Clinical trial NCT02510261
Conditions: Amyloidosis
Keywords: RNAi therapeutic FAP Familial Amyloid Polyneuropathy TTR Transthyretin Amyloidosis
Sponsor: Alnylam Pharmaceuticals
Start date: 2015-07-16; Completion date: 2022-11-23
Enrollment: 211 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of long-term dosing with ALN-TTR02 (patisiran) in participants with transthyretin (TTR) mediated amyloidosis (ATTR).

Detailed description:

Arms: arm 1: Participants who received placebo and completed parent study ALN-TTR02-004 (NCT01960348) were enrolled to receive 0.3 milligrams per kilogram (mg/kg) patisiran intravenously (IV) once every 3 weeks (Q3W) up to 65.5 months. arm 2: Participants who received patisiran and completed parent study ALN-TTR02-004 (NCT01960348) were enrolled to receive 0.3 mg/kg patisiran IV Q3W up to 66.9 months. arm 3: Participants who received patisiran and completed parent study ALN-TTR02-003 (NCT01961921) were enrolled to receive 0.3 mg/kg patisiran IV Q3W up to 61.4 months.
Interventions: intervention 1: Patisiran
Intervention descriptions: intervention 1: Patisiran was administered IV.

Protocol documents:
Prot_000.pdf: 
Official Title:  A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE THE LONG-TERM 
SAFETY AND EFFICACY OF PATISIRAN IN PATIENTS WITH FAMILIAL AMYLOIDOTIC 
POLYNEUROPATHY WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH PATISIRAN 
NCT Number: 
NCT02510261 
Document Date: 
Protocol, Version 3.0, 05 January 2017 


PPD


Patisiran (ALN-TTR02) 
Clinical Protocol 
ALN-TTR02-006 
Version 3.0 (Amendment 2) OS January 2017 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 3.0 (Incorporating Amendment 2) 
05 January 2017 
117395 
2014-003877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Signature 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
Alnylam Pharmaceuticals 
Confidential 
1 
PPD
PPD


Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 – Global 
08 September 2015 
Incorporating Global Amendment 1 
2.1 – Japan 
14 October 2015 
Incorporating Japan-specific Amendment 1 
2.1 – Taiwan 
10 December 2015 
Incorporating Taiwan-specific Amendment 1 
2.1 – France/Germany 
17 December 2015 
Incorporating France/Germany-specific 
Amendment 1 
2.2 – Japan 
14 March 2016 
Incorporating Japan-specific Amendment 2 
3.0 - Global 
05 January 2017 
Incorporating Global Amendment 2 (including 
Japan-, Taiwan- and France/Germany-specific 
changes) 
 


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SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate dosing 
in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to this timing 
may be allowed for medical or regulatory considerations only after consultation with the Medical 
Monitor.  The last testing visit in the parent study will serve as the baseline for this study, unless more 
than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.  
Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days. Where 
applicable country and local regulations allow, patients may receive the patisiran infusions at home by 
a healthcare professional trained on the protocol and delivery of premedications and patisiran.  Patients 
who are receiving patisiran infusions at home will have a phone contact with the site at least every 30 
(±5) days.  Patients will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and 
yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 


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occur if deemed necessary by the study personnel. 
Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) and, 
in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤2 x ULN is eligible 
if the elevation is secondary to documented Gilbert’s syndrome (elevation of unconjugated 
bilirubin with normal conjugated bilirubin) and the patient has ALT and AST levels within 
normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing on Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court 


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Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
 
Intravenous dexamethasone (10 mg) or equivalent 
 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine 25 mg per os (PO, orally) or fexofenadine 30 mg 
or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who does not 
tolerate IV diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test 
 
Polyneuropathy disability (PND) score and FAP stage 
 
Nutritional status using modified body mass index (mBMI) 
 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
 
Magnetic resonance (MR) neurography (as regionally applicable) 
 
Cardiac structure and function through echocardiograms and serum levels of terminal 


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prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
 
New York Heart Association (NYHA) classification of heart failure 
 
Serum TTR 
 
Vitamin A 
 
Thyroid stimulating hormone 
 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; ophthalmology 
examinations; and assessment of suicidal ideation and behavior. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Associations between pharmacodynamic and efficacy data will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 


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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test (urine) 
Xi 
 
X 
X 
X 
X 
X 
C-SSRS Questionnaire 
 
 
X 
X 
X 
X 
X 


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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TTR Protein (ELISA) 
Xd 
 
X 
X 
X 
X 
X 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
Blood Sample for Long-term Storage 
X 
X 
X 
X 
X 
X 
X 
mNIS+7j 
Xd 
 
 
X 
 
 
[X]f 
NIS+7k 
Xd 
 
 
X 
 
 
[X]f 
NIS only 
 
 
 
 
Xl 
Xm 
Xm 
Grip Strength Testn 
Xd 
 
 
X 
 
 
[X]f 
10-Meter Walk Testp 
Xd 
 
 
X 
 
 
[X]f 
Ophthalmology Examinationq 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) r 
 
 
 
X 
X 
Xo 
Xo 
MR Neurographys (Germany & France only) 
X 
 
X 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNt 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,u 
 
 
X 
 
 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
 
[X]f 
Anti-Drug Antibody Testingv 
 
 
X 
X 
X 
X 
X 


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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Premedication / Patisiran Administrationw 
X 
X 
 
 
Phone Contactx (In applicable regions only) 
 
X 
 
 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
Table 1 Footnotes: 
Abbreviations:  C-SSRS = Columbia-Suicide Severity Rating Scale; COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked 
immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified 
body mass index; mNIS = Modified Neuropathy Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-
terminal prohormone of B-type natriuretic peptide; NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-
Diabetic Neuropathy; R-ODS = Rasch-built Overall Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = 
transthyretin 
a. 
Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may 
occur within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with 
the Medical Monitor. 
b. Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c. 
Assessment does not need to be repeated.  Information will be obtained from parent study. 
d. Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e. 
mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f. 
Assessment/procedure required only if patient withdraws before the 52-week visit. 
g. Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h. Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
i. 
Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the first dose. 


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j. 
The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days 
after the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who 
performed the assessments for the patient in the patisiran study in which they were previously enrolled.   
k. The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS 5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
l. 
One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
m. Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the 
previous 26 weeks. 
n. Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second 
(repeat) assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
o. Assessment does not need to be repeated if done within the previous 26 weeks. 
p. The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed 
on separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days 
after the first assessment. 
q. Examination will include visual acuity, visual fields, and slit-lamp evaluation. An electroretinogram may also be performed, as described in Section 9.1.6  
r. 
Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin 
biopsies in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies 
taken from the distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
s. 
MR neurography will only be conducted at sites in Germany and France. In these countries, neurography may be conductedfor patients who had MR 
neurography in the parent study and for a subset of patients providing informed consent who did not have MR neurography previously in their parent study. 
Patients who had imaging in the parent study should have Day 0 imaging if they did not undergo MR neurography within the past 3 months. 
t. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to 
complete this assessment. 
u. Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
v. Serum samples for anti-drug antibodies will be collected as specified. 
w. Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study in the 21 (±3) day timeframe.  
Doses may be administered at the clinical site or, where applicable country and local regulations allow, at home by a healthcare professional trained in the 
protocol. 
x. Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 30 (±5) days for assessment of adverse 
events and concomitant medication use. During phone contact, patients may also be asked additional questions about their general experience receiving 
infusions at home. 


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TABLE OF CONTENTS 
 
SYNOPSIS 3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
 
Infusion-Related Reactions .........................................................................................20 
 
Liver function test abnormalities ................................................................................20 
 
Vitamin A Lowering ...................................................................................................20 
 
Osteoporosis ...............................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 


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6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration.........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................36 
8.1.1.2. 
Neurological Impairment Score ..................................................................................37 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Magnetic Resonance Neurography (Germany and France Only) ...............................37 
8.1.5. 
Modified Body Mass Index ........................................................................................38 
8.1.6. 
Timed 10-meter Walk Test .........................................................................................38 
8.1.7. 
Grip Strength Test .......................................................................................................38 
8.1.8. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.10. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.11. 
Rasch-built Overall Disability Scale ..........................................................................39 
8.1.12. 
Pharmacoeconomics Questionnaire ............................................................................39 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.14. 
Transthyretin ...............................................................................................................39 
8.1.15. 
Thyroid-Stimulating Hormone ...................................................................................39 
8.1.16. 
Vitamin A ...................................................................................................................39 
8.1.17. 
Anti-Drug Antibodies .................................................................................................39 


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8.1.18. 
Blood Sample for Long-term Storage .........................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................41 
9.1. 
Safety Parameters .......................................................................................................41 
9.1.1. 
Demographic and Medical History .............................................................................41 
9.1.2. 
Vital Signs ..................................................................................................................41 
9.1.3. 
Weight and Height ......................................................................................................41 
9.1.4. 
Physical Examination .................................................................................................41 
9.1.5. 
Laboratory Assessments .............................................................................................41 
9.1.5.1. 
Hematology .................................................................................................................42 
9.1.5.2. 
Blood Chemistry .........................................................................................................42 
9.1.5.3. 
Urinalysis ....................................................................................................................42 
9.1.5.4. 
Coagulation .................................................................................................................43 
9.1.5.5. 
Pregnancy Screen ........................................................................................................43 
9.1.6. 
Ophthalmology Examination ......................................................................................43 
9.1.7. 
Columbia-Suicide Severity Rating Scale ....................................................................43 
9.2. 
Adverse Events and Serious Adverse Events .............................................................43 
9.2.1. 
Definition of Adverse Events .....................................................................................43 
9.2.1.1. 
Adverse Event .............................................................................................................43 
9.2.1.2. 
Serious Adverse Event ................................................................................................43 
9.3. 
Relationship to Study Drug ........................................................................................44 
9.4. 
Recording Adverse Events .........................................................................................44 
9.5. 
Reporting Adverse Events ..........................................................................................45 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................45 
9.5.2. 
Pregnancy Reporting ..................................................................................................47 
10. 
STATISTICS ..............................................................................................................48 
10.1. 
Sample Size ................................................................................................................48 
10.2. 
Statistical Methodology ..............................................................................................48 
10.2.1. 
Populations to be Analyzed ........................................................................................48 
10.2.2. 
Baseline Evaluations ...................................................................................................48 
10.2.3. 
Efficacy Analyses .......................................................................................................48 
10.2.4. 
Safety Analyses ..........................................................................................................49 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................49 


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10.2.6. 
Interim Analysis ..........................................................................................................49 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................50 
11.1. 
Study Monitoring ........................................................................................................50 
11.2. 
Audits and Inspections ................................................................................................50 
11.3. 
Institutional Review Board .........................................................................................50 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................51 
13. 
ETHICS ......................................................................................................................52 
13.1. 
Ethics Review .............................................................................................................52 
13.2. 
Ethical Conduct of the Study ......................................................................................52 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................52 
13.3. 
Written Informed Consent ..........................................................................................53 
13.4. 
Compensation for Health Damages ............................................................................53 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................54 
14.1. 
Case Report Forms .....................................................................................................54 
14.2. 
Confidentiality ............................................................................................................54 
14.3. 
Inspection of Records .................................................................................................55 
14.4. 
Retention of Records ..................................................................................................55 
15. 
PUBLICATION POLICY ..........................................................................................56 
16. 
LIST OF REFERENCES ............................................................................................57 
17. 
APPENDICES ............................................................................................................58 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 


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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 


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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RBP 
retinol binding protein 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH 
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WT 
wild type 


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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 


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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran Investigator’s Brochure. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 


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circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 

Infusion-Related Reactions
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an
IRR with patisiran, all patients in this study will be premedicated prior to dosing with
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR.

Liver function test abnormalities
In preclinical studies, patisiran-related increased serum liver markers and histopathology in
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In
general, all of the findings were not observed or were observed at lower severity at the end of
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical
studies to date, there have been no clinically significant changes in liver function tests in
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver
function via serial laboratory assessments.

Vitamin A Lowering
The suppression of serum levels of TTR and retinol binding protein (RBP) is expected to 
result in the lowering of circulating vitamin A levels.  Preclinical and clinical data have 
shown that the lowering of circulating vitamin A associated with suppression of RBP does 
not result in severe vitamin A deficiency.  Furthermore, there are individuals with RBP/TTR 
mutations who have life-long low levels of circulating vitamin A and are essentially in good 
health, suggesting that there are compensatory transport mechanisms for vitamin A that are 
yet undescribed.13  This has also been confirmed in TTR knockout mice, which do not exhibit 
any manifestations of vitamin A deficiency, with vitamin A uptake by most tissues 
continuing in the absence of RBP.14  Provided there is adequate vitamin A in the diet, tissue 
stores of vitamin A should not be affected by the lowering of TTR and RBP.  However, as 
the vitamin A content of the diet may vary between different countries and different 
individuals within a country, all patients on the study will be asked to take a daily 
supplement containing the recommended daily allowance of vitamin A.  Patients should have 
started vitamin A supplementation by the time they start his/her first dose of patisiran.

Osteoporosis
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone


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mineralization.  If there are no medical contraindications, and per investigator judgment and 
local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the Investigator’s Brochure. 
 


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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Patients in this study will have completed “parent” study ALN-TTR02-003 or ALN-TTR02-004.  
Note that Study ALN-TTR02-003 is not being conducted in Japan.  
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days.  Where applicable country and local regulations allow,  patients may receive the 
patisiran infusions at home by a healthcare professional trained on the protocol and delivery of 
premedications and patisiran.  Patients who are receiving patisiran infusions at home will have a 
phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the 
clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 


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after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor (Alnylam Pharmaceuticals, Inc). 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or Medpace, 
and the Investigators, Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
and Regulatory Authorities will be promptly informed of the termination and the reason for the 
decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up. 


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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on 
anticoagulant therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing on Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 


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5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting 
his/her interests due to a medically diagnosed impairment of his/her mental faculties that 
may limit or prevent the expression of his will”), decided by a court 
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
 Is in violation of the protocol 
 Experiences a serious or intolerable AE 
 Becomes pregnant 
 Requires a prohibited medication (see Section 5.2) 
 Requests to be withdrawn from the study 
 Is found to be considerably noncompliant with the protocol-required patisiran dosing 
visits 
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not 
known whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients 
who are male or who are women of child bearing potential will affect reproduction.  
Histopathological evaluations of all of the reproductive organs have been conducted in the rat 
and non-human primate (NHP) toxicology studies including a chronic NHP study in sexually 
mature animals, where there were no adverse effects in males (including sperm analyses and 
spermatogenic staging) or females.  In a dose range-finding rat embryo/fetal development study 


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conducted with patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
Women of child-bearing potential are defined as any woman or adolescent who has begun 
menstruation. A post-menopausal woman is defined as a woman who has 12 months of 
spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels 
>40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
 Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
 Placement of an intrauterine device (IUD) 
 Placement of an intrauterine system (IUS) 
 Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
 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); 
 Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
 Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
 IUD in conjunction with condom or diaphragm and spermicide 
 Surgical sterilization of partner in conjunction with condom or diaphragm and 
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Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
In Japan it is recommended that the Investigators select appropriate contraception methods, as 
available. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 


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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
 Any investigational agent other than patisiran 
 Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
 Tafamidis 
 Diflunisal 
 Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take the recommended daily allowance of vitamin A. 
Patients will receive this daily dose for the duration of their participation in the study while being 
administered patisiran. In Japan, the clinical sites will provide patients with a prescription for 
vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 


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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff or (in applicable regions) trained home healthcare professionals.  A 
dose will be considered completed if 80% or more of the total volume of the IV solution was 
administered to the patient.  Patients will be permitted to miss an occasional dose of patisiran; 
however, if a patient misses 3 consecutive doses, the Investigator, in consultation with the 
Medical Monitor, will discuss whether the patient will be able to continue on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 


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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 


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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 

Intravenous dexamethasone (10 mg) or equivalent

Oral paracetamol/acetaminophen (500 mg) or equivalent

Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2
blocker dose)

Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker
available at the clinical site).  Hydroxyzine 25 mg per os (PO, orally) or fexofenadine
30 mg or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who
does not tolerate IV diphenhydramine or other IV H1 blocker.
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 

If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.

If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid
premedication will be lowered, then the following steps must be followed:
1)
If the current steroid dosage is 10 mg or less of intravenous dexamethasone or
equivalent, then the patient may be lowered in increments no greater than 2.5 mg
intravenous dexamethasone or equivalent.
2)
After each incremental lowering of intravenous dexamethasone or equivalent, the patient
must receive three consecutive intravenous doses of patisiran without IRR and continued
signs or symptoms of steroid intolerance before further reductions in steroid
premedications.
3)
The premedication steroid dosage should not be reduced below 5 mg intravenous
dexamethasone or equivalent.
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone 
or equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 


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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
Patients who have received at least 3 doses of patisiran on this study at the clinical site with no 
evidence of IRRs or other adverse effects may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be done by 
a healthcare professional trained on the protocol and delivery of premedications and patisiran. 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 

If the patient experiences an IRR the infusion time may be extended up to 3 hours in the
event of a mild or moderate IRR.
1)
If the patient experiences a mild or moderate IRR that resolves by slowing the infusion
rate then no further premedication changes are recommended.
2)
If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).

If the infusion time for a patient was already extended on the parent study due to an IRR, that
modified infusion duration may be continued on this study for that particular patient.
Returning the patient’s infusion duration to 70 minutes will require a discussion with the
Medical Monitor.

For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following
completion of dosing.
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A .  Patients will receive this daily dose for the duration of their participation in the 
study while being administered patisiran.  In Japan the clinical sites will provide the subjects 
with a prescription for vitamin A.. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 

In the event of an IRR, the infusion of patisiran may be stopped and the patient closely
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and
permit resumption of patisiran administration include, but are not limited to:
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids.

Following resolution of a mild or moderate IRR that required interruption of the patisiran
infusion, resumption of administration may occur at the Investigator’s discretion at a slower


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infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of 
patisiran.  If the infusion is delayed, the administration of the infusion should be completed 
no more than 6 hours from the initial start of the infusion.   
 Patisiran 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee (or in Japan, the responsible pharmacist designated according to the 
Japan local regulations) will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 


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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 


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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place at the CAS.  Patients will not receive study drug at this visit.  
A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
 Clinical exam-based NIS (weakness and reflexes) 
 Electrophysiologic measures of small and large nerve fiber function (+7) including: 
 Nerve conduction studies (NCS) 5 attributes (Σ5) 
 Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
 Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
 Full NIS (including weakness, sensation, and reflexes) 
 Electrophysiologic measures of small and large nerve fiber function (+7) including: 
 NCS 5 
 Vibration detection threshold (VDT) 
 Heart rate response to deep breathing (HRdb) 


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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Magnetic Resonance Neurography (Germany and France Only) 
Magnetic resonance (MR) neurography will only be performed at sites in Germany and France. 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional 
images for the evaluation of peripheral nerve disorders.16  This procedure produces detailed 
images of nerve morphology to evaluate degeneration and regeneration.  Nerves in the lumbar 
plexus and lower extremity may be imaged for patients in Germany and France who have 
previously had MR neurography in the parent study and for  a subset of patients providing 
informed consent who did not have MR neurography previously in the parent study.  A central 
reader will be used for MR neurography. 


