 
myocardial infarction with documented history of cardiac enzymes and 
electrocardiogram [ECG] changes). 
15. Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive 
pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation). 
16. Recent or planned orthopedic procedure during the double-blind period (eg, lower 
extremity or back surgery) that could impact 6-MWT. 
17. Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of 
screening required to achieve optimal treatment of CHF). 
18. Had acute coronary syndrome or unstable angina within the past 3 months. 
19. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.  
20. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a 
pacemaker is indicated but will not be placed. 
21. Has persistent elevation of systolic (˃180 mmHg) and diastolic (˃100 mmHg) blood 
pressure that is considered uncontrolled by physician. 
22. Has untreated hypo- or hyperthyroidism. 
23. Prior or planned heart, liver, or other organ transplant. 
24. Had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix that has been successfully treated. 
25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation; or, in the opinion of the 
Investigator, taking part in the study would jeopardize the safety of the patient.   
26. Has a history of severe hypersensitivity (eg, anaphylaxis) to any of the excipients in 
patisiran.  Also see exclusion Criterion 11, which excludes all patients with prior TTR-
lowering treatment including patisiran. 
Contraception, Pregnancy, and Breastfeeding 
27. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.5.1.   
28. Female patient is pregnant or breast-feeding.    
Alcohol Use 
29. Has a known history of alcohol abuse within the past 2 years or daily heavy alcohol 
consumption (for females, more than 14 units of alcohol per week; for males, more than 
21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ 
pint of beer]); 
30. History of illicit drug abuse within the past 5 years that in the opinion of the Investigator 
would interfere with compliance with study procedures or follow-up visits. 
221

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
40 
4.3. 
Removal from Study Drug 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 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; which includes required treatment with 
prohibited medication (as defined in Section 5.3) per investigator discretion 
• Adverse event  
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.7.7 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.   
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1 and Table 2), 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 AEs, and must document this decision in the 
patient’s medical records. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.5.7.  When a patient discontinues study drug dosing, the primary reason 
222

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
41 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable. 
Patients who discontinue from study drug during the 12-month double-blind period, defined as 
the time the first dose of study drug is administered on Day 1 through completion of the 
Month 12 Efficacy Visit (primary endpoint assessment), will be encouraged to remain on the 
study and complete assessments through Month 12 (excluding PK assessments), including a 
Modified Month 12 Efficacy Visit (Table 1).  They will also be asked to complete an Early 
Treatment Discontinuation Visit (7-14 days after their last dose) and the safety follow-up visit, 
28 days after the last dose of study drug (Table 2); see Section 3.3.1. 
Patients who discontinue patisiran during the open-label extension period will be asked to 
complete an Early Treatment Discontinuation Visit (7-14 days after their last dose) and the safety 
follow-up visit, per the Schedule of Assessments (Table 2), 28 days after the last dose of 
patisiran; see Section 3.3.1. 
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 the patient's participation in the study at any time.  A 
patient or legal guardian considering stopping participation in the study should be informed that 
the patient can discontinue study drug and/or decline procedural assessments and remain in the 
study to complete their study assessments, through the Modified Month 12 Efficacy Visit, and 
the 28-day follow-up visit, or alternatively may complete any minimal assessments for which the 
patient or legal guardian consents as described in Section 4.3.1.  If a patient or legal guardian still 
chooses to discontinue study drug and stop participation in all follow-up prior to the completion 
of the Month 12 visit, every effort should be made to conduct the assessments scheduled to be 
performed at the Modified Efficacy Visit (Table 1). 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, 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, and 
use biological samples and, as applicable, other personal data, informing the study doctor at any 
time in writing or in any other form that may be locally required.  The Sponsor will continue to 
keep and use the patient’s study information (including any data resulting from the analysis of 
the patient’s biological samples until the time of withdrawal) according to applicable law.  The 
223

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
42 
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 or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes (for the patient) 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 or legal guardian (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 or legal guardian 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.    
224

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
43 
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 and returned unused must not be re-dispensed. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of study drug 
(patisiran and placebo) 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. 
Premedication 
All patients will receive premedication prior to study drug administration to reduce the risk of 
IRRs.  Each of the following medicinal products should be given on the day of study drug 
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.   
If a patient is having difficulty tolerating the steroid premedication regimen (eg, patient develops 
uncontrolled hyperglycemia, altered mental status, or other complication), then lowering of the 
steroid premedication may be allowed for that patient after consultation with the medical monitor 
at any time during the study (double-blind and open-label periods).   
In the open-label extension period only, for patients who are tolerating their drug infusions well 
with their current corticosteroid premedication regimen (ie, no IRRs during the past 3 or more 
infusions), corticosteroid dose may be reduced in 2.5 mg increments to a minimum dose of 5 mg 
of dexamethasone (IV) or equivalent.    
Infusions during corticosteroid tapering (and the 2 infusions after the new and stable lower 
corticosteroid dose is established) should be performed in the clinic, as described in detail in the 
Pharmacy Manual.    
Additional or higher doses of 1 or more of the premedications may be administered to reduce the 
risk of IRRs, if needed.  For suggested guidelines for management of IRRs, see Section 5.2.4; 
further details can be found in the Pharmacy Manual.   
225

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
44 
5.2.2. 
Study Drug Description 
Patisiran is a RNAi therapeutic consisting of a double-stranded siRNA targeting TTR mRNA 
formulated in an LNP.  The patisiran drug product is a sterile formulation of ALN-18328 (siRNA 
targeting TTR) formulated as LNPs with lipid excipients (1,2-Dilinoleyloxy-N,N-
dimethylpropylamine [DLin-MC3-DMA], 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.  Patisiran Solution for 
IV infusion contains 2 mg/mL of patisiran. 
See the Pharmacy Manual for further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (normal saline 0.9% for IV administration).  
Control drug will be provided by a central supplier (or, if necessary, by a local supplier, with 
prior Sponsor approval).  
5.2.3. 
Dose and Administration 
Detailed instructions for study drug preparation and administration are found in the Pharmacy 
Manual. 
5.2.3.1. 
Double-bind Study Drug (Patisiran or Placebo) 
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs (Section 5.2.1).   
An IV infusion of double-blind study drug (patisiran 0.3 mg/kg or placebo) will be administered 
under the supervision of the site personnel once every 3 weeks ±3 days.   
The amount (in mg) of double-blind patisiran 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.  
Weight from the previous visit may be used for calculating dose.  Weight must be collected prior 
to dosing with study drug.  Study drug will be administered as an approximately 80-minute IV 
infusion (approximately 1 mL/minute for the first 15-minutes followed by approximately 
3 mL/minute for the remainder of the infusion).  The 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. 
Missed doses of double-blind study drug   
If a patient does not receive a dose of study drug within the dosing window (±3 days), the 
delayed dose may be taken up to 7 days after the scheduled visit (with the following infusion 
taken on schedule, per the Schedule of Assessments), after consultation with the Medical 
Monitor.  
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. 
226

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
45 
5.2.3.2. 
Open-label Extension Period (Patisiran) 
The last dose of double-blind study drug will be at Week 51 and the first dose of open-label 
patisiran will be 3 weeks later (at Week 54) and thereafter every 3 weeks (±3 days) for the 
remainder of the study.  Open-label patisiran will be administered per the schedule and dose as is 
described in Section 5.2.3.1 for double-blind patisiran. 
As noted in Section 3.6, blinding will be maintained until the last patient completes their 
Month 12 visit. 
During the open-label extension period, patients who have received at least 3 consecutive doses 
of patisiran on this study at the clinical site with no evidence of IRRs or other drug-related 
adverse effects impacting safety and tolerability of the infusion may have patisiran administered 
at home, where applicable country and local regulations allow.  Home administration of patisiran 
will be performed by a healthcare professional trained on the protocol and administration of 
premedications and patisiran infusion. 
All patients will receive premedications prior to open-label patisiran administration to reduce the 
risk of IRRs (Section 5.2.1).   
Missed doses of open-label patisiran   
If a patient does not receive a dose of open-label patisiran within the dosing window (±3 days), 
the delayed dose may be taken up to 7 days after the scheduled visit (with the following infusion 
taken on schedule, per the Schedule of Assessments), after consultation with the Medical 
Monitor. 
5.2.4. 
Suggested Guidelines for Management of Infusion-related Reactions 
Criteria for categorizing IRRs are provided in Section 10.3. 
• In the event of an IRR, the infusion of study drug may be slowed or stopped and the patient 
closely monitored until resolution of the reaction.  Drugs that may be used to facilitate 
resolution and permit resumption of study drug administration include but are not limited to:  
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), nonsteroidal anti-inflammatory drugs (NSAIDs), adrenaline, supplemental 
oxygen, IV fluids, and/or corticosteroids. 
• Following resolution of a mild or moderate IRR that required interruption of the study drug 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate for that dose and for subsequent doses of study drug.  If the infusion is delayed, 
the administration of the infusion should be completed no more than 16 hours after study 
drug is first diluted in saline (including infusion time). 
• Study drug administration will not be resumed for any patient following a severe IRR until 
the case is discussed with the Medical Monitor. 
• If after consultation with the Medical Monitor it is agreed that an individual patient’s steroid 
premedication will be increased, then the following steps are recommended: 
1. If the IRR occurred while the patient received 10 mg IV dexamethasone or equivalent at 
least 60 minutes before the infusion and did not resolve with slowing of the infusion rate, 
227

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
46 
then the patient should be increased by multiples of 5 mg IV dexamethasone or 
equivalent at least 60 minutes before the infusion.  
2. Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
IV dexamethasone or equivalent on the day of infusion.  
3. If the IRR occurred while the patient received less than 10 mg IV dexamethasone or 
equivalent, then the patient should return to the prior dose of IV dexamethasone or 
equivalent that did not result in an IRR. 
Patients will be instructed to call the Investigator if they experience symptoms such as fever, 
chills, myalgia, or nausea/vomiting after discharge from the site. 
5.2.5. 
Dose Modifications 
Dose modifications are not permitted.   
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
5.2.6. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of study drug (patisiran and placebo) 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. 
5.2.7. 
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. 
5.2.8. 
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. 
228

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
47 
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 and Procedures 
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs (Section 5.2.1).   
Use of the following medications/treatments are prohibited during study participation: 
• Any investigational agent other than study drug. 
• Inotersen, doxycycline, ursodeoxycholic acid, tauroursodeoxycholic acid, and 
diflunisal are also prohibited during the study.   
All patients will be asked to take the recommended daily allowance of vitamin A for the duration 
of their participation in the study while being administered study drug.  In countries where 
relevant, the clinical sites will provide patients with a prescription for vitamin A at a dose 
consistent with local guidelines.  
Standard vitamins and topical medications are permitted.  Any concomitant medication or 
treatment that is required for the patient’s welfare may be given by the Investigator.  However, it 
is the responsibility of the Investigator to ensure that details regarding the medication are 
recorded on the CRF, as specified in the Schedule of Assessments (Table 1 and Table 2).  
Concomitant medications include 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 CRF.  Concomitant medication will be coded using an internationally 
recognized and accepted coding dictionary.  
5.3.1. 
Concomitant Tafamidis Use 
Per inclusion Criterion 4, at baseline patients are either: 1) tafamidis naïve or 2) currently on 
tafamidis for ≥6 months with demonstrated disease progression, as determined by the 
Investigator.  Patients who have been on tafamidis for ≤30 days total and have not received any 
tafamidis in the 6 months prior to baseline will be considered tafamidis naïve and may qualify 
for the study.   
For patients on tafamidis at baseline, the reasons for considering the patient to have 
demonstrated disease progression will be recorded in the eCRF.  Patients who are on tafamidis at 
baseline are encouraged, if it is medically appropriate in the opinion of the investigator, to 
remain on tafamidis for the duration of the double-blind period. 
Per exclusion Criterion 8, patients who are tafamidis naïve at baseline, for whom the investigator 
actively plans or anticipates commencing treatment with tafamidis during the 12-month 
double-blind period (taking into consideration clinical status, patient preference, and/or 
commercial availability of tafamidis), should not be enrolled in the trial. 
However, if tafamidis is granted approval by a Health Agency for treatment in patients with 
ATTR amyloidosis with cardiomyopathy in a given region, all enrolled patients in this region 
229

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
48 
will be made aware of its potential benefits and risks at the time of regulatory approval and all 
patients will be reconsented.  In such circumstances, tafamidis is not considered prohibited and 
the investigator may, using their medical judgement, commence concomitant on-label tafamidis 
during the study, if it is felt to be in the best interest of the patient and if it is commercially 
available in the country.   
Patients who are tafamidis naïve at baseline, but begin taking commercial tafamidis (ie, 
“tafamidis drop-in”), will remain in the study.  Prior to commencing concomitant tafamidis, the 
investigator will perform assessments (including primary and select secondary efficacy 
assessments) at the Pre-tafamidis Drop-in Visit, as outlined in the Schedule of Assessments 
(Table 1).  In all cases, the Pre tafamidis Drop-in Visit should occur prior to starting concomitant 
tafamidis; where possible, this visit should occur between 1-2 weeks after the last dose of study 
drug (ie, 7 to 14 days post study drug dose).  Thereafter, the patient will continue with all 
assessments per the Schedule of Assessments (Table 1 and Table 2).  In addition, at the time of 
tafamidis drop-in, the reason for starting tafamidis will be recorded in the CRF. 
Initiation of TTR stabilizer therapies other than tafamidis (eg, diflunisal) is not allowed during 
the double-blind period of this study. 
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 a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 12 weeks 
after the last dose of study drug in this study.    
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 low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. 
• 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 
230

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
49 
start heterosexual relationships during the study and for up to 12 weeks 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, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements as described in the corresponding patient informed consent forms.   
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.2).    
6. 
STUDY ASSESSMENTS 
The Schedule of Assessments is provided in Table 1 (double-blind period) and Table 2 
(open-label extension period).  Additional information on the collection of study assessments 
will be detailed in the respective reference manuals.  
6.1. 
Screening Assessments  
An ICF 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.  In addition, a medical records release form will be required of all patients for the 
purpose of obtaining vital status information from the patient’s physician or from death 
registries.    
See the Schedule of Assessments (Table 1) for a list of Screening visit assessments.   
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening (once) of patients is permitted with consultation of the Medical 
Monitor (see Section 6.1.2). 
Patient demographic data and medical history/disease history will be obtained, including 
completion of ophthalmologic history in the eCRF.  Any changes to medical history occurring 
between the screening assessment and Day 1 will be updated prior to study drug administration. 
If a genetic test result that shows the presence or absence of a TTR pathogenic mutation, which 
would be consistent with either wtATTR or hATTR, is not available at Screening for the 
assessment of eligibility (Section 4.1, inclusion criterion 2a), genotyping may be conducted at a 
laboratory selected by the site in consultation with the Medical Monitor. 
231

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
50 
The study eligibility biopsies and technetium scintigraphy noted in inclusion Criterion 2 are 
intended to be historical, as part of the patient’s clinical care and diagnosis, and are not 
performed as part of the study.    
An echocardiogram will be performed at screening Visit 1 and results confirmed centrally to 
assess study eligibility, as indicated in the Schedule of Assessments (Table 1). 
6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then 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.  Any 
additional repeat testing may be considered after discussion with the Medical Monitor. 
6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening, or who fails to complete screening activities due to unforeseen or unavoidable 
circumstances, may be rescreened once after consultation with the Medical Monitor after a 
minimum of 5 days have elapsed from a patient’s last screening assessment.  A patient will be re-
consented if rescreening occurs outside of the 45-day screening window.  In this case, all 
screening procedures must be repeated.   
6.2. 
Efficacy Assessments 
6.2.1. 
6-Minute Walk Test (6-MWT) 
The 6-MWT, which will be assessed as the primary endpoint, is an assessment of functional 
exercise capacity.  The 6-MWT will be administered by staff trained in the procedure per the 
relevant study manual.  The staff administering the 6-MWT will be different from the 
Investigator or designee managing the care of the patient. 
The 6-MWT will be performed at each of the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2).  At screening Visit 1, the 6-MWT will be administered for 
study eligibility purposes (per inclusion Criterion 6 [Section 4.1]).  At screening Visit 1, prior to 
conducting the 6-MWT, the site staff will familiarize the patient with the purpose and conduct of 
the 6-MWT, as described in detail in the relevant study manual.  Familiarization can be repeated 
at other timepoints if deemed helpful. 
On Day 1 (baseline), which is a dosing day, the 6-MWT will be performed prior to study drug 
administration.  (No other dosing days have a 6-MWT assessment.)   
Patients who are hospitalized during the study should wait at least 2 weeks after hospitalization 
before completing a 6-MWT assessment; less time post-hospitalization may be permitted if, in 
the opinion of the investigator, the patient is unencumbered due to the recent hospitalization.  In 
addition, if a patient is not feeling well due to an external factor (eg, flu, sprained ankle, pulled 
back muscle) at a visit when the 6-MWT will be performed, the test should not be done and 
should be rescheduled for another day within the permitted visit window. 
232

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
51 
For each 6-MWT assessment, the site should make every effort to have this assessment 
performed by the same assessor and to perform the test at approximately the same time of day.  
If the test is interrupted or deemed unusable by the 6-MWT core laboratory, the 6-MWT should 
be repeated as soon as possible within the allowed visit window. 
Further details regarding the 6-MWT are provided in the relevant study manual. 
A 1.5-month window will be used to group 6-MWT assessments to the Month 6 (Weeks 25-26), 
Month 9 (Weeks 37-38), and Month 12 (Weeks 52-53) visits.  During the double-blind period, a 
patient may opt to begin tafamidis treatment or to discontinue study treatment, in which case 
they would complete a Pre-tafamidis Drop-in Visit (Table 1) or Early Treatment Discontinuation 
Visit (Table 2), respectively.  To avoid the potential training effect from repeated assessments of 
the 6-MWT within a short period of time, only one 6-MWT assessment should be collected for 
the following time periods:  Day 2 to Day 214 (for Month 6), Day 215 to Day 319 (for Month 9), 
and Day 320 to Day 372 (for Month 12).   
Within a given time period, the 6-MWT assessment should be performed at whichever visit 
occurs first (scheduled assessment, Pre-tafamidis Drop-in Visit, or Early Treatment 
Discontinuation Visit); no additional 6-MWT assessments should be made in that time period.  
In later time periods, the 6-MWT should be assessed per the Schedule of Assessments (Table 1).  
6.2.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ)   
The KCCQ [Green 2000] is a 23-item self-administered questionnaire developed to 
independently measure the patient’s perception of health status, which includes heart failure 
symptoms, impact on physical and social function, and how their heart failure impacts their 
quality of life within a 2-week recall period. 
The KCCQ quantifies 6 domains (symptoms, physical function, quality of life, social limitation, 
self-efficacy, and symptom stability) and 2 summary scores (clinical and overall summary [OS]).  
The KCCQ-OS will be assessed for the first secondary endpoint. 
The KCCQ questionnaire will be completed at the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2). 
6.2.3. 
Deaths and Hospitalizations 
All deaths and hospitalizations will be recorded at Day 1 post dose and throughout the study as 
specified as part of AEs monitoring (see Section 6.5.7) and per the Schedule of Assessments 
(Table 1 and Table 2).  
Reasons for deaths and hospitalizations will be adjudicated by an independent Adjudication 
Committee (see Section 3.8). 
6.2.4. 
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).   
233