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8.1.5. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.6. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.7. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.8. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.10. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 


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8.1.11. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.12. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.14. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.15. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.16. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A. 
8.1.17. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1. 
8.1.18. 
Blood Sample for Long-term Storage 
To permit exploratory investigations and the application of novel approaches to bioanalysis that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action and/or efficacy of patisiran, blood samples will be collected for 
long-term storage. These samples will be securely stored in a central biorepository for up to 10 


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years following the last patient last visit in this clinical study. After 10 years have elapsed, 
samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of samples will be provided in 
the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
All study participants will be advised during the informed consent process of these biobanking 
details and the potential for exploratory investigation of their samples. Those who do not wish to 
contribute specimens to the biorepository will be asked to sign an “opt out” form. Moreover, 
patients who subsequently decide to withdraw consent for the utilization of such stored samples 
will be able to do so, with the understanding that any data arising from samples already analyzed 
will be the property of Alnylam Pharmaceuticals. 


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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 


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In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
 Hematocrit 
 Neutrophils, absolute and % 
 Hemoglobin 
 Lymphocytes, absolute and % 
 Red blood cell (RBC) count 
 Monocytes, absolute and % 
 White blood cell (WBC) count 
 Eosinophils, absolute and % 
 Mean corpuscular volume 
 Basophils, absolute and % 
 Mean corpuscular hemoglobin 
 Platelet count 
 Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
 Aspartate transaminase (AST) 
 Alkaline phosphatase 
 Alanine transaminase (ALT) 
 Bilirubin (total and direct) 
 Sodium 
 Glucose 
 Potassium 
 Phosphate 
 Blood urea nitrogen (BUN) 
 Albumin 
 Creatinine 
 Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
 Visual inspection for color and appearance 
 Leukocytes 
 pH 
 Bilirubin 
 Specific gravity 
 Nitrite 
 Ketones 
 Urobilinogen 
 Protein 
 Microscopic inspection of sediment 
 Glucose 
 


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9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to 
determine if there is damage to rods and cones.  ERG testing should be performed if visual 
changes raise the suspicion for this sort of retinal disease and if clinically indicated.  
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.1.7. 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to assess each patient's 
mental status as it relates to suicidal ideation and behavior. 
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 


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 Results in death 
 Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 


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Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
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). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 
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Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 


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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
 Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
 Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Associations between PD (serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the 5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.   
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 


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and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
A listing of healthcare utilization data will be  presented. 
10.2.6. 
Interim Analysis 
Interim data examinations may be performed, but these will be of a descriptive nature and will 
not involve any formal hypothesis testing. 


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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator and the site will permit study-related monitoring, audits and review by the IEC 
or IRB and/or Regulatory Authorities, providing direct access to source data/documents.  The 
study may be subject to audit by the Sponsor or its representatives or by regulatory authorities.  
If such an audit occurs, the Investigator must agree to allow access to the required patient 
records.  In the event of an audit, the Investigator agrees to allow the Sponsor, representatives 
from the Sponsor, or regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 


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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
The Investigator should not start any study procedure with the patient until documentation of the 
approval by the IEC/IRB and written notification of the approval from the head of the study site 
to the Investigator and Alnylam Pharmaceuticals, Inc. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Medical Association Declaration of Helsinki, 
the ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use, the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) in the US, and all other 
applicable medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 


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13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
13.4. 
Compensation for Health Damages 
A copy of the certificate of insurance as a measure to compensation for health damages will be 
submitted to the IRB/IEC if required per local regulations. 
 


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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 


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14.3. 
Inspection of Records 
The Sponsor 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, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 


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15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 


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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2 
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3 
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4 
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5 
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6 
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7 
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8 
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9 
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10 
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11 
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13 
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14 
Episkopou, V., 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. 90: p. 2375-2379. 
15
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy 
and in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
16 
Kollmer J, Hund E, Hornung B, Schönland S, et al. MR-neurography: In-vivo detection of nerve 
injury in systemic light chain (AL) amyloidosis. XIVth International Symposium on 
Amyloidosis, 2014. 


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17. 
APPENDICES 
 
Appendix 1: Karnofsky Scale 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 


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


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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 


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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
 
Weakness (192) 
 
Sensation (32) 
 
Reflexes (20) 
 
Nerve conduction studies ∑5 (18.6)a 
 
Sural SNAP, tibial motor n. distal latency, peroneal 
CMAP/motor n. conduction velocity/motor n. distal 
latency 
 
Vibration detection threshold (3.7) 
 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
 
Weakness (192) 
 
Reflexes (20) 
 
Nerve conduction studies ∑5 (10)a 
 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 


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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 


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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 


ALN-TTR02  
 
Clinical Study Protocol ALN-TTR02-006 
 
 Amendment 2 Summary of Changes_05 January 2017 
 
ALN-TTR02-006 Protocol Amendment 2 
Summary of Changes (dated 05 January 2017)  
compared to Protocol Amendment 1 (dated 08 September 2015) 
A Multicenter, Open-label, Extension Study to Evaluate the Long-Term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy who have 
Completed a Prior Clinical Study with Patisiran 
 
Rationale for Protocol Amendment 
The primary purpose of this amendment is to add the Columbia-Suicide Severity Rating Scale 
(C-SSRS) to the study assessments, which was inadvertently left out of previous versions of the 
protocol. The inclusion of the C-SSRS addresses a regulatory requirement to prospectively 
assess suicidality in clinical trials involving all drugs for neurological indications.  Overall, this 
amendment includes the following changes: 
• The Columbia-Suicide Severity Rating Scale has been added as an assessment of suicidal 
ideation and behavior. 
• Country-specific versions of the protocol have been integrated in order to increase 
consistency in the execution of the clinical study globally 
• Electroretinograms are now recommended to be performed in the case of suspected 
retinal disease. 
• The premedication regimen has been updated to align with commercially available doses. 
• Blood samples for long-term storage have been added in order to permit future 
exploratory investigations. 
• During scheduled phone contact, clinical sites may now ask patients who are receiving 
home infusions about their general experience receiving these infusions 
A detailed summary of the above changes, in addition to changes made for clarity, is provided in 
Table 1.  Corrections to abbreviations, typographical errors and formatting are not detailed. 
 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment 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: Added Columbia-Suicide Severity Rating Scale to the study assessments 
The primary change occurs in Table 1 Schedule of Assessments 
Added text: 
Added row to Schedule of Assessments indicating that the Columbia-Suicide Severity Rating Scale is to be 
collected at 26 weeks and 52 weeks after baseline and annually thereafter, as well as at the End of Study and Early 
Withdrawal visits. 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Criteria for Evaluation, Safety 
• 
Section 9.1.7 Columbia-Suicide Severity Rating Scale (section added) 
Purpose: As part of global protocol integration, specified that home infusions are allowed only where applicable country and local regulations 
allow. 
The primary change occurs in Section 3.1 Overall Study Design 
Added text: 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 21 (±3) days, or. 
Where applicable country and local regulations allow, patients may receive the patisiran infusions at home by a 
healthcare professional trained on the protocol and delivery of premedications and patisiran. 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Methodology 
• 
Table 1, Schedule of Assessments 
• 
Section 5.3 Treatment Compliance 
• 
Section 6.4.2 Study Drug Administration 
Purpose: As part of global protocol integration, specified that MR neurography is only to be conducted in Germany and France 
The primary change occurs in Table 1 Schedule of Assessments, footnote s 
Now reads: 
Required only forMR neurography will only be conducted at sites in Germany and France. In these countries, 
neurography may be conducted for patients who had MR neurography in the parent study and may be imaged for 
consentingfor a subset of patients providing informed consent who did not have MR neurography previously in 
their parent study.  Patients who had imaging in the parent study should have Day 0 imaging if they did not 
undergo MR neurography within the past 3 months. 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Criteria for evaluation, Efficacy 
• 
Section 8.1 Efficacy Parameters 
• 
Section 8.1.4 Magnetic Resonance Neurography (Germany and France Only) (Section has been added) 
Purpose: As part of global protocol integration, specified which studies patients may roll in from, and that the ALN-TTR02-003 study is not being 
conducted in Japan. 
The primary change occurs in Section 3.1 Overall Study Design 
Added text: 
Patients in this study will have completed “parent” study ALN-TTR02-003 or ALN-TTR02-004.  Note that 
Study ALN-TTR02-003 is not being conducted in Japan. 
Purpose: As part of global protocol integration, added Japan-specific recommendations regarding contraception. 
The primary change occurs in Section 4.4 Pregnancy and Breastfeeding Restrictions / Contraception Requirements 
Added text: 
In Japan it is recommended that the Investigators select appropriate contraception methods, as available. 
Purpose: As part of global protocol integration, added Japan-specific instructions regarding duties related to study drug accountability. 
The primary change occurs in Section 6.5 Study Drug Accountability 
Added text: 
The Investigator or designee (or in Japan, the responsible pharmacist designated according to the Japan local 
regulations) will maintain accurate records of receipt and the condition of the patisiran supplied for this study, 
including dates of receipt. 
Purpose: As part of global protocol integration, added statement on compensation for health damages as per local regulations. 
The primary change occurs in Section 13.4 Compensation for Health Damages (section added) 
Added text: 
13.4    Compensation for Health Damages 
 
A copy of the certificate of insurance as a measure to compensation for health damages will be submitted to 
the IRB/IEC if required per local regulations 
Purpose: To update premedication regimen so that it aligns with commercially available doses. 
The primary change occurs in Section 6.4.1 Premedication 
Now reads: 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker available at the clinical site).  
Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or fexofenadine 30 mg or 60 mg PO or cetirizine 10 mg 
PO may be substituted for any patient who does not tolerate IV diphenhydramine or other IV H1 blocker. 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Investigational product, dosage and mode of administration 
Purpose: Added recommendation to collect an electroretinogram in the case of suspected retinal injury 
The primary change occurs in Section 9.1.6 Ophthalmology Examination 
Added text: 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to determine if there 
is damage to rods and cones.  ERG testing should be performed if visual changes raise the suspicion for this 
sort of retinal disease and if clinically indicated. 
Section(s) also containing this change or similar changes: 
• 
Table 1, Schedule of Assessments 
Purpose: Updated description of statistical analysis to align with currently planned analytic approach. 
The primary change occurs in Section 10.2.3 Efficacy Analyses 
Now reads: 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the subset of patients 
that have previously received placebo in the parent study, comparisons for the various efficacy assessments will be 
made between rates of change pre- and post-administration of patisiran, and relative to the treatment group in the 
parent study.  Additional analyses will compare rates of change with rates estimated from previous studies, 
including cross-sectional, natural history, and interventional studies of other drugs.  Associations between PD 
(serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the mNIS +7 composite 
score.  Summaries will also be provided for the components of the composite score (ie, the NIS weakness and reflex 
scores, the Σ5 NCS, and QST values).  The NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS 
will be summarized also.  Values of the individual components of the mNIS weakness and reflex scores will be 
depicted graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Statistical Methods 
• 
Section 10.2.5 Healthcare Utilization Assessments 
• 
Section 10.2.6 Interim Analysis 
Purpose: Added blood sampling for long-term storage in order to permit future exploratory investigations. 
The primary change occurs in Table 1 Schedule of Assessments 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
Added text: 
Added row to Schedule of Assessments indicating a blood sample for long-term storage is to be collected at each 
clinic visit. 
Section(s) also containing this change or similar changes: 
• 
Section 8.1.18 Blood Sample for Long-term Storage (section added) 
Purpose: Added questionnaire regarding experience of home infusions to scheduled phone contact for home infusion patients. 
The primary change occurs in Table 1 Schedule of Assessments, footnote x 
Added text: 
x. Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 
30 (±5) days for assessment of adverse events and concomitant medication use. During phone contact, patients 
may also be asked additional questions about their general experience receiving infusions at home. 
Purpose: Added a definition of “woman of child-bearing potential”. 
The primary change occurs in Section 4.4 Pregnancy and Breastfeeding Restrictions / Contraception Requirements 
Added text: 
Women of child-bearing potential are defined as any woman or adolescent who has begun menstruation. A 
post-menopausal woman is defined as a woman who has 12 months of spontaneous amenorrhea or 6 months 
of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks postsurgical bilateral 
oophorectomy with or without hysterectomy. 
Purpose: Clarified language on Vitamin A dosing and added Japan-specific instructions. 
The primary change occurs in Section 5.2 Concomitant Medications 
Now reads: 
All patients will be asked to continue to take an oral daily supplement containing the recommended daily allowance 
of vitamin A. Patients will receive this daily dose for the duration of their participation in the study while 
being administered patisiran. In Japan, the clinical sites will provide patients with a prescription for vitamin 
A. 
Section(s) also containing this change or similar changes: 
• 
Section 6.4.2 Study Drug Administration 
• 
Section 8.1.16 Vitamin A 
Purpose: Clarified procedures for efficacy assessments, adding the location at which to conduct assessments, and removing specified duration. 
The primary change occurs in Section 8.1 Efficacy Parameters 
Now reads: 
Efficacy assessments will occur for all patients at the 52-week visit, which will take place over 2 daysat the CAS. 
Purpose: Removed language indicating that anti-drug antibodies would only be analyzed if clinically indicated. 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
The primary change occurs in Section 8.1.17 Efficacy Parameters 
Deleted text: 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may be analyzed, if 
clinically indicated. 
Section(s) also containing this change or similar changes: 
• 
Table 1, Schedule of Assessments 
Purpose: Clarified that no study procedures may occur until approval is granted by all appropriate parties. 
The primary change occurs in Section 13.1 Ethics Review 
Added text: 
The Investigator should not start any study procedure with the patient until documentation of the approval 
by the IEC/IRB and written notification of the approval from the head of the study site to the Investigator 
and Alnylam Pharmaceuticals, Inc. 
 
 
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70
Patisiran (ALN-TTR02) 
Clinical Protocol 
ALN-TTR02-006 
Version 2.0 (Amendment 1) 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 2.0 (Incorporating Amendment 1) 
08 September 2015 
117395 
2014-003877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
Alnylam Pharmaceuticals 
Confidential 
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PPD


Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
Version 2.0 (Amendment 1) 
 
Alnylam Pharmaceuticals 
Confidential 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 
08 September 2015 
Incorporating Global Amendment 1 
 
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SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior 
Clinical Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate 
dosing in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to 
this timing may be allowed for medical or regulatory considerations only after consultation with the 
Medical Monitor.  The last testing visit in the parent study will serve as the baseline for this study, 
unless more than 45 days have elapsed, in which case the baseline tests will need to be repeated on 
Day 0.  Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days, or 
receive the patisiran infusions at home by a healthcare professional trained on the protocol and 
delivery of premedications and patisiran.  Patients who are receiving patisiran infusions at home will 
have a phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the 
clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
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Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN are 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing 
in this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation and 
for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit 
or prevent the expression of his will”), decided by a court 
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Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
• 
Intravenous dexamethasone (10 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or 
cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
• 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
• 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
• 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
• 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
• 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk 
test, and grip strength test 
• 
Polyneuropathy disability (PND) score and FAP stage 
• 
Nutritional status using modified body mass index (mBMI) 
• 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
• 
Magnetic resonance (MR) neurography  
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• 
Cardiac structure and function through echocardiograms and serum levels of terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
• 
New York Heart Association (NYHA) classification of heart failure 
• 
Serum TTR 
• 
Vitamin A 
• 
Thyroid Stimulating Hormone 
• 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical 
laboratory tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; 
measurement of anti-drug antibodies (if clinically indicated); vital signs; physical examinations; and 
ophthalmology examinations. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Efficacy analyses will examine between- and within-subject rates of change over time.  For the subset 
of patients that have previously received placebo in the parent study, comparisons for the various 
efficacy assessments will be made between rates of change pre- and post-administration of patisiran, 
and relative to the treatment group in the parent study.  Additional exploratory analyses will compare 
rates of change with rates estimated from previous studies, including cross-sectional, natural history, 
and interventional studies of other drugs.  Associations between pharmacodynamic and efficacy data 
will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to 
each on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
[X]f 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test (urine) 
Xk 
 
X 
X 
X 
X 
X 
TTR Protein (ELISA) 
X 
 
X 
X 
X 
X 
X 
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Clinical Protocol 
 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
mNIS+7l 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS+7m 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS only 
 
 
 
 
Xn 
Xn,p 
Xn,p 
Grip Strength Testq 
Xd 
 
 
X 
 
[X]f 
[X]f 
10-Meter Walk Testr 
Xd 
 
 
X 
 
[X]f 
[X]f 
Ophthalmology Examinations 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) t 
 
 
 
X 
X 
Xo 
Xo 
MR Neurographyu 
 
 
 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNv 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
[X]f 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
[X]f 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,w 
 
 
X 
 
[X]f 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
[X]f 
[X]f 
Anti-Drug Antibody Testingx 
 
 
X 
X 
X 
X 
X 
Premedication / Patisiran Administration 
Xy 
Xy 
 
 
Phone Contact 
 
Xz 
 
 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
Table 1 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = 
familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified body mass index; mNIS = Modified Neuropathy 
Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; 
NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; R-ODS = Rasch-built Overall 
Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = transthyretin 
a Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may occur 
within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with the 
Medical Monitor. 
b Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c Assessment does not need to be repeated.  Information will be obtained from parent study. 
d Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f Assessment/procedure required only if patient withdraws before the 52-week visit. 
g Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
k Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the first dose. 
l The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (Σ5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
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separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after 
the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who performed the 
assessments for the patient in the patisiran study in which they were previously enrolled.   
m The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
n One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
o Assessment does not need to be repeated if done within the previous 26 weeks. 
p Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the previous 
26 weeks. 
q Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
r The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed on separate 
days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after the first 
assessment. 
s Examination will include visual acuity, visual fields, and slit-lamp evaluation. 
t Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin biopsies 
in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies taken from the 
distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
u Required only for patients who had MR neurography in the parent study and may be imaged for consenting patients who did not have MR neurography 
previously in their parent study.   
v Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to complete 
this assessment. 
w Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
x Serum samples for anti-drug antibodies will be collected as specified.  Samples may be analyzed, if clinically indicated. 
y Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study within the 21 (±3) days 
timeframe.  Doses may be administered at the clinical site or at home by a healthcare professional trained in the protocol. 
z Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 30 (±5) days for assessment of adverse events 
and concomitant medication use. 
 