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
52 
Weight, height, and serum albumin (collected as part of the serum chemistry panel) will be 
collected pre-dose at the timepoints specified in the Schedule of Assessments (Table 1 and 
Table 2).  The site will not perform the calculation for mBMI.   
6.2.5. 
Cardiac Assessments   
Manifestations of cardiac amyloid involvement will be assessed via cardiac biomarker, NYHA 
class, echocardiograms, CMR, and technetium scintigraphy imaging, as described. 
Qualified personnel will be required to administer cardiac imaging assessments as specified in 
the respective reference manuals. 
6.2.5.1. 
Cardiac Biomarkers   
The cardiac biomarkers NT-proBNP and troponin I will be used to assess cardiac stress and heart 
failure severity.  These biomarkers have been shown to be prognostic of outcomes in HF, 
including in ATTR amyloidosis.[Damy 2016; Kristen 2017; Merlini 2016]  Blood samples will 
be drawn to measure cardiac biomarker levels at the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2) and will be measured at a central laboratory.  At screening 
Visit 1, only NT-proBNP will be assessed for eligibility purposes.    
Details on cardiac biomarker sample collection, processing, and storage will be provided in a 
Study Laboratory Manual. 
6.2.5.2. 
ATTR Amyloidosis Disease Stage 
Based on published data from Gillmore et al, the ATTR amyloidosis disease staging used for this 
protocol stratifies patients with ATTR amyloidosis with cardiomyopathy (both hATTR and 
wtATTR) into prognostic categories using the serum biomarkers NT-proBNP and 
eGFR.[Gillmore 2018]  Patients are categorized as follows: 
• Stage 1 (lower risk):  NT-proBNP ≤3000 ng/L and eGFR ≥45 ml/min/1.73 m2 
• Stage 2 (intermediate risk):  all other patients not meeting criteria for Stages 1 or 3 
• Stage 3 (higher risk):  NT-proBNP >3000 ng/L and eGFR <45 ml/min/1.73 m2 
Based on published data, this staging system discriminates between patients with median 
survival of ~6 years, ~4 years, and ~2 years for Stage 1, Stage 2, and Stage 3, respectively. 
6.2.5.3. 
New York Heart Association (NYHA) Class 
NYHA class is a clinical assessment of symptoms resulting from HF and is assessed according to 
the table in Section 10.2.  NYHA class will be evaluated at the timepoints specified in the 
Schedule of Assessments (Table 1 and Table 2).  The score collected at screening will be used to 
determine eligibility. 
6.2.5.4. 
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 and Table 2), and analyzed at a central cardiac imaging core lab.   
234

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
53 
Image acquisition, storage, and transfer guidelines will be provided in the relevant study manual. 
6.2.5.5. 
Technetium Scintigraphy Imaging  
At select sites, in a subset of approximately 100 patients, technetium scintigraphy will be 
collected according to the Schedule of Assessments (Table 1 and Table 2), as an optional 
exploratory imaging assessment, to assess cardiac amyloid involvement.  Based on local practice 
standards, either 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD-Tc], 99mTc-
pyrophosphate [PYP-Tc], or 99mTc-hydroxymethylene diphosphonate (99mTc-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 relevant 
study manual.   
For patients in whom technetium scintigraphy is performed as a study efficacy parameter, the 
results of the baseline scan must be reviewed by the central reader and confirmed to be consistent 
with the diagnosis of ATTR amyloidosis prior to randomization. 
At select sites where technetium scintigraphy is being performed as an exploratory efficacy 
assessment, patients may be exempt from the baseline scan if technetium scintigraphy has been 
performed prior to study entry as part of the patient’s clinical care within 6 months prior to the 
baseline assessment.  In such cases, the historical technetium scintigraphy examination 
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; if the historical scan cannot 
be transferred to the central reader, or is deemed by the central reader to be of inadequate quality 
for interpretation, the patient should not participate in this optional efficacy assessment. 
6.2.5.6. 
Cardiac Magnetic Resonance (CMR)   
At select sites, in a subset of patients (≤60 patients), CMR will be collected according to the 
Schedule of Assessments (Table 1 and Table 2), as an optional exploratory imaging assessment 
to assess cardiac amyloid involvement.  CMR imaging with late gadolinium enhancement will 
only be performed on patients without contraindications (ie, pacemakers, severe renal failure 
with eGFR <30 mL/min/1.73 m2, defibrillators, or allergy to gadolinium).  
Details for image acquisition and upload for central review can be found in the relevant study 
manual. 
6.2.6. 
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 and Table 2). 
235

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
54 
6.2.7. 
Polyneuropathy Disability (PND)   
Physician assessment of ambulation via PND score [Coutinho 1980; Yamamoto 2007] will be 
evaluated only at screening to assess eligibility for the study as specified in the Schedule of 
Assessments (Table 1).  PND scoring is described in Section 10.1. 
6.3. 
Pharmacodynamic Assessments 
In this study, serum samples for measurement of TTR levels will be collected for the assessment 
of PD effects.  TTR levels will be determined by a validated enzyme-linked immunoassay 
(ELISA).  Details regarding sample volumes to be collected, and the processing, shipping, and 
analysis of the samples will be provided in the Laboratory Manual.   
For this assessment, blood samples will be collected prior to dosing according to the timepoints 
specified in the Schedule of Assessments (Table 1 and Table 2).   
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of plasma concentrations of ALN-18328 (siRNA 
component of patisiran) and 2 lipid excipients (DLin-MC3-DMA and PEG2000-C-DMG) during 
the double-blind period at the timepoints specified in the Schedule of Assessments (Table 1).  
Plasma PK samples will be collected:  predose (within 1 hour of planned study drug dosing); at 
the end of the infusion (+5 minutes); and 30 minutes after the end of the infusion (+15 minutes) 
at the specified visits.   
For patients who discontinue treatment early during the double-blind period, a single PK sample 
will be taken at any time during the Early Treatment Discontinuation Visit, per the Schedule of 
Assessment (Table 2).   
Actual dates and times of sample collection will be recorded. 
Plasma concentrations of the 3 analytes will be determined using validated assay methods.  
Details regarding sample volumes to be collected, and the processing, shipping, and analysis of 
the samples will be provided in the Laboratory Manual. 
PK parameters will be analyzed, whenever possible, as outlined in Section 7.2.7.  
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight 
and height, 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. 
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1 and Table 2) 
and include blood pressure, heart rate, body temperature, and respiratory rate.  Vital signs will be 
236

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
55 
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.  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 medically 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 as specified in the Schedule of Assessments 
(Table 1 and Table 2) and will be recorded in the eCRF. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1 and Table 2); 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 
12-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, and QT 
interval will be obtained, as specified in the Schedule of Assessments (Table 1 and Table 2).  
Patients should be supine for at least 5 minutes before each ECG is obtained.  The 12-lead ECGs 
will be performed in triplicate at baseline, with readings approximately 1 minute apart.  At all 
other time points, a single 12-lead ECG will be performed. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn, when possible. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded in the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator.  Recordings will be archived in the patient’s files. 
237

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
56 
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  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, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality.  Additional safety laboratory tests and assessments as indicated by the 
clinical situation may be requested.  Clinical laboratory assessments are listed in Table 3 and will 
be assessed as specified in the Schedule of Assessments (Table 1 and Table 2).   
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 3, 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 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 3: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Carbon dioxide 
Creatinine and eGFR (using the MDRD formula) 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Coagulation (at Screening) 
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time   
 
Immunogenicity (see Section 6.5.5.1) 
Antidrug antibodies 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.2) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal women 
only) 
238

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
57 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone; 
MDRD=modification of diet in renal disease; PCR=polymerase chain reaction; RBCs=red blood cells; 
RNA=ribonucleic acid. 
6.5.5.1. 
Immunogenicity 
Serum samples will be collected to evaluate the presence of antidrug antibodies (ADA) as 
outlined in the Schedule of Assessments (Table 1).  Details regarding the blood volume, 
processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
A validated ELISA will be used that specifically detects antibodies to PEG2000-C-DMG, which is 
a component of patisiran-LNP.  Serum samples will first be analyzed with a screening assay.  
Samples testing positive for ADA in the screening assay will be further evaluated in a 
confirmatory assay.  For the samples that tested positive for ADA in the confirmatory assay, the 
ADA titer will then be determined as the reciprocal of the highest dilution of the sample that 
yielded a positive ADA test result. 
6.5.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential at the timepoints 
specified in the Schedule of Assessments (Table 1 and Table 2).   
A serum pregnancy test will be performed at Screening and urine pregnancy tests will be 
performed thereafter at the timepoints specified in the Schedule of Assessments (Table 1 and 
Table 2).  More frequent pregnancy testing may be performed where required per local 
requirements.  The results of the pregnancy test must be known before study drug administration.  
Patients who are pregnant at Screening are not eligible for study participation.  Any woman with 
a positive urine pregnancy test, subsequently confirmed by a positive serum pregnancy test, 
during the study will be discontinued from study drug but will continue to be followed for safety.  
Patients determined to be pregnant while on study will be followed at least until the pregnancy 
outcome is known (see Section 6.5.7.7 for follow-up instructions). 
Follicle-stimulating hormone testing will be performed in all women suspected to be post-
menopausal to confirm post-menopausal status. 
6.5.6. 
Vital Status Check 
A vital status check will be performed at the timepoints specified in the Schedule of Assessments 
(Table 1 and Table 2).      
Due to the inclusion of all-cause mortality in the secondary endpoint analysis, a medical records 
release form will be required of all patients for the purpose of obtaining vital status information 
from the patient’s physician or from death registries.  The signing of this medical records release 
form is in addition to the ICF.  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.  
239

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
58 
6.5.7. 
Adverse Events 
6.5.7.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an 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 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability 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 
No AEs of clinical interest are defined for this study.  
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). 
240

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
59 
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 AE. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  AEs characterized as intermittent require 
documentation of the start and stop of each incidence.  When changes in the severity of an AE 
occur more frequently than once a day, the maximum severity for the experience that day should 
be noted.  If the severity category changes over a number of days, then those changes should be 
recorded separately (with distinct onset dates). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?”  A “yes” response indicates that the event is considered as related to 
the study drug. 
6.5.7.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
study drug through the end of study.  Non-serious AEs will be followed until the end of study.  
Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1), while AEs that occur after study drug administration, and  
baseline events that worsen after study drug administration, must be recorded as AEs.    
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study drug 
through the end of study.  SAEs will be followed until satisfactory resolution, until baseline level 
241

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
60 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
All IRRs will be recorded as AEs.  All information on IRRs is to be recorded on the applicable 
eCRF per the CRF completion guidelines. 
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 
Not applicable.  There were no AEs of Clinical Interest identified for this study. 
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. 
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. 
242

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
61 
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 12 weeks 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 12 weeks 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, 
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.  In the event of an overdose, the actual dose administered must be recorded as specified 
in the Pharmacy Manual. 
All reports of overdose (with or without an AE) must be reported within 24 hours following the 
instructions outlined in the Pharmacy Manual for reporting an overdose. 
6.6. 
Biomarkers 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 ATTR amyloidosis with 
cardiomyopathy, as well as their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
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 
243

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
62 
study, or potentially advance understanding of the safety, mechanism of action, and/or efficacy 
of patisiran.   
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1 and Table 2).  Potential exploratory investigations may include 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. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principal features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
The planned enrollment for this study is 300 patients.  For the change from baseline at Month 12 
in the 6-MWT, assuming a treatment difference of 33 meters between patisiran and placebo in 
the treatment-naïve group and 20 meters in patients with baseline tafamidis, the weighted 
average treatment difference between patisiran and placebo in the overall population is 
approximately 29 meters (standard deviation = 75 meters) assuming 70% are in the treatment-
naïve group and 30% are in the baseline tafamidis group.  A sample size of 300 patients provides 
>90% power for a 2-sided test to detect a mean difference between treatment groups at a 2-sided 
alpha = 0.05.  Additional patients may be enrolled based on a recommendation to increase the 
sample size in the interim assessment (Section 7.2.10). 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses for 
the primary analysis, conducted at the completion of the 12-month, double-blind period.  More 
complete plans, including planned analyses for the open-label extension period, will be detailed 
in the SAP.  Changes to the methods described in the final SAP will be described and justified as 
needed in the clinical study report.  For information on study endpoints, see Section 2. 
244

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
63 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
• Full Analysis Set (FAS):  All randomized patients who received any amount of study 
drug, grouped according to the randomized treatment arm.   
• Safety Analysis Set:  All patients who received any amount of study drug, grouped 
according to the treatment actually received.  
• PK Analysis Set:  All patients who received any amount of study drug and have at 
least 1 postdose blood sample for PK parameters and have evaluable PK data. 
• PD Analysis Set:  All patients who received any amount of study drug and who have 
an evaluable baseline and at least 1 evaluable post-baseline serum TTR measurement 
will be included in the PD analyses. 
Efficacy endpoints will be analyzed using the Full Analysis Set.  Safety will be analyzed using 
the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct PK and PD 
analyses, respectively. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized by 
treatment arm and overall for the FAS and Safety Analysis Set. 
7.2.5. 
Efficacy Analyses 
The overall Type I error rate will be strongly controlled at a 2-sided 0.05 significance level for 
the primary and secondary endpoints using a fixed sequential testing procedure at the final 
analysis.  The primary endpoint will be compared between treatment arms at the 0.05 
significance level.  If the test of the primary endpoint is statistically significant, then the 
secondary endpoints will each be tested in the order specified in the Secondary Endpoints section 
(see Section 2).  If a test of the primary or a secondary endpoint is not statistically significant, the 
testing of the remaining endpoints in the sequence will stop. 
For patients who were tafamidis treatment-naïve at baseline and start tafamidis during the 
double-blind period, the primary analysis of the primary endpoint will censor data collected after 
the initiation of tafamidis treatment post-randomization.   
7.2.5.1. 
Primary Endpoint  
The primary endpoint, change from baseline at Month 12 in the 6-MWT, will be analyzed using 
a mixed-effects model repeated measures (MMRM) approach.  The outcome variable is change 
245

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
64 
from baseline in the 6-MWT.  The model will include the baseline value as a covariate, 
treatment, visit, the treatment-by-visit interaction, baseline tafamidis (yes vs no), genotype 
(hATTR vs wtATTR), and age (<75 vs ≥75 years) as fixed factors, and patient as a random 
effect.  The primary comparison is the contrast (difference in least squares [LS] means) between 
the patisiran and placebo groups at Month 12. 
Sensitivity analyses will be detailed in the SAP. 
7.2.5.2. 
Secondary Endpoints  
Secondary endpoints are described in Section 2.   
KCCQ-OS will be analyzed using a similar MMRM model as used for the primary endpoint. 
The composite endpoint of all-cause mortality, frequency of CV-related hospitalizations and 
change from baseline in 6-MWT will be analyzed using a generalized rank-based win ratio 
method, which makes pairwise comparisons (for all possible patisiran/placebo patient pairs) of 
the 3 components in the hierarchical order specified above.  The point estimate for the win ratio 
is defined as the total number of better outcomes divided by the total number of worse outcomes 
in the patisiran group.  The detailed algorithm for assessment of this endpoint will be provided in 
the SAP.     
The composite endpoint of all-cause mortality and all-cause hospitalizations will be analyzed 
using an Andersen-Gill model stratified by baseline tafamidis (yes vs no), including treatment, 
genotype (hATTR vs wtATTR), NYHA Class (I/II vs III), and age (<75 vs ≥75 years) as 
covariates. 
Patients who undergo a heart transplantation and/or ventricular assist device placement after 
randomization will be handled in the same manner as death in the primary analyses of mortality 
related endpoints. 
To control the overall Type I error rate, secondary endpoints will be tested in a prespecified 
hierarchical order. 
7.2.5.3. 
Exploratory Endpoints 
Descriptive summaries will be provided for the exploratory endpoints (Section 2), and additional 
analyses may be conducted.  Details will be described in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
The PD endpoint is serum TTR.  Summary tables will be provided for observed values, change 
and percentage change from baseline for each scheduled time point.  In addition, the maximum 
and mean percentage reduction over 12 months will be summarized.   
7.2.7. 
Pharmacokinetic Analysis 
7.2.7.1. 
Pharmacokinetic Analysis 
Plasma concentrations of ALN-18328, DLin-MC3-DMA, and PEG2000-C-DMG will be obtained 
using a model-independent method.  PK exposure parameters will include:  maximum plasma 
concentration at the end of infusion (Cmax), 30-minute post-infusion concentration (Cp(30min)), and 
246

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
65 
pre-infusion concentration (Cmin).  In addition, the steady-state Cmax (Cmax,ss), steady-state 
Cp(30min) (Cp,ss(30min)), and steady-state Cmin (Cmin,ss) will be calculated as the average of the 
respective values at Week 24, Week 36, and Month 12. 
The PK exposure parameters will be summarized by visit, and the steady-state PK parameters 
will be summarized. 
7.2.7.2. 
Exposure-Response Analysis  
Mean and maximum percent TTR reduction from baseline will be summarized by quartiles of the 
steady state PK parameters for all 3 analytes.  Change from baseline at Month 12 in clinical 
efficacy parameters may also be summarized by quartiles of the steady-state PK parameters for 
all 3 analytes.  
PK exposure will be summarized by mortality status.  In addition, the incidence of AEs and 
SAEs will be summarized by quartiles of the steady-state PK parameters for all 3 analytes. 
7.2.7.3. 
Population PK, PK/PD, and Disease Progression Modelling Analysis 
Population PK, PK/PD, and disease progression modelling analyses may be performed, if 
appropriate.  If performed, the analyses would be conducted according to a pre-specified analysis 
plan and reported separately. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical exams.  The extent of exposure will be summarized.   
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary.  Results will be tabulated by the Anatomical Therapeutic Chemical classification 
system and Preferred Term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term.  The frequency and percentage of patients 
experiencing AEs, SAEs, related AEs, and AEs leading to discontinuation will be summarized 
by System Organ Class (SOC) and PT.  By patient listings will be provided for deaths, SAEs, 
and AEs leading to discontinuation.   
Descriptive statistics will be provided for clinical laboratory data, ECG, and vital signs data, 
summarizing the observed values and change from baseline over time.  Laboratory shift tables 
from baseline at the worst post-baseline values will be presented.  Abnormal physical 
examination findings and 12-lead ECG data will be presented in by-patient listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 
7.2.9. 
Immunogenicity Analyses 
 The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized.  The titer results for patients with 
247

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
66 
confirmed positive ADA results will be summarized.  The impact of ADA on PK, PD, efficacy 
and safety endpoints will be explored.  Details will be described in the SAP. 
7.2.10. 
Sample Size Re-assessment 
Patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis 
drop-in”) during the double-blind period, which could result in a loss of statistical power.  An 
interim assessment may be performed to assess the impact of tafamidis drop-in on the power and 
the potential need to increase the sample size.  The interim assessment, if conducted, would 
examine the overall tafamidis drop-in rate in a blinded manner (ie, a non-comparative assessment 
of the drop-in rate); therefore, no impact on the type I error is expected and no multiplicity 
adjustment will be made.  A detailed sample size re-estimation plan will be outlined in a separate 
document prior to implementation. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the informed consent form 
(see Section 4.3.2). 
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 is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The patient’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. 
A medical records release form will be required of all patients for the purpose of obtaining vital 
status information from the patient’s physician or from death registries.  The signing of this 
medical records release form is in addition to the ICF. 
248

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
67 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study.  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 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 
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. 
249

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
68 
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.  CRFs 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. 
250

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
69 
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). 
251

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
70 
9. 
LIST OF REFERENCES 
Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, 
an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 
5;379(1):11-21. 
Adams D, Suhr OB, Hund E, Obici L, Tournev I, Campistol JM, et al. First European consensus 
for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr 
Opin Neurol. 2016 Feb;29 Suppl 1:S14-26. 
Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, et al. Targeted 
delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol 
Ther. 2010 Jul;18(7):1357-64. 
Ando Y, Coelho T, Berk J, Waddington Cruz M, Ericzon B, Ikeda S, et al. Guideline of 
transthyretin-related hereditary amyloidosis for clinicians. Orphanet J of Rare Dis. 2013;8(31). 
Benson M,Kincaid J. The molecular biology and clinical features of amyloid neuropathy. Muscle 
Nerve. 2007;36(4):411-23. 
Biesalski HK, Frank J, Beck SC, Heinrich F, Illek B, Reifen R, et al. Biochemical but not clinical 
vitamin A deficiency results from mutations in the gene for retinol binding protein. Am J Clin 
Nutr. 1999 May;69(5):931-6. 
Bittner V, Weiner DH, Yusuf S, Rogers WJ, McIntyre KM, Bangdiwala SI, et al. Prediction of 
mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. 
SOLVD Investigators. JAMA. 1993 Oct 13;270(14):1702-7. 
Bumcrot D, Manoharan M, Koteliansky V,Sah DW. RNAi therapeutics: a potential new class of 
pharmaceutical drugs. Nat Chem Biol. 2006 Dec;2(12):711-9. 
Castano A, Drachman BM, Judge D,Maurer MS. Natural history and therapy of TTR-cardiac 
amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and 
silencer drugs. Heart Fail Rev. 2015 Mar;20(2):163-78. 
Coelho T, Merlini G, Bulawa CE, Fleming JA, Judge DP, Kelly JW, et al. Mechanism of Action 
and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis. Neurol Ther. 
2016 Jun;5(1):1-25. 
Connors L, Yamashita T, Yazaki M, Skinner M,Benson M. A rare transthyretin mutation 
(Asp18Glu) associated with cardiomyopathy. Amyloid. 2004;11(1):61-6. 
Connors LH, Lim A, Prokaeva T, Roskens VA,Costello CE. Tabulation of human transthyretin 
(TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. 
Coutinho P, DeSilva A, Lima J,Barbosa A. Forty years of experience with type I amyloid 
neuropathy: review of 483 cases. In: Glenner G,Pinho P,Costa E,Falcao de Frietas A, editors. 
Amyloid and Amyloidosis: Excerpta Medica. Amsterdam1980. p. 88-98. 
Damy T, Jaccard A, Guellich A, Lavergne D, Galat A, Deux JF, et al. Identification of 
prognostic markers in transthyretin and AL cardiac amyloidosis. Amyloid. 2016 Sep;23(3):194-
202. 
252