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TABLE OF CONTENTS 
 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
1.4.1. 
Infusion-Related Reactions .........................................................................................20 
1.4.2. 
Vitamin A Lowering ...................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 
6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
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6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration.........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................36 
8.1.1.2. 
Neurological Impairment Score ..................................................................................37 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Magnetic Resonance Neurography .............................................................................37 
8.1.5. 
Modified Body Mass Index ........................................................................................38 
8.1.6. 
Timed 10-meter Walk Test .........................................................................................38 
8.1.7. 
Grip Strength Test .......................................................................................................38 
8.1.8. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.10. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.11. 
Rasch-built Overall Disability Scale ..........................................................................39 
8.1.12. 
Pharmacoeconomics Questionnaire ............................................................................39 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.14. 
Transthyretin ...............................................................................................................39 
8.1.15. 
Vitamin A ...................................................................................................................39 
8.1.16. 
Anti-Drug Antibodies .................................................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................40 
9.1. 
Safety Parameters .......................................................................................................40 
9.1.1. 
Demographic and Medical History .............................................................................40 
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9.1.2. 
Vital Signs ..................................................................................................................40 
9.1.3. 
Weight and Height ......................................................................................................40 
9.1.4. 
Physical Examination .................................................................................................40 
9.1.5. 
Laboratory Assessments .............................................................................................40 
9.1.5.1. 
Hematology .................................................................................................................41 
9.1.5.2. 
Blood Chemistry .........................................................................................................41 
9.1.5.3. 
Urinalysis ....................................................................................................................41 
9.1.5.4. 
Pregnancy Screen ........................................................................................................42 
9.1.6. 
Ophthalmology Examination ......................................................................................42 
9.2. 
Adverse Events and Serious Adverse Events .............................................................42 
9.2.1. 
Definition of Adverse Events .....................................................................................42 
9.2.1.1. 
Adverse Event .............................................................................................................42 
9.2.1.2. 
Serious Adverse Event ................................................................................................42 
9.3. 
Relationship to Study Drug ........................................................................................43 
9.4. 
Recording Adverse Events .........................................................................................43 
9.5. 
Reporting Adverse Events ..........................................................................................44 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................44 
9.5.2. 
Pregnancy Reporting ..................................................................................................46 
10. 
STATISTICS ..............................................................................................................47 
10.1. 
Sample Size ................................................................................................................47 
10.2. 
Statistical Methodology ..............................................................................................47 
10.2.1. 
Populations to be Analyzed ........................................................................................47 
10.2.2. 
Baseline Evaluations ...................................................................................................47 
10.2.3. 
Efficacy Analyses .......................................................................................................47 
10.2.4. 
Safety Analyses ..........................................................................................................48 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................48 
10.2.6. 
Interim Analysis ..........................................................................................................48 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................49 
11.1. 
Study Monitoring ........................................................................................................49 
11.2. 
Audits and Inspections ................................................................................................49 
11.3. 
Institutional Review Board .........................................................................................49 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................50 
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13. 
ETHICS ......................................................................................................................51 
13.1. 
Ethics Review .............................................................................................................51 
13.2. 
Ethical Conduct of the Study ......................................................................................51 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................51 
13.3. 
Written Informed Consent ..........................................................................................51 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................53 
14.1. 
Case Report Forms .....................................................................................................53 
14.2. 
Confidentiality ............................................................................................................53 
14.3. 
Inspection of Records .................................................................................................53 
14.4. 
Retention of Records ..................................................................................................54 
15. 
PUBLICATION POLICY ..........................................................................................55 
16. 
LIST OF REFERENCES ............................................................................................56 
17. 
APPENDICES ............................................................................................................57 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
Σ5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WHO 
World Health Organization 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
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serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran IB. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
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nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
• Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an 
IRR with patisiran, all patients in this study will be premedicated prior to dosing with 
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a 
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing 
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
• Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in 
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the end of 
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical 
studies to date, there have been no clinically significant changes in liver function tests in 
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver 
function via serial laboratory assessments. 
• Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of 
circulating vitamin A levels.  Preclinical and clinical data have shown that the lowering of 
circulating vitamin A associated with suppression of RBP does not result in severe vitamin A 
deficiency.  Furthermore, there are individuals with RBP/TTR mutations who have life-long 
low levels of circulating vitamin A and are essentially in good health, suggesting that there 
are compensatory transport mechanisms for vitamin A that are yet undescribed.13  This has 
also been confirmed in TTR knockout mice, which do not exhibit any manifestations of 
vitamin A deficiency, with vitamin A uptake by most tissues continuing in the absence of 
RBP.14  Provided there is adequate vitamin A in the diet, tissue stores of vitamin A should 
not be affected by the lowering of TTR and RBP.  However, as the vitamin A content of the 
diet may vary between different countries and different individuals within a country, all 
patients on the study will be asked to take a daily supplement containing the recommended 
daily allowance of vitamin A.  Patients should have started vitamin A supplementation by the 
time they start his/her first dose of patisiran. 
• Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone 
mineralization.  If there are no medical contraindications, and per investigator judgment and 
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local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the IB. 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days, or receive the patisiran infusions at home by a healthcare professional trained on 
the protocol and delivery of premedications and patisiran.  Patients who are receiving patisiran 
infusions at home will have a phone contact with the site at least every 30 (±5) days.  Patients 
will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly 
thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
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which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or its 
representative, and the Investigators, Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) and Regulatory Authorities will be promptly informed of the termination and the 
reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
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4.
SELECTION AND WITHDRAWAL OF PATIENTS
4.1. 
Patient Inclusion Criteria
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study)
and, in the opinion of the investigator, tolerated study drug
2. Be considered fit for the study by the Investigator
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on
anticoagulant therapy with an INR of ≤3.5 will be allowed)
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST
levels within normal ranges.
5. Have a serum creatinine ≤2 × ULN
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study. 
Highly effective methods of birth control are defined in Section 4.4.
7. Males with partners of child-bearing potential must agree to use 1 barrier method
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study
participation and for 75 days after the last dose of patisiran in this study; males must also
abstain from sperm donation after the first dose of patisiran through study participation
and for 75 days after last dose of patisiran in this study
8. Be willing and able to comply with the protocol-required visit schedule and visit
requirements and provide written informed consent
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not
be completed before the first dose of patisiran administration
2. Has poorly controlled diabetes mellitus
3. Has uncontrolled cardiac arrhythmia or unstable angina
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid
(TUDCA), unless previously allowed per the parent study
5. Is unable to take the required premedications, unless modifications to the premedication
regimen were previously allowed per the parent study
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6. Is under legal protection (defined as “any person who becomes incapable of protecting
his/her interests due to a medically diagnosed impairment of his/her mental faculties that
may limit or prevent the expression of his will”), decided by a court
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
•
Is in violation of the protocol
•
Experiences a serious or intolerable AE
•
Becomes pregnant
•
Requires a prohibited medication (see Section 5.2)
•
Requests to be withdrawn from the study
•
Is found to be considerably noncompliant with the protocol-required patisiran dosing
visits
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not 
known whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients 
who are male or who are women of child bearing potential will affect reproduction.  
Histopathological evaluations of all of the reproductive organs have been conducted in the rat 
and non-human primate (NHP) toxicology studies including a chronic NHP study in sexually 
mature animals, where there were no adverse effects in males (including sperm analyses and 
spermatogenic staging) or females.  In a dose range-finding rat embryo/fetal development study 
conducted with patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
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or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
• Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
• Placement of an intrauterine device (IUD) 
• Placement of an intrauterine system (IUS) 
• Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
• 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); 
• Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
• Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
• IUD in conjunction with condom or diaphragm and spermicide 
• Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
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CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
• Any investigational agent other than patisiran 
• Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
• Tafamidis 
• Diflunisal 
• Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take an oral daily supplement containing the 
recommended daily allowance of vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 
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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff or trained home healthcare professionals.  A dose will be considered 
completed if 80% or more of the total volume of the IV solution was administered to the patient.  
Patients will be permitted to miss an occasional dose of patisiran; however, if a patient misses 
3 consecutive doses, the Investigator, in consultation with the Medical Monitor, will discuss 
whether the patient will be able to continue on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 
•
Intravenous dexamethasone (10 mg) or equivalent
•
Oral paracetamol/acetaminophen (500 mg) or equivalent
•
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2
blocker dose)
•
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker
available at the clinical site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally)
or cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV
diphenhydramine or other IV H1 blocker.
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 
•
If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.
•
If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid
premedication will be lowered, then the following steps must be followed:
1)
If the current steroid dosage is 10 mg or less of intravenous dexamethasone or
equivalent, then the patient may be lowered in increments no greater than 2.5 mg
intravenous dexamethasone or equivalent.
2)
After each incremental lowering of intravenous dexamethasone or equivalent, the patient
must receive three consecutive intravenous doses of patisiran without IRR and continued
signs or symptoms of steroid intolerance before further reductions in steroid
premedications.
3)
The premedication steroid dosage should not be reduced below 5 mg intravenous
dexamethasone or equivalent.
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone or 
equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
Patients who have received at least 3 doses of patisiran on this study at the clinical site with no 
evidence of IRRs or other adverse effects may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be done 
according to a site-specific plan by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran. 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 
•
If the patient experiences an IRR the infusion time may be extended up to 3 hours in the
event of a mild or moderate IRR.
1)
If the patient experiences a mild or moderate IRR that resolves by slowing the infusion
rate then no further premedication changes are recommended.
2)
If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).
•
If the infusion time for a patient was already extended on the parent study due to an IRR, that
modified infusion duration may be continued on this study for that particular patient.
Returning the patient’s infusion duration to 70 minutes will require a discussion with the
Medical Monitor.
•
For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following
completion of dosing.
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A in an oral supplement. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
•
In the event of an IRR, the infusion of patisiran may be stopped and the patient closely
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and
permit resumption of patisiran administration include, but are not limited to:
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids.
•
Following resolution of a mild or moderate IRR that required interruption of the patisiran
infusion, resumption of administration may occur at the Investigator’s discretion at a slower
infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of
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patisiran.  If the infusion is delayed, the administration of the infusion should be completed 
no more than 6 hours from the initial start of the infusion.   
• Patisiran 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place over 2 days.  Patients will not receive study drug at this 
visit.  A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
• Clinical exam-based NIS (weakness and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− Nerve conduction studies (NCS) 5 attributes (Σ5) 
− Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
• Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
• Full NIS (including weakness, sensation, and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− NCS Σ5 
− Vibration detection threshold (VDT) 
• Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Magnetic Resonance Neurography 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional 
images for the evaluation of peripheral nerve disorders.16  This procedure produces detailed 
images of nerve morphology to evaluate degeneration and regeneration.  Nerves in the lumbar 
plexus and lower extremity will be imaged for patients who have previously had MR 
neurography in the parent study and may be imaged for consenting patients who did not have 
MR neurography previously in the parent study.  A central reader will be used for MR 
neurography. 
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8.1.5. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.6. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.7. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.8. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.10. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
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8.1.11. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.12. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.14. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.15. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.16. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A supplementation. 
8.1.17. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may 
be analyzed, if clinically indicated. 
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9.
ASSESSMENT OF SAFETY
9.1. 
Safety Parameters
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran administration, the test should be repeated and followed up at the discretion of the 
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Investigator until it has returned to the normal range or stabilized, and/or a diagnosis is made to 
adequately explain the abnormality. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
• Aspartate transaminase (AST) 
• Alkaline phosphatase 
• Alanine transaminase (ALT) 
• Bilirubin (total and direct) 
• Sodium 
• Glucose 
• Potassium 
• Phosphate 
• Blood urea nitrogen (BUN) 
• Albumin 
• Creatinine 
• Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
• Visual inspection for color and appearance 
• Leukocytes 
• pH 
• Bilirubin 
• Specific gravity 
• Nitrite 
• Ketones 
• Urobilinogen 
• Protein 
• Microscopic inspection of sediment 
• Glucose 
 
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9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
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• Is a congenital anomaly or birth defect 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
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Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 causality
Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
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completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
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9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
• Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
• Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the 
subset of patients that have previously received placebo in the parent study, comparisons for the 
various efficacy assessments will be made between rates of change pre- and post-administration 
of patisiran, and relative to the treatment group in the parent study.  Additional analyses will 
compare rates of change with rates estimated from previous studies, including cross-sectional, 
natural history, and interventional studies of other drugs.  Associations between PD (serum TTR) 
and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the Σ5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.  
Values of the individual components of the mNIS weakness and reflex scores will be depicted 
graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
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Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
The observed values and changes from baseline in healthcare utilization will be evaluated and 
summarized using descriptive statistics. 
10.2.6. 
Interim Analysis 
There is no formal interim analysis planned for this study.  Interim data examinations may be 
performed, but these will be of a descriptive nature and will not involve any formal hypothesis 
testing. 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB and/or 
Regulatory Authorities, providing direct access to source data/documents.  The study may be 
subject to audit by the Sponsor or its representatives or by regulatory authorities.  If such an audit 
occurs, the Investigator must agree to allow access to the required patient records.  In the event 
of an audit, the Investigator agrees to allow the Sponsor, representatives from the Sponsor, or 
regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Health Organization (WHO) Declaration of 
Helsinki, the ICH of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other 
applicable medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
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requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 
14.3. 
Inspection of Records 
The Sponsor 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 
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drug storage area, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16. 
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2  
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3  
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4  
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5  
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6  
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7  
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8  
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9  
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10  
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11  
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13  
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14  
Episkopou, V., 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. 90: p. 2375-2379. 
15  
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy and 
in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
16  
Kollmer J, Hund E, Hornung B, Schönland S, et al. MR-neurography: In-vivo detection of nerve 
injury in systemic light chain (AL) amyloidosis. XIVth International Symposium on 
Amyloidosis, 2014. 
 
                                                 
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17. 
APPENDICES 
 
Appendix 1: Karnofsky Scale 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
 
 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 
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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
• 
Weakness (192) 
• 
Sensation (32) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (18.6)a 
• 
Sural SNAP, tibial motor n. distal latency, peroneal 
SNAP/motor n. conduction velocity/motor n. distal 
latency 
• 
Vibration detection threshold (3.7) 
• 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
• 
Weakness (192) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (10)a 
• 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
• 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
• 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 
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ALN-TTR02-006 Amendment 1 Summary of Changes: 
Protocol Version 2.0 (Amendment 1), dated 08 September 2015, compared to Protocol 
Version 1.0 (Original Protocol), dated 06 November 2014 
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior 
Clinical Study with Patisiran 
 
Rationale for Amendment 1 
The changes in this amendment have been made to the following sections as indicated below; a rationale 
for the changes is also provided, followed by a detailed summary of changes. 
Modification of Premedication Regimen 
To date, per the ALN-TTR02-004/ALN-TTR02-006 protocol, patients in this study were to receive a 
premedication regimen that included 8 mg of dexamethasone or equivalent the night before and 20 
mg IV dexamethasone or equivalent the day of the infusion. Some patients on this premedication 
regimen for an extended amount of time in the ongoing Phase 2 open-label extension (OLE) study 
(Study ALN-TTR02-003) have reported recurrent episodes of flushing after the infusion that the 
Investigator(s) reported as an infusion-related reaction (IRR) and/or related to the premedication 
dexamethasone.  In a prior Phase 2 multi-dose study (Study ALN-TTR02-002), a less intensive 
premedication regimen was tested, consisting of 10 mg of dexamethasone given only on the day of 
infusion in 9 FAP patients, which did not lead to an increase in IRRs.  Based on the prior Phase 2 
experience in Study ALN-TTR02-002, the premedication regimen for the 9 patients in the OLE study 
(Study ALN-TTR02-003) who were experiencing post infusion flushing was reduced to include only 
10 mg dexamethasone on the day of infusion.  In addition, after discussion with the investigator two 
additional patients without flushing also received the lower dose of dexamethasone in the OLE study 
(Study ALN-TTR02-003).  These 11 patients in the OLE study (Study ALN-TTR02-003) have been 
followed for a mean (range) of 6 (1-8) months on this less intensive premedication regimen and 
appeared to tolerate the infusions without any worsening or increased frequency of IRRs, and some 
reported less flushing. Based on this information, it is appropriate to change to the less intensive 
premedication regimen for patients in Study ALN-TT02-004/TTR02-006. 
In addition, after consultation with the medical monitor, specified patients who are intolerant of 10 mg IV 
dexamethasone or equivalent on the day of infusion may be considered for further step-wise reduction in 
dexamethasone or equivalent as specified in the protocol (See Protocol Section 6.4.1). Alternatively, after 
consultation with the medical monitor, if the patient develops infusion related reactions on 10 mg IV or 
less of dexamethasone, even after slowing of the infusion, that patient will be allowed to increase the 
steroid premeditation dose in a step-wise manner as indicated per protocol (See Protocol Section 6.4.3). 
Clarification of Risk Benefit Assessment 
The risk benefit assessment has been updated to reflect liver function test abnormalities and risk for 
osteoporosis.  Because patients with FAP may be at risk for osteoporosis, it has been added that, if there 
is no medical contraindication, and per investigator judgment and local standard of care, study 
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participants should, if appropriate, receive therapy for the prevention and early treatment of osteoporosis 
such as: calcium and vitamin D supplementation, bisphosphonates, calcitonin, parathyroid hormone, 
estrogen agonist/antagonist or combination therapies. 
Clarification of the Inclusion Criterion about Total Bilirubin 
The inclusion criterion about total bilirubin has been updated to be consistent with the inclusion critierion 
about total bilirubin in Study ALN-TTR02-004.  Specifically the updated criterion states that patients 
must have total bilirubin within normal limits, but states that a patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of unconjugated 
bilirubin with normal conjugated bilirubin) and the patient has ALT and AST levels within normal 
ranges. 
Clarification about Exclusion Criterion about Uncontrolled Cardiac Arrhythmia and Unstable Angina 
This amendment also clarified that patients with any uncontrolled cardiac arrhythmia or unstable angina 
are not permitted to enroll in the study (Exclusion Criterion #3). Patients with uncontrolled clinically 
significant cardiac arrhythmia or unstable angina were not permitted to enroll in this study in the previous 
version of the protocol; the change was made to remove the subjective determination of clinical 
significance from the criterion. 
Clarification about the Duration of the Study 
This amendment also clarified that the duration of the study was determined to allow the collection for 
long-term safety, tolerability, and efficacy data of patisiran. 
Additional Clarifications 
The following clarifications have also been made in this amendment: 
• 
The collection of thyroid stimulating hormone (TSH) is an efficacy assessment in Section 8.  
• 
Blood for serum vitamin A level will be collected before the administration of vitamin A 
supplementation (and not before patisiran administration because these assessments are performed 
at non-dosing visits). 
• 
Magnetic resonance neurography is to be performed in the subset of patients who completed it in 
their parent study and may be performed for patients who did not complete it in their parent study.  
• 
The same examiner should perform the mNIS+7 and NIS+7 assessments at the Week 52 visit as in 
the patient’s parent study. 
• 
All clinical laboratory samples will be processed by the central laboratory. 
• 
Concomitant medications that continue from the parent study should be entered into the database. 
• 
Added INR assessment as a safety laboratory assessment. 
• 
Added a 12-Week visit to collect samples for safety laboratory assessments. 
• 
Added to the Schedule of Events that inclusion and exclusion criteria are to be evaluated at the 
Day 0 Visit. 
• 
Separated the End of Study Visit and the Early Withdrawal Visits on the Schedule of Events. 
• 
Clarified study drug preparation. 
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• 
Clarified the follow-up for SAEs 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, punctuation, 
grammar, abbreviations, and formatting are not detailed.  
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Table 1: 
Amendment 1 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in this amendment are indicated.  The corresponding text has been 
revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
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Purpose:   
To explore tolerability of patients with lower dexamethasone in premedication regimen 
Primary change (1 of 
3): 
Section 6.4.1 Premedication 
Formerly read: 
Prior to dosing, patients will receive 2 sets of premedications in order to reduce the risk of experiencing an IRR. 
For all patients, the first set of premedications will be administered on the evening before patisiran administration as follows: 
• 
Oral dexamethasone (8 mg) or equivalent 
• 
Oral paracetamol/ acetaminophen (500 mg) or equivalent 
• 
Oral H2 blocker (ranitidine 150 mg, famotidine 20 mg, or equivalent other H2 blocker dose) 
• 
Oral H1 blocker, 10 mg cetirizine (hydroxyzine 25 mg, fexofenadine, or equivalent may be substituted if patient does 
not tolerate cetirizine) 
If the evening premedications (first set) are missed, they should be administered a minimum of 6 hours before the second set (see 
below) of premedications on the day of dosing (ie, at least 7 hours before patisiran dosing). 
Prior to each dose of patisiran, patients will also receive the following premedications (ie, second set) at least 60 minutes before the 
infusion: 
• 
Intravenous dexamethasone (20 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker available at the clinical site).  
Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or cetirizine 10 mg PO may be substituted for any patient who 
does not tolerate IV diphenhydramine or other IV H1 blocker. 
Further details (including a table of equivalent premedications) can be found in the patisiran Pharmacy Manual. 
Modifications to the premedication regimen may be allowed due to lack of tolerability of one or more of the premedications by the 
patient (eg, lowering of the corticosteroid dose if a patient develops uncontrolled hyperglycemia or altered mental status).  Such 
modifications may be allowed for that patient only after consultation with the Medical Monitor.  If the premedication regimen was 
already modified for this reason on the parent study, the modification for that particular patient will be carried over into this study. 
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Now reads: 
Prior to each dose of patisiran, patients will receive the following premedications in order to reduce the risk of experiencing an 
IRR at least 60 minutes before the infusion: 
• 
Intravenous dexamethasone (10 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker available at the clinical site).  
Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or cetirizine 10 mg PO may be substituted for any patient who 
does not tolerate IV diphenhydramine or other IV H1 blocker. 
Further details (including a table of equivalent premedications) can be found in the patisiran Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be made to the premedication 
regimen after consultation with the medical monitor either due to a patient’s inability to tolerate one or more of the 
premedications or to the occurrence of IRRs unresponsive to slowing of the infusion rate. 
• 
If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.  
• 
If after consultation with the medical monitor, it is agreed that an individual patient’s steroid premedication will be 
lowered, then the following steps must be followed: 
1) 
If the current steroid dosage is 10 mg or less of intravenous dexamethasone or equivalent, then the patient may be 
lowered in increments no greater than 2.5 mg intravenous dexamethasone or equivalent. 
2) 
After each incremental lowering of intravenous dexamethasone or equivalent, the patient must receive three 
consecutive intravenous doses of patisiran without IRR and continued signs or symptoms of steroid intolerance 
before further reductions in steroid premedications.   
3) 
The premedication steroid dosage should not be reduced below 5 mg intravenous dexamethasone or equivalent. 
Alternatively if a patient experiences an IRR when 10 mg or less of intravenous dexamethasone or equivalent is used as the 
steroid premedication, then proceed to Section 6.4.3. 
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If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the patient may continue on that 
modified premedication regimen. 
Primary change (2 of 
3): 
Section 6.4.2 Study Drug Administration 
Formerly read: 
On all dosing days, patisiran will be administered as a 70-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 infusion time may be extended up to 3 hours in the event of a mild or moderate IRR; patisiran administration will not be resumed 
for any patient following a severe IRR until the case is discussed with the Medical Monitor (see Section 6.4.3).  If the infusion time 
for a patient was already extended on the parent study due to an IRR, that modified infusion duration may be continued on this study 
for that particular patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the Medical Monitor.  
For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following 
completion of dosing. 
Now reads: 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15 minutes 
followed by approximately 3 mL/minute for the remainder of the infusion). 
•
If the patient experiences an IRR the infusion time may be extended up to 3 hours in the event of a mild or moderate IRR.
1)
If the patient experiences a mild or moderate IRR that resolves by slowing the infusion rate then no further
premedication changes are recommended.
2)
If the patient experiences a severe IRR, then patisiran administration will not be resumed until the case is discussed
with the Medical Monitor (see Section 6.4.3).
•
If the infusion time for a patient was already extended on the parent study due to an IRR, that modified infusion duration
may be continued on this study for that particular patient.  Returning the patient’s infusion duration to 70 minutes will
require a discussion with the Medical Monitor.
•
For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site
for 1 hour following completion of dosing.
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Primary change (3 of 
3): 
Section 6.4.3 Suggested Guidelines for Management of Infusion-Related Reactions 
Added Text: 
Criteria for categorizing IRRs are provided in Appendix 3. 
• 
In the event of an IRR, the infusion of patisiran may be stopped and the patient closely monitored until resolution of the reaction.  
Drugs that may be used to facilitate resolution and permit resumption of patisiran administration include, but are not limited to: 
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists (eg, ranitidine), NSAIDs, 
adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids. 
• 
Following resolution of a mild or moderate IRR that required interruption of the patisiran infusion, resumption of administration 
may occur at the Investigator’s discretion at a slower infusion rate (but not to exceed 3 hours) for that dose and for all subsequent 
doses of patisiran.  If the infusion is delayed, the administration of the infusion should be completed no more than 6 hours from 
the initial start of the infusion.   
• 
Patisiran 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 intravenous 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 intravenous dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) 
Increased dose of premedication steroids should NOT exceed the combination of 20 mg intravenous 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 intravenous dexamethasone or equivalent, then the 
patient should return to the prior dose of intravenous 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. 
Section(s) also 
containing this change: 
• 
Synopsis 
• 
Section 3.1 Overall Design 
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Purpose:   
Provide updated risk benefit language 
Primary change: 
Section 1.4 Risk-Benefit Assessment 
Formerly read: 
1.4 
Risk-Benefit Assessment 
Please see the IB for an expanded risk/benefit assessment. 
1.4.1 
Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological agents such as liposomes or monoclonal 
antibodies.  In order to reduce the potential for an IRR with patisiran, all patients in this study will be premedicated prior to dosing 
with patisiran or placebo.  The step-wise infusion regimen over approximately 70 minutes (starting with a slower infusion rate of 
approximately 1 mL/minute for the first 15 minutes before increasing to 3 mL/minute for the remainder of the infusion), may further 
reduce the risk of an IRR. 
1.4.2 
Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of circulating vitamin A levels.  Preclinical and 
clinical data have shown that the lowering of circulating vitamin A associated with suppression of RBP does not result in severe 
vitamin A deficiency.  Furthermore, there are individuals with RBP/TTR mutations who have life-long low levels of circulating 
vitamin A and are essentially in good health, suggesting that there are compensatory transport mechanisms for vitamin A that are yet 
undescribed.13 This has also been confirmed in TTR knockout mice, which do not exhibit any manifestations of vitamin A deficiency, 
with vitamin A uptake by most tissues continuing in the absence of RBP.14  Provided there is adequate vitamin A in the diet, tissue 
stores of vitamin A should not be affected by the lowering of TTR and RBP.  However, as the vitamin A content of the diet may vary 
between different countries and different individuals within a country, all patients on the study will be asked to take continue taking 
daily supplement containing the recommended daily allowance of vitamin A. 
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Now Reads: 
1.4 Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-threatening orphan disease with 
limited treatment options. The therapeutic hypothesis that systemic amyloidoses can be managed by reducing circulating 
levels of amyloidogenic protein has been established in other acquired and hereditary amyloidoses.  The experience from these 
systemic amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the circulating 
amyloidogenic protein could impact the clinical course of the disease.  Based on nonclinical and clinical data that showed 
suppression in levels of WT and mutant TTR upon administration of 0.3 mg/kg patisiran once every 21 days, it is possible that 
long term treatment with patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and 
that further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-TTR02-003), single and multiple 
doses of patisiran have been generally well tolerated.  Potential risks of patisiran include the following: 
• 
Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological agents such as liposomes or 
monoclonal antibodies.  In order to reduce the potential for an IRR with patisiran, all patients in this study will be premedicated 
prior to dosing with patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a slower infusion 
rate of approximately 1 mL/minute for the first 15 minutes before increasing to 3 mL/minute for the remainder of the infusion), 
may further reduce the risk of an IRR. 
• 
Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in the liver were observed at 
dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In general, all of the findings were not observed or were 
observed at lower severity at the end of the 60-90 day dose free period, indicating that the toxicities were reversible.  In 
clinical studies to date, there have been no clinically significant changes in liver function tests in either the single-dose or 
multiple-dose studies. Patients in the study are monitored for liver function via serial laboratory assessments. 
• 
Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of circulating vitamin A levels.  Preclinical 
and clinical data have shown that the lowering of circulating vitamin A associated with suppression of RBP does not result in 
severe vitamin A deficiency.  Furthermore, there are individuals with RBP/TTR mutations who have life-long low levels of 
circulating vitamin A and are essentially in good health, suggesting that there are compensatory transport mechanisms for vitamin 
A that are yet undescribed.40  This has also been confirmed in TTR knockout mice, which do not exhibit any manifestations of 
vitamin A deficiency, with vitamin A uptake by most tissues continuing in the absence of RBP.41  Provided there is adequate 
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vitamin A in the diet, tissue stores of vitamin A should not be affected by the lowering of TTR and RBP.  However, as the 
vitamin A content of the diet may vary between different countries and different individuals within a country, all patients on the 
study will be asked to take a daily supplement containing the recommended daily allowance of vitamin A.  Patients should have 
started vitamin A supplementation by the time they start his/her first dose of patisiran. 
• 
Osteoporosis 
Patients with FAP may be at risk for osteoporosis.42 In addition, as part of the premedication regimen administered prior 
to patisiran dosing every three weeks, FAP patients participating in this study are given glucocorticoids, a drug known to 
have the potential to reduce bone mineralization.  If there are no medical contraindications, and per investigator 
judgment and local standard of care, study participants should, if appropriate, receive therapy for the prevention and 
early treatment of osteoporosis such as: calcium and vitamin D supplementation, bisphosphonates, calcitonin, parathyroid 
hormone, estrogen agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the IB. 
Purpose 
Clarify inclusion criterion about total bilirubin level to align with Study TTR02-004 
Primary Change 
Section 4.1 Patient Inclusion Criteria 
Formerly Read: 
4. Have a total bilirubin ≤1.5 × ULN, unless greater elevation above normal limits is due to Gilbert’s syndrome 
Now Reads: 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN are eligible if the elevation is 
secondary to documented Gilbert’s syndrome (elevation of unconjugated bilirubin with normal conjugated bilirubin) and 
the patient has ALT and AST levels within normal ranges. 
Section(s) also 
containing this change: 
• 
Synopsis 
Purpose 
Clarification about exclusion criterion about uncontrolled cardiac arrhythmia and unstable angina 
Primary change: 
Section 4.2 Patient Exclusion Criteria 
Formerly Read: 
3. Has uncontrolled clinically significant cardiac arrhythmia or unstable angina 
Now Reads: 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
Section(s) also 
containing this change: 
• 
Synopsis 
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Purpose:   
Clarified that the duration of the study was determined to allow the collection for long-term safety, tolerability, and efficacy data of 
patisiran 
Primary change: 
Section 1.3 
Formerly Read: 
This study will allow patients to receive treatment with patisiran until it becomes commercially available in their region, or until the 
study is otherwise terminated by the Sponsor. 
Now Reads: 
The duration of the study has been determined to allow the collection of long-term safety, tolerability and efficacy data of 
patisiran in patients FAP who have completed a prior study with patisiran.  The estimated duration of the study is 5 years. 
Section(s) also 
containing this change: 
• 
Synopsis 
• 
Section 3.1 Overall Study Design 
Purpose:   
Clarified that the collection of thyroid stimulating hormone (TSH) is an efficacy assessment  
Primary change: 
Deleted from Section 9.1.5.2 Blood Chemistry; Added to Section 8.1.15 Thyroid Stimulating Hormone  
Formerly Read: 
9.1.5.2 Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
• 
Aspartate transaminase (AST) 
• 
Alkaline phosphatase 
• 
Alanine transaminase (ALT) 
• 
Bilirubin (total and direct) 
• 
Sodium 
• 
Glucose 
• 
Potassium 
• 
Phosphate 
• 
Blood urea nitrogen (BUN) 
• 
Albumin 
• 
Creatinine 
• 
Calcium 
• 
Thyroid stimulating hormone 
 
Now Reads: 
8.1.15 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
Section(s) also 
containing this change: 
• 
Synopsis 
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Purpose:   
Clarification that blood for serum vitamin A level will be collected before the administration of vitamin A supplementation (and 
not before patisiran administration because these assessments are performed at non-dosing visits). 
Primary change: 
Section 8.1.16 Vitamin A 
Now Reads: 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration of patisiran and vitamin A 
supplementation. 
Purpose:   
Clarification that magnetic resonance neurography is to be performed only in the subset of patients who completed it in their 
parent study and may be performed for patients who did not complete it in their parent study 
Primary change: 
Section 8.1.4 Magnetic Resonance Neurography (Subset of Patients) 
Added Text: 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional images for the evaluation of 
peripheral nerve disorders.1  This procedure produces detailed images of nerve morphology to evaluate degeneration and regeneration.  
Nerves in the lumbar plexus and lower extremity will be imaged for patients who have previously had MR neurography in the parent 
study and may be imaged for consenting patients who did not have MR neurography previously in their parent study.  A 
central reader will be used for MR neurography. 
Section(s) also 
containing this change: 
• 
Synopsis 
• 
Table 1 Schedule of Assessments, footnote u 
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Purpose:   
Clarification that the same examiner should perform the mNIS+7 and NIS+7 assessments at the Week 52 visit as in the patient’s 
parent study 
Primary change: 
Section 8.1.1.1 
Formerly read: 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at each time point at a CAS.  Each site will 
make every effort to have these assessments performed by the same study personnel, who will be different from the Investigator and 
other personnel managing the patient.  Assessments are to be performed at least 24 hours (approximately) apart from each other but no 
greater than 7 days apart.  In order to limit potential intra-operator bias, results of any of the prior assessments will not be available to 
the examiner when performing the second assessment. 
Now reads: 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at each time point at a CAS.  Assessments 
are to be performed at least 24 hours (approximately) apart from each other but no greater than 7 days apart.  In order to limit potential 
intra-operator bias, results of any of the prior assessments will not be available to the examiner when performing the second 
assessment.  Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel 
who performed the assessments for the patient in the patisiran study in which they were previously enrolled.  Assessments of 
the NIS during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
Section(s) also 
containing this change: 
Table 1 Schedule of Events, footnotes l, m, and n 
Purpose:   
Clarification that all clinical laboratory samples will be processed by the central laboratory. 
Primary change: 
Section 9.1.5 Laboratory Assessments 
Formerly read: 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time points listed in Table 1.  Samples 
collected at the Day 0, 26-week, and 52-week visits will be sent to a central laboratory for analysis.  Samples collected at the annual 
visits and End of Study or Early Withdrawal visits will be analyzed at the local laboratory.  Details on sample collection, processing, 
and shipping will be provided in a Laboratory Manual. 
Now reads: 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time points listed in Table 1. All samples 
will be sent to a central laboratory for analysis.  Details on sample collection, processing, and shipping will be provided in a 
Laboratory Manual. 
Section(s) also 
containing this change: 
Table 1 Schedule of Assessment, footnotes i and j (deleted) 
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Purpose: 
Concomitant medications that continue from the parent study should be entered into the database. 
Primary change: 
Section 5.2 Concomitant Medications 
Now reads: 
 
Any concomitant medication or treatment that is required for the patient’s welfare may be given by the Investigator.  Use of all 
concomitant medications and treatments will be recorded on the patient’s CRF through the end of the patient’s participation in the 
study.  This will include all prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and minerals.  Any 
changes in medications during the study will also be recorded on the CRF. Similarly, concomitant medications that continue from 
the parent study will be entered into the database. 
Section(s) also 
containing this change: 
Table 1 Schedule of Assessments, footnote b 
Purpose:   
Added INR assessment as a safety laboratory assessment. 
Primary change: 
Section 9.1.5.4 Coagulation (new section) 
Now reads: 
9.1.5.4 Coagulation 
A sample for INR assessment will be collected. 
Section(s) also 
containing this change: 
• 
Table 1 Schedule of Events 
Purpose:   
Added a 12-Week visit to collect samples for safety laboratory assessments 
Primary change: 
Table 1 Schedule of Events 
Description of 
Change: 
A 12-Week visit column was added to the Schedule of Events to denote the collection of samples for safety laboratory assessments at 
Week 12. 
Section(s) also 
containing this change: 
• 
Synopsis 
• 
Section 3.1 Overall Study Design 
Purpose:   
Clarified on the Schedule of Events that inclusion and exclusion criteria are to be evaluated at the Day 0 Visit 
Primary change: 
Table 1 Schedule of Events 
Description of 
Change: 
A row was added to the Schedule of Events to denote that inclusion and exclusion criteria must be reviewed on the Day 0 visit. 
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Purpose:   
Separated the End of Study Visit and the Early Withdrawal Visits on the Schedule of Events 
 
Primary change: 
Table 1 Schedule of Events 
Description of 
Change: 
Separate columns were added for the End of Study and Early Withdrawal Visits. 
Purpose:   
Clarification about study drug preparation 
Primary change: 
Section 6.3 Study Drug Preparation 
Now reads: 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each patient at each dosing visit will be 
200 mL.  Sterile normal saline (0.9% NaCl) will be added to a sterile infusion bag, and the calculated volume of patisiran will 
be withdrawn from the vials and injected into the infusion bag. 
Purpose:   
Clarification of follow-up time for SAEs 
Primary change: 
Section 9.5 Reporting Adverse Events 
Formerly read: 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution or 28 days from last dose, whichever 
occurs first.  Serious AEs will be followed through 28 days from the last dose of patisiran, or until satisfactory resolution, or until the 
SAE is considered by the Investigator to be chronic or the patient is stable, whichever occurs first. 
Now reads: 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution or 28 days from last dose, whichever 
occurs first.  SAEs will be followed by the Investigator until satisfactory resolution or the Investigator deems the SAE to be 
chronic or stable. 
Purpose:  Correct typographical errors, punctuation, grammar, and formatting 
These changes are not listed individually. 
 