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
71 
Damy T, Judge DP, Kristen AV, Berthet K, Li H,Aarts J. Cardiac findings and events observed 
in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile 
hereditary transthyretin amyloidosis. J Cardiovasc Transl Res. 2015 Mar;8(2):117-27. 
Dungu JN, Anderson LJ, Whelan CJ,Hawkins PN. Cardiac transthyretin amyloidosis. Heart. 
2012 Nov;98(21):1546-54. 
Episkopou V, Maeda S, Nishiguchi S, Shimada K, Gaitanaris GA, Gottesman ME, et al. 
Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and 
thyroid hormone. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2375-9. 
Flynn KE, Lin L, Ellis SJ, Russell SD, Spertus JA, Whellan DJ, et al. Outcomes, health policy, 
and managed care: relationships between patient-reported outcome measures and clinical 
measures in outpatients with heart failure. Am Heart J. 2009 Oct;158(4 Suppl):S64-71. 
Flynn KE, Lin L, Moe GW, Howlett JG, Fine LJ, Spertus JA, et al. Relationships between 
changes in patient-reported health status and functional capacity in outpatients with heart failure. 
Am Heart J. 2012 Jan;163(1):88-94 e3. 
Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A 
new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018 Aug 7;39(30):2799-
806. 
Green CP, Porter CB, Bresnahan DR,Spertus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll 
Cardiol. 2000 Apr;35(5):1245-55. 
Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D,Suhr OB. Evolving 
landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38. 
Hou X, Aguilar MI,Small DH. Transthyretin and familial amyloidotic polyneuropathy. Recent 
progress in understanding the molecular mechanism of neurodegeneration. FEBS J. 2007 
Apr;274(7):1637-50. 
Jacobson D, Tagoe C, Schwartzbard A, Shah A, Koziol J,Buxbaum J. Relation of clinical, 
echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of 
the transthyretin V122I allele in older African-American men. Am J Cardiol. 2011 Aug 
1;108(3):440-4. 
Kristen AV, Maurer MS, Rapezzi C, Mundayat R, Suhr OB,Damy T. Impact of genotype and 
phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the 
Transthyretin Amyloidosis Outcome Survey (THAOS). PLoS One. 2017;12(4):e0173086. 
Liz MA, Mar FM, Franquinho F,Sousa MM. Aboard transthyretin: From transport to cleavage. 
IUBMB Life. 2010 Jun;62(6):429-35. 
Mangla A, Kane J, Beaty E, Richardson D, Powell LH,Calvin JE, Jr. Comparison of predictors 
of heart failure-related hospitalization or death in patients with versus without preserved left 
ventricular ejection fraction. Am J Cardiol. 2013 Dec 15;112(12):1907-12. 
Masoudi FA, Rumsfeld JS, Havranek EP, House JA, Peterson ED, Krumholz HM, et al. Age, 
functional capacity, and health-related quality of life in patients with heart failure. J Card Fail. 
2004 Oct;10(5):368-73. 
253

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
72 
Maurer M, Judge D, Rosas G, Mandel F,Aarts J. Interim analysis of long-term, open-label 
tafamidis treatment in transthyretin amyloid cardiomyopathy after up to 5 years of treatment.  
XIVth International Symposium on Amyloidosis; Indianapolis, Indiana2014. 
Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. 
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 
2018 Sep 13;379(11):1007-16. 
Merlini G, Lousada I, Ando Y, Dispenzieri A, Gertz MA, Grogan M, et al. Rationale, application 
and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in 
patients with AL amyloidosis. Leukemia. 2016 Oct;30(10):1979-86. 
Mohty D, Damy T, Cosnay P, Echahidi N, Casset-Senon D, Virot P, et al. Cardiac amyloidosis: 
updates in diagnosis and management. Arch Cardiovasc Dis. 2013 Oct;106(10):528-40. 
Okamoto S, Wixner J, Obayashi K, Ando Y, Ericzon BG, Friman S, et al. Liver transplantation 
for familial amyloidotic polyneuropathy: impact on Swedish patients' survival. Liver Transpl. 
2009;15:1229-35. 
Parman Y, Adams D, Obici L, Galan L, Guergueltcheva V, Suhr OB, et al. Sixty years of 
transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A 
European network approach to defining the epidemiology and management patterns for TTR-
FAP. Curr Opin Neurol. 2016 Feb;29 Suppl 1:S3-S13. 
Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, et al. The 
amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015 Jan 
1;372(1):21-9. 
Ruberg FL,Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012 Sep 
04;126(10):1286-300. 
Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective 
evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid 
cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012 
Aug;164(2):222-8 e1. 
Solomon SAD, Kristen A et al. Effects of Patisiran, an RNA Interference Therapeutic, on 
Cardiac Parameters in Patients with Hereditary Transthyretin-Mediated Amyloidosis: An 
Analysis of the APOLLO Study. Circulation. 2018;10.1161/CIRCULATIONAHA.118.035831. 
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. 
Westermark P, Bergstrom J, Solomon A, Murphy C,Sletten K. Transthyretin-derived senile 
systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 2003 Aug;10 
Suppl 1:48-54. 
254

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
73 
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. 
 
255

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
74 
10. 
APPENDICES 
10.1. 
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 
10.2. 
New York Heart Association Class (NYHA) 
  
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs does not 
cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, in cold weather, in wind or when under 
emotional stress causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to two blocks on the 
level and climbing more than one flight of stairs in normal conditions causes undue fatigue 
or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or dyspnea. 
10.3. 
Categorization of Infusion-Related Reactions 
Signs and symptoms of an IRR usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Signs/symptoms may 
include: allergic reaction/hypersensitivity (including drug fever), arthralgia (joint pain), 
bronchospasm, cough, dizziness, dyspnea (shortness of breath), fatigue (asthenia, lethargy, 
malaise), headache, hypertension, hypotension, myalgia (muscle pain), nausea, pruritus/itching, 
256

Clinical Study Protocol ALN-TTR02-011  
patisiran 
Amendment 1, 20 December 2019 
Alnylam Pharmaceuticals 
Confidential 
75 
rash/desquamation, rigors/chills, sweating (diaphoresis), tachycardia, urticaria (hives, welts, 
wheals), vomiting. 
Categorization of IRRs is as follows: 
Categorization 
Description 
Mild 
Mild reaction:  infusion may be continued; if intervention is indicated it is 
minimal and additional treatment (other than paracetamol for delayed 
reactions) is not required. 
Moderate 
Moderate reaction:  requires treatment including more intensive therapy 
(eg, IV fluids, NSAIDs) in addition to infusion interruption but responds 
promptly to medication.  Treatment is indicated for ≤24 hours. 
Severe 
More than moderate reaction:  not rapidly responsive to medication or to 
interruption of infusion; and/ or prolonged (treatment is indicated for 
>24 hours); recurrence of severe symptoms following initial improvement. 
 
257

Clinical Study Protocol ALN-TTR02-011 
 patisiran 
Amendment 1 –Summary of Changes, 20 December 2019 
 
Alnylam Pharmaceuticals 
Confidential 
1 
ALN-TTR02-011 PROTOCOL AMENDMENT 1 
SUMMARY OF CHANGES DATED 20 DECEMBER 2019 
APOLLO-B:  A Phase 3, Randomized, Double blind, Placebo-controlled Multicenter Study 
to Evaluate the Efficacy and Safety of Patisiran in Patients with Transthyretin Amyloidosis 
with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)   
 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to address comments from Competent 
Authorities that requested changes to the protocol as part of their approval of the study. 
In addition, other protocol modifications or clarifications include: 
• Adding a study visit window for Week 3 (Day 22) that was erroneously left out and 
Adding a window for randomization to the Schedule of Assessments. 
• Adding ursodeoxycholic acid to the list of prohibited medications detailed in 
exclusion criterion 10, as it is commonly prescribed for the same reasons as 
tauroursodeoxycholic acid which is already prohibited, and was left out in error. 
• Clarifying instructions for the time limit for administration after study drug is 
prepared 
• Removing reference to steroid doses the night before IV infusion as these references 
were included in error. 
• Adding guidance to allowing for local TTR genotype testing if results are not 
available at Screening. 
• Increasing the possible number of patients to be included in the subset who will have  
technetium scintigraphy during the study as an optional exploratory imaging 
assessment. 
• Clarifying that follicle-stimulating hormone testing will be performed in all post-
menopausal women to confirm suspected post-menopausal status. 
• Broadening rescreening criteria to allow more flexibility.  
• Clarifying that DNA will not be collected as biological samples for potential 
exploratory investigations. 
• Removing baseline NYHA from the mixed-effects model repeated measures 
(MMRM) for the primary analysis to create a more parsimonious model. 
A detailed summary of changes is provided in Table 1.  Minor changes such as corrections to 
typographical errors, punctuation, grammar, abbreviations, and formatting (including 
administrative changes between the original protocol and this amendment) are not detailed. 
 
 
258

Clinical Study Protocol ALN-TTR02-011 
 patisiran 
Amendment 1 –Summary of Changes, 20 December 2019 
 
Alnylam Pharmaceuticals 
Confidential 
2 
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: Clarified study visit window for Week 3 (Day 22) is ±3 as this was left out in error; added a window for randomization 
based on questions from sites. 
The primary change occurs in Table 1: Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy 
Assessments). 
Study Day ±Visit Window column header above Week 3 now reads: D22±3 
The cell in the randomization row under the details column now reads: 3.5 Window: 5D prior to Day 1 
 
Purpose:  Added ursodeoxycholic acid to the list of prohibited medications as it is commonly prescribed for the same reasons as 
tauroursodeoxycholic acid which is already prohibited. 
The primary change occurs in Section 4.2, Exclusion Criterion 10 
Now reads: 
10. Is currently taking doxycycline, ursodeoxycholic acid, or tauroursodeoxycholic acid; if previously on any of these agents, must 
have completed a 30-day wash-out prior to dosing (Day 1). 
Section(s) also containing this change:   
• 
5.3. Concomitant Medications and Procedures 
 
Purpose:  Based on feedback from competent authorities, clarified that the prior TTR-lowering treatment mentioned in exclusion 
criterion 11 includes prior treatment with patisiran. 
The primary change occurs in Section 4.2, exclusion Criterion 11   
Now reads: 
11. Received prior TTR-lowering treatment (including patisiran) or participated in a gene therapy trial for hATTR amyloidosis.    
259

Clinical Study Protocol ALN-TTR02-011 
 patisiran 
Amendment 1 –Summary of Changes, 20 December 2019 
 
Alnylam Pharmaceuticals 
Confidential 
3 
 
Purpose:  Based on feedback from a competent authority, revised exclusion criterion 25 to broaden possible reasons that 
Investigators could exclude patients from the study. 
The primary change occurs in Section 4.2, exclusion Criterion 25   
Now reads: 
25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or 
data interpretation; or, in the opinion of the Investigator, taking part in the study would jeopardize the safety of the patient.      
 
Purpose:  Added exclusion Criterion 26 based on feedback from competent authorities. 
The primary change occurs in Section 4.2, exclusion Criterion 26   
Added text: 
26. Has a history of severe hypersensitivity (eg, anaphylaxis) to any of the excipients in patisiran.  Also see exclusion Criterion 11, which 
excludes all patients with prior TTR-lowering treatment including patisiran.   
 
Purpose:  Revised a category of reasons for discontinuation of study drug based on feedback from a competent authority. 
The primary change occurs in Section 4.3.1, Discontinuation of Study Drug or Declining Procedural Assessments  
The relevant bullet now reads: 
• 
Significant violation of the protocol; which includes required treatment with prohibited medication (as defined in Section 
5.3) per investigator discretion   
 
Purpose:  Clarified instructions for the time limit for administration after study drug is prepared; Removed reference to steroid doses 
the night before IV infusion as these references were included in error. 
5.2.4. Suggested Guidelines for Management of Infusion-related Reactions 
Relevant bullets now read: 
260

Clinical Study Protocol ALN-TTR02-011 
 patisiran 
Amendment 1 –Summary of Changes, 20 December 2019 
 
Alnylam Pharmaceuticals 
Confidential 
4 
• Following resolution of a mild or moderate IRR that required interruption of the study drug infusion, resumption of administration 
may occur at the Investigator’s discretion at a slower infusion rate for that dose and for subsequent doses of study drug.  If the 
infusion is delayed, the administration of the infusion should be completed no more than 16 hours from the initial start of the 
infusion.  after study drug is first diluted in saline (including infusion time). 
• If after consultation with the Medical Monitor it is agreed that an individual patient’s steroid premedication will be increased, then 
the following steps are recommended: 
1. If the IRR occurred while the patient received 10 mg IV dexamethasone or equivalent at least 60 minutes before the infusion 
and did not resolve with slowing of the infusion rate, then the patient should be increased by multiples of 5 mg IV 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral dexamethasone or equivalent the night 
before the IV infusion.  
2. Increased dose of premedication steroids should NOT exceed the combination of 20 mg IV dexamethasone or equivalent on 
the day of infusion and 8 mg oral dexamethasone or equivalent taken the night before the infusion. 
 
Purpose:  Clarification regarding use of vitamin A added based on feedback from a competent authority. 
The primary change occurs in Section 5.3, Concomitant Medications and Procedures 
Now reads: All patients will be asked to take the recommended daily allowance of vitamin A for the duration of their participation in 
the study while being administered study drug.  In countries where relevant, the clinical sites will provide patients with a prescription 
for vitamin A at a dose consistent with local guidelines. 
 
Purpose:  Clarification regarding obtaining of patient medical history/disease history added based on feedback from a competent 
authority.  
The primary change occurs in Section 6.1, Screening Assessments  
Now reads: Patient demographic data and medical history/disease history will be obtained, including completion of ophthalmologic 
history in the eCRF.  Any changes to medical history occurring between the screening assessment and Day 1 will be updated prior to 
study drug administration. 
 
Purpose: Guidance added to allow local genotype testing.  
261

Clinical Study Protocol ALN-TTR02-011 
 patisiran 
Amendment 1 –Summary of Changes, 20 December 2019 
 
Alnylam Pharmaceuticals 
Confidential 
5 
The primary change occurs in Section 6.1, Screening Assessments  
Added text: If a genetic test result that shows the presence or absence of a TTR pathogenic mutation, which would be 
consistent with either wtATTR or hATTR, is not available at Screening for the assessment of eligibility (Section 4.1, inclusion 
criterion 2a), genotyping may be conducted at a laboratory selected by the site in consultation with the Medical Monitor. 
 
Purpose:  Rescreening criteria for eligibility requirements have been broadened to allow more flexibility. 
The primary change occurs in Section 6.1.2, Rescreening 
Now reads: A  patient who does not meet all study eligibility criteria due to a transient clinical condition observed at screening, or 
who fails to complete screening activities due to unforeseen or unavoidable circumstances, may be rescreened once after 
consultation with the Medical Monitor after a minimum of 5 days have elapsed from a patient’s last screening assessment.  (eg, 
prohibited medications that were subsequently discontinued), in conjunction with the decision of the Medical Monitor(s), may be 
allowed to rescreen after a minimum of 5 days have elapsed from their last screening assessment.  A patient will be re-consented if 
rescreening occurs outside of the 45-day screening window.  In this case, all screening procedures must be repeated.   
 
Purpose:  Increased the possible number of patients to be included in the subset who will have technetium scintigraphy during the 
study as an optional exploratory imaging assessment. 
The primary change occurs in 6.2.5.5. Technetium Scintigraphy Imaging  
Now reads: At select sites, in a subset of the approximately 100 patients (≤60 patients), technetium scintigraphy will be collected 
according to the Schedule of Assessments (Table 1 and Table 2), as an optional exploratory imaging assessment, to assess cardiac 
amyloid involvement.   
 
 
Purpose:  Clarified that follicle-stimulating hormone testing will be performed in all post-menopausal women. This was changed to 
match guidance in other parts of the protocol in which this was clear. 
The primary change occurs in Section 6.5.5.2, Pregnancy Testing 
262

Clinical Study Protocol ALN-TTR02-011 
 patisiran 
Amendment 1 –Summary of Changes, 20 December 2019 
 
Alnylam Pharmaceuticals 
Confidential 
6 
Now reads: Follicle-stimulating hormone testing may will be performed in all women suspected to be post-menopausal to confirm 
suspected post-menopausal status. 
 
Purpose:  Based on feedback from a competent authority, removed text so Investigators will be able to decide whether a dose can be 
considered an overdose without consulting the Sponsor. In addition added language referencing the Pharmacy Manual for dose 
recording and reporting requirements. 
The primary change occurs in Section 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 as 
specified in the Pharmacy Manual. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor or designee following the 
instructions outlined in the Pharmacy Manual for reporting an overdose. 
 
Purpose:  Clarified that DNA will not be collected as biological samples for potential exploratory investigations. 
The primary change occurs in Section 6.6, Biomarkers and Biospecimen Repository. 
Now reads: Biological specimens will be collected at the intervals indicated in the Schedule of Assessments (Table 1 and Table 2).  
Potential exploratory investigations may include   DNA, RNA, or biochemical metabolite assessments as they relate to disease 
progression, efficacy or safety.   
 
Purpose:  For the primary analysis of 6-MWT, the MMRM model previously specified in the protocol included baseline NYHA class 
as a factor.  Baseline NYHA class is associated with disease severity, however, it correlates with baseline 6-MWT which is included as 
a continuous covariate in the model. In the protocol amendment, baseline NYHA class has been removed from the MMRM in order to 
create a more parsimonious model. 
The primary change occurs in 7.2.5.1, Primary Endpoint 
263

Clinical Study Protocol ALN-TTR02-011 
 patisiran 
Amendment 1 –Summary of Changes, 20 December 2019 
 
Alnylam Pharmaceuticals 
Confidential 
7 
The model description now reads: The model will include the baseline value as a covariate, treatment, visit, the treatment-by-visit 
interaction, baseline tafamidis (yes vs no), genotype (hATTR vs wtATTR), NYHA Class (I/II vs III), and age (<75 vs ≥75 years) as 
fixed factors, and patient as a random effect. 
Section(s) also containing this change:   
• 
Synopsis 
 
Purpose:  Added details added based on a comment from a competent authority on how data from patients who undergo a heart 
transplantation and/or ventricular assist device placement will be treated with respect to the mortality analysis. 
The primary change occurs in 7.2.5.2, Secondary Endpoints 
Added text: Patients who undergo a heart transplantation and/or ventricular assist device placement after randomization will 
be handled in the same manner as death in the primary analyses of mortality related endpoints. 
 
Purpose:  Modified the interim sample size re-assessment so it is based on the overall tafamidis drop-in rate from blinded data based 
on a comment from a competent authority.  
The primary change occurs in Section 7.2.10 Sample Size Re-assessment 
Now reads: 
Patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis drop-in”) during the double-blind 
period, which could result in a loss of statistical power.  An interim assessment may be performed to assess the impact of tafamidis 
drop-in on the power and the potential need to increase the sample size.  The interim assessment, if conducted, would examine the 
overall tafamidis drop-in rates in each treatment arm in an unblinded blinded manner (ie, a non-comparative assessment of the 
drop-in rate) without looking at the unblinded efficacy or safety data; therefore, no impact on the type I error is expected and no 
multiplicity adjustment will be made.  To maintain the blind for the study team, the interim assessment would be performed by a third 
party (ie, not the Sponsor) according to a prespecified plan. A detailed sample size re-estimation plan will be outlined in a separate 
document prior to implementation. 
 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting  
264

Clinical Study Protocol ALN-TTR02-011 
 patisiran 
Amendment 1 –Summary of Changes, 20 December 2019 
 
Alnylam Pharmaceuticals 
Confidential 
8 
These changes are not listed individually. 
 