147


148
Patisiran (ALN-TTR02) 
Clinical Protocol 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
ALN-TTR02-006 
Version 1.0 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Final Protocol: 
fND Number: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 1.0, 06 November 2014 
117395 
2014-003 877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Signature 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
Alnylam Pharmaceuticals 
Confidential 
PPD


Patisiran (ALN-TTR02) 
ALN-TTR02-006
Clinical Protocol 
Version 1.0 
Alnylam Pharmaceuticals 
Confidential 
2 
INVESTIGATOR’S AGREEMENT 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
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SYNOPSIS 
Name of Sponsor/Company:
Alnylam Pharmaceuticals, Inc
Name of Investigational Product:
Patisiran
Title of Study: 
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran
Study Centers:
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study.
Objectives:
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP).
Methodology:
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study.
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV)
once every 21 (±3) days for the duration of the study. In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study. However, if necessary, a patient may initiate dosing 
in this study up to 45 days from the time of the last dose in the parent study. Exceptions to this timing 
may be allowed for medical or regulatory considerations only after consultation with the Medical 
Monitor. The last testing visit in the parent study will serve as the baseline for this study, unless more 
than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.
Eligibility for this study will be confirmed before administration of the first dose on Day 0.
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days, or 
receive the patisiran infusions at home by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran.  Patients who are receiving patisiran infusions at home will have a 
phone contact with the site at least every 30 (±5) days. Patients will also have visits at the clinical site 
at approximately 26 and 52 weeks, and yearly thereafter.
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study. Yearly efficacy assessments after the 52-week visit may be done at a PCS.
Safety will be assessed throughout the study. Patients will return to the clinical site for safety
evaluations 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 
occur if deemed necessary by the study personnel.
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Number of patients (planned): 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study.
Diagnosis and eligibility criteria: 
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0:
1.
Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) and, 
in the opinion of the investigator, tolerated study drug
2.
Be considered fit for the study by the Investigator
3.
Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed)
4.
Have a total bilirubin ≤1.5 × ULN, unless greater elevation above normal limits is due to 
Gilbert’s syndrome
5.
Have a serum creatinine ≤2 × ULN
6.
Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study.
7.
Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study
8.
Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0:
1.
Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration
2.
Has poorly controlled diabetes mellitus
3.
Has uncontrolled clinically significant cardiac arrhythmia or unstable angina
4.
Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the parent study
5.
Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study
6.
Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court
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Investigational product, dosage and mode of administration: 
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device.
Patients will receive 2 sets of premedications as described below, unless changes were approved by the 
Medical Monitor.
On the evening before patisiran administration (or at least 6 hours before administration of the second 
set of premedications on the day of dosing), patients will receive the following:

Oral dexamethasone (8 mg) or equivalent

Oral paracetamol/ acetaminophen (500 mg) or equivalent

Oral H2 blocker (ranitidine 150 mg, famotidine 20 mg, or equivalent other H2 blocker 
dose)

Oral H1 blocker, 10 mg cetirizine (hydroxyzine 25 mg, fexofenadine, or equivalent may be 
substituted if patient does not tolerate cetirizine)
Patients will also receive the following premedications (ie, second set) at least 60 minutes before the
start of the patisiran infusion:

Intravenous dexamethasone (20 mg) or equivalent

Oral paracetamol/acetaminophen (500 mg) or equivalent

Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose)

Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or 
cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker.
Duration of treatment: 
It is anticipated that a patient on this study will receive treatment with open-label patisiran until the
patient is able to obtain commercially available patisiran in their respective country.  The study will be 
completed when all patients are receiving commercially available patisiran. The study may be 
terminated if patisiran does not obtain marketing approval or the development of patisiran is no longer 
being pursued by the Sponsor.  The Sponsor also reserves the right to discontinue the study for clinical 
or administrative reasons at any time.
Reference therapy, dosage and mode of administration: 
Not applicable.
Criteria for evaluation:
Efficacy:
The efficacy of patisiran will be assessed by the following evaluations:

Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7

Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires
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Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS)

Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31)

Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test

Polyneuropathy disability (PND) score and FAP stage

Nutritional status using modified body mass index (mBMI)

Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study)

Magnetic resonance (MR) neurography (only for patients having this assessment in the
parent study)

Cardiac structure and function through echocardiograms and serum levels of terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I

New York Heart Association (NYHA) classification of heart failure

Serum TTR

Vitamin A

Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire
Safety:
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; and ophthalmology 
examinations.
Statistical methods:
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests.
Efficacy analyses will examine between- and within-subject rates of change over time. For the subset 
of patients that have previously received placebo in the parent study, comparisons for the various 
efficacy assessments will be made between rates of change pre- and post-administration of patisiran,
and relative to the treatment group in the parent study. Additional exploratory analyses will compare 
rates of change with rates estimated from previous studies, including cross-sectional, natural history, 
and interventional studies of other drugs.  Associations between pharmacodynamic and efficacy data 
will be explored via correlation.
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented.
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
26 Week Visit 
52 Week Visit 
Annual Visit 
End of Study / Early 
Withdrawal Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±6 Weeks 
4 (+1) Weeks from 
Last Dose 
Procedure 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Medical History 
Xb 
 
 
 
 
Demographics 
Xc 
 
 
 
 
Physical Examination 
Xd 
 
X 
X 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
mBMIe 
Xd 
 
X 
X 
Xo 
Height 
Xc 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
X 
X 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
NYHA Classification 
X 
 
X 
 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
Safety Laboratory Assessmentsh 
Xd,i 
Xi 
Xi 
Xj 
Xj 
Pregnancy Test (urine) 
Xk 
X 
X 
X 
X 
TTR Protein (ELISA) 
X 
X 
X 
X 
X 
TSH and Vitamin A 
 
 
X 
X 
Xo 
mNIS+7l 
Xd 
 
X 
 
[X]f 
NIS+7m 
Xd 
 
X 
 
[X]f 
NIS only 
 
 
 
Xn 
Xn,p 
Grip Strength Testq 
Xd 
 
X 
 
[X]f 
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Window 
Day 0 Visit 
26 Week Visit 
52 Week Visit 
Annual Visit 
End of Study / Early 
Withdrawal Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±6 Weeks 
4 (+1) Weeks from 
Last Dose 
Procedure 
 
 
 
 
 
10-Meter Walk Testr 
Xd 
 
X 
 
[X]f 
Ophthalmology Examinations 
Xd 
 
X 
X 
Xo 
Skin Punch Biopsy (IENFD and 
SGNFD) t 
 
 
X 
X 
Xo 
MR Neurographyu 
 
 
X 
X 
Xo 
Pharmacoeconomics 
Questionnaire 
X 
 
X 
X 
Xo 
Norfolk QOL-DNv 
Xd 
 
X 
X 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
X 
 
[X]f 
R-ODS Disability 
Xd 
 
X 
 
[X]f 
EQ-5D QOL 
Xd 
 
X 
X 
Xo 
Echocardiogram 
Xd,w 
 
X 
 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
X 
 
[X]f 
Anti-Drug Antibody Testingx 
 
X 
X 
X 
X 
Premedication / Patisiran 
Administration 
Xy 
 
Phone Contact 
 
Xz 
 
Adverse Events 
X 
Continuous Monitoring 
Concomitant Medications 
X 
Continuous Monitoring 
 
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Table 1 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = 
familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified body mass index; mNIS = Modified Neuropathy 
Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; 
NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; R-ODS = Rasch-built Overall 
Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = transthyretin 
a Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may occur 
within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with the 
Medical Monitor. 
b Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). 
c Assessment does not need to be repeated.  Information will be obtained from parent study. 
d Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f Assessment/procedure required only if patient withdraws before the 52-week visit. 
g Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific safety laboratory assessments. 
i Analysis of blood samples obtained at Day 0, 26 weeks, and 52 weeks will be performed at a central laboratory.  Urinalysis is not required at Day 0. 
j Analysis of blood samples obtained at the Annual visits and the End of Study or Early Withdrawal visit will be performed at the local laboratory. 
k Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the first dose. 
l The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after 
the first assessment. 
m The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS 5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. 
n One assessment of the NIS will be performed at each specified visit. 
o Assessment does not need to be repeated if done within the previous 26 weeks. 
p Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the previous 
26 weeks. 
q Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
r The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed on separate 
days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after the first 
assessment. 
s Examination will include visual acuity, visual fields, and slit-lamp evaluation. 
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t
u
v
w
x
y
z
Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin biopsies 
in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies taken from the 
distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
 Required only for patients who had MR neurography in the parent study. 
 Patients who are entering this stud y fro m a protocol that does not include the Norfolk QOL -DN questionnaire (eg, ALN -TTR02-003) do not have to complete 
this assessment. 
 Patients entering this stud y from stud y ALN -TTR02-003, who were not previously particip ating in the cardiac sub gro up, will be required to have an 
echocardiogram before dosing on Day 0. 
 Serum samples for anti-drug antibodies will be collected as specified.  Samples may be analyzed, if clinically indicated. 
 Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study within the 21 (±3) days 
timeframe.  Doses may be administered at the clinical site or at home by a healthcare professional trained in the protocol. 
 Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 30 (±5) days for assessment of adverse events 
and concomitant medication use. 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
1.4.1. 
Infusion-Related Reactions .........................................................................................19 
1.4.2. 
Vitamin A Lowering ...................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................21 
3. 
INVESTIGATIONAL PLAN .....................................................................................22 
3.1. 
Overall Study Design ..................................................................................................22 
3.2. 
Number of Patients .....................................................................................................23 
3.3. 
Treatment Assignment ................................................................................................23 
3.4. 
Criteria for Study Termination ...................................................................................23 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................24 
4.1. 
Patient Inclusion Criteria ............................................................................................24 
4.2. 
Patient Exclusion Criteria ...........................................................................................24 
4.3. 
Patient Withdrawal Criteria ........................................................................................25 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................25 
5. 
TREATMENT OF PATIENTS ..................................................................................28 
5.1. 
Description of Study Drug ..........................................................................................28 
5.2. 
Concomitant Medications ...........................................................................................28 
5.3. 
Treatment Compliance ................................................................................................28 
5.4. 
Randomization and Blinding ......................................................................................29 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................30 
6.1. 
Study Drug Packaging and Labeling ..........................................................................30 
6.2. 
Study Drug Storage .....................................................................................................30 
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6.3. 
Study Drug Preparation ..............................................................................................30 
6.4. 
Administration ............................................................................................................31 
6.4.1. 
Premedication .............................................................................................................31 
6.4.2. 
Study Drug Administration.........................................................................................31 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................32 
6.5. 
Study Drug Accountability .........................................................................................32 
6.6. 
Study Drug Handling and Disposal ............................................................................33 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................34 
8. 
ASSESSMENT OF EFFICACY ................................................................................35 
8.1. 
Efficacy Parameters ....................................................................................................35 
8.1.1. 
Neurological Testing ..................................................................................................35 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................35 
8.1.1.2. 
Neurological Impairment Score ..................................................................................36 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................36 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............36 
8.1.4. 
Magnetic Resonance Neurography .............................................................................36 
8.1.5. 
Modified Body Mass Index ........................................................................................37 
8.1.6. 
Timed 10-meter Walk Test .........................................................................................37 
8.1.7. 
Grip Strength Test .......................................................................................................37 
8.1.8. 
Composite Autonomic Symptom Score .....................................................................37 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................37 
8.1.10. 
EuroQoL Quality of Life Questionnaire .....................................................................37 
8.1.11. 
Rasch-built Overall Disability Scale ..........................................................................38 
8.1.12. 
Pharmacoeconomics Questionnaire ............................................................................38 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................38 
8.1.14. 
Transthyretin ...............................................................................................................38 
8.1.15. 
Vitamin A ...................................................................................................................38 
8.1.16. 
Anti-Drug Antibodies .................................................................................................38 
9. 
ASSESSMENT OF SAFETY .....................................................................................39 
9.1. 
Safety Parameters .......................................................................................................39 
9.1.1. 
Demographic and Medical History .............................................................................39 
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9.1.2. 
Vital Signs ..................................................................................................................39 
9.1.3. 
Weight and Height ......................................................................................................39 
9.1.4. 
Physical Examination .................................................................................................39 
9.1.5. 
Laboratory Assessments .............................................................................................39 
9.1.5.1. 
Hematology .................................................................................................................40 
9.1.5.2. 
Blood Chemistry .........................................................................................................40 
9.1.5.3. 
Urinalysis ....................................................................................................................40 
9.1.5.4. 
Pregnancy Screen ........................................................................................................41 
9.1.6. 
Ophthalmology Examination ......................................................................................41 
9.2. 
Adverse Events and Serious Adverse Events .............................................................41 
9.2.1. 
Definition of Adverse Events .....................................................................................41 
9.2.1.1. 
Adverse Event .............................................................................................................41 
9.2.1.2. 
Serious Adverse Event ................................................................................................41 
9.3. 
Relationship to Study Drug ........................................................................................42 
9.4. 
Recording Adverse Events .........................................................................................42 
9.5. 
Reporting Adverse Events ..........................................................................................43 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................43 
9.5.2. 
Pregnancy Reporting ..................................................................................................44 
10. 
STATISTICS ..............................................................................................................46 
10.1. 
Sample Size ................................................................................................................46 
10.2. 
Statistical Methodology ..............................................................................................46 
10.2.1. 
Populations to be Analyzed ........................................................................................46 
10.2.2. 
Baseline Evaluations ...................................................................................................46 
10.2.3. 
Efficacy Analyses .......................................................................................................46 
10.2.4. 
Safety Analyses ..........................................................................................................47 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................47 
10.2.6. 
Interim Analysis ..........................................................................................................47 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................48 
11.1. 
Study Monitoring ........................................................................................................48 
11.2. 
Audits and Inspections ................................................................................................48 
11.3. 
Institutional Review Board .........................................................................................48 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................49 
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13. 
ETHICS ......................................................................................................................50 
13.1. 
Ethics Review .............................................................................................................50 
13.2. 
Ethical Conduct of the Study ......................................................................................50 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................50 
13.3. 
Written Informed Consent ..........................................................................................50 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................52 
14.1. 
Case Report Forms .....................................................................................................52 
14.2. 
Confidentiality ............................................................................................................52 
14.3. 
Inspection of Records .................................................................................................53 
14.4. 
Retention of Records ..................................................................................................53 
15. 
PUBLICATION POLICY ..........................................................................................54 
16. 
LIST OF REFERENCES ............................................................................................55 
17. 
APPENDICES ............................................................................................................56 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation
Definition
AE
adverse event
ALT
alanine transaminase 
AST
aspartate transaminase
ATTR
transthyretin-mediated amyloidosis
BUN
blood urea nitrogen
CAS
Central Assessment Sites
CFR
Code of Federal Regulations
COMPASS 31
Composite Autonomic Symptom Score
CRF
case report form
CRO
clinical research organization 
CYP
cytochrome P450
DLin-MC3-DMA
1,2-Dilinoleyloxy-N,N-dimethylpropylamine
DN
diabetic neuropathy
DSPC
1,2-Distearoyl-sn-glycero-3-phosphocholine
EDC
electronic data capture
ELISA
enzyme linked immunosorbent assay
EP
European Pharmacopoeia
EQ-5D
EuroQOL
EU
European Union
5
5 attributes
FAC
familial amyloidotic cardiomyopathy
FAP
familial amyloidotic polyneuropathy
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HEENT
head, ears, eyes, nose, and throat
HIPAA
Health Insurance Portability and Accountability Act of 1996
HP
heat pain
HRdb
heart rate response to deep breathing
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Abbreviation
Definition
IB
Investigators Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IENFD
intraepidermal nerve fiber density
INN
International Nonproprietary Name
INR
international normalized ratio
IRB
Institutional Review Board
IRR
infusion-related reaction
IRS
interactive response system
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
LNP
lipid nanoparticle
mBMI
modified body mass index
MedDRA
Medical Dictionary for Regulatory Activities
mNIS
Modified Neuropathy Impairment Score
mRNA
messenger RNA
MR
magnetic resonance
NCS
nerve conduction studies
NHP
non-human primate
NIS
Neuropathy Impairment Score
NIS-W
Neuropathy Impairment Score- Weakness
NSAID
nonsteroidal anti-inflammatory drug
NT-proBNP
N-terminal prohormone of B-type natriuretic peptide
NYHA
New York Heart Association
OTC
over-the-counter
PCS
Patient Care Sites
PD
pharmacodynamic
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Abbreviation
Definition
PEG2000-C-DMG
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride
PK
pharmacokinetic
PND
polyneuropathy disability
PO
per os (orally)
QOL
quality of life
QOL-DN
Quality of Life-Diabetic Neuropathy
QST
quantitative sensory testing
RBC
red blood cell
RNAi
ribonucleic acid interference
R-ODS
Rasch-built Overall Disability Scale
SAE
serious adverse event
SGNFD
sweat gland nerve fiber density
siRNA
small interfering ribonucleic acid
SUSAR
Suspected Unexpected Serious Adverse Reaction
TP
touch pressure
TSH 
thyroid stimulating hormone
TTR
transthyretin
TUDCA
tauroursodeoxycholic acid
ULN
upper limit of normal
USP
United States Pharmacopeia
V30M
Val30Met
VDT
vibration detection threshold
WBC
white blood cell
WHO
World Health Organization
WT
wild type
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1.
INTRODUCTION
1.1.
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10 The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2.
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators 
Brochure (IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12 A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran IB. 
1.3.
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  This study will allow patients to receive 
treatment with patisiran until it becomes commercially available in their region, or until the study 
is otherwise terminated by the Sponsor. 
1.4. 
Risk-Benefit Assessment 
Please see the IB for an expanded risk/benefit assessment. 
1.4.1.
Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an IRR 
with patisiran, all patients in this study will be premedicated prior to dosing with patisiran or 
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placebo.  The step-wise infusion regimen over approximately 70 minutes (starting with a slower 
infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing to 
3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
1.4.2.
Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of 
circulating vitamin A levels.  Preclinical and clinical data have shown that the lowering of 
circulating vitamin A associated with suppression of RBP does not result in severe vitamin A 
deficiency.  Furthermore, there are individuals with RBP/TTR mutations who have life-long low 
levels of circulating vitamin A and are essentially in good health, suggesting that there are 
compensatory transport mechanisms for vitamin A that are yet undescribed.13 This has also been 
confirmed in TTR knockout mice, which do not exhibit any manifestations of vitamin A 
deficiency, with vitamin A uptake by most tissues continuing in the absence of RBP.14 Provided 
there is adequate vitamin A in the diet, tissue stores of vitamin A should not be affected by the 
lowering of TTR and RBP.  However, as the vitamin A content of the diet may vary between 
different countries and different individuals within a country, all patients on the study will be 
asked to take continue taking daily supplement containing the recommended daily allowance of 
vitamin A. 
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2.
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3.
INVESTIGATIONAL PLAN 
3.1.
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
It is anticipated that a patient on this study will receive treatment with open-label patisiran until 
the patient is otherwise able to obtain commercially available patisiran in their respective 
country.  The study will be completed when all patients are receiving commercially available 
patisiran. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
2 sets of premedications before dosing with patisiran in order to reduce the risk of experiencing 
an IRR.  The first set of premedications will be administered the evening before patisiran 
administration (or at least 6 hours before the second set of premedications on the day of dosing).  
The second set of premedications will be administered at least 60 minutes before the start of the 
patisiran infusion.  Patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15-minutes followed by approximately 3 mL/minute for the remainder 
of the infusion).  If the infusion duration for a patient was lengthened beyond 70 minutes due to 
the occurrence of an IRR while on the parent study, that infusion duration may be continued on 
this study for that particular patient.  Returning the patient’s infusion duration to 70 minutes will 
require a discussion with the Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days, or receive the patisiran infusions at home by a healthcare professional trained on 
the protocol and delivery of premedications and patisiran.  Patients who are receiving patisiran 
infusions at home will have a phone contact with the site at least every 30 (±5) days.  Patients 
will also have visits at the clinical site at approximately 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients. There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
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the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2.
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3.
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4.
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or its 
representative, and the Investigators, Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) and Regulatory Authorities will be promptly informed of the termination and the 
reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
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4.
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1.
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on 
anticoagulant therapy with an INR of ≤3.5 will be allowed)
4. Have a total bilirubin ≤1.5 × ULN, unless greater elevation above normal limits is due to 
Gilbert’s syndrome
5. Have a serum creatinine ≤2 × ULN
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4.
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2.
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0:
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled clinically significant cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
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6. Is under legal protection (defined as “any person who becomes incapable of protecting 
his/her interests due to a medically diagnosed impairment of his/her mental faculties that 
may limit or prevent the expression of his will”), decided by a court 
4.3.
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 

Is in violation of the protocol 

Experiences a serious or intolerable AE 

Becomes pregnant 

Requires a prohibited medication (see Section 5.2) 

Requests to be withdrawn from the study 

Is found to be considerably noncompliant with the protocol-required patisiran dosing 
visits 
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4.
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14 It is not 
known whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients 
who are male or who are women of child bearing potential will affect reproduction.  
Histopathological evaluations of all of the reproductive organs have been conducted in the rat 
and non-human primate (NHP) toxicology studies including a chronic NHP study in sexually 
mature animals, where there were no adverse effects in males (including sperm analyses and 
spermatogenic staging) or females.  In a dose range-finding rat embryo/fetal development study 
conducted with patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
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or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 

Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 

Placement of an intrauterine device (IUD) 

Placement of an intrauterine system (IUS) 

Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 

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); 

Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  

Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 

IUD in conjunction with condom or diaphragm and spermicide 

Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity. None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9,
CYP2C19, CYP2D6 and CYP3A4/5). In addition, there was no induction of CYP1A2, 
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CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
Pregnancy reporting guidelines are provided in Section 9.5.2.
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5.
TREATMENT OF PATIENTS 
5.1.
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2.
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 

Any investigational agent other than patisiran 

Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 

Tafamidis 

Diflunisal

Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take an oral daily supplement containing the 
recommended daily allowance of vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
5.3.
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
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scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff or trained home healthcare professionals.  A dose will be considered 
completed if 80% or more of the total volume of the IV solution was administered to the patient.  
Patients will be permitted to miss an occasional dose of patisiran; however, if a patient misses 
3 consecutive doses, the Investigator, in consultation with the Medical Monitor, will discuss 
whether the patient will be able to continue on the study. 
5.4.
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6.
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1.
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran and placebo will be in compliance with 
Good Manufacturing Practice (GMP) specifications, as described in the Manufacture of 
Investigational Medicinal Products Volume 4 Annex 13, and any other or local applicable 
regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2.
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee.
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records.
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3.
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual.
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg). For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions. 
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6.4.
Administration 
6.4.1.
Premedication 
Prior to dosing, patients will receive 2 sets of premedications in order to reduce the risk of 
experiencing an IRR. 
For all patients, the first set of premedications will be administered on the evening before 
patisiran administration as follows: 

Oral dexamethasone (8 mg) or equivalent 

Oral paracetamol/ acetaminophen (500 mg) or equivalent 

Oral H2 blocker (ranitidine 150 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 

Oral H1 blocker, 10 mg cetirizine (hydroxyzine 25 mg, fexofenadine, or equivalent 
may be substituted if patient does not tolerate cetirizine) 
If the evening premedications (first set) are missed, they should be administered a minimum of 
6 hours before the second set (see below) of premedications on the day of dosing (ie, at least 
7 hours before patisiran dosing). 
Prior to each dose of patisiran, patients will also receive the following premedications (ie, second 
set) at least 60 minutes before the infusion: 

Intravenous dexamethasone (20 mg) or equivalent 

Oral paracetamol/acetaminophen (500 mg) or equivalent 

Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 

Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the clinical site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) 
or cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Modifications to the premedication regimen may be allowed due to lack of tolerability of one or 
more of the premedications by the patient (eg, lowering of the corticosteroid dose if a patient 
develops uncontrolled hyperglycemia or altered mental status).  Such modifications may be 
allowed for that patient only after consultation with the Medical Monitor.  If the premedication 
regimen was already modified for this reason on the parent study, the modification for that 
particular patient will be carried over into this study. 
6.4.2.
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
Patients who have received at least 3 doses of patisiran on this study at the clinical site with no 
evidence of IRRs or other adverse effects may have patisiran administered at home, where 
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applicable country and local regulations allow.  Home administration of patisiran will be done 
according to a site-specific plan by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran. 
On all dosing days, patisiran will be administered as a 70-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 infusion time may be extended up to 3 hours in the event of a mild or moderate IRR; 
patisiran administration will not be resumed for any patient following a severe IRR until the case 
is discussed with the Medical Monitor (see Section 6.4.3).  If the infusion time for a patient was 
already extended on the parent study due to an IRR, that modified infusion duration may be 
continued on this study for that particular patient.  Returning the patient’s infusion duration to 
70 minutes will require a discussion with the Medical Monitor.  For the first 3 infusions of 
patisiran on this study, 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, and the patient will 
remain at the clinical site for 1 hour following completion of dosing. 
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A in an oral supplement. 
6.4.3.
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
In the event of an IRR, the infusion of patisiran may be stopped and the patient closely 
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and 
permit resumption of patisiran administration include, but are not limited to: 
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids. 
Following resolution of a mild or moderate IRR that required interruption of the patisiran 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of patisiran.  If 
the infusion is delayed, the administration of the infusion should be completed no more than 
6 hours from the initial start of the infusion.  Patisiran administration will not be resumed for any 
patient following a severe IRR until the case is discussed with the Medical Monitor. 
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. 
6.5.
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
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patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6.
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7.
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8.
ASSESSMENT OF EFFICACY
8.1.
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place over 2 days.  Patients will not receive study drug at this 
visit.  A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter. The specific timing for each assessment is presented in Table 1.
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1.
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1.
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 

Clinical exam-based NIS (weakness and reflexes) 

Electrophysiologic measures of small and large nerve fiber function (+7) including: 

Nerve conduction studies (NCS) 5 attributes (Σ5) 

Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 

Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 

Full NIS (including weakness, sensation, and reflexes) 

Electrophysiologic measures of small and large nerve fiber function (+7) including: 

NCS 5 

Vibration detection threshold (VDT) 

Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Each site will make every effort to have these assessments performed 
by the same study personnel, who will be different from the Investigator and other personnel 
managing the patient.  Assessments are to be performed at least 24 hours (approximately) apart 
from each other but no greater than 7 days apart.  In order to limit potential intra-operator bias, 
results of any of the prior assessments will not be available to the examiner when performing the 
second assessment. 
8.1.1.2.
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2.
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3.
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh.
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4.
Magnetic Resonance Neurography 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional 
images for the evaluation of peripheral nerve disorders.15 This procedure produces detailed 
images of nerve morphology to evaluate degeneration and regeneration.  Nerves in the lumbar 
plexus and lower extremity will be imaged for those patients who had MR neurography in the 
parent study.  A central reader will be used for MR neurography. 
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8.1.5.
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.6.
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.7.
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.8.
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.9.
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.10.
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
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8.1.11.
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.12.
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit.
8.1.13.
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not 
previously participating in the cardiac subgroup study will also be required to have an 
echocardiogram performed before dosing on Day 0.  Image acquisition, storage, and transfer 
guidelines will be provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.14.
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.15.
Vitamin A
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of patisiran and vitamin A supplementation. 
8.1.16.
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may 
be analyzed, if clinically indicated. 
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9.
ASSESSMENT OF SAFETY 
9.1.
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF. Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1.
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2.
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3.
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2.
Height will be measured only if it was not obtained in the parent study. 
9.1.4.
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5.
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  Samples collected at the Day 0, 26-week, and 52-week visits will be 
sent to a central laboratory for analysis.  Samples collected at the annual visits and End of Study 
or Early Withdrawal visits will be analyzed at the local laboratory.  Details on sample collection, 
processing, and shipping will be provided in a Laboratory Manual. 
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In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1.
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 

Hematocrit

Neutrophils, absolute and %

Hemoglobin

Lymphocytes, absolute and %

Red blood cell (RBC) count

Monocytes, absolute and %

White blood cell (WBC) count

Eosinophils, absolute and %

Mean corpuscular volume

Basophils, absolute and %

Mean corpuscular hemoglobin

Platelet count

Mean corpuscular hemoglobin concentration
9.1.5.2.
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 

Aspartate transaminase (AST)

Alkaline phosphatase

Alanine transaminase (ALT)

Bilirubin (total and direct)

Sodium

Glucose

Potassium

Phosphate

Blood urea nitrogen (BUN)

Albumin

Creatinine

Calcium

Thyroid stimulating hormone (TSH)
9.1.5.3.
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 

Visual inspection for color and appearance

Leukocytes

pH

Bilirubin

Specific gravity

Nitrite

Ketones

Urobilinogen

Protein

Microscopic inspection of sediment

Glucose
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9.1.5.4.
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6.
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.2.
Adverse Events and Serious Adverse Events 
9.2.1.
Definition of Adverse Events 
9.2.1.1.
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2.
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 

Results in death 

Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 

Requires inpatient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity 

Is a congenital anomaly or birth defect 

An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
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prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3.
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4.
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
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 
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should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
9.5.
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  Serious AEs will be followed through 28 days 
from the last dose of patisiran, or until satisfactory resolution, or until the SAE is considered by 
the Investigator to be chronic or the patient is stable, whichever occurs first. 
9.5.1.
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 causality 
Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
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system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
9.5.2.
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
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pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10.
STATISTICS 
10.1.
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2.
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1.
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 

Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 

Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2.
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3.
Efficacy Analyses 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the 
subset of patients that have previously received placebo in the parent study, comparisons for the 
various efficacy assessments will be made between rates of change pre- and post-administration 
of patisiran, and relative to the treatment group in the parent study.  Additional analyses will 
compare rates of change with rates estimated from previous studies, including cross-sectional, 
natural history, and interventional studies of other drugs.  Associations between PD (serum TTR) 
and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the 5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.  
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Values of the individual components of the mNIS weakness and reflex scores will be depicted 
graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4.
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5.
Healthcare Utilization Assessments 
The observed values and changes from baseline in healthcare utilization will be evaluated and 
summarized using descriptive statistics. 
10.2.6.
Interim Analysis 
There is no formal interim analysis planned for this study.  Interim data examinations may be 
performed, but these will be of a descriptive nature and will not involve any formal hypothesis 
testing. 
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11.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1.
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2.
Audits and Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB and/or 
Regulatory Authorities, providing direct access to source data/documents.  The study may be 
subject to audit by the Sponsor or its representatives or by regulatory authorities.  If such an audit 
occurs, the Investigator must agree to allow access to the required patient records.  In the event 
of an audit, the Investigator agrees to allow the Sponsor, representatives from the Sponsor, or 
regulatory agencies access to all study records. 
11.3.
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12.
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13.
ETHICS 
13.1.
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2.
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Health Organization (WHO) Declaration of 
Helsinki, the ICH of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other 
applicable medical privacy laws and regulations. 
13.2.1.
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3.
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
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The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record.
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14.
DATA HANDLING AND RECORD KEEPING 
14.1.
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files.
14.2.
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures.
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. 
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14.3.
Inspection of Records 
The Sponsor 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, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4.
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense.
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15.
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2  
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3  
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4  
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5  
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6  
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7  
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8  
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9  
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10  
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11  
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13  
Biesalski, HK, et al. Biochemical but not clinical vitamin A deficiency results from mutations in 
the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14  
Episkopou V, et al. Disruption of the transthyretin gene results in mice with depressed levels of 
plasma retinol and thyroid hormone. Proc Natl Acad Sci USA, 1993. 90: p. 2375-2379. 
15  
Kollmer J, Hund E, Hornung B, Schönland S, et al. MR-neurography: In-vivo detection of nerve 
injury in systemic light chain (AL) amyloidosis. XIVth International Symposium on 
Amyloidosis, 2014. 
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17.
APPENDICES 
Appendix 1: Karnofsky Scale 
Able to carry on normal activity 
and to work; no special care 
needed.
100
Normal no complaints; no evidence of 
disease.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
80
Normal activity with effort; some signs or 
symptoms of disease. 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed.
70
Cares for self; unable to carry on normal 
activity or to do active work.
60
Requires occasional assistance, but is able 
to care for most of his personal needs.
50
Requires considerable assistance and 
frequent medical care. 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly.
40
Disabled; requires special care and 
assistance.
30
Severely disabled; hospital admission is 
indicated although death not imminent.
20
Very sick; hospital admission necessary; 
active supportive treatment necessary.
10
Moribund; fatal processes progressing 
rapidly.
0
Dead
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Appendix 2: New York Heart Association Classification of Heart Failure 
Class
Symptomatology
I
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea.
II
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea.
III
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea.
IV
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea.
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Appendix 3: Categorization of Infusion-Related Reactions 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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.
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Appendix 4: Neuropathy Scores and Their Components 
Assessment Tool
Total 
Points
Components (points)
NIS+7 
270

Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa)

Weakness (192)

Sensation (32)

Reflexes (20)

Nerve conduction studies ∑5 (18.6)a

Sural SNAP, tibial motor n. distal latency, peroneal 
SNAP/motor n. conduction velocity/motor n. distal 
latency

Vibration detection threshold (3.7)

Heart rate response to deep breathing (3.7)
Modified NIS+7
304

Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa)

Weakness (192)

Reflexes (20)

Nerve conduction studies ∑5 (10)a

Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP

Quantitative sensory testing: QST-BSATP+HP5 (80)

Postural blood pressure (2)
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
Stage
Description
0
No symptoms
I
Sensory disturbances but preserved walking capability
II
Impaired walking capacity but ability to walk without a stick or crutches
IIIA
IIIB
Walking with the help of one stick or crutch.
Walking with the help of two sticks or crutches.
IV
Confined to a wheelchair or bedridden.
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
Stage
Description
0
No symptoms
I
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs
II
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk.
III
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs.
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ALN-TTR02-006 
Version 3.1-Argentina (Amendment 2) 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 3 .1-Argentina (Incorporating Amendment 
2) 
20 January 2017 
117395 
2014-003 877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
Alnylam Pharmaceuticals 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 – Global 
08 September 2015 
Incorporating Global Amendment 1 
3.1 – Argentina 
20 January 2017 
Incorporating Global Amendment 2 and 
Argentina-specific clarification letter dated 
03 November 2016 
 
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SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study: 
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate dosing 
in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to this timing 
may be allowed for medical or regulatory considerations only after consultation with the Medical 
Monitor.  The last testing visit in the parent study will serve as the baseline for this study, unless more 
than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.  
Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days.  Patients 
will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 
occur if deemed necessary by the study personnel. 
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Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) and, 
in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤2 x ULN is eligible 
if the elevation is secondary to documented Gilbert’s syndrome (elevation of unconjugated 
bilirubin with normal conjugated bilirubin) and the patient has ALT and AST levels within 
normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing on Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court 
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Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
 
Intravenous dexamethasone (10 mg) or equivalent 
 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine 25 mg per os (PO, orally) or fexofenadine 30 mg 
or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who does not 
tolerate IV diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test 
 
Polyneuropathy disability (PND) score and FAP stage 
 
Nutritional status using modified body mass index (mBMI) 
 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
 
Cardiac structure and function through echocardiograms and serum levels of terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
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 
New York Heart Association (NYHA) classification of heart failure 
 
Serum TTR 
 
Vitamin A 
 
Thyroid stimulating hormone 
 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; ophthalmology 
examinations; and assessment of suicidal ideation and behavior. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Associations between pharmacodynamic and efficacy data will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test (urine) 
Xi 
C-SSRS Questionnaire 
 
 
X 
X 
X 
X 
X 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TTR Protein (ELISA) 
Xd 
 
X 
X 
X 
X 
X 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
mNIS+7j 
Xd 
 
 
X 
 
 
[X]f 
NIS+7k 
Xd 
 
 
X 
 
 
[X]f 
NIS only 
 
 
 
 
Xl 
Xm 
Xm 
Grip Strength Testn 
Xd 
 
 
X 
 
 
[X]f 
10-Meter Walk Testp 
Xd 
 
 
X 
 
 
[X]f 
Ophthalmology Examinationq 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) r 
 
 
 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNs 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,t 
 
 
X 
 
 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
 
[X]f 
Anti-Drug Antibody Testingu 
 
 
X 
X 
X 
X 
X 
Premedication / Patisiran Administrationv 
X 
X 
 
 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
Table 1 Footnotes: 
Abbreviations:  C-SSRS = Columbia-Suicide Severity Rating Scale; COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked 
immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified 
body mass index; mNIS = Modified Neuropathy Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-
terminal prohormone of B-type natriuretic peptide; NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-
Diabetic Neuropathy; R-ODS = Rasch-built Overall Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = 
transthyretin 
a. 
Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may 
occur within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with 
the Medical Monitor. 
b. Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c. 
Assessment does not need to be repeated.  Information will be obtained from parent study. 
d. Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e. 
mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f. 
Assessment/procedure required only if patient withdraws before the 52-week visit. 
g. Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h. Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
i. 
Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the first dose.  Pregnancy testing will 
be done on a monthly basis during study duration. 
j. 
The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days 
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after the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who 
performed the assessments for the patient in the patisiran study in which they were previously enrolled.   
k. The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS 5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
l. 
One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
m. Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the 
previous 26 weeks. 
n. Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second 
(repeat) assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
o. Assessment does not need to be repeated if done within the previous 26 weeks. 
p. The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed 
on separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days 
after the first assessment. 
q. Examination will include visual acuity, visual fields, and slit-lamp evaluation. An electroretinogram may also be performed, as described in Section 9.1.6  
r. 
Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin 
biopsies in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies 
taken from the distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
s. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to 
complete this assessment. 
t. 
Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
u. Serum samples for anti-drug antibodies will be collected as specified. 
v. Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study in the 21 (±3) day timeframe.   
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TABLE OF CONTENTS 
 