265

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
1 
 
CLINICAL STUDY PROTOCOL 
ALN-TTR02-011 
DATED 18 APRIL 2019 
 
Protocol Title: 
APOLLO-B:  A Phase 3, Randomized, 
Double-blind, Placebo-controlled Multicenter 
Study to Evaluate the Efficacy and Safety of 
Patisiran in Patients with Transthyretin 
Amyloidosis with Cardiomyopathy (ATTR 
Amyloidosis with Cardiomyopathy)   
Short Title: 
APOLLO-B:  A Study to Evaluate Patisiran in 
Patients with Transthyretin Amyloidosis with 
Cardiomyopathy (ATTR Amyloidosis with 
Cardiomyopathy) 
Study Drug: 
Patisiran (ALN-TTR02)  
EudraCT Number: 
2019-001458-24 
IND Number: 
141240 
Protocol Date: 
Original protocol, 18 April 2019  
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. 
 
266

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-011 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 
268

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
6 
population is anticipated to have hATTR and 80% wtATTR.  In addition, at baseline, patients are 
either: 
 Tafamidis naïve; or 
 Currently on tafamidis (for ≥6 months), with disease progression in the opinion of the 
investigator.  This group will be capped at 30% of total enrollment in the study.   
The study consists of a screening period of up to 45 days, a 12-month, double-blind, placebo-
controlled period, a 12-month, open-label extension period (during which all patients will receive 
patisiran), and a 28-day follow-up period. 
After screening, during the 12-month double-blind period, eligible patients will be randomized to 
receive intravenous (IV) treatment every 3 weeks with either patisiran or placebo.  Prior to 
receiving randomized, double-blind study drug (patisiran or placebo), to reduce the potential for 
an IRR with patisiran, all patients will receive premedications at least 60 minutes before the start 
of their infusion.  Study drug will be administered in the clinic as an approximately 80-minute IV 
infusion.  
During the 12-month open-label extension period, all patients will receive treatment with 
open-label patisiran.  Furthermore, patients who have received ≥3 consecutive doses of patisiran 
on this study at the clinical site with no evidence of IRRs or other drug-related adverse effects 
impacting safety and tolerability of the infusion may have patisiran administered at home during 
the open-label extension period, where applicable country and local regulations allow.  Home 
administration of patisiran will be performed by a healthcare professional trained on the protocol 
and on administration of premedications and patisiran infusion. 
To evaluate the efficacy of treatment with patisiran versus placebo in patients with ATTR 
amyloidosis with cardiomyopathy, the change from baseline in 6-MWT will be assessed at 
Month 12 (Weeks 52-53) as the primary endpoint; this assessment will also be performed at 
Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) in the double-blind period, and during the 
open-label extension period.  The first secondary endpoint will assess change from baseline at 
Month 12 in the KCCQ-OS score.    
Safety will be assessed throughout the double-blind and open-label extension periods of the 
study. 
Number of Planned Patients 
Approximately 300 patients are planned for enrollment in this study.   
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, inclusive, with ATTR amyloidosis with cardiomyopathy (hereditary or wild-type [wt]) who, 
at baseline, are either:  1) tafamidis naïve (on tafamidis for ≤30 days and none within 6 months 
prior to baseline); or 2) currently on tafamidis (for ≥6 months) with disease progression in the 
opinion of the investigator. 
Study Drug, Dose, and Mode of Administration 
Patisiran is a ribonucleic acid (RNA) interference (RNAi) therapeutic consisting of a double-
stranded small interfering RNA (siRNA) targeting TTR mRNA formulated in a lipid 
271

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
7 
nanoparticle (LNP).  The patisiran drug product is a sterile formulation of ALN-18328 (siRNA 
targeting TTR) formulated as LNPs with lipid excipients (1,2-Dilinoleyloxy-N,N-
dimethylpropylamine [DLin-MC3-DMA], 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.   
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs. 
An IV infusion of double-blind study drug (patisiran 0.3 mg/kg or placebo) will be administered 
under the supervision of the site personnel once every 3 weeks ±3 days.  Dosing is based on 
actual body weight.  For patients weighing ≥100 kg, the maximum recommended patisiran dose 
is 30 mg.  
The last dose of double-blind study drug will be at Week 51 and the first dose of open-label 
patisiran will be 3 weeks later (at Week 54) and thereafter every 3 weeks (±3 days) for the 
remainder of the study.  Open-label patisiran will be administered per the schedule and dose as is 
described above for double-blind patisiran. 
Reference Treatment, Dose, and Mode of Administration 
The control drug for this study will be a placebo (normal saline 0.9% for IV administration).  
Control drug will be provided by a central supplier (or, if necessary, by a local supplier, with 
prior Sponsor approval).    
Duration of Treatment and Study Participation 
The treatment duration in this study is up to 24 months, inclusive of a 12-month, double-blind, 
treatment period, and a 12-month, open-label, treatment period.  The estimated total time on 
study for each patient is up to 26.5 months, including up to 45 days of screening, up to 
24 months of treatment, and a 28-day safety follow-up period. 
Statistical Methods 
The planned enrollment for this study is 300 patients.  Randomization (1:1) will be stratified by:  
1) baseline tafamidis (yes vs no); 2) genotype (hATTR vs wtATTR); and 3) NYHA Class I or II 
and age < 75 years vs all other. 
For the change from baseline at Month 12 in the 6-MWT, assuming a treatment difference of 
33 meters between patisiran and placebo in the treatment-naïve group and 20 meters in patients 
with baseline tafamidis, the weighted average treatment difference between patisiran and placebo 
in the overall population is approximately 29 meters (standard deviation = 75 meters) assuming 
70% are in the treatment-naïve group and 30% are in the baseline tafamidis group.  A sample 
size of 300 patients provides >90% power for a 2-sided test to detect a treatment difference at a 
2-sided alpha = 0.05.  Additional patients may be enrolled based on a recommendation to 
increase the sample size in the interim assessment. 
The primary endpoint, change from baseline at Month 12 in the 6-MWT, will be analyzed using 
a mixed-effects model repeated measures (MMRM) approach.  The outcome variable is change 
from baseline in the 6-MWT.  The model will include the baseline value as a covariate, 
treatment, visit, the treatment-by-visit interaction, baseline tafamidis (yes vs no), genotype 
(hATTR vs wtATTR), NYHA Class (I/II vs III), and age (<75 vs ≥75 years) as fixed factors, and 
272

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
8 
patient as a random effect.  The primary comparison is the contrast (difference in least squares 
[LS] means) between the patisiran and placebo groups at Month 12. 
To control the overall Type I error rate, secondary endpoints will be tested in a prespecified 
hierarchical order. 
For patients who are tafamidis treatment-naïve at baseline and start tafamidis during the double-
blind period, the primary analysis of the primary endpoint will censor data collected after the 
initiation of tafamidis treatment post-randomization.  
Safety data will be summarized descriptively. 
 
273

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
9 
Figure 1: 
Study Design 
  
 
 
274

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
10 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NAb 
Informed Consent 
6.1  
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion Criteria 
4.1, 
4.2  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / 
Medical History 
6.1  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PND Score 
6.2.7  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
6.5.2  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
X 
X 
 
 
 
 
 
 
 
 
 
X
d 
 
 
 
 
X
d 
 
 
 
 
 
X 
d 
X 
d 
X
d 
KCCQ 
6.2.2 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
mBMI 
6.2.4 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Cardiac Biomarker 
Samples 
6.2.5.1 
NT-
proBNP 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
ATTR amyloidosis 
disease stage 
6.2.5.2  
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
NYHA Class 
6.2.5.3 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Echocardiogram 
6.2.5.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CMR, technetium 
(select sites only) 
6.2.5.6,  
6.2.5.5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Norfolk QoL-DN 
6.2.6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
275

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
11 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NAb 
Pharmacodynamic Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
X 
X 
  
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Exploratory 
Biomarkers 
(plasma, serum) 
6.6 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
6.5.2 
X  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
(symptom-directed 
unless noted as full) 
6.5.3 
X  
Full 
X 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Full 
 
X 
Full 
X 
Single 12-lead ECG 
(unless otherwise 
indicated) 
6.5.4 
 
X (in 
triplicate, 
either visit) 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Serum Chemistry, 
Liver Function 
Tests 
6.5.5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Xe 
Xe 
X 
Hematology 
6.5.5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Coagulation 
6.5.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin A Levels 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA (on dosing 
days, prior to 
dosing) 
6.5.5.1 
 
 
X 
 
X 
  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
276

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
12 
Table 1: 
Schedule of Assessments – Double-blind Period (Screening to Month 12 Efficacy Assessments)  
 
 
Screen-
ing 
Baseline 
Double-blind Treatment Period 
Month 12 
Efficacy Visit   
Modified M12 Efficacy Visit (for  
patients w/ early treatment disc)b 
Pre-tafamidis Drop-in Visitc 
 
 
V1 
V2 
Pre-
dose 
Post-
dose 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
 Day -45 to 
Day -1 
Day 1 
D22 
D43±3 
D64±3 
D85±3 
D106±3 
D127±3 
D148±3 
D169±3 
D176-D183a 
D190±3 
D211±3 
D232±3 
D253±3 
D260-D267a 
D274±3 
D295±3 
D316±3 
D337±3 
D358±3 
D365-D372a 
Study Week 
 
 
 
Week 1 
3 
6 
9 
12 
15 
18 
21 
24 
25-26 
27 
30 
33 
36 
37-38 
39 
42 
45 
48 
51 
52-53 
52-53 
NAb 
FSH (to confirm 
postmenopausal, if 
applicable) 
Table 3, 
6.5.5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
Table 3, 
6.5.5.2 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
  
  
Review/Record 
Hospitalization, 
Urgent Care Visits, 
and Procedures 
 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
 
Review/Record 
AEs, Con Meds 
6.5.7, 
5.3 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
6.4 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Drug Administration 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
3.5 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication/ 
Study Drug 
5.2.1, 
5.2.3 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; CMR=cardiac magnetic resonance; D=day; Disc=discontinuation; 
ECG=electrocardiogram; FSH=follicle-stimulating hormone; KCCQ=Kansas City Cardiomyopathy Questionnaire; M=month; mBMI=modified body mass index; 
6-MWT=6-minute walk test; NA=not applicable; NT-proBNP=N-terminal prohormone B-type natriuretic peptide; NYHA=New York Heart Association; PK=pharmacokinetics; 
PND=Polyneuropathy Disability; QoL-DN=Quality of Life-Diabetic Neuropathy; TTR=transthyretin; V=visits. 
a  This efficacy visit is conducted 7 to 14 days after the prior visit.   
277

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
13 
b  This Modified Month 12 Efficacy Visit is to be performed at Month 12 for patients who discontinued treatment early (ie, prior to Month 12), and choose to remain in the study.  
All patients who discontinue from study drug during the double-blind period will be encouraged to remain on the study and complete assessments through Month 12 (excluding 
PK assessments), including this Modified Month 12 Efficacy Visit.  Such patients will also receive assessments at the Early Treatment Discontinuation Visit (7 to 14 days after 
their last dose of study drug); and the safety follow-up visit (28 days after the last dose of study drug) (Table 2), as described in Section 4.3.1.    
c See Section 5.3.1; patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis drop-in”) during the double-blind period.  In all cases, the 
Pre-tafamidis Drop-in Visit should occur prior to starting concomitant tafamidis; where possible, this visit should occur between 1-2 weeks after the last dose of double-blind 
study drug (ie, 7 to 14 days post dose).  Thereafter, the patient will continue with all assessments per the Schedule of Assessments, including the Month 12 Efficacy Visit.  At the 
time of tafamidis drop-in, the reason for starting tafamidis will be recorded in the CRF.    
d As described in Section 6.2.1, to avoid a potential training effect resulting from repeated assessments of the 6-MWT within a short period of time, only one 6-MWT assessment 
should be performed within each of the following time periods:  Day 2 to Day 214 (includes the scheduled Weeks 25-26 assessment); Day 215 to Day 319 (includes the 
scheduled Weeks 37-38 assessment); and Day 320 to Day 372 (includes the scheduled Weeks 52-53 assessment).  Within a given time period, the 6-MWT assessment should be 
performed at whichever visit occurs first (scheduled assessment, Pre-tafamidis Drop-in Visit, or Early Treatment Discontinuation Visit [Table 2]); no additional 6-MWT 
assessments should be made in that time period.  In later time periods, the 6-MWT should be assessed as scheduled. 
e Serum creatinine only. 
  
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 24), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
7- 14 Days 
after Last 
Dose 
D764±10 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
NA 
109 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-MWT 
6.2.1 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
KCCQ 
6.2.2 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
mBMI 
6.2.4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Cardiac Biomarker 
Samples 
6.2.5.1 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
ATTR amyloidosis 
disease stage 
6.2.5.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
278

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
14 
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 24), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
7- 14 Days 
after Last 
Dose 
D764±10 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
NA 
109 
NYHA Class 
6.2.5.3 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Echocardiogram 
6.2.5.4 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CMR, technetium (select 
sites only) 
6.2.5.6, 
6.2.5.5 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Norfolk QoL-DN 
6.2.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacodynamic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTR Protein 
6.3 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Exploratory Biomarkers 
(plasma, serum) 
6.6  
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (symptom-
directed) 
6.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Single 12-lead ECG 
6.5.4  
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Serum Chemistry, Liver 
Function Tests 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X
c 
X 
X 
Hematology 
6.5.5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Pregnancy Test 
Table 3, 
6.5.5.2 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
Review/Record 
Hospitalization, Urgent 
Care Visits, and 
Procedures 
 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
279

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
15 
Table 2: 
Schedule of Assessments – Open-label Extension Period (Through Month 24), Early Treatment 
Discontinuation Visit, and Follow-up 
 
  
Open-label Extension Period  
Early 
Treatment 
Disc Visitb 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Study Day  
±Visit Window 
For 
Details 
see 
Section 
D379±3 
D400±3 
D421±3 
D442+3 
D463±3 
D484±3 
D505±3 
D526±3 
D547±3 
D554-D561a 
D568±3 
D589±3 
D610±3 
D631±3 
D638-D645a 
D652±3 
D673±3 
D694±3 
D715±3 
D736±3 
D743-D750a 
7- 14 Days 
after Last 
Dose 
D764±10 
Study Week 
 
54 
57 
60 
63 
66 
69 
72 
75 
78 
79-80 
81 
84 
87 
90 
91-92 
93 
96 
99 
102 
105 
106-107 
NA 
109 
Review/Record AEs,  
Con Meds 
6.5.7, 
5.3 
---------------------------------------------------------------------------X--------------------------------------------------------------------------- 
Vital Status Check 
6.5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
 6.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication, Study 
Drug 
5.2.1, 
5.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Abbreviations:  AE=adverse event; ADA=antidrug antibodies; Con Meds=concomitant medications; CMR=cardiac magnetic resonance; D=day; Disc=discontinuation; 
ECG=electrocardiogram; EOS=End of Study (visit); KCCQ=Kansas City Cardiomyopathy Questionnaire; mBMI=modified body mass index; 6-MWT=6-minute walk test; 
NA=not applicable; NT-proBNP=N-terminal prohormone B-type natriuretic peptide; NYHA=New York Heart Association; PK=pharmacokinetics; QoL-DN=Quality of Life-
Diabetic Neuropathy; TTR=transthyretin; V=visits.  
a  This efficacy visit is conducted 7 to 14 days after the prior visit.   
b Patients who discontinue early from study drug will be asked to complete the Early Treatment Discontinuation Visit (7-14 days after their last dose) and the safety follow-up 
visit, 28 days after the last dose of study drug.  In addition, patients discontinuing early from study drug during the double-blind period will be encouraged to remain on the 
study and complete assessments through Month 12 and complete the Modified Month 12 Efficacy Visit (see Table 1); they will also be asked to complete an Early Treatment 
Discontinuation Visit (7-14 days after their last dose) and the safety follow-up visit, 28 days after the last dose of study drug as described in Section 4.3.1.    
c Serum creatinine only. 
280

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
16 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................21 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Disease Overview .......................................................................................................24 
1.2. 
Current Treatments .....................................................................................................25 
1.3. 
Patisiran Clinical Development ..................................................................................26 
1.3.1. 
The Phase 3 APOLLO Study ......................................................................................27 
1.3.1.1. 
Cardiac Results and Cardiac Subpopulation Data from APOLLO ............................27 
1.3.2. 
Phase 3, Open-label Extension Study .........................................................................28 
1.4. 
Study Design Rationale ..............................................................................................28 
1.5. 
Dose Rationale ............................................................................................................29 
1.6. 
Benefit-risk Assessment .............................................................................................29 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................31 
3. 
INVESTIGATIONAL PLAN .....................................................................................32 
3.1. 
Summary of Study Design ..........................................................................................32 
3.2. 
Duration of Treatment ................................................................................................33 
3.3. 
Duration of Study Participation ..................................................................................33 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................33 
3.4. 
Number of Planned Patients .......................................................................................33 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................34 
3.6. 
Blinding ......................................................................................................................34 
3.6.1. 
Emergency Unblinding ...............................................................................................34 
3.7. 
Data Monitoring Committee .......................................................................................35 
3.8. 
Adjudication Committee .............................................................................................35 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................35 
4.1. 
Inclusion Criteria ........................................................................................................35 
4.2. 
Exclusion Criteria .......................................................................................................36 
4.3. 
Removal from Study Drug or Assessment .................................................................38 
281

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
17 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................39 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................40 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................40 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................40 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................40 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................41 
4.3.3. 
Lost to Follow-up .......................................................................................................41 
4.3.4. 
Replacement of Study Patients ...................................................................................41 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................41 
5.1. 
Treatments Administered ............................................................................................41 
5.2. 
Study Drug ..................................................................................................................41 
5.2.1. 
Premedication .............................................................................................................42 
5.2.2. 
Study Drug Description ..............................................................................................42 
5.2.3. 
Dose and Administration ............................................................................................43 
5.2.3.1. 
Double-bind Study Drug (Patisiran or Placebo) .........................................................43 
5.2.3.2. 
Open-label Extension Period (Patisiran) ....................................................................43 
5.2.4. 
Suggested Guidelines for Management of Infusion-related Reactions ......................44 
5.2.5. 
Dose Modifications .....................................................................................................45 
5.2.6. 
Preparation, Handling, and Storage ............................................................................45 
5.2.7. 
Packaging and Labeling ..............................................................................................45 
5.2.8. 
Accountability .............................................................................................................45 
5.3. 
Concomitant Medications and Procedures .................................................................45 
5.3.1. 
Concomitant Tafamidis Use .......................................................................................46 
5.4. 
Treatment Compliance ................................................................................................47 
5.5. 
Other Requirements ....................................................................................................47 
5.5.1. 
Contraception ..............................................................................................................47 
6. 
STUDY ASSESSMENTS ..........................................................................................48 
6.1. 
Screening Assessments ...............................................................................................48 
6.1.1. 
Retesting .....................................................................................................................48 
6.1.2. 
Rescreening .................................................................................................................48 
6.2. 
Efficacy Assessments .................................................................................................49 
6.2.1. 
6-Minute Walk Test (6-MWT) ...................................................................................49 
6.2.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ...............................................50 
282

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
18 
6.2.3. 
Deaths and Hospitalizations .......................................................................................50 
6.2.4. 
Modified Body Mass Index (mBMI) ..........................................................................50 
6.2.5. 
Cardiac Assessments ..................................................................................................50 
6.2.5.1. 
Cardiac Biomarkers ....................................................................................................50 
6.2.5.2. 
ATTR Amyloidosis Disease Stage .............................................................................51 
6.2.5.3. 
New York Heart Association (NYHA) Class .............................................................51 
6.2.5.4. 
Echocardiogram ..........................................................................................................51 
6.2.5.5. 
Technetium Scintigraphy Imaging .............................................................................51 
6.2.5.6. 
Cardiac Magnetic Resonance (CMR) .........................................................................52 
6.2.6. 
Norfolk Quality of Life  Diabetic Neuropathy (Norfolk QoL-DN) .........................52 
6.2.7. 
Polyneuropathy Disability (PND)...............................................................................52 
6.3. 
Pharmacodynamic Assessments .................................................................................52 
6.4. 
Pharmacokinetic Assessments ....................................................................................52 
6.5. 
Safety Assessments .....................................................................................................53 
6.5.1. 
Vital Signs ..................................................................................................................53 
6.5.2. 
Weight and Height ......................................................................................................53 
6.5.3. 
Physical Examination .................................................................................................53 
6.5.4. 
Electrocardiogram .......................................................................................................54 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................54 
6.5.5.1. 
Immunogenicity ..........................................................................................................55 
6.5.5.2. 
Pregnancy Testing ......................................................................................................56 
6.5.6. 
Vital Status Check ......................................................................................................56 
6.5.7. 
Adverse Events ...........................................................................................................56 
6.5.7.1. 
Definitions ..................................................................................................................56 
6.5.7.2. 
Eliciting and Recording Adverse Events ....................................................................58 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................58 
6.5.7.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........58 
6.5.7.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................59 
6.5.7.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................59 
6.5.7.7. 
Pregnancy Reporting ..................................................................................................59 
6.5.7.8. 
Overdose Reporting ....................................................................................................60 
6.6. 
Biomarkers and Biospecimen Repository ..................................................................60 
283

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
19 
7. 
STATISTICS ..............................................................................................................61 
7.1. 
Determination of Sample Size ....................................................................................61 
7.2. 
Statistical Methodology ..............................................................................................61 
7.2.1. 
Populations to be Analyzed ........................................................................................61 
7.2.2. 
Examination of Subgroups .........................................................................................61 
7.2.3. 
Handling of Missing Data ...........................................................................................62 
7.2.4. 
Baseline Evaluations ...................................................................................................62 
7.2.5. 
Efficacy Analyses .......................................................................................................62 
7.2.5.1. 
Primary Endpoint ........................................................................................................62 
7.2.5.2. 
Secondary Endpoints ..................................................................................................62 
7.2.5.3. 
Exploratory Endpoints ................................................................................................63 
7.2.6. 
Pharmacodynamic Analysis........................................................................................63 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................63 
7.2.7.1. 
Pharmacokinetic Analysis ..........................................................................................63 
7.2.7.2. 
Exposure-Response Analysis......................................................................................63 
7.2.7.3. 
Population PK, PK/PD, and Disease Progression Modelling Analysis ......................63 
7.2.8. 
Safety Analyses ..........................................................................................................63 
7.2.9. 
Immunogenicity Analyses ..........................................................................................64 
7.2.10. 
Sample Size Re-assessment ........................................................................................64 
7.2.11. 
Optional Additional Research .....................................................................................64 
8. 
STUDY ADMINISTRATION ...................................................................................64 
8.1. 
Ethical and Regulatory Considerations ......................................................................64 
8.1.1. 
Informed Consent and Medical Records Release Form .............................................65 
8.1.2. 
Ethical Review ............................................................................................................65 
8.1.3. 
Serious Breach of Protocol .........................................................................................66 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................66 
8.1.5. 
End of Study ...............................................................................................................66 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................66 
8.2. 
Data Quality Control and Quality Assurance .............................................................67 
8.2.1. 
Data Handling .............................................................................................................67 
8.2.2. 
Study Monitoring ........................................................................................................67 
8.2.3. 
Audits and Inspections ................................................................................................67 
8.3. 
Publication Policy .......................................................................................................67 
284

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
20 
9. 
LIST OF REFERENCES ............................................................................................69 
10. 
APPENDICES ............................................................................................................73 
10.1. 
Polyneuropathy Disability (PND) Scores ...................................................................73 
10.2. 
New York Heart Association Class (NYHA) .............................................................73 
10.3. 
Categorization of Infusion-Related Reactions ............................................................73 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments  Double-blind Period (Screening to Month 12 
Efficacy Assessments) ................................................................................................10 
Table 2: 
Schedule of Assessments  Open-label Extension Period (Through Month 
24), Early Treatment Discontinuation Visit, and Follow-up ......................................13 
Table 3: 
Clinical Laboratory Assessments ...............................................................................55 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 
285

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALN-18328 
siRNA targeting TTR 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APOLLO 
Patisiran pivotal Phase 3 clinical study ALN-TTR02-004 
AST 
Aspartate aminotransferase 
ATTR 
Amyloid transthyretin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CHF 
Congestive heart failure 
Cmax 
Maximum plasma concentration at end of infusion 
Cmax,ss 
Steady-state Cmax   
Cmin 
Minimum pre-infusion concentration 
Cmin,ss 
Steady-state Cmin   
CMR 
Cardiac magnetic resonance 
Con Meds 
Concomitant medication 
Cp(30min) 
30-minute post-infusion concentration 
Cp,ss(30min) 
Steady-state Cp(30min) 
CRF 
Case report form 
CFR 
Code of Federal Regulations 
CV 
Cardiovascular 
DLin-MC3-DMA  
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DMC 
Data Monitoring Committee 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunoassay 
EOS 
End of study 
FAS 
Full analysis set 
286

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
22 
Abbreviation  
Definition 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
H1 
Histamine 1 receptor 
H2 
Histamine 2 receptor 
hATTR 
Hereditary ATTR 
HF 
Heart failure 
ICF 
Informed consent form  
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IRS 
Interactive Response System 
IV 
Intravenous(ly) 
KCCQ 
Kansas City Cardiomyopathy Questionnaire  
KCCQ-OS 
Kansas City Cardiomyopathy Questionnaire– Overall Summary 
LNP 
Lipid nanoparticle 
LS 
Least squares 
mBMI 
Modified body mass index 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGUS 
Monoclonal gammopathy of undetermined significance 
MMRM 
Mixed-effects model repeated measures 
mNIS+7 
Modified neurological impairment score +7 
mRNA 
Messenger ribonucleic acid 
6-MWT 
6-minute walk test 
NA 
Not applicable 
Norfolk QoL-DN 
Norfolk Quality of Life - Diabetic Neuropathy 
NSAID 
Nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone B-type natriuretic peptide 
NYHA 
New York Heart Association 
287

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
23 
Abbreviation  
Definition 
OLT 
Orthotopic liver transplantation 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PEG2000-C-DMG 
3-N-[(ω-methoxy poly(ethylene glycol)2000) carbamoyl]-1,2-
dimyristyloxy-propylamine 
PK 
Pharmacokinetic 
PND 
Polyneuropathy disability 
PT 
Preferred term 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RISC 
RNA-induced silencing complex 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
siRNA 
Small interfering RNA 
Tc 
Technetium 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
US 
United States 
V30M 
Valine to methionine mutation at position 30 
V122I 
Valine to isoleucine mutation at position 122 
wt 
Wild type 
wtTTR 
Wild type transthyretin 
 
288

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
24 
1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) is a rare, serious, life-
threatening, multisystemic disease encompassing hereditary ATTR (hATTR) amyloidosis and 
wild-type ATTR (wtATTR) amyloidosis, which result from either hereditary (genetic mutation) 
or nonhereditary (ageing) causes, respectively.  In ATTR amyloidosis, deposition of TTR in 
various organs results in progressive, chronically debilitating morbidity and mortality.  The most 
common manifestations of ATTR amyloidosis are polyneuropathy and cardiomyopathy (ie, 
ATTR amyloidosis with cardiomyopathy). 
TTR, also known as prealbumin, is a tetrameric protein produced by hepatocytes, the choroid 
plexus, and retina.[Liz 2010]  More than 95% of TTR in the circulation is derived from the liver.  
The primary physiological role of TTR is to serve as a carrier of retinol (also known as vitamin 
A), which involves TTR binding to the retinol binding protein (RBP): vitamin A complex.  
However, there is evidence to suggest that vitamin A transport and tissue uptake can occur in the 
absence of circulating RBP.[Biesalski 1999; Episkopou 1993] 
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 amyloidosis, and 
almost all patients are heterozygous for the mutated TTR allele.[Ando 2013; Connors 2003]  The 
phenotypic expression varies depending on the predominant site of deposition of the amyloid 
fibrils with some mutations associated with predominantly polyneuropathy manifestations and 
others associated with predominantly cardiomyopathy manifestations.  However, most patients 
experience both over the course of their disease.   
The most common TTR mutation is the valine to methionine mutation at position 30 (V30M), 
accounting for approximately 50% of cases worldwide, and occurring primarily in families with 
heritage from Portugal, Sweden, Japan, and Brazil.[Parman 2016]  This genotype is most 
commonly associated with multisystemic polyneuropathy.  The valine to isoleucine at position 
122 (V122I) mutation is most commonly associated with cardiomyopathy and occurs primarily 
in African Americans.  In these individuals, the mean age at diagnosis is approximately 65 to 
70 years, with symptom onset typically occurring after the age of 65.[Jacobson 2011; Quarta 
2015]  While there appears to be an association between carrier status and the development of 
heart failure (HF) and echocardiographic features of cardiac amyloidosis, the exact penetrance of 
this particular allele is unknown, and estimates vary widely. 
Normal, nonmutant wtTTR alone can also be amyloidogenic; this is the basis for the 
nonhereditary, wtATTR amyloidosis.  This is a progressive disease typically seen in patients 
older than 70 years and is predominantly seen in men.[Westermark 2003]  Patients with this 
289

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
25 
condition do not have a pathogenic mutation in the TTR gene and the amyloid fibrils consist only 
of wtTTR protein, which form amyloid deposits typically found in heart tissue.   
Cardiac infiltration of the extracellular matrix by TTR amyloid fibrils leads to a progressive 
increase of ventricular wall thickness and a marked increase in chamber stiffness, resulting in 
impaired diastolic function.  Systolic function is also impaired, typically reflected by abnormal 
longitudinal strain despite a normal ejection fraction, which is preserved until late stages of the 
disease.[Castano 2015; Dungu 2012; Mohty 2013; Ruberg 2012]  Cardiac infiltration by amyloid 
can also lead to conduction disturbances and arrhythmias.[Adams 2016; Ando 2013; Benson and 
Kincaid 2007; Connors 2004]  Patients with symptomatic HF experience rapid progression of 
their amyloidosis with cardiomyopathy, with substantial worsening of echocardiographic and 
biomarker measures of cardiac function, in addition to clinical measurements of ambulation, and 
quality of life.  Progression of disease in this population can be seen over a period of 12 months 
as demonstrated by differences in 6-minute walk test (6-MWT) and Kansas City 
Cardiomyopathy Questionnaire (KCCQ)  Overall Summary (KCCQ-OS) in the Phase 3 ATTR-
ACT study.[Maurer 2018]  Based on natural history data, patients typically experience 
progressive symptoms of HF resulting in hospitalization and with death typically occurring 2.5 to 
5 years after diagnosis.[Castano 2015; Damy 2015; Dungu 2012; Hawkins 2015] 
1.2. 
Current Treatments 
The treatment of ATTR amyloidosis requires a multidisciplinary approach primarily involving 
cardiology, neurology, and gastroenterology specialties.  While there are treatments for 
polyneuropathy that are available to hATTR amyloidosis patients, for most regions no treatments 
are currently available for the cardiomyopathy phenotype for either the hATTR or wtATTR 
forms.  Palliative/symptomatic therapies directed at specific symptoms, including volume control 
and treatment of cardiac arrhythmias and conduction system disturbances, including cardiac 
pacemakers where appropriate, have been the mainstay of treatment despite their limited 
effectiveness. 
Given that the liver is the primary source of TTR, orthotopic liver transplantation (OLT) has 
been used for hATTR amyloidosis patients since the early 1990s.  However, OLT is intended to 
eliminate mutant TTR from circulation, but has no effect on the hepatic production of wtTTR, 
which continues to be made by the transplanted liver and can continue to deposit in the heart.  
OLT has also only been shown to be effective in slowing the progression of disease in patients 
with an early age of onset (<50 years of age) [Okamoto 2009], and especially for those with the 
V30M mutation and short disease duration before transplant.  Consequently, almost two-thirds of 
patients with hATTR amyloidosis are not transplant-eligible.   
Tafamidis, a TTR tetramer stabilizer that acts by binding to the thyroxine-binding site on TTR to 
reduce its dissociation into misfolded amyloidogenic monomers, is currently approved in 
Europe, Japan, Mexico, and select countries in South America, but not in the United States (US), 
for the treatment of patients with hATTR amyloidosis with polyneuropathy.[Coelho 2016]  
Recently, tafamidis was evaluated in the Phase 3 ATTR-ACT trial in patients with ATTR 
amyloidosis with cardiomyopathy (including hereditary and wt).[Maurer 2018]  This study 
demonstrated that tafamidis treatment over 30 months was associated with lower all-cause 
mortality and cardiovascular (CV)-related hospitalizations compared with placebo treatment.  
Additionally, tafamidis treatment resulted in a slowing of the decline in functional capacity 
290

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
26 
(6-MWT) and quality of life (KCCQ-OS) compared to placebo.  However, consistent with the 
expected pharmacodynamic (PD) effect of TTR stabilization, the effects of tafamidis on 
mortality outcomes was not observed until late in treatment, with differentiation between 
treatment groups occurring only after 18 months of treatment.  Furthermore, although 
improvements with tafamidis relative to placebo were observed in 6-MWT and KCCQ-OS, 
minimal changes in echocardiographic parameters were observed, and tafamidis-treated patients 
still progressed during the study.   
As of early 2019, tafamidis was not approved in the US for patients with ATTR amyloidosis 
(neither polyneuropathy nor cardiomyopathy phenotypes); however, it is anticipated that 
tafamidis may become available for patients with the cardiomyopathy phenotype in the US and 
in other regions, based on the ATTR-ACT study results.  In Japan, tafamidis was approved in 
2019 for use in transthyretin-type cardiac amyloidosis (wt and mutant), in addition to approval 
for transthyretin-type familial amyloid polyneuropathy. 
The results of the ATTR-ACT study support the general therapeutic hypothesis that modifying 
TTR has the potential to result in beneficial outcomes in patients with ATTR amyloidosis with 
cardiomyopathy.  However, the disease progression that was observed in both treatment arms in 
ATTR-ACT highlights an important unmet medical need and suggests that a more direct 
therapeutic mechanism of action, such as specifically targeting the production of the disease-
causing protein with a ribonucleic acid (RNA) interference (RNAi) therapeutic, may be required 
to halt or reverse the debilitating and ultimately fatal course of disease.    
1.3. 
Patisiran Clinical Development 
Patisiran is a small interfering RNA (siRNA) specific for TTR, which is formulated in a 
hepatotropic lipid nanoparticle (LNP) for intravenous (IV) administration.[Akinc 2010]  The 
patisiran drug product (ALN-TTR02; patisiran-LNP, hereafter referred to as “patisiran”) is 
designed to significantly suppress liver production of both wt and all mutant forms of TTR, 
thereby having the potential to reduce amyloid formation and provide clinical benefit to patients 
with ATTR amyloidosis.   
Patisiran utilizes the mechanism of RNAi to selectively degrade TTR messenger RNA (mRNA) 
and thereby reduce the expression of its corresponding protein.[Bumcrot 2006] Patisiran is 
formulated (via the 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 Pharmaceuticals, Inc. (the Sponsor) is developing patisiran for the treatment of patients 
with ATTR amyloidosis.  Based on results from the pivotal Phase 3 APOLLO study 
(Section 1.3.1), patisiran is approved in the US for the treatment of the polyneuropathy of 
hATTR amyloidosis in adults and in the European Union for the treatment of hATTR 
291

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
27 
amyloidosis in adult patients with stage 1 and stage 2 polyneuropathy.  Ongoing development is 
intended to establish patisiran for the treatment of ATTR (hereditary and wt) amyloidosis with 
cardiomyopathy based on exploratory cardiac results from the APOLLO study (Section 1.3.1.1), 
which provides preliminary evidence in support of the use of patisiran for the treatment of the 
cardiomyopathy manifestations of the disease.  
The nonclinical pharmacology, pharmacokinetics (PK), and toxicology of patisiran were 
evaluated in a series of in vitro and in vivo studies that have enabled chronic dosing in clinical 
studies.   
1.3.1. 
The Phase 3 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 (modified neurological 
impairment score +7 [mNIS+7]) relative to placebo at 18 months (primary endpoint), as well as 
significant improvement in quality of life (Norfolk Quality of Life - Diabetic Neuropathy 
[Norfolk QoL-DN], key secondary endpoint) 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.    
In the patisiran group, serum TTR reduction was seen after the first dose and was stably 
maintained over the duration of the study; the mean TTR percent reduction from baseline was 
82.6% and 84.3% at Months 9 and 18, respectively.  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). 
1.3.1.1. 
Cardiac Results and Cardiac Subpopulation Data from APOLLO 
In APOLLO, evidence of potential cardiac amyloid involvement was seen in most patients in the 
study; 80% had left ventricular wall thickness >13 mm and 79% had abnormal levels of the 
cardiac biomarker N-terminal prohormone B-type natriuretic peptide (NT-proBNP).[Solomon 
2018]  As well, 56% of the population met the prespecified criteria for inclusion in a 
subpopulation of patients with evidence of cardiac amyloid involvement (ie, the cardiac 
subpopulation, with baseline left ventricular wall thickness ≥13 mm and no history of 
hypertension or aortic valve disease).  In these patients, treatment with patisiran for up to 
18 months resulted in improvement relative to placebo in important measures of cardiac structure 
and function.  These included reduction in ventricular wall thickness and decrease 
(improvement) in global longitudinal strain.[Solomon 2018]  In addition, patisiran treatment led 
to a reduction (improvement) in NT-proBNP and an improvement in functional capacity, as 
measured by 10-meter walk test assessment of gait speed, relative to the placebo group.   
292

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
28 
Overall, patisiran had an acceptable safety profile, based on an in-depth analysis of cardiac 
events in both the overall (modified intent-to-treat) population and the cardiac subpopulation.  
Importantly, in a post hoc analysis of safety data in the modified intent-to-treat population, rates 
of any hospitalization and/or all-cause death were 71.8 and 34.7 per 100 patient-years in the 
placebo and patisiran groups respectively, while the rates of cardiac hospitalizations and/or 
all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups 
respectively.  This approximates a reduction in event rate of approximately 50% for all-cause 
hospitalization and mortality and approximately 45% for cardiac hospitalization and all-cause 
mortality for patients in the patisiran group compared to those in the placebo group.[Solomon 
2018]  Similar reductions in the event rates were observed in the cardiac subpopulation in 
APOLLO (approximately 55% for all-cause hospitalization and mortality and approximately 
45% for cardiac hospitalization and all-cause mortality; data on file). 
The observed cardiac data from the APOLLO study support the therapeutic hypothesis that 
patisiran may halt or reverse the progression of the cardiac manifestations of hATTR 
amyloidosis and warrant ongoing development for this indication. 
1.3.2. 
Phase 3, Open-label Extension Study 
Study ALN-TTR02-006 is an ongoing multicenter, open-label extension study designed to 
evaluate the long-term safety and efficacy of patisiran in patients with hATTR amyloidosis who 
have completed a prior Phase 2 or 3 parent study with patisiran (ALN-TTR02-003 or ALN-
TTR02-004 [APOLLO]).  The interim data from this open-label extension study were consistent 
with, and extended, the acceptable safety profile and clinical efficacy of patisiran observed in the 
Phase 3 APOLLO study.   
No new safety signals have emerged for patients with long-term patisiran treatment. 
1.4. 
Study Design Rationale 
This study is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study 
designed to evaluate the efficacy and safety of patisiran in adult patients with ATTR amyloidosis 
with cardiomyopathy.  The efficacy of patisiran on functional capacity will be evaluated via 
change at Month 12 in the 6-MWT (primary endpoint).  The study will include patients with 
wtATTR and hATTR amyloidosis with cardiomyopathy who, at baseline, are either tafamidis 
naïve or have been on tafamidis for ≥6 months with disease progression, in the opinion of the 
investigator.   
Confidence in a beneficial treatment effect with patisiran in this patient population with ATTR 
amyloidosis with cardiomyopathy comes from the Phase 3 APOLLO study of patisiran in 
patients with hATTR amyloidosis with polyneuropathy.  As described in Section 1.3.1 and 
Section 1.3.1.1, TTR lowering with patisiran demonstrated multiple benefits in a broad range of 
disease manifestations, including a substantial improvement in neuropathy and quality of life, as 
well as autonomic symptoms, motor strength, ambulatory ability, disability, and nutritional 
status.[Adams 2018]  Furthermore, in a prespecified subgroup of patients with evidence of 
cardiac involvement, which was a majority (56%) of the overall study population, a beneficial 
treatment effect of patisiran compared to placebo was observed for assessments of cardiac 
structure and function as well as the cardiac biomarker NT-proBNP.[Solomon 2018]   
293