SYNOPSIS 3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 
6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
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6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration.........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................36 
8.1.1.2. 
Neurological Impairment Score ..................................................................................37 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Modified Body Mass Index ........................................................................................37 
8.1.5. 
Timed 10-meter Walk Test .........................................................................................37 
8.1.6. 
Grip Strength Test .......................................................................................................38 
8.1.7. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.8. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.9. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.10. 
Rasch-built Overall Disability Scale ..........................................................................38 
8.1.11. 
Pharmacoeconomics Questionnaire ............................................................................38 
8.1.12. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.13. 
Transthyretin ...............................................................................................................39 
8.1.14. 
Thyroid-Stimulating Hormone ...................................................................................39 
8.1.15. 
Vitamin A ...................................................................................................................39 
8.1.16. 
Anti-Drug Antibodies .................................................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................40 
9.1. 
Safety Parameters .......................................................................................................40 
9.1.1. 
Demographic and Medical History .............................................................................40 
9.1.2. 
Vital Signs ..................................................................................................................40 
9.1.3. 
Weight and Height ......................................................................................................40 
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9.1.4. 
Physical Examination .................................................................................................40 
9.1.5. 
Laboratory Assessments .............................................................................................40 
9.1.5.1. 
Hematology .................................................................................................................41 
9.1.5.2. 
Blood Chemistry .........................................................................................................41 
9.1.5.3. 
Urinalysis ....................................................................................................................41 
9.1.5.4. 
Coagulation .................................................................................................................42 
9.1.5.5. 
Pregnancy Screen ........................................................................................................42 
9.1.6. 
Ophthalmology Examination ......................................................................................42 
9.1.7. 
Columbia-Suicide Severity Rating Scale ....................................................................42 
9.2. 
Adverse Events and Serious Adverse Events .............................................................42 
9.2.1. 
Definition of Adverse Events .....................................................................................42 
9.2.1.1. 
Adverse Event .............................................................................................................42 
9.2.1.2. 
Serious Adverse Event ................................................................................................42 
9.3. 
Relationship to Study Drug ........................................................................................43 
9.4. 
Recording Adverse Events .........................................................................................43 
9.5. 
Reporting Adverse Events ..........................................................................................44 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................44 
9.5.2. 
Pregnancy Reporting ..................................................................................................46 
10. 
STATISTICS ..............................................................................................................47 
10.1. 
Sample Size ................................................................................................................47 
10.2. 
Statistical Methodology ..............................................................................................47 
10.2.1. 
Populations to be Analyzed ........................................................................................47 
10.2.2. 
Baseline Evaluations ...................................................................................................47 
10.2.3. 
Efficacy Analyses .......................................................................................................47 
10.2.4. 
Safety Analyses ..........................................................................................................48 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................48 
10.2.6. 
Interim Analysis ..........................................................................................................48 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................49 
11.1. 
Study Monitoring ........................................................................................................49 
11.2. 
Audits and Inspections ................................................................................................49 
11.3. 
Institutional Review Board .........................................................................................49 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................50 
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13. 
ETHICS ......................................................................................................................51 
13.1. 
Ethics Review .............................................................................................................51 
13.2. 
Ethical Conduct of the Study ......................................................................................51 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................51 
13.3. 
Written Informed Consent ..........................................................................................51 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................53 
14.1. 
Case Report Forms .....................................................................................................53 
14.2. 
Confidentiality ............................................................................................................53 
14.3. 
Inspection of Records .................................................................................................54 
14.4. 
Retention of Records ..................................................................................................54 
15. 
PUBLICATION POLICY ..........................................................................................55 
16. 
LIST OF REFERENCES ............................................................................................56 
17. 
APPENDICES ............................................................................................................57 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RBP 
retinol binding protein 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran Investigator’s Brochure. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
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circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
 Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an 
IRR with patisiran, all patients in this study will be premedicated prior to dosing with 
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a 
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing 
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
 Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in 
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the end of 
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical 
studies to date, there have been no clinically significant changes in liver function tests in 
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver 
function via serial laboratory assessments. 
 Vitamin A Lowering 
The suppression of serum levels of TTR and retinol binding protein (RBP) is expected to 
result in the lowering of circulating vitamin A levels.  Preclinical and clinical data have 
shown that the lowering of circulating vitamin A associated with suppression of RBP does 
not result in severe vitamin A deficiency.  Furthermore, there are individuals with RBP/TTR 
mutations who have life-long low levels of circulating vitamin A and are essentially in good 
health, suggesting that there are compensatory transport mechanisms for vitamin A that are 
yet undescribed.13  This has also been confirmed in TTR knockout mice, which do not 
exhibit any manifestations of vitamin A deficiency, with vitamin A uptake by most tissues 
continuing in the absence of RBP.14  Provided there is adequate vitamin A in the diet, tissue 
stores of vitamin A should not be affected by the lowering of TTR and RBP.  However, as 
the vitamin A content of the diet may vary between different countries and different 
individuals within a country, all patients on the study will be asked to take a daily 
supplement containing the recommended daily allowance of vitamin A.  Patients should have 
started vitamin A supplementation by the time they start his/her first dose of patisiran. 
 Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone 
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mineralization.  If there are no medical contraindications, and per investigator judgment and 
local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the Investigator’s Brochure. 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days  Patients will also have visits at the clinical site at approximately 12, 26 and 52 
weeks, and yearly thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
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Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or its 
representative, and the Investigators, Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) and Regulatory Authorities will be promptly informed of the termination and the 
reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on 
anticoagulant therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing on Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 
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5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting 
his/her interests due to a medically diagnosed impairment of his/her mental faculties that 
may limit or prevent the expression of his will”), decided by a court 
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
 Is in violation of the protocol 
 Experiences a serious or intolerable AE 
 Becomes pregnant 
 Requires a prohibited medication (see Section 5.2) 
 Requests to be withdrawn from the study 
 Is found to be considerably noncompliant with the protocol-required patisiran dosing 
visits 
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not 
known whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients 
who are male or who are women of child bearing potential will affect reproduction.  
Histopathological evaluations of all of the reproductive organs have been conducted in the rat 
and non-human primate (NHP) toxicology studies including a chronic NHP study in sexually 
mature animals, where there were no adverse effects in males (including sperm analyses and 
spermatogenic staging) or females.  In a dose range-finding rat embryo/fetal development study 
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conducted with patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
 Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
 Placement of an intrauterine device (IUD) 
 Placement of an intrauterine system (IUS) 
 Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
 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); 
 Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
 Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
 IUD in conjunction with condom or diaphragm and spermicide 
 Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
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CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
 Any investigational agent other than patisiran 
 Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
 Tafamidis 
 Diflunisal 
 Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take an oral daily supplement containing the 
recommended daily allowance of. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 
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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff.  A dose will be considered completed if 80% or more of the total 
volume of the IV solution was administered to the patient.  Patients will be permitted to miss an 
occasional dose of patisiran; however, if a patient misses 3 consecutive doses, the Investigator, in 
consultation with the Medical Monitor, will discuss whether the patient will be able to continue 
on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 

Intravenous dexamethasone (10 mg) or equivalent

Oral paracetamol/acetaminophen (500 mg) or equivalent

Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2
blocker dose)

Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker
available at the clinical site).  Hydroxyzine 25 mg per os (PO, orally) or fexofenadine
30 mg or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who
does not tolerate IV diphenhydramine or other IV H1 blocker.
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 

If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.

If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid
premedication will be lowered, then the following steps must be followed:
1)
If the current steroid dosage is 10 mg or less of intravenous dexamethasone or
equivalent, then the patient may be lowered in increments no greater than 2.5 mg
intravenous dexamethasone or equivalent.
2)
After each incremental lowering of intravenous dexamethasone or equivalent, the patient
must receive three consecutive intravenous doses of patisiran without IRR and continued
signs or symptoms of steroid intolerance before further reductions in steroid
premedications.
3)
The premedication steroid dosage should not be reduced below 5 mg intravenous
dexamethasone or equivalent.
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone 
or equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 

If the patient experiences an IRR the infusion time may be extended up to 3 hours in the
event of a mild or moderate IRR.
1)
If the patient experiences a mild or moderate IRR that resolves by slowing the infusion
rate then no further premedication changes are recommended.
2)
If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).

If the infusion time for a patient was already extended on the parent study due to an IRR, that
modified infusion duration may be continued on this study for that particular patient.
Returning the patient’s infusion duration to 70 minutes will require a discussion with the
Medical Monitor.

For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following
completion of dosing.
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A in an oral supplement. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 

In the event of an IRR, the infusion of patisiran may be stopped and the patient closely
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and
permit resumption of patisiran administration include, but are not limited to:
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids.

Following resolution of a mild or moderate IRR that required interruption of the patisiran
infusion, resumption of administration may occur at the Investigator’s discretion at a slower
infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of
patisiran.  If the infusion is delayed, the administration of the infusion should be completed
no more than 6 hours from the initial start of the infusion.

Patisiran administration will not be resumed for any patient following a severe IRR until the
case is discussed with the Medical Monitor.
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 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place at the CAS.  Patients will not receive study drug at this visit.  
A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
 Clinical exam-based NIS (weakness and reflexes) 
 Electrophysiologic measures of small and large nerve fiber function (+7) including: 
 Nerve conduction studies (NCS) 5 attributes (Σ5) 
 Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
 Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
 Full NIS (including weakness, sensation, and reflexes) 
 Electrophysiologic measures of small and large nerve fiber function (+7) including: 
 NCS 5 
 Vibration detection threshold (VDT) 
 Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.5. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
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Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.6. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.7. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.8. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.9. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
8.1.10. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.11. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
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8.1.12. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.13. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.14. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.15. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A supplementation. 
8.1.16. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1. 
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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
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In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
 Hematocrit 
 Neutrophils, absolute and % 
 Hemoglobin 
 Lymphocytes, absolute and % 
 Red blood cell (RBC) count 
 Monocytes, absolute and % 
 White blood cell (WBC) count 
 Eosinophils, absolute and % 
 Mean corpuscular volume 
 Basophils, absolute and % 
 Mean corpuscular hemoglobin 
 Platelet count 
 Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
 Aspartate transaminase (AST) 
 Alkaline phosphatase 
 Alanine transaminase (ALT) 
 Bilirubin (total and direct) 
 Sodium 
 Glucose 
 Potassium 
 Phosphate 
 Blood urea nitrogen (BUN) 
 Albumin 
 Creatinine 
 Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
 Visual inspection for color and appearance 
 Leukocytes 
 pH 
 Bilirubin 
 Specific gravity 
 Nitrite 
 Ketones 
 Urobilinogen 
 Protein 
 Microscopic inspection of sediment 
 Glucose 
 
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9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to 
determine if there is damage to rods and cones.  ERG testing should be performed if visual 
changes raise the suspicion for this sort of retinal disease and if clinically indicated.  
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.1.7. 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to assess each patient's 
mental status as it relates to suicidal ideation and behavior. 
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
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 Results in death 
 Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
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Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
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). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 causality 
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Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
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transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
 Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
 Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Associations between PD (serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the 5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.   
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
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and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
A listing of healthcare utilization data will be  presented. 
10.2.6. 
Interim Analysis 
Interim data examinations may be performed, but these will be of a descriptive nature and will 
not involve any formal hypothesis testing. 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator and the site will permit study-related monitoring, audits and review by the IEC 
or IRB and/or Regulatory Authorities, providing direct access to source data/documents.  The 
study may be subject to audit by the Sponsor or its representatives or by regulatory authorities.  
If such an audit occurs, the Investigator must agree to allow access to the required patient 
records.  In the event of an audit, the Investigator agrees to allow the Sponsor, representatives 
from the Sponsor, or regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Medical Association Declaration of Helsinki, 
the ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use, the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other applicable 
medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
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The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 
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14.3. 
Inspection of Records 
The Sponsor 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, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2 
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3 
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4 
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5 
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6 
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7 
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8 
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9 
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10 
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11 
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13 
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14 
Episkopou, V., 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. 90: p. 2375-2379. 
15
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy and 
in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
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17.
APPENDICES
Appendix 1: Karnofsky Scale 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
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Appendix 2: New York Heart Association Classification of Heart Failure 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
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Appendix 3: Categorization of Infusion-Related Reactions 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
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Appendix 4: Neuropathy Scores and Their Components 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7 
270 

Neurologic exam of lower limbs, upper limbs and cranial
nerves (NISa)

Weakness (192)

Sensation (32)

Reflexes (20)

Nerve conduction studies ∑5 (18.6)a

Sural SNAP, tibial motor n. distal latency, peroneal
CMAP/motor n. conduction velocity/motor n. distal
latency

Vibration detection threshold (3.7)

Heart rate response to deep breathing (3.7)
Modified NIS+7 
304 

Neurologic exam of lower limbs, upper limbs and cranial
nerves (mNISa)

Weakness (192)

Reflexes (20)

Nerve conduction studies ∑5 (10)a

Ulnar CMAP and SNAP, sural SNAP, tibial CMAP,
peroneal CMAP

Quantitative sensory testing: QST-BSATP+HP5 (80)

Postural blood pressure (2)
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
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ALN-TTR02-006 Protocol Version 3.1 Argentina 
Summary of Changes (dated 20 January 2017)  
compared to Protocol Version 2 (dated 08 September 2015) 
A Multicenter, Open-label, Extension Study to Evaluate the Long-Term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy who have 
Completed a Prior Clinical Study with Patisiran 
Rationale for Protocol Amendment 
The primary purpose of this amendment is to add the Columbia-Suicide Severity Rating Scale 
(C-SSRS) to the study assessments, which was inadvertently left out of previous versions of the 
protocol. The inclusion of the C-SSRS addresses a regulatory requirement to prospectively 
assess suicidality in clinical trials involving all drugs for neurological indications.  Overall, this 
amendment includes the following changes: 

The Columbia-Suicide Severity Rating Scale has been added as an assessment of suicidal
ideation and behavior.

Electroretinograms are now recommended to be performed in the case of suspected
retinal disease.

The premedication regimen has been updated to align with commercially available doses.

Reference to home infusions and to magnetic resonance neurography have been removed
as they will not be performed in Argentina.

The protocol was updated to include changes specified in the clarification letter dated
03 November 2016, clarifying the timing of pregnancy testing.
A detailed summary of these changes, in addition to changes made for clarity, is provided in 
Table 1.  Corrections to abbreviations, typographical errors and formatting are not detailed. 
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Table 1: 
Protocol Version 3.1 Argentina Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment 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: Added Columbia-Suicide Severity Rating Scale to the study assessments 
The primary change occurs in Table 1 Schedule of Assessments 
Added text: 
Added row to Schedule of Assessments indicating that the Columbia-Suicide Severity Rating Scale is to be 
collected at 26 weeks and 52 weeks after baseline and annually thereafter, as well as at the End of Study and Early 
Withdrawal visits. 
Section(s) also containing this change or similar changes: 
 
Synopsis, Criteria for Evaluation, Safety 
 
Section 9.1.7 Columbia-Suicide Severity Rating Scale (section added) 
Purpose: Added clarity on timing of pregnancy testing, per clarification letter dated 03 November 2016. 
The primary change occurs in Table 1 Schedule of Assessments, footnote i 
Added text: 
x. Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the 
first dose.  Pregnancy testing will be done on a monthly basis during study duration. 
Section(s) also containing this change or similar changes: 
 
Table 1 Schedule of Assessments, Pregnancy Test row 
Purpose: To remove reference to home infusions as this will not be performed in Argentina.  
The primary change occurs in Section 3.1 Overall Study Design 
Deleted text: 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 21 (±3) 
days, or receive the patisiran infusions at home by a healthcare professional trained on the protocol and 
delivery of premedications and patisiran.  Patients who are receiving patisiran infusions at home will have 
a phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the clinical site at 
approximately 12, 26 and 52 weeks, and yearly thereafter. 
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Clinical Study Protocol ALN-TTR02-006 
 
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Section(s) also containing this change or similar changes: 
 
Synopsis methodology 
 
Table 1 Schedule of Assessments, Phone Contact row (removed) 
 
Table 1 Schedule of Assessments, Footnote w and Footnote x 
 
Section 5.3 Treatment Compliance 
 
Section 6.4.2 Study Drug Administration 
Purpose: To update premedication regimen so that it aligns with commercially available doses. 
The primary change occurs in Section 6.4.1 Premedication 
Now reads: 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker available at the clinical site).  
Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or fexofenadine 30 mg or 60 mg PO or cetirizine 10 mg 
PO may be substituted for any patient who does not tolerate IV diphenhydramine or other IV H1 blocker. 
Section(s) also containing this change or similar changes: 
 
Synopsis, Investigational product, dosage and mode of administration 
Purpose: To remove reference to magnetic resonance neurography as this will not be performed in Argentina. 
The primary change occurs in Section 8.1.4 Magnetic Resonance Neurography (removed section) 
Deleted Section: 
8.1.4 Magnetic Resonance Neurography 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional images 
for the evaluation of peripheral nerve disorders.i  This procedure produces detailed images of nerve 
morphology to evaluate degeneration and regeneration.  Nerves in the lumbar plexus and lower extremity 
will be imaged for patients who have previously had MR neurography in the parent study and may be 
imaged for consenting patients who did not have MR neurography previously in the parent study.  A 
central reader will be used for MR neurography. 
Section(s) also containing this change or similar changes: 
 
Synopsis, Criteria for evaluation, Efficacy 
 
Table 1 Schedule of Assessments, MR neurography row (deleted) 
 
Table 1 Schedule of Assessments, footnote u (deleted) 
 
Section 8.1 Efficacy parameters 
Purpose: Added recommendation to collect an electroretinogram in the case of suspected retinal injury 
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The primary change occurs in Section 9.1.6 Ophthalmology Examination 
Added text: 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to determine if there 
is damage to rods and cones.  ERG testing should be performed if visual changes raise the suspicion for this 
sort of retinal disease and if clinically indicated. 
Section(s) also containing this change or similar changes: 
 
Table 1, Schedule of Assessments, footnote q 
Purpose: Updated description of statistical analysis to align with currently planned analytic approach. 
The primary change occurs in Section 10.2.3 Efficacy Analyses 
Now reads: 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the subset of patients 
that have previously received placebo in the parent study, comparisons for the various efficacy assessments will be 
made between rates of change pre- and post-administration of patisiran, and relative to the treatment group in the 
parent study.  Additional analyses will compare rates of change with rates estimated from previous studies, 
including cross-sectional, natural history, and interventional studies of other drugs.  Associations between PD 
(serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the mNIS +7 composite 
score.  Summaries will also be provided for the components of the composite score (ie, the NIS weakness and reflex 
scores, the 5 NCS, and QST values).  The NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS 
will be summarized also.  Values of the individual components of the mNIS weakness and reflex scores will be 
depicted graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Section(s) also containing this change or similar changes: 
 
Synopsis, Statistical Methods 
 
Section 10.2.5 Healthcare Utilization Assessments 
 
Section 10.2.6 Interim Analysis 
Purpose: Clarified procedures for efficacy assessments, adding the location at which to conduct assessments, and removing specified duration. 
The primary change occurs in Section 8.1 Efficacy Parameters 
Now reads: 
Efficacy assessments will occur for all patients at the 52-week visit, which will take place over 2 daysat the CAS. 
Purpose: Removed language indicating that anti-drug antibodies would only be analyzed if clinically indicated. 
The primary change occurs in Section 8.1.17 Anti-drug Antibodies 
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Deleted text: 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may be analyzed, if 
clinically indicated. 
Section(s) also containing this change or similar changes: 

Table 1, Schedule of Assessments, footnote u
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Patisiran (ALN-TTR02) 
Clinical Protocol 
ALN-TTR02-006 
Version 3.1-Brazil (Amendment 2) 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 3.1-Brazil (Incorporating Amendment 2) 
20 January 2017 
117395 
2014-003877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
Alnylam Pharmaceuticals 
Confidential 
1 
PPD


Patisiran (ALN-TTR02) 
ALN-TTR02-006 
Clinical Protocol 
Version 3.1-Brazil (Amendment 2) 
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2 
INVESTIGATOR’S AGREEMENT 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 
08 September 2015 
Incorporating Global Amendment 1 
2.1 
16 September 2015 
Incorporating Brazil-Specific Amendment 
3.1 
20 January 2017 
Incorporating Global Amendment 2 
- Brazil
- Brazil
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SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate dosing 
in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to this timing 
may be allowed for medical or regulatory considerations only after consultation with the Medical 
Monitor.  The last testing visit in the parent study will serve as the baseline for this study, unless more 
than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.  
Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days  Patients 
will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 
occur if deemed necessary by the study personnel. 
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Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) and, 
in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is eligible 
if the elevation is secondary to documented Gilbert’s syndrome (elevation of unconjugated 
bilirubin with normal conjugated bilirubin) and the patient has ALT and AST levels within 
normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing on Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court 
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Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
 
Intravenous dexamethasone (10 mg) or equivalent 
 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine 25 mg per os (PO, orally) or fexofenadine 30 mg 
or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who does not 
tolerate IV diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test 
 
Polyneuropathy disability (PND) score and FAP stage 
 
Nutritional status using modified body mass index (mBMI) 
 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
 
Cardiac structure and function through echocardiograms and serum levels of terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
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 
New York Heart Association (NYHA) classification of heart failure 
 
Serum TTR 
 
Vitamin A 
 
Thyroid stimulating hormone 
 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; ophthalmology 
examinations; and assessment of suicidal ideation and behavior. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Associations between pharmacodynamic and efficacy data will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
 
[X]f 
Vital Signsg 
X  
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test 
Xi 
Xi (Prior to each dose) 
X 
X 
C-SSRS Questionnaire 
 
 
X 
X 
X 
X 
X 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TTR Protein (ELISA) 
Xd 
 
X 
X 
X 
X 
X 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
Blood Sample for Long-term Storage 
X 
X 
X 
X 
X 
X 
X 
mNIS+7j 
Xd 
 
 
X 
 
 
[X]f 
NIS+7k 
Xd 
 
 
X 
 
 
[X]f 
NIS only 
 
 
 
 
Xl 
Xm 
Xm 
Grip Strength Testn 
Xd 
 
 
X 
 
 
[X]f 
10-Meter Walk Testp 
Xd 
 
 
X 
 
 
[X]f 
Ophthalmology Examinationq 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) r 
 
 
 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNs 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,t 
 