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
29 
The 6-MWT (primary endpoint assessment) is a clinically relevant assessment of functional 
capacity that has been used as a primary endpoint in pivotal clinical trials in pulmonary arterial 
hypertension (Gabler 2012) and has been used in the evaluation of patients with HF.[Bittner 
1993; Flynn 2009; Flynn 2012; Mangla 2013; Masoudi 2004; Maurer 2014]  The KCCQ-OS 
(first secondary endpoint assessment) has been used as a common assessment in HF 
interventional studies and has been shown to be an independent predictor of prognosis in 
HF.(Heidenreich et al.  2006)  Both 6-MWT and KCCQ-OS were shown to rapidly and 
consistently decline over time in cardiac ATTR amyloidosis patients and, in the Phase 3 ATTR-
ACT study, these measures were used to demonstrate a reduction of decline with tafamidis 
treatment.[Maurer 2018]  These data support the use of 6-MWT and KCCQ-OS as clinically 
relevant primary and key secondary endpoints, respectively.   
Assessment of the primary endpoint at Month 12 is supported by placebo-arm data from the 
ATTR-ACT study showing substantial disease progression (via the 6-MWT) over an equivalent 
time; as well, data from APOLLO demonstrated a patisiran treatment effect as early as 9 months 
on multiple manifestations of hATTR amyloidosis (neuropathy, quality of life, NT-proBNP, and 
functional capacity [ie, gait speed]).[Maurer 2018] 
The inclusion of placebo as a control allows for a rigorous analysis of the treatment effect of 
patisiran.  If tafamidis becomes an approved therapy for ATTR amyloidosis with 
cardiomyopathy in a given region while this study is in progress, patients who are naïve to 
tafamidis treatment at baseline may commence concomitant on-label tafamidis during the study 
(ie, tafamidis drop-in) (Section 5.3.1).    
1.5. 
Dose Rationale 
The approved and recommended dosage of patisiran for the treatment of the polyneuropathy in 
patients with hATTR amyloidosis is 0.3 mg/kg administered IV every 3 weeks for patients 
weighing <100 kg and a fixed dose of 30 mg administered every 3 weeks for patients weighing 
100 kg or more.  This dosage was selected based on dose-response analyses from three Phase 1 
and 2 studies demonstrating dose-dependent TTR reduction, with the maximum reduction 
achieved at 0.3 mg/kg.  This regimen was further confirmed in the pivotal Phase 3 APOLLO 
study, where this dosage showed significant clinical activity and was well tolerated by patients 
with hATTR amyloidosis with polyneuropathy, including those in the cardiac subpopulation.  
The approved dosing regimen used in the treatment of polyneuropathy is being employed in this 
study since the mechanism of action of patisiran (ie, serum TTR lowering) for treatment of 
polyneuropathy and cardiomyopathy is the same.  
1.6. 
Benefit-risk Assessment 
ATTR amyloidosis with cardiomyopathy is a rare, serious, life-threatening, multisystemic 
disease characterized by deposition of TTR in various organs.  Without treatment, the disease 
progresses, resulting in chronically debilitating morbidity and mortality, with the most common 
manifestations being cardiomyopathy and polyneuropathy.  Patients with symptomatic HF 
experience rapid progression of their amyloidosis with 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]   
294

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
30 
The benefit-risk profile of patisiran has been established in extensive clinical development; in 
Phase 1, 2, and 3 clinical studies, patisiran administered IV demonstrated a potent, 
dose-dependent inhibition of TTR.  In the Phase 3 APOLLO study of patisiran, the primary and 
all secondary endpoints were met.[Adams 2018]  Furthermore, exploratory cardiac results from 
the APOLLO study suggest that patisiran may halt or reverse the progression of the cardiac 
manifestations of hATTR amyloidosis [Solomon 2018] and provide preliminary evidence in 
support of the use of patisiran for the treatment patients with ATTR amyloidosis with 
cardiomyopathy (Section 1.3.1.1). 
In APOLLO, as well as in the ongoing Phase 3, open-label extension study (ALN-TTR02-006), 
an acceptable safety profile with patisiran was demonstrated.  Most AEs were mild or moderate 
in severity.  Transient infusion-related reactions (IRRs) were observed, but all IRRs were mild or 
moderate in severity, none were reported as serious AEs (SAEs).  No clinically significant 
laboratory or hematologic changes were observed.  Furthermore, in APOLLO, an acceptable 
safety profile was also observed in a prespecified subgroup of patients with evidence of cardiac 
amyloid involvement. [Solomon 2018] 
For patisiran, important identified risks include IRRs.  To minimize this risk, all patients must 
receive premedication with a corticosteroid, paracetamol/acetaminophen, and H1 and H2 
blockers prior to patisiran administration (Section 5.2.1).  The infusion may be interrupted or 
slowed if an IRR occurs (Sections 5.2.3 and 5.2.4).  Important potential risks also include severe 
hypersensitivity (eg, anaphylaxis) to the active substance or any of the excipients.  Patisiran is 
contraindicated in patients with a history of severe hypersensitivity (eg, anaphylaxis or 
anaphylactoid reactions) to patisiran or any of the excipients. 
Vitamin A deficiency is also considered an important potential risk.  Nonclinical and clinical 
data with patisiran have shown that the lowering of circulating vitamin A associated with the 
reduction in TTR (a carrier of retinol) does not result in 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 (Section 5.3).  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 patisiran.  
Detailed information about the known and expected benefits and risks of patisiran may be found 
in the current edition of the Investigator’s Brochure.  
During the study, patients will be monitored, including evaluation of laboratory monitoring for 
liver function test abnormalities, renal function, and other standard hematology and blood 
chemistries.  As the risk of embryofetal toxicity is currently unknown, females of child-bearing 
potential participating in the study must have a negative pregnancy test, cannot be breast feeding, 
and must be willing to use a highly effective method of contraception as specified in the 
protocol. 
An external, independent Data Monitoring Committee (DMC) will monitor and ensure the safety 
of trial participants (see Section 3.7).   
In conclusion, exploratory cardiac results from the APOLLO study suggesting that patisiran may 
halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis [Solomon 
295

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
33 
randomized, double-blind study drug (patisiran or placebo), to reduce the potential for an IRR 
with patisiran, all patients will receive premedications at least 60 minutes before the start of their 
infusion.  (Patients randomized to placebo will also receive premedications to maintain the 
blind.)  Study drug will be administered in the clinic as an approximately 80-minute IV infusion.  
During the 12-month open-label extension period, all patients will receive treatment with 
open-label patisiran.  Furthermore, patients who have received ≥3 consecutive doses of patisiran 
on this study at the clinical site with no evidence of IRRs or other drug-related adverse effects 
impacting safety and tolerability of the infusion may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be 
performed by a healthcare professional trained on the protocol and on administration of 
premedications and patisiran infusion. 
To evaluate the efficacy of treatment with patisiran versus placebo in patients with ATTR 
amyloidosis with cardiomyopathy, the change from baseline in 6-MWT will be assessed at 
Month 12 (Weeks 52-53) as the primary endpoint (Section 2); this assessment will also be 
performed at Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) in the double-blind period, 
and during the open-label extension period at the time points noted in the Schedule of 
Assessments (Table 1 and Table 2).  The first secondary endpoint will assess change from 
baseline at Month 12 in the KCCQ-OS score.     
Safety will be assessed throughout the study, as described in the Schedule of Assessments for the 
double-blind period (Table 1) and for the open-label extension period (Table 2).   
3.2. 
Duration of Treatment  
The treatment duration in this study is up to 24 months, inclusive of a 12-month, double-blind, 
treatment period, and a 12-month, open-label, treatment period. 
3.3. 
Duration of Study Participation  
The estimated total time on study for each patient is up to 26.5 months, including up to 45 days 
of screening, up to 24 months of treatment (see Section 3.2), and a 28-day safety follow-up 
period. 
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 end of study (EOS; Month 24) visit, or 
 the patient has completed the follow-up visit 28 days after the last dose of patisiran.    
3.4. 
Number of Planned Patients 
The planned enrollment for this study is 300 patients with wtATTR and hATTR amyloidosis 
with cardiomyopathy.  Approximately 20% of the study population is anticipated to have hATTR 
and 80% wtATTR. 
298

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
34 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the interactive response system (IRS), patients will be randomized 1:1 to the patisiran or 
placebo arm.  Randomization will be stratified by: 
1. Baseline tafamidis (yes vs no) 
2. Genotype (hATTR vs wtATTR amyloidosis with cardiomyopathy) 
3. NYHA Class I or II and age < 75 years vs all other     
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 
During the double-blind period of the study, all site personnel will be blinded to the study 
treatment, except the pharmacist and designated pharmacy personnel who will set-up, dispense, 
and prepare the infusion.  Patisiran confers a slightly opalescent color relative to the clear saline 
(placebo) infusate; therefore, all infusion bags and lines will be covered with amber bags and line 
covers by the unblinded personnel to prevent visualization by the blinded study personnel and 
patient, as described in detail in the Pharmacy Manual.   
After the pharmacist (and designated pharmacy personnel) has prepared the infusion, separate 
blinded personnel will administer study drug and monitor the patient during and after the 
infusion.  All patients will be blinded to treatment and will receive an IV infusion once every 
3 weeks using identical volumes for patisiran and placebo.    
Study personnel performing assessments related to the primary and secondary endpoints will be 
different from the Investigator and other personnel managing the patient, and all of these study 
personnel will be blinded to any clinical laboratory results that could potentially unblind them 
(eg, TTR levels).  In addition, the study personnel performing assessments related to the primary 
and secondary efficacy endpoints will also be blinded to the results of any previous assessments. 
Furthermore, unblinded source documentation containing all descriptions of pharmacy 
preparations and infusions or distribution of study drug or randomization data will be stored 
separate from all other study data/records and from other pharmacy staff not participating on the 
study. 
Blinding will be maintained until the last patient completes their Month 12 visit. 
3.6.1. 
Emergency Unblinding 
During the double-blind period of the study, if the treating physician determines that the clinical 
management of the patient requires knowledge of the study drug assignment, the Investigator 
may break the blind, as necessary.  If time permits, clinical study center personnel should contact 
the Medical Monitor before unblinding to discuss the need to unblind the patient but must do so 
within 1 working day after the unblinding event.  Unblinding information should be limited to 
the fewest number of people on a need-to-know basis.  A record of when the blind was broken, 
299

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
35 
who was unblinded, who broke the blind, and why it was broken, will be maintained in the trial 
master file. 
Refer to the IRS instructions for details on emergency unblinding. 
3.7. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study through the 
double-blind period (through Month 12), 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.  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 (CV versus non-CV) 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 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive.  
Patient and Disease Characteristics 
2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either 
hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with 
cardiomyopathy: 
Hereditary ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of 
the following criteria: 
a. TTR pathogenic mutation consistent with hATTR.  
b. Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness >12 mm (based on central echocardiogram 
reading at screening).   
c. Amyloid deposits in cardiac or noncardiac tissue (eg, fat pad aspirate, salivary gland, 
median nerve connective sheath) confirmed by Congo Red (or equivalent) staining 
OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 
or 3 cardiac uptake, if monoclonal gammopathy of undetermined significance 
(MGUS) has been excluded. 
d. If MGUS, confirm TTR protein in tissue with immunohistochemistry (IHC) or mass 
spectrometry. 
300

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
36 
Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of 
the following criteria: 
a. Absence of pathogenic TTR mutation.  
b. Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness >12mm (based on central echocardiogram 
reading at screening).   
c. Amyloid deposits in cardiac tissue with TTR precursor identification by IHC, mass 
spectrometry, OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid [DPD-Tc] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 
or 3 cardiac uptake, if MGUS has been excluded. 
d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry  
3. Medical history of HF with at least 1 prior hospitalization for HF (not due to arrhythmia 
or a conduction system disturbance treated with a permanent pacemaker) OR clinical 
evidence of HF (with or without hospitalization) manifested by signs and symptoms of 
volume overload or elevated intracardiac pressures (eg, elevated jugular venous pressure, 
shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral 
edema) that currently requires treatment with a diuretic. 
4. Patient meets one of the following criteria: 
a. Tafamidis naïve; in addition to patients who have never taken tafamidis, those who 
have been on tafamidis for ≤30 days total and have not received any tafamidis in the 
6 months prior to baseline will be considered tafamidis naïve and may qualify for the 
study. 
b. Currently on tafamidis (for ≥6 months) and has demonstrated disease progression, as 
determined by the Investigator.  (At the time of study entry, tafamidis treatment must 
be on-label use of commercial tafamidis.) 
5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to 
randomization, as assessed by the Investigator.   
6. Able to complete ≥150 m on the 6-MWT at screening. 
7. Screening NT-proBNP >600 ng/L and <8500 ng/L. 
Informed Consent 
8. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent; and patient agrees to sign the 
medical records release form for collection of vital status.   
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Has known primary amyloidosis (AL) or leptomeningeal amyloidosis.  
301

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
37 
2. NYHA Class III AND ATTR amyloidosis disease Stage 3 (defined as both NT-proBNP 
>3000 ng/L and estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 
m2).[Gillmore 2018] 
3. NYHA Class IV at the Screening visit. 
4. Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to 
walk, or is wheelchair bound) at the Screening visit. 
Laboratory Assessments 
5. Has any of the following laboratory parameter assessments at screening:  
a. Aspartate transaminase (AST) or alanine transaminase (ALT) levels ˃2.0 × the upper 
limit of normal (ULN). 
b. Total bilirubin ˃ULN.  Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if total bilirubin <2 × ULN. 
c. International normalized ratio (INR) ˃1.5 (unless patient is on anticoagulant therapy, 
in which case excluded if INR ˃3.5).  
6. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] 
formula). 
7. Has known human immunodeficiency virus infection; or evidence of current or chronic 
hepatitis C virus or hepatitis B virus infection.    
Prior/Concomitant Therapy 
8. Tafamidis naïve patients (at baseline) for whom the Investigator actively plans or 
anticipates commencing treatment with tafamidis during the 12-month double-blind 
period, taking into consideration clinical status, patient preference and/or commercial 
availability of tafamidis. 
9. Is currently taking diflunisal; if previously on this agent, must have at least a 6-month 
wash-out prior to dosing (Day 1). 
10. Is currently taking doxycycline, or tauroursodeoxycholic acid; if previously on any of 
these agents, must have completed a 30-day wash-out prior to dosing (Day 1). 
11. Received prior TTR-lowering treatment or participated in a gene therapy trial for hATTR 
amyloidosis. 
12. Current or future participation in another investigational device or drug study, scheduled 
to occur during this study, or has received an investigational agent or device within 
30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing 
(Day 1).  In the case of investigational TTR stabilizer drugs, washout for 6 months prior 
to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at 
baseline (per inclusion Criterion 4).   
13. Requires treatment with calcium channel blockers (eg, verapamil, diltiazem) or digitalis. 
Medical Conditions 
14. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to 
valvular heart disease, or cardiomyopathy due to ischemic heart disease (eg, prior 
302

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
38 
myocardial infarction with documented history of cardiac enzymes and 
electrocardiogram [ECG] changes). 
15. Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive 
pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation). 
16. Recent or planned orthopedic procedure during the double-blind period (eg, lower 
extremity or back surgery) that could impact 6-MWT. 
17. Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of 
screening required to achieve optimal treatment of CHF). 
18. Had acute coronary syndrome or unstable angina within the past 3 months. 
19. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.  
20. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a 
pacemaker is indicated but will not be placed. 
21. Has persistent elevation of systolic (˃180 mmHg) and diastolic (˃100 mmHg) blood 
pressure that is considered uncontrolled by physician. 
22. Has untreated hypo- or hyperthyroidism. 
23. Prior or planned heart, liver, or other organ transplant. 
24. Had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix that has been successfully treated. 
25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation.   
Contraception, Pregnancy, and Breastfeeding 
26. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.5.1.   
27. Female patient is pregnant or breast-feeding.    
Alcohol Use 
28. Has a known history of alcohol abuse within the past 2 years or daily heavy alcohol 
consumption (for females, more than 14 units of alcohol per week; for males, more than 
21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ 
pint of beer]); 
29. History of illicit drug abuse within the past 5 years that in the opinion of the Investigator 
would interfere with compliance with study procedures or follow-up visits. 
4.3. 
Removal from Study Drug or Assessment 
Patients 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 
303

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
39 
of the patient’s participation in the study must be fully documented 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-AE) 
 Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.7.7 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.   
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1 and Table 2), 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 AEs, and must document this decision in the 
patient’s medical records. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.5.7.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable. 
Patients who discontinue from study drug during the 12-month double-blind period, defined as 
the time the first dose of study drug is administered on Day 1 through completion of the 
Month 12 Efficacy Visit (primary endpoint assessment), will be encouraged to remain on the 
study and complete assessments through Month 12 (excluding PK assessments), including a 
Modified Month 12 Efficacy Visit (Table 1).  They will also be asked to complete an Early 
304

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
40 
Treatment Discontinuation Visit (7-14 days after their last dose) and the safety follow-up visit, 
28 days after the last dose of study drug (Table 2); see Section 3.3.1. 
Patients who discontinue patisiran during the open-label extension period will be asked to 
complete an Early Treatment Discontinuation Visit (7-14 days after their last dose) and the safety 
follow-up visit, per the Schedule of Assessments (Table 2), 28 days after the last dose of 
patisiran; see Section 3.3.1. 
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 the patient's participation in the study at any time.  A 
patient or legal guardian considering stopping participation in the study should be informed that 
the patient can discontinue study drug and/or decline procedural assessments and remain in the 
study to complete their study assessments, through the Modified Month 12 Efficacy Visit, and 
the 28-day follow-up visit, or alternatively may complete any minimal assessments for which the 
patient or legal guardian consents as described in Section 4.3.1.  If a patient or legal guardian still 
chooses to discontinue study drug and stop participation in all follow-up prior to the completion 
of the Month 12 visit, every effort should be made to conduct the assessments scheduled to be 
performed at the Modified Efficacy Visit (Table 1). 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, 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, and 
use biological samples and, as applicable, other personal data, informing the study doctor at any 
time in writing or in any other form that may be locally required.  The Sponsor will continue to 
keep and use the patient’s study information (including any data resulting from the analysis of 
the patient’s biological samples until the time of withdrawal) according to applicable law.  The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements.    
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
305

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
41 
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 or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes (for the patient) 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 or legal guardian (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 or legal guardian 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 and returned unused must not be re-dispensed. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of study drug 
(patisiran and placebo) is provided in the Pharmacy Manual. 
306

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
42 
All patients will be instructed to take the recommended daily allowance of vitamin A while on 
the study. 
5.2.1. 
Premedication 
All patients will receive premedication prior to study drug administration to reduce the risk of 
IRRs.  Each of the following medicinal products should be given on the day of study drug 
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.   
If a patient is having difficulty tolerating the steroid premedication regimen (eg, patient develops 
uncontrolled hyperglycemia, altered mental status, or other complication), then lowering of the 
steroid premedication may be allowed for that patient after consultation with the medical monitor 
at any time during the study (double-blind and open-label periods).   
In the open-label extension period only, for patients who are tolerating their drug infusions well 
with their current corticosteroid premedication regimen (ie, no IRRs during the past 3 or more 
infusions), corticosteroid dose may be reduced in 2.5 mg increments to a minimum dose of 5 mg 
of dexamethasone (IV) or equivalent.    
Infusions during corticosteroid tapering (and the 2 infusions after the new and stable lower 
corticosteroid dose is established) should be performed in the clinic, as described in detail in the 
Pharmacy Manual.    
Additional or higher doses of 1 or more of the premedications may be administered to reduce the 
risk of IRRs, if needed.  For suggested guidelines for management of IRRs, see Section 5.2.4; 
further details can be found in the Pharmacy Manual.   
5.2.2. 
Study Drug Description 
Patisiran is a RNAi therapeutic consisting of a double-stranded siRNA targeting TTR mRNA 
formulated in an LNP.  The patisiran drug product is a sterile formulation of ALN-18328 (siRNA 
targeting TTR) formulated as LNPs with lipid excipients (1,2-Dilinoleyloxy-N,N-
dimethylpropylamine [DLin-MC3-DMA], 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 
cholesterol, and PEG2000-C-DMG) in isotonic phosphate buffered saline.  Patisiran Solution for 
IV infusion contains 2 mg/mL of patisiran. 
See the Pharmacy Manual for further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (normal saline 0.9% for IV administration).  
Control drug will be provided by a central supplier (or, if necessary, by a local supplier, with 
prior Sponsor approval).  
307

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
43 
5.2.3. 
Dose and Administration 
Detailed instructions for study drug preparation and administration are found in the Pharmacy 
Manual. 
5.2.3.1. 
Double-bind Study Drug (Patisiran or Placebo) 
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs (Section 5.2.1).   
An IV infusion of double-blind study drug (patisiran 0.3 mg/kg or placebo) will be administered 
under the supervision of the site personnel once every 3 weeks ±3 days.   
The amount (in mg) of double-blind patisiran 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.  
Weight from the previous visit may be used for calculating dose.  Weight must be collected prior 
to dosing with study drug.  Study drug will be administered as an approximately 80-minute IV 
infusion (approximately 1 mL/minute for the first 15-minutes followed by approximately 
3 mL/minute for the remainder of the infusion).  The 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. 
Missed doses of double-blind study drug   
If a patient does not receive a dose of study drug within the dosing window (±3 days), the 
delayed dose may be taken up to 7 days after the scheduled visit (with the following infusion 
taken on schedule, per the Schedule of Assessments), after consultation with the Medical 
Monitor.  
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. 
5.2.3.2. 
Open-label Extension Period (Patisiran) 
The last dose of double-blind study drug will be at Week 51 and the first dose of open-label 
patisiran will be 3 weeks later (at Week 54) and thereafter every 3 weeks (±3 days) for the 
remainder of the study.  Open-label patisiran will be administered per the schedule and dose as is 
described in Section 5.2.3.1 for double-blind patisiran. 
As noted in Section 3.6, blinding will be maintained until the last patient completes their 
Month 12 visit. 
During the open-label extension period, patients who have received at least 3 consecutive doses 
of patisiran on this study at the clinical site with no evidence of IRRs or other drug-related 
adverse effects impacting safety and tolerability of the infusion may have patisiran administered 
at home, where applicable country and local regulations allow.  Home administration of patisiran 
308

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
44 
will be performed by a healthcare professional trained on the protocol and administration of 
premedications and patisiran infusion. 
All patients will receive premedications prior to open-label patisiran administration to reduce the 
risk of IRRs (Section 5.2.1).   
Missed doses of open-label patisiran   
If a patient does not receive a dose of open-label patisiran within the dosing window (±3 days), 
the delayed dose may be taken up to 7 days after the scheduled visit (with the following infusion 
taken on schedule, per the Schedule of Assessments), after consultation with the Medical 
Monitor. 
5.2.4. 
Suggested Guidelines for Management of Infusion-related Reactions 
Criteria for categorizing IRRs are provided in Section 10.3. 
 In the event of an IRR, the infusion of study drug may be slowed or stopped and the patient 
closely monitored until resolution of the reaction.  Drugs that may be used to facilitate 
resolution and permit resumption of study drug administration include but are not limited to:  
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), nonsteroidal anti-inflammatory drugs (NSAIDs), adrenaline, supplemental 
oxygen, IV fluids, and/or corticosteroids. 
 Following resolution of a mild or moderate IRR that required interruption of the study drug 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate for that dose and for subsequent doses of study drug.  If the infusion is delayed, 
the administration of the infusion should be completed no more than 16 hours from the initial 
start of the infusion.   
 Study drug administration will not be resumed for any patient following a severe IRR until 
the case is discussed with the Medical Monitor. 
 If after consultation with the Medical Monitor it is agreed that an individual patient’s steroid 
premedication will be increased, then the following steps are recommended: 
1. If the IRR occurred while the patient received 10 mg IV dexamethasone or equivalent at 
least 60 minutes before the infusion and did not resolve with slowing of the infusion rate, 
then the patient should be increased by multiples of 5 mg IV dexamethasone or 
equivalent at least 60 minutes before the infusion and/or 5 mg oral dexamethasone or 
equivalent the night before the IV infusion.  
2. Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
IV dexamethasone or equivalent on the day of infusion and 8 mg oral dexamethasone or 
equivalent taken the night before the infusion.  
3. If the IRR occurred while the patient received less than 10 mg IV dexamethasone or 
equivalent, then the patient should return to the prior dose of IV dexamethasone or 
equivalent that did not result in an IRR. 
Patients will be instructed to call the Investigator if they experience symptoms such as fever, 
chills, myalgia, or nausea/vomiting after discharge from the site. 
309

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
45 
5.2.5. 
Dose Modifications 
Dose modifications are not permitted.   
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
5.2.6. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of study drug (patisiran and placebo) 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. 
5.2.7. 
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. 
5.2.8. 
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 and Procedures 
All patients will receive premedications prior to study drug administration to reduce the risk of 
IRRs (Section 5.2.1).   
Use of the following medications/treatments are prohibited during study participation: 
 Any investigational agent other than study drug. 
310

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
46 
 Inotersen, doxycycline, tauroursodeoxycholic acid, and diflunisal are also prohibited 
during the study.   
All patients will be asked to take the recommended daily allowance of vitamin A for the duration 
of their participation in the study while being administered study drug.  In countries where 
relevant, the clinical sites will provide patients with a prescription for vitamin A.  
Standard vitamins and topical medications are permitted.  Any concomitant medication or 
treatment that is required for the patient’s welfare may be given by the Investigator.  However, it 
is the responsibility of the Investigator to ensure that details regarding the medication are 
recorded on the CRF, as specified in the Schedule of Assessments (Table 1 and Table 2).  
Concomitant medications include 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 CRF.  Concomitant medication will be coded using an internationally 
recognized and accepted coding dictionary.  
5.3.1. 
Concomitant Tafamidis Use 
Per inclusion Criterion 4, at baseline patients are either: 1) tafamidis naïve or 2) currently on 
tafamidis for ≥6 months with demonstrated disease progression, as determined by the 
Investigator.  Patients who have been on tafamidis for ≤30 days total and have not received any 
tafamidis in the 6 months prior to baseline will be considered tafamidis naïve and may qualify 
for the study.   
For patients on tafamidis at baseline, the reasons for considering the patient to have 
demonstrated disease progression will be recorded in the eCRF.  Patients who are on tafamidis at 
baseline are encouraged, if it is medically appropriate in the opinion of the investigator, to 
remain on tafamidis for the duration of the double-blind period. 
Per exclusion Criterion 8, patients who are tafamidis naïve at baseline, for whom the investigator 
actively plans or anticipates commencing treatment with tafamidis during the 12-month 
double-blind period (taking into consideration clinical status, patient preference, and/or 
commercial availability of tafamidis), should not be enrolled in the trial. 
However, if tafamidis is granted approval by a Health Agency for treatment in patients with 
ATTR amyloidosis with cardiomyopathy in a given region, all enrolled patients in this region 
will be made aware of its potential benefits and risks at the time of regulatory approval and all 
patients will be reconsented.  In such circumstances, tafamidis is not considered prohibited and 
the investigator may, using their medical judgement, commence concomitant on-label tafamidis 
during the study, if it is felt to be in the best interest of the patient and if it is commercially 
available in the country.   
Patients who are tafamidis naïve at baseline, but begin taking commercial tafamidis (ie, 
“tafamidis drop-in”), will remain in the study.  Prior to commencing concomitant tafamidis, the 
investigator will perform assessments (including primary and select secondary efficacy 
assessments) at the Pre-tafamidis Drop-in Visit, as outlined in the Schedule of Assessments 
(Table 1).  In all cases, the Pre tafamidis Drop-in Visit should occur prior to starting concomitant 
tafamidis; where possible, this visit should occur between 1-2 weeks after the last dose of study 
drug (ie, 7 to 14 days post study drug dose).  Thereafter, the patient will continue with all 
311

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
47 
assessments per the Schedule of Assessments (Table 1 and Table 2).  In addition, at the time of 
tafamidis drop-in, the reason for starting tafamidis will be recorded in the CRF. 
Initiation of TTR stabilizer therapies other than tafamidis (eg, diflunisal) is not allowed during 
the double-blind period of this study. 
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 a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 12 weeks 
after the last dose of study drug in this study.    
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 low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. 
 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 12 weeks 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.   
312

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
48 
For male patients, no contraception is required.  However, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements as described in the corresponding patient informed consent forms.   
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.2).    
6. 
STUDY ASSESSMENTS 
The Schedule of Assessments is provided in Table 1 (double-blind period) and Table 2 
(open-label extension period).  Additional information on the collection of study assessments 
will be detailed in the respective reference manuals.  
6.1. 
Screening Assessments  
An ICF 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.  In addition, a medical records release form will be required of all patients for the 
purpose of obtaining vital status information from the patient’s physician or from death 
registries.    
See the Schedule of Assessments (Table 1) for a list of Screening visit assessments.   
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening (once) of patients is permitted with consultation of the Medical 
Monitor (see Section 6.1.2). 
Patient demographic data and medical history/disease history will be obtained.  Any changes to 
medical history occurring between the screening assessment and Day 1 will be updated prior to 
study drug administration. 
The study eligibility biopsies and technetium scintigraphy noted in inclusion Criterion 2 are 
intended to be historical, as part of the patient’s clinical care and diagnosis, and are not 
performed as part of the study.    
An echocardiogram will be performed at screening Visit 1 and results confirmed centrally to 
assess study eligibility, as indicated in the Schedule of Assessments (Table 1). 
6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then 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.  Any 
additional repeat testing may be considered after discussion with the Medical Monitor. 
6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening (eg, prohibited medications that were subsequently discontinued), in conjunction with 
313

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
49 
the decision of the Medical Monitor(s), may be allowed to rescreen after a minimum of 5 days 
have elapsed from their last screening assessment.  A patient will be re-consented, if rescreening 
occurs outside of the 45-day screening window.  In this case, all screening procedures must be 
repeated.   
6.2. 
Efficacy Assessments 
6.2.1. 
6-Minute Walk Test (6-MWT) 
The 6-MWT, which will be assessed as the primary endpoint, is an assessment of functional 
exercise capacity.  The 6-MWT will be administered by staff trained in the procedure per the 
relevant study manual.  The staff administering the 6-MWT will be different from the 
Investigator or designee managing the care of the patient. 
The 6-MWT will be performed at each of the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2).  At screening Visit 1, the 6-MWT will be administered for 
study eligibility purposes (per inclusion Criterion 6 [Section 4.1]).  At screening Visit 1, prior to 
conducting the 6-MWT, the site staff will familiarize the patient with the purpose and conduct of 
the 6-MWT, as described in detail in the relevant study manual.  Familiarization can be repeated 
at other timepoints if deemed helpful. 
On Day 1 (baseline), which is a dosing day, the 6-MWT will be performed prior to study drug 
administration.  (No other dosing days have a 6-MWT assessment.)   
Patients who are hospitalized during the study should wait at least 2 weeks after hospitalization 
before completing a 6-MWT assessment; less time post-hospitalization may be permitted if, in 
the opinion of the investigator, the patient is unencumbered due to the recent hospitalization.  In 
addition, if a patient is not feeling well due to an external factor (eg, flu, sprained ankle, pulled 
back muscle) at a visit when the 6-MWT will be performed, the test should not be done and 
should be rescheduled for another day within the permitted visit window. 
For each 6-MWT assessment, the site should make every effort to have this assessment 
performed by the same assessor and to perform the test at approximately the same time of day.  
If the test is interrupted or deemed unusable by the 6-MWT core laboratory, the 6MWT should 
be repeated as soon as possible within the allowed visit window. 
Further details regarding the 6-MWT are provided in the relevant study manual. 
A 1.5-month window will be used to group 6-MWT assessments to the Month 6 (Weeks 25-26), 
Month 9 (Weeks 37-38), and Month 12 (Weeks 52-53) visits.  During the double-blind period, a 
patient may opt to begin tafamidis treatment or to discontinue study treatment, in which case 
they would complete a Pre-tafamidis Drop-in Visit (Table 1) or Early Treatment Discontinuation 
Visit (Table 2), respectively.  To avoid the potential training effect from repeated assessments of 
the 6-MWT within a short period of time, only one 6-MWT assessment should be collected for 
the following time periods:  Day 2 to Day 214 (for Month 6), Day 215 to Day 319 (for Month 9), 
and Day 320 to Day 372 (for Month 12).   
Within a given time period, the 6-MWT assessment should be performed at whichever visit 
occurs first (scheduled assessment, Pre-tafamidis Drop-in Visit, or Early Treatment 
Discontinuation Visit; no additional 6-MWT assessments should be made in that time period.  In 
later time periods, the 6-MWT should be assessed per the Schedule of Assessments (Table 1).  
314

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
50 
6.2.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ)   
The KCCQ [Green 2000] is a 23-item self-administered questionnaire developed to 
independently measure the patient’s perception of health status, which includes heart failure 
symptoms, impact on physical and social function, and how their heart failure impacts their 
quality of life within a 2-week recall period. 
The KCCQ quantifies 6 domains (symptoms, physical function, quality of life, social limitation, 
self-efficacy, and symptom stability) and 2 summary scores (clinical and overall summary [OS]).  
The KCCQ-OS will be assessed for the first secondary endpoint. 
The KCCQ questionnaire will be completed at the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2). 
6.2.3. 
Deaths and Hospitalizations 
All deaths and hospitalizations will be recorded at Day 1 post dose and throughout the study as 
specified as part of AEs monitoring (see Section 6.5.7) and per the Schedule of Assessments 
(Table 1 and Table 2).  
Reasons for deaths and hospitalizations will be adjudicated by an independent Adjudication 
Committee (see Section 3.8). 
6.2.4. 
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 pre-dose at the timepoints specified in the Schedule of Assessments (Table 1 and 
Table 2).  The site will not perform the calculation for mBMI.   
6.2.5. 
Cardiac Assessments   
Manifestations of cardiac amyloid involvement will be assessed via cardiac biomarker, NYHA 
class, echocardiograms, CMR, and technetium scintigraphy imaging, as described. 
Qualified personnel will be required to administer cardiac imaging assessments as specified in 
the respective reference manuals. 
6.2.5.1. 
Cardiac Biomarkers   
The cardiac biomarkers NT-proBNP and troponin I will be used to assess cardiac stress and heart 
failure severity.  These biomarkers have been shown to be prognostic of outcomes in HF, 
including in ATTR amyloidosis.[Damy 2016; Kristen 2017; Merlini 2016]  Blood samples will 
be drawn to measure cardiac biomarker levels at the timepoints specified in the Schedule of 
Assessments (Table 1 and Table 2) and will be measured at a central laboratory.  At screening 
Visit 1, only NT-proBNP will be assessed for eligibility purposes.    
Details on cardiac biomarker sample collection, processing, and storage will be provided in a 
Study Laboratory Manual. 
315

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
51 
6.2.5.2. 
ATTR Amyloidosis Disease Stage 
Based on published data from Gillmore et al, the ATTR amyloidosis disease staging used for this 
protocol stratifies patients with ATTR amyloidosis with cardiomyopathy (both hATTR and 
wtATTR) into prognostic categories using the serum biomarkers NT-proBNP and 
eGFR.[Gillmore 2018]  Patients are categorized as follows: 
 Stage 1 (lower risk):  NT-proBNP ≤3000 ng/L and eGFR ≥45 ml/min/1.73 m2 
 Stage 2 (intermediate risk):  all other patients not meeting criteria for Stages 1 or 3 
 Stage 3 (higher risk):  NT-proBNP >3000 ng/L and eGFR <45 ml/min/1.73 m2 
Based on published data, this staging system discriminates between patients with median 
survival of ~6 years, ~4 years, and ~2 years for Stage 1, Stage 2, and Stage 3, respectively. 
6.2.5.3. 
New York Heart Association (NYHA) Class 
NYHA class is a clinical assessment of symptoms resulting from HF and is assessed according to 
the table in Section 10.2.  NYHA class will be evaluated at the timepoints specified in the 
Schedule of Assessments (Table 1 and Table 2).  The score collected at screening will be used to 
determine eligibility. 
6.2.5.4. 
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 and Table 2), and analyzed at a central cardiac imaging core lab.   
Image acquisition, storage, and transfer guidelines will be provided in the relevant study manual. 
6.2.5.5. 
Technetium Scintigraphy Imaging  
At select sites, in a subset of the patients (≤60 patients), technetium scintigraphy will be 
collected according to the Schedule of Assessments (Table 1 and Table 2), as an optional 
exploratory imaging assessment, to assess cardiac amyloid involvement.  Based on local practice 
standards, either 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD-Tc], 99mTc-
pyrophosphate [PYP-Tc], or 99mTc-hydroxymethylene diphosphonate (99mTc-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 relevant 
study manual.   
For patients in whom technetium scintigraphy is performed as a study efficacy parameter, the 
results of the baseline scan must be reviewed by the central reader and confirmed to be consistent 
with the diagnosis of ATTR amyloidosis prior to randomization. 
At select sites where technetium scintigraphy is being performed as an exploratory efficacy 
assessment, patients may be exempt from the baseline scan if technetium scintigraphy has been 
performed prior to study entry as part of the patient’s clinical care within 6 months prior to the 
baseline assessment.  In such cases, the historical technetium scintigraphy examination 
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; if the historical scan cannot 
316

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
52 
be transferred to the central reader, or is deemed by the central reader to be of inadequate quality 
for interpretation, the patient should not participate in this optional efficacy assessment. 
6.2.5.6. 
Cardiac Magnetic Resonance (CMR)   
At select sites, in a subset of patients (≤60 patients), CMR will be collected according to the 
Schedule of Assessments (Table 1 and Table 2), as an optional exploratory imaging assessment 
to assess cardiac amyloid involvement.  CMR imaging with late gadolinium enhancement will 
only be performed on patients without contraindications (ie, pacemakers, severe renal failure 
with eGFR <30 mL/min/1.73 m2, defibrillators, or allergy to gadolinium).  
Details for image acquisition and upload for central review can be found in the relevant study 
manual. 
6.2.6. 
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 and Table 2). 
6.2.7. 
Polyneuropathy Disability (PND)   
Physician assessment of ambulation via PND score [Coutinho 1980; Yamamoto 2007] will be 
evaluated only at screening to assess eligibility for the study as specified in the Schedule of 
Assessments (Table 1).  PND scoring is described in Section 10.1. 
6.3. 
Pharmacodynamic Assessments 
In this study, serum samples for measurement of TTR levels will be collected for the assessment 
of PD effects.  TTR levels will be determined by a validated enzyme-linked immunoassay 
(ELISA).  Details regarding sample volumes to be collected, and the processing, shipping, and 
analysis of the samples will be provided in the Laboratory Manual.   
For this assessment, blood samples will be collected prior to dosing according to the timepoints 
specified in the Schedule of Assessments (Table 1 and Table 2).   
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of plasma concentrations of ALN-18328 (siRNA 
component of patisiran) and 2 lipid excipients (DLin-MC3-DMA and PEG2000-C-DMG) during 
the double-blind period at the timepoints specified in the Schedule of Assessments (Table 1).  
Plasma PK samples will be collected:  predose (within 1 hour of planned study drug dosing); at 
the end of the infusion (+5 minutes); and 30 minutes after the end of the infusion (+15 minutes) 
at the specified visits.   
317

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
53 
For patients who discontinue treatment early during the double-blind period, a single PK sample 
will be taken at any time during the Early Treatment Discontinuation Visit, per the Schedule of 
Assessment (Table 2).   
Actual dates and times of sample collection will be recorded. 
Plasma concentrations of the 3 analytes will be determined using validated assay methods.  
Details regarding sample volumes to be collected, and the processing, shipping, and analysis of 
the samples will be provided in the Laboratory Manual. 
PK parameters will be analyzed, whenever possible, as outlined in Section 7.2.7.  
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight 
and height, 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. 
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1 and Table 2) 
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.  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 as specified in the Schedule of Assessments 
(Table 1 and Table 2) and will be recorded in the eCRF. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1 and Table 2); 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, 
318

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
54 
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 
12-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, and QT 
interval will be obtained, as specified in the Schedule of Assessments (Table 1 and Table 2).  
Patients should be supine for at least 5 minutes before each ECG is obtained.  The 12-lead ECGs 
will be performed in triplicate at baseline, with readings approximately 1 minute apart.  At all 
other time points, a single 12-lead ECG will be performed. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn, when possible. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded in the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator.  Recordings will be archived in the patient’s files. 
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  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, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality.  Additional safety laboratory tests and assessments as indicated by the 
clinical situation may be requested.  Clinical laboratory assessments are listed in Table 3 and will 
be assessed as specified in the Schedule of Assessments (Table 1 and Table 2).   
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 3, 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 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. 
319

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
55 
Table 3: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Carbon dioxide 
Creatinine and eGFR (using the MDRD formula) 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Coagulation (at Screening) 
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time   
 
Immunogenicity (see Section 6.5.5.1) 
Antidrug antibodies 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.2) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal women 
only) 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone; 
MDRD=modification of diet in renal disease; PCR=polymerase chain reaction; RBCs=red blood cells; 
RNA=ribonucleic acid. 
6.5.5.1. 
Immunogenicity 
Serum samples will be collected to evaluate the presence of antidrug antibodies (ADA) as 
outlined in the Schedule of Assessments (Table 1).  Details regarding the blood volume, 
processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
A validated ELISA will be used that specifically detects antibodies to PEG2000-C-DMG, which is 
a component of patisiran-LNP.  Serum samples will first be analyzed with a screening assay.  
Samples testing positive for ADA in the screening assay will be further evaluated in a 
confirmatory assay.  For the samples that tested positive for ADA in the confirmatory assay, the 
ADA titer will then be determined as the reciprocal of the highest dilution of the sample that 
yielded a positive ADA test result. 
320

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
56 
6.5.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential at the timepoints 
specified in the Schedule of Assessments (Table 1 and Table 2).   
A serum pregnancy test will be performed at Screening and urine pregnancy tests will be 
performed thereafter at the timepoints specified in the Schedule of Assessments (Table 1 and 
Table 2).  More frequent pregnancy testing may be performed where required per local 
requirements.  The results of the pregnancy test must be known before study drug administration.  
Patients who are pregnant at Screening are not eligible for study participation.  Any woman with 
a positive urine pregnancy test, subsequently confirmed by a positive serum pregnancy test, 
during the study will be discontinued from study drug but will continue to be followed for safety.  
Patients determined to be pregnant while on study will be followed at least until the pregnancy 
outcome is known (see Section 6.5.7.7 for follow-up instructions). 
Follicle-stimulating hormone testing may be performed to confirm suspected post-menopausal 
status. 
6.5.6. 
Vital Status Check 
A vital status check will be performed at the timepoints specified in the Schedule of Assessments 
(Table 1 and Table 2).      
Due to the inclusion of all-cause mortality in the secondary endpoint analysis, a medical records 
release form will be required of all patients for the purpose of obtaining vital status information 
from the patient’s physician or from death registries.  The signing of this medical records release 
form is in addition to the ICF.  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.  
6.5.7. 
Adverse Events 
6.5.7.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an 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 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
321

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
57 
 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 
No AEs of clinical interest are defined for this study.  
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 AE. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  AEs characterized as intermittent require 
documentation of the start and stop of each incidence.  When changes in the severity of an AE 
occur more frequently than once a day, the maximum severity for the experience that day should 
be noted.  If the severity category changes over a number of days, then those changes should be 
recorded separately (with distinct onset dates). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?”  A “yes” response indicates that the event is considered as related to 
the study drug. 
322

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
58 
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 the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
study drug through the end of study.  Non-serious AEs will be followed until the end of study.  
Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1), while AEs that occur after study drug administration, and  
baseline events that worsen after study drug administration, must be recorded as AEs.    
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study drug 
through the end of study.  SAEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
All IRRs will be recorded as AEs.  All information on IRRs is to be recorded on the applicable 
eCRF per the CRF completion guidelines. 
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 
Not applicable.  There were no AEs of Clinical Interest identified for this study. 
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 
323

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
59 
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. 
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 12 weeks 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 12 weeks 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 
324

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
60 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 
or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 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 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 ATTR amyloidosis with 
cardiomyopathy, as well as their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
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 patisiran.   
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1 and Table 2).  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. 
325

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
61 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principal features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
The planned enrollment for this study is 300 patients.  For the change from baseline at Month 12 
in the 6-MWT, assuming a treatment difference of 33 meters between patisiran and placebo in 
the treatment-naïve group and 20 meters in patients with baseline tafamidis, the weighted 
average treatment difference between patisiran and placebo in the overall population is 
approximately 29 meters (standard deviation = 75 meters) assuming 70% are in the treatment-
naïve group and 30% are in the baseline tafamidis group.  A sample size of 300 patients provides 
>90% power for a 2-sided test to detect a mean difference between treatment groups at a 2-sided 
alpha = 0.05.  Additional patients may be enrolled based on a recommendation to increase the 
sample size in the interim assessment (Section 7.2.10). 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses for 
the primary analysis, conducted at the completion of the 12-month, double-blind period.  More 
complete plans, including planned analyses for the open-label extension period, will be detailed 
in the SAP.  Changes to the methods described in the final SAP will be described and justified as 
needed in the clinical study report.  For information on study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
 Full Analysis Set (FAS):  All randomized patients who received any amount of study 
drug, grouped according to the randomized treatment arm.   
 Safety Analysis Set:  All patients who received any amount of study drug, grouped 
according to the treatment actually received.  
 PK Analysis Set:  All patients who received any amount of study drug and have at 
least 1 postdose blood sample for PK parameters and have evaluable PK data. 
 PD Analysis Set:  All patients who received any amount of study drug and who have 
an evaluable baseline and at least 1 evaluable post-baseline serum TTR measurement 
will be included in the PD analyses. 
Efficacy endpoints will be analyzed using the Full Analysis Set.  Safety will be analyzed using 
the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct PK and PD 
analyses, respectively. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
326

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
62 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized by 
treatment arm and overall for the FAS and Safety Analysis Set. 
7.2.5. 
Efficacy Analyses 
The overall Type I error rate will be strongly controlled at a 2-sided 0.05 significance level for 
the primary and secondary endpoints using a fixed sequential testing procedure at the final 
analysis.  The primary endpoint will be compared between treatment arms at the 0.05 
significance level.  If the test of the primary endpoint is statistically significant, then the 
secondary endpoints will each be tested in the order specified in the Secondary Endpoints section 
(see Section 2).  If a test of the primary or a secondary endpoint is not statistically significant, the 
testing of the remaining endpoints in the sequence will stop. 
For patients who were tafamidis treatment-naïve at baseline and start tafamidis during the 
double-blind period, the primary analysis of the primary endpoint will censor data collected after 
the initiation of tafamidis treatment post-randomization.   
7.2.5.1. 
Primary Endpoint  
The primary endpoint, change from baseline at Month 12 in the 6-MWT, will be analyzed using 
a mixed-effects model repeated measures (MMRM) approach.  The outcome variable is change 
from baseline in the 6-MWT.  The model will include the baseline value as a covariate, 
treatment, visit, the treatment-by-visit interaction, baseline tafamidis (yes vs no), genotype 
(hATTR vs wtATTR), NYHA Class (I/II vs III), and age (<75 vs ≥75 years) as fixed factors, and 
patient as a random effect.  The primary comparison is the contrast (difference in least squares 
[LS] means) between the patisiran and placebo groups at Month 12. 
Sensitivity analyses will be detailed in the SAP. 
7.2.5.2. 
Secondary Endpoints  
Secondary endpoints are described in Section 2. 
KCCQ-OS will be analyzed using a similar MMRM model as used for the primary endpoint. 
The composite endpoint of all-cause mortality, frequency of CV-related hospitalizations and 
change from baseline in 6-MWT will be analyzed using a generalized rank-based win ratio 
method, which makes pairwise comparisons (for all possible patisiran/placebo patient pairs) of 
the 3 components in the hierarchical order specified above.  The point estimate for the win ratio 
is defined as the total number of better outcomes divided by the total number of worse outcomes 
in the patisiran group.  The detailed algorithm for assessment of this endpoint will be provided in 
the SAP.     
The composite endpoint of all-cause mortality and all-cause hospitalizations will be analyzed 
using an Andersen-Gill model stratified by baseline tafamidis (yes vs no), including treatment, 
327

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
63 
genotype (hATTR vs wtATTR), NYHA Class (I/II vs III), and age (<75 vs ≥75 years) as 
covariates. 
To control the overall Type I error rate, secondary endpoints will be tested in a prespecified 
hierarchical order. 
7.2.5.3. 
Exploratory Endpoints 
Descriptive summaries will be provided for the exploratory endpoints (Section 2), and additional 
analyses may be conducted.  Details will be described in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
The PD endpoint is serum TTR.  Summary tables will be provided for observed values, change 
and percentage change from baseline for each scheduled time point.  In addition, the maximum 
and mean percentage reduction over 12 months will be summarized.   
7.2.7. 
Pharmacokinetic Analysis 
7.2.7.1. 
Pharmacokinetic Analysis 
Plasma concentrations of ALN-18328, DLin-MC3-DMA, and PEG2000-C-DMG will be obtained 
using a model-independent method.  PK exposure parameters will include:  maximum plasma 
concentration at the end of infusion (Cmax), 30-minute post-infusion concentration (Cp(30min)), and 
pre-infusion concentration (Cmin).  In addition, the steady-state Cmax (Cmax,ss), steady-state 
Cp(30min) (Cp,ss(30min)), and steady-state Cmin (Cmin,ss) will be calculated as the average of the 
respective values at Week 24, Week 36, and Month 12. 
The PK exposure parameters will be summarized by visit, and the steady-state PK parameters 
will be summarized. 
7.2.7.2. 
Exposure-Response Analysis  
Mean and maximum percent TTR reduction from baseline will be summarized by quartiles of the 
steady state PK parameters for all 3 analytes.  Change from baseline at Month 12 in clinical 
efficacy parameters may also be summarized by quartiles of the steady-state PK parameters for 
all 3 analytes.  
PK exposure will be summarized by mortality status.  In addition, the incidence of AEs and 
SAEs will be summarized by quartiles of the steady-state PK parameters for all 3 analytes. 
7.2.7.3. 
Population PK, PK/PD, and Disease Progression Modelling Analysis 
Population PK, PK/PD, and disease progression modelling analyses may be performed, if 
appropriate.  If performed, the analyses would be conducted according to a pre-specified analysis 
plan and reported separately. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical exams.  The extent of exposure will be summarized.   
328

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
64 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary.  Results will be tabulated by the Anatomical Therapeutic Chemical classification 
system and Preferred Term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term.  The frequency and percentage of patients 
experiencing AEs, SAEs, related AEs, and AEs leading to discontinuation will be summarized 
by System Organ Class (SOC) and PT.  By patient listings will be provided for deaths, SAEs, 
and AEs leading to discontinuation.   
Descriptive statistics will be provided for clinical laboratory data, ECG, and vital signs data, 
summarizing the observed values and change from baseline over time.  Laboratory shift tables 
from baseline at the worst post-baseline values will be presented.  Abnormal physical 
examination findings and 12-lead ECG data will be presented in by-patient listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 
7.2.9. 
Immunogenicity Analyses 
 The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized.  The titer results for patients with 
confirmed positive ADA results will be summarized.  The impact of ADA on PK, PD, efficacy 
and safety endpoints will be explored.  Details will be described in the SAP. 
7.2.10. 
Sample Size Re-assessment 
Patients who are tafamidis-naïve at baseline may opt to begin tafamidis treatment (ie, “tafamidis 
drop-in”) during the double-blind period, which could result in a loss of power.  An interim 
assessment may be performed to assess the impact of tafamidis drop-in on the power and the 
potential need to increase the sample size.  The interim assessment, if conducted, would examine 
the tafamidis drop-in rates in each treatment arm in an unblinded manner without looking at the 
unblinded efficacy or safety data; therefore, no impact on the type I error is expected and no 
multiplicity adjustment will be made.  To maintain the blind for the study team, the interim 
assessment would be performed by a third party (ie, not the Sponsor) according to a prespecified 
plan. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the informed consent form 
(see Section 4.3.2). 
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 
329

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
65 
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 is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The patient’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. 
A medical records release form will be required of all patients for the purpose of obtaining vital 
status information from the patient’s physician or from death registries.  The signing of this 
medical records release form is in addition to the ICF. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study.  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 
330

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
66 
IEC and the Regulatory Authority for approval before patients are randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a potential 
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, 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 
331

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
67 
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.  CRFs 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 copy of any proposed 
publication (eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this 
332

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
68 
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). 
333

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
69 
9. 
LIST OF REFERENCES 
Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, 
an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 
5;379(1):11-21. 
Adams D, Suhr OB, Hund E, Obici L, Tournev I, Campistol JM, et al. First European consensus 
for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr 
Opin Neurol. 2016 Feb;29 Suppl 1:S14-26. 
Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, et al. Targeted 
delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol 
Ther. 2010 Jul;18(7):1357-64. 
Ando Y, Coelho T, Berk J, Waddington Cruz M, Ericzon B, Ikeda S, et al. Guideline of 
transthyretin-related hereditary amyloidosis for clinicians. Orphanet J of Rare Dis. 2013;8(31). 
Benson M,Kincaid J. The molecular biology and clinical features of amyloid neuropathy. Muscle 
Nerve. 2007;36(4):411-23. 
Biesalski HK, Frank J, Beck SC, Heinrich F, Illek B, Reifen R, et al. Biochemical but not clinical 
vitamin A deficiency results from mutations in the gene for retinol binding protein. Am J Clin 
Nutr. 1999 May;69(5):931-6. 
Bittner V, Weiner DH, Yusuf S, Rogers WJ, McIntyre KM, Bangdiwala SI, et al. Prediction of 
mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. 
SOLVD Investigators. JAMA. 1993 Oct 13;270(14):1702-7. 
Bumcrot D, Manoharan M, Koteliansky V,Sah DW. RNAi therapeutics: a potential new class of 
pharmaceutical drugs. Nat Chem Biol. 2006 Dec;2(12):711-9. 
Castano A, Drachman BM, Judge D,Maurer MS. Natural history and therapy of TTR-cardiac 
amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and 
silencer drugs. Heart Fail Rev. 2015 Mar;20(2):163-78. 
Coelho T, Merlini G, Bulawa CE, Fleming JA, Judge DP, Kelly JW, et al. Mechanism of Action 
and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis. Neurol Ther. 
2016 Jun;5(1):1-25. 
Connors L, Yamashita T, Yazaki M, Skinner M,Benson M. A rare transthyretin mutation 
(Asp18Glu) associated with cardiomyopathy. Amyloid. 2004;11(1):61-6. 
Connors LH, Lim A, Prokaeva T, Roskens VA,Costello CE. Tabulation of human transthyretin 
(TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. 
Coutinho P, DeSilva A, Lima J,Barbosa A. Forty years of experience with type I amyloid 
neuropathy: review of 483 cases. In: Glenner G,Pinho P,Costa E,Falcao de Frietas A, editors. 
Amyloid and Amyloidosis: Excerpta Medica. Amsterdam1980. p. 88-98. 
Damy T, Jaccard A, Guellich A, Lavergne D, Galat A, Deux JF, et al. Identification of 
prognostic markers in transthyretin and AL cardiac amyloidosis. Amyloid. 2016 Sep;23(3):194-
202. 
334

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
70 
Damy T, Judge DP, Kristen AV, Berthet K, Li H,Aarts J. Cardiac findings and events observed 
in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile 
hereditary transthyretin amyloidosis. J Cardiovasc Transl Res. 2015 Mar;8(2):117-27. 
Dungu JN, Anderson LJ, Whelan CJ,Hawkins PN. Cardiac transthyretin amyloidosis. Heart. 
2012 Nov;98(21):1546-54. 
Episkopou V, Maeda S, Nishiguchi S, Shimada K, Gaitanaris GA, Gottesman ME, et al. 
Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and 
thyroid hormone. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2375-9. 
Flynn KE, Lin L, Ellis SJ, Russell SD, Spertus JA, Whellan DJ, et al. Outcomes, health policy, 
and managed care: relationships between patient-reported outcome measures and clinical 
measures in outpatients with heart failure. Am Heart J. 2009 Oct;158(4 Suppl):S64-71. 
Flynn KE, Lin L, Moe GW, Howlett JG, Fine LJ, Spertus JA, et al. Relationships between 
changes in patient-reported health status and functional capacity in outpatients with heart failure. 
Am Heart J. 2012 Jan;163(1):88-94 e3. 
Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A 
new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018 Aug 7;39(30):2799-
806. 
Green CP, Porter CB, Bresnahan DR,Spertus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll 
Cardiol. 2000 Apr;35(5):1245-55. 
Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D,Suhr OB. Evolving 
landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38. 
Hou X, Aguilar MI,Small DH. Transthyretin and familial amyloidotic polyneuropathy. Recent 
progress in understanding the molecular mechanism of neurodegeneration. FEBS J. 2007 
Apr;274(7):1637-50. 
Jacobson D, Tagoe C, Schwartzbard A, Shah A, Koziol J,Buxbaum J. Relation of clinical, 
echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of 
the transthyretin V122I allele in older African-American men. Am J Cardiol. 2011 Aug 
1;108(3):440-4. 
Kristen AV, Maurer MS, Rapezzi C, Mundayat R, Suhr OB,Damy T. Impact of genotype and 
phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the 
Transthyretin Amyloidosis Outcome Survey (THAOS). PLoS One. 2017;12(4):e0173086. 
Liz MA, Mar FM, Franquinho F,Sousa MM. Aboard transthyretin: From transport to cleavage. 
IUBMB Life. 2010 Jun;62(6):429-35. 
Mangla A, Kane J, Beaty E, Richardson D, Powell LH,Calvin JE, Jr. Comparison of predictors 
of heart failure-related hospitalization or death in patients with versus without preserved left 
ventricular ejection fraction. Am J Cardiol. 2013 Dec 15;112(12):1907-12. 
Masoudi FA, Rumsfeld JS, Havranek EP, House JA, Peterson ED, Krumholz HM, et al. Age, 
functional capacity, and health-related quality of life in patients with heart failure. J Card Fail. 
2004 Oct;10(5):368-73. 
335

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
71 
Maurer M, Judge D, Rosas G, Mandel F,Aarts J. Interim analysis of long-term, open-label 
tafamidis treatment in transthyretin amyloid cardiomyopathy after up to 5 years of treatment.  
XIVth International Symposium on Amyloidosis; Indianapolis, Indiana2014. 
Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. 
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 
2018 Sep 13;379(11):1007-16. 
Merlini G, Lousada I, Ando Y, Dispenzieri A, Gertz MA, Grogan M, et al. Rationale, application 
and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in 
patients with AL amyloidosis. Leukemia. 2016 Oct;30(10):1979-86. 
Mohty D, Damy T, Cosnay P, Echahidi N, Casset-Senon D, Virot P, et al. Cardiac amyloidosis: 
updates in diagnosis and management. Arch Cardiovasc Dis. 2013 Oct;106(10):528-40. 
Okamoto S, Wixner J, Obayashi K, Ando Y, Ericzon BG, Friman S, et al. Liver transplantation 
for familial amyloidotic polyneuropathy: impact on Swedish patients' survival. Liver Transpl. 
2009;15:1229-35. 
Parman Y, Adams D, Obici L, Galan L, Guergueltcheva V, Suhr OB, et al. Sixty years of 
transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A 
European network approach to defining the epidemiology and management patterns for TTR-
FAP. Curr Opin Neurol. 2016 Feb;29 Suppl 1:S3-S13. 
Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, et al. The 
amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015 Jan 
1;372(1):21-9. 
Ruberg FL,Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012 Sep 
04;126(10):1286-300. 
Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective 
evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid 
cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012 
Aug;164(2):222-8 e1. 
Solomon SAD, Kristen A et al. Effects of Patisiran, an RNA Interference Therapeutic, on 
Cardiac Parameters in Patients with Hereditary Transthyretin-Mediated Amyloidosis: An 
Analysis of the APOLLO Study. Circulation. 2018;10.1161/CIRCULATIONAHA.118.035831. 
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. 
Westermark P, Bergstrom J, Solomon A, Murphy C,Sletten K. Transthyretin-derived senile 
systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 2003 Aug;10 
Suppl 1:48-54. 
336

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
72 
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. 
 
337

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
73 
10. 
APPENDICES 
10.1. 
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 
10.2. 
New York Heart Association Class (NYHA) 
  
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs does not 
cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, in cold weather, in wind or when under 
emotional stress causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to two blocks on the 
level and climbing more than one flight of stairs in normal conditions causes undue fatigue 
or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or dyspnea. 
10.3. 
Categorization of Infusion-Related Reactions 
Signs and symptoms of an IRR usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Signs/symptoms may 
include: allergic reaction/hypersensitivity (including drug fever), arthralgia (joint pain), 
bronchospasm, cough, dizziness, dyspnea (shortness of breath), fatigue (asthenia, lethargy, 
malaise), headache, hypertension, hypotension, myalgia (muscle pain), nausea, pruritus/itching, 
338

Clinical Study Protocol ALN-TTR02-011  
Patisiran 
Original, 18 April 2019 
Alnylam Pharmaceuticals 
Confidential 
74 
rash/desquamation, rigors/chills, sweating (diaphoresis), tachycardia, urticaria (hives, welts, 
wheals), vomiting. 
Categorization of IRRs is as follows: 
Categorization 
Description 
Mild 
Mild reaction:  infusion may be continued; if intervention is indicated it is 
minimal and additional treatment (other than paracetamol for delayed 
reactions) is not required. 
Moderate 
Moderate reaction:  requires treatment including more intensive therapy 
(eg, IV fluids, NSAIDs) in addition to infusion interruption but responds 
promptly to medication.  Treatment is indicated for ≤24 hours. 
Severe 
More than moderate reaction:  not rapidly responsive to medication or to 
interruption of infusion; and/ or prolonged (treatment is indicated for 
>24 hours); recurrence of severe symptoms following initial improvement. 
 
339