 
X 
 
 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
 
[X]f 
Anti-Drug Antibody Testingu 
 
 
X 
X 
X 
X 
X 
Premedication / Patisiran Administrationv 
Xy 
X 
 
 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
Table 1 Footnotes: 
Abbreviations:  C-SSRS = Columbia-Suicide Severity Rating Scale; COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked 
immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified 
body mass index; mNIS = Modified Neuropathy Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-
terminal prohormone of B-type natriuretic peptide; NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-
Diabetic Neuropathy; R-ODS = Rasch-built Overall Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = 
transthyretin 
a Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may occur 
within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with the 
Medical Monitor. 
b Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c
d
e
f
g
h
i
 Assessment does not need to be repeated.  Information will be obtained from parent study. 
 Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
 mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
Assessment/procedure required only if patient withdraws before the 52-week visit. 
 Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
 Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
A urine-based pregnancy test will be performed on all females of child-bearing potential prior to dosing at all visits.   In cases where a positive urine pregnancy 
test result is observed, a serum pregnancy test will be administered and the dose will be held.  No dose will be administered until a negative pregnancy test 
is observed. Pregnancy test on  the Day 0 Visit does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the 
first dose.   
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j The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after 
the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who performed the 
assessments for the patient in the patisiran study in which they were previously enrolled.   
k The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS 5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
l One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
m Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the previous 
26 weeks. 
n Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
 o
p
q
r
s
t
u
v
  Assessment does not need to be repeated if done within the previous 26 weeks. 
 The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed on separate 
days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after the first 
assessment. 
 Examination will include visual acuity, visual fields, and slit-lamp evaluation.  An electroretinogram may also be performed, as described in Section 9.1.6. 
Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin biopsies 
in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies taken from the 
distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
 Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to complete 
this assessment. 
Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
 Serum samples for anti-drug antibodies will be collected as specified. 
 Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study in the 21 (±3) day timeframe.   
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TABLE OF CONTENTS 
 
SYNOPSIS 3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 
6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
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6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration.........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Modified Body Mass Index ........................................................................................37 
8.1.5. 
Timed 10-meter Walk Test .........................................................................................37 
8.1.6. 
Grip Strength Test .......................................................................................................38 
8.1.7. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.8. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.9. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.10. 
Rasch-built Overall Disability Scale ..........................................................................38 
8.1.11. 
Pharmacoeconomics Questionnaire ............................................................................38 
8.1.12. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.13. 
Transthyretin ...............................................................................................................39 
8.1.14. 
Thyroid-Stimulating Hormone ...................................................................................39 
8.1.15. 
Vitamin A ...................................................................................................................39 
8.1.16. 
Anti-Drug Antibodies .................................................................................................39 
8.1.17. 
Blood Sample for Long-term Storage .........................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................41 
9.1. 
Safety Parameters .......................................................................................................41 
9.1.1. 
Demographic and Medical History .............................................................................41 
9.1.2. 
Vital Signs ..................................................................................................................41 
9.1.3. 
Weight and Height ......................................................................................................41 
9.1.4. 
Physical Examination .................................................................................................41 
9.1.5. 
Laboratory Assessments .............................................................................................41 
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9.1.6. 
Ophthalmology Examination ......................................................................................43 
9.1.7. 
Columbia-Suicide Severity Rating Scale ....................................................................43 
9.2. 
Adverse Events and Serious Adverse Events .............................................................43 
9.2.1. 
Definition of Adverse Events .....................................................................................43 
9.3. 
Relationship to Study Drug ........................................................................................44 
9.4. 
Recording Adverse Events .........................................................................................44 
9.5. 
Reporting Adverse Events ..........................................................................................45 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................45 
9.5.2. 
Pregnancy Reporting ..................................................................................................47 
10. 
STATISTICS ..............................................................................................................48 
10.1. 
Sample Size ................................................................................................................48 
10.2. 
Statistical Methodology ..............................................................................................48 
10.2.1. 
Populations to be Analyzed ........................................................................................48 
10.2.2. 
Baseline Evaluations ...................................................................................................48 
10.2.3. 
Efficacy Analyses .......................................................................................................48 
10.2.4. 
Safety Analyses ..........................................................................................................49 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................49 
10.2.6. 
Interim Analysis ..........................................................................................................49 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................50 
11.1. 
Study Monitoring ........................................................................................................50 
11.2. 
Audits and Inspections ................................................................................................50 
11.3. 
Institutional Review Board .........................................................................................50 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................51 
13. 
ETHICS ......................................................................................................................52 
13.1. 
Ethics Review .............................................................................................................52 
13.2. 
Ethical Conduct of the Study ......................................................................................52 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................52 
13.3. 
Written Informed Consent ..........................................................................................52 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................54 
14.1. 
Case Report Forms .....................................................................................................54 
14.2. 
Confidentiality ............................................................................................................54 
14.3. 
Inspection of Records .................................................................................................55 
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14.4. 
Retention of Records ..................................................................................................55 
15. 
PUBLICATION POLICY ..........................................................................................56 
16. 
LIST OF REFERENCES ............................................................................................57 
17. 
APPENDICES ............................................................................................................58 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RBP 
retinol binding protein 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran Investigator’s Brochure. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
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circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
 Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an 
IRR with patisiran, all patients in this study will be premedicated prior to dosing with 
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a 
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing 
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
 Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in 
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the end of 
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical 
studies to date, there have been no clinically significant changes in liver function tests in 
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver 
function via serial laboratory assessments. 
 Vitamin A Lowering 
The suppression of serum levels of TTR and retinol binding protein (RBP) is expected to 
result in the lowering of circulating vitamin A levels.  Preclinical and clinical data have 
shown that the lowering of circulating vitamin A associated with suppression of RBP does 
not result in severe vitamin A deficiency.  Furthermore, there are individuals with RBP/TTR 
mutations who have life-long low levels of circulating vitamin A and are essentially in good 
health, suggesting that there are compensatory transport mechanisms for vitamin A that are 
yet undescribed.13  This has also been confirmed in TTR knockout mice, which do not 
exhibit any manifestations of vitamin A deficiency, with vitamin A uptake by most tissues 
continuing in the absence of RBP.14  Provided there is adequate vitamin A in the diet, tissue 
stores of vitamin A should not be affected by the lowering of TTR and RBP.  However, as 
the vitamin A content of the diet may vary between different countries and different 
individuals within a country, all patients on the study will be asked to take a daily 
supplement containing the recommended daily allowance of vitamin A.  Patients should have 
started vitamin A supplementation by the time they start his/her first dose of patisiran. 
 Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone 
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mineralization.  If there are no medical contraindications, and per investigator judgment and 
local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the Investigator’s Brochure. 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days.  Patients will also have visits at the clinical site at approximately 12, 26 and 52 
weeks, and yearly thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
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Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or its 
representative, and the Investigators, Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) and Regulatory Authorities will be promptly informed of the termination and the 
reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study)
and, in the opinion of the investigator, tolerated study drug
2. Be considered fit for the study by the Investigator
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on
anticoagulant therapy with an INR of ≤3.5 will be allowed)
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST
levels within normal ranges.
5. Have a serum creatinine ≤2 × ULN
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study. 
Highly effective methods of birth control are defined in Section 4.4.
7. Males with partners of child-bearing potential must agree to use 1 barrier method
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study
participation and for 75 days after the last dose of patisiran in this study; males must also
abstain from sperm donation after the first dose of patisiran through study participation
and for 75 days after last dose of patisiran in this study
8. Be willing and able to comply with the protocol-required visit schedule and visit
requirements and provide written informed consent
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing on Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not
be completed before the first dose of patisiran administration
2. Has poorly controlled diabetes mellitus
3. Has uncontrolled cardiac arrhythmia or unstable angina
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid
(TUDCA), unless previously allowed per the parent study
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5. Is unable to take the required premedications, unless modifications to the premedication
regimen were previously allowed per the parent study
6. Is under legal protection (defined as “any person who becomes incapable of protecting
his/her interests due to a medically diagnosed impairment of his/her mental faculties that
may limit or prevent the expression of his will”), decided by a court
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 

Is in violation of the protocol

Experiences a serious or intolerable AE

Becomes pregnant

Requires a prohibited medication (see Section 5.2)

Requests to be withdrawn from the study

Is found to be considerably noncompliant with the protocol-required patisiran dosing
visits
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not
known whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients 
who are male or who are women of child bearing potential will affect reproduction.  
Histopathological evaluations of all of the reproductive organs have been conducted in the rat 
and non-human primate (NHP) toxicology studies including a chronic NHP study in sexually 
mature animals, where there were no adverse effects in males (including sperm analyses and 
spermatogenic staging) or females.  In a dose range-finding rat embryo/fetal development study 
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conducted with patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
 Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
 Placement of an intrauterine device (IUD) 
 Placement of an intrauterine system (IUS) 
 Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
 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); 
 Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
 Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
 IUD in conjunction with condom or diaphragm and spermicide 
 Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
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CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
 Any investigational agent other than patisiran 
 Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
 Tafamidis 
 Diflunisal 
 Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take an oral daily supplement containing the 
recommended daily allowance of vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 
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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff.  A dose will be considered completed if 80% or more of the total 
volume of the IV solution was administered to the patient.  Patients will be permitted to miss an 
occasional dose of patisiran; however, if a patient misses 3 consecutive doses, the Investigator, in 
consultation with the Medical Monitor, will discuss whether the patient will be able to continue 
on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 

Intravenous dexamethasone (10 mg) or equivalent

Oral paracetamol/acetaminophen (500 mg) or equivalent

Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2
blocker dose)

Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker
available at the clinical site).  Hydroxyzine 25 mg per os (PO, orally) or fexofenadine
30 mg or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who
does not tolerate IV diphenhydramine or other IV H1 blocker.
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 

If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.

If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid
premedication will be lowered, then the following steps must be followed:
1)
If the current steroid dosage is 10 mg or less of intravenous dexamethasone or
equivalent, then the patient may be lowered in increments no greater than 2.5 mg
intravenous dexamethasone or equivalent.
2)
After each incremental lowering of intravenous dexamethasone or equivalent, the patient
must receive three consecutive intravenous doses of patisiran without IRR and continued
signs or symptoms of steroid intolerance before further reductions in steroid
premedications.
3)
The premedication steroid dosage should not be reduced below 5 mg intravenous
dexamethasone or equivalent.
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone 
or equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 

If the patient experiences an IRR the infusion time may be extended up to 3 hours in the
event of a mild or moderate IRR.
1)
If the patient experiences a mild or moderate IRR that resolves by slowing the infusion
rate then no further premedication changes are recommended.
2)
If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).

If the infusion time for a patient was already extended on the parent study due to an IRR, that
modified infusion duration may be continued on this study for that particular patient.
Returning the patient’s infusion duration to 70 minutes will require a discussion with the
Medical Monitor.

For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following
completion of dosing.
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A in an oral supplement. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 

In the event of an IRR, the infusion of patisiran may be stopped and the patient closely
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and
permit resumption of patisiran administration include, but are not limited to:
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids.

Following resolution of a mild or moderate IRR that required interruption of the patisiran
infusion, resumption of administration may occur at the Investigator’s discretion at a slower
infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of
patisiran.  If the infusion is delayed, the administration of the infusion should be completed
no more than 6 hours from the initial start of the infusion.

Patisiran administration will not be resumed for any patient following a severe IRR until the
case is discussed with the Medical Monitor.
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 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place at the CAS.  Patients will not receive study drug at this visit.  
A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
 Clinical exam-based NIS (weakness and reflexes) 
 Electrophysiologic measures of small and large nerve fiber function (+7) including: 
 Nerve conduction studies (NCS) 5 attributes (Σ5) 
 Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
 Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
 Full NIS (including weakness, sensation, and reflexes) 
 Electrophysiologic measures of small and large nerve fiber function (+7) including: 
 NCS 5 
 Vibration detection threshold (VDT) 
 Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.5. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
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Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.6. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.7. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.8. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.9. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
8.1.10. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.11. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
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8.1.12. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.13. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.14. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.15. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A supplementation. 
8.1.16. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1. 
8.1.17. 
Blood Sample for Long-term Storage 
To permit exploratory investigations and the application of novel approaches to bioanalysis that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action and/or efficacy of patisiran, blood samples will be collected for 
long-term storage. These samples will be securely stored in a central biorepository for up to 10 
years following the last patient last visit in this clinical study. After 10 years have elapsed, 
samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of samples will be provided in 
the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
All study participants will be advised during the informed consent process of these biobanking 
details and the potential for exploratory investigation of their samples. Those who do not wish to 
contribute specimens to the biorepository will be asked to sign an “opt out” form. Moreover, 
patients who subsequently decide to withdraw consent for the utilization of such stored samples 
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will be able to do so, with the understanding that any data arising from samples already analyzed 
will be the property of Alnylam Pharmaceuticals. 
 
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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points. 
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
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In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
 Hematocrit 
 Neutrophils, absolute and % 
 Hemoglobin 
 Lymphocytes, absolute and % 
 Red blood cell (RBC) count 
 Monocytes, absolute and % 
 White blood cell (WBC) count 
 Eosinophils, absolute and % 
 Mean corpuscular volume 
 Basophils, absolute and % 
 Mean corpuscular hemoglobin 
 Platelet count 
 Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
 Aspartate transaminase (AST) 
 Alkaline phosphatase 
 Alanine transaminase (ALT) 
 Bilirubin (total and direct) 
 Sodium 
 Glucose 
 Potassium 
 Phosphate 
 Blood urea nitrogen (BUN) 
 Albumin 
 Creatinine 
 Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
 Visual inspection for color and appearance 
 Leukocytes 
 pH 
 Bilirubin 
 Specific gravity 
 Nitrite 
 Ketones 
 Urobilinogen 
 Protein 
 Microscopic inspection of sediment 
 Glucose 
 
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9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Testing 
A urine-based pregnancy test will be performed on all females of child-bearing potential prior to 
dosing at all visits, as specified in Table 1.   In cases where a positive urine pregnancy test result 
is observed, a serum pregnancy test will be administered and the dose will be held.  No dose will 
be administered until a negative pregnancy test is observed. Pregnancy test on  the Day 0 Visit 
does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 
14 days of the first dose. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction.  
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to 
determine if there is damage to rods and cones.  ERG testing should be performed if visual 
changes raise the suspicion for this sort of retinal disease and if clinically indicated. 
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.1.7. 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to assess each patient's 
mental status as it relates to suicidal ideation and behavior. 
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
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9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
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In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
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). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
The initial report should include at least the following information: 

Patient’s study number
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
Description and date of onset of the event

Criterion for serious

Preliminary assignment of causality
Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
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The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
 Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
 Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Associations between PD (serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the 5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.   
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
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and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
A listing of healthcare utilization data will be presented. 
10.2.6. 
Interim Analysis 
Interim data examinations may be performed, but these will be of a descriptive nature and will 
not involve any formal hypothesis testing. 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB and/or 
Regulatory Authorities, providing direct access to source data/documents.  The study may be 
subject to audit by the Sponsor or its representatives or by regulatory authorities.  If such an audit 
occurs, the Investigator must agree to allow access to the required patient records.  In the event 
of an audit, the Investigator agrees to allow the Sponsor, representatives from the Sponsor, or 
regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Medical Association Declaration of Helsinki, 
the ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use, the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other applicable 
medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
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The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 
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14.3. 
Inspection of Records 
The Sponsor 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, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15.
PUBLICATION POLICY
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2 
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3 
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4 
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5 
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6 
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7 
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8 
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9 
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10 
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11 
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13 
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14 
Episkopou, V., 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. 90: p. 2375-2379. 
15
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy and 
in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
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17. 
APPENDICES 
 
Appendix 1: Karnofsky Scale 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
 
 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 
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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
 
Weakness (192) 
 
Sensation (32) 
 
Reflexes (20) 
 
Nerve conduction studies ∑5 (18.6)a 
 
Sural SNAP, tibial motor n. distal latency, peroneal 
CMAP/motor n. conduction velocity/motor n. distal 
latency 
 
Vibration detection threshold (3.7) 
 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
 
Weakness (192) 
 
Reflexes (20) 
 
Nerve conduction studies ∑5 (10)a 
 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 
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ALN-TTR02-006 Protocol Version 3.1 Brazil 
Summary of Changes (dated 20 January 2017)  
compared to Protocol Version 2.1 Brazil (dated 16 September 2015) 
A Multicenter, Open-label, Extension Study to Evaluate the Long-Term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy who have 
Completed a Prior Clinical Study with Patisiran 
 
Rationale for Protocol Amendment 
The primary purpose of this amendment is to add the Columbia-Suicide Severity Rating Scale 
(C-SSRS) to the study assessments, which was inadvertently left out of previous versions of the 
protocol. The inclusion of the C-SSRS addresses a regulatory requirement to prospectively 
assess suicidality in clinical trials involving all drugs for neurological indications.  Overall, this 
amendment includes the following changes: 
 The Columbia-Suicide Severity Rating Scale has been added as an assessment of suicidal 
ideation and behavior. 
 Electroretinograms are now recommended to be performed in the case of suspected 
retinal disease. 
 The premedication regimen has been updated to align with commercially available doses. 
 Blood samples for long-term storage have been added in order to permit future 
exploratory investigations. 
 Reference to home infusions and to magnetic resonance neurography have been removed 
as they will not be performed in Brazil. 
A detailed summary of the above changes, in addition to changes made for clarity, is provided in 
Table 1.  Corrections to abbreviations, typographical errors and formatting are not detailed. 
 
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Table 1: 
Protocol Version 3.1 Brazil Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment 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: Added Columbia-Suicide Severity Rating Scale to the study assessments 
The primary change occurs in Table 1 Schedule of Assessments 
Added text: 
Added row to Schedule of Assessments indicating that the Columbia-Suicide Severity Rating Scale is to be 
collected at 26 weeks and 52 weeks after baseline and annually thereafter, as well as at the End of Study and Early 
Withdrawal visits. 
Section(s) also containing this change or similar changes: 
 
Synopsis, Criteria for Evaluation, Safety 
 
Section 9.1.7 Columbia-Suicide Severity Rating Scale (section added) 
Purpose: To remove reference to home infusions as this will not be performed in Brazil.  
The primary change occurs in Section 3.1 Overall Study Design 
Deleted text: 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 21 (±3) 
days, or receive the patisiran infusions at home by a healthcare professional trained on the protocol and 
delivery of premedications and patisiran.  Patients who are receiving patisiran infusions at home will have 
a phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the clinical site at 
approximately 12, 26 and 52 weeks, and yearly thereafter. 
Section(s) also containing this change or similar changes: 
 
Synopsis methodology 
 
Table 1 Schedule of Assessments, Phone Contact row (removed) 
 
Table 1 Schedule of Assessments, Footnote y and Footnote z 
 
Section 5.3 Treatment Compliance 
 
Section 6.4.2 Study Drug Administration 
Purpose: To update premedication regimen so that it aligns with commercially available doses. 
The primary change occurs in Section 6.4.1 Premedication 
Now reads: 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker available at the clinical site).  
Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or fexofenadine 30 mg or 60 mg PO or cetirizine 10 mg 
PO may be substituted for any patient who does not tolerate IV diphenhydramine or other IV H1 blocker. 
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Section(s) also containing this change or similar changes: 
 
Synopsis, Investigational product, dosage and mode of administration 
Purpose: Added recommendation to collect an electroretinogram in the case of suspected retinal injury 
The primary change occurs in Section 9.1.6 Ophthalmology Examination 
Added text: 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to determine if there 
is damage to rods and cones.  ERG testing should be performed if visual changes raise the suspicion for this 
sort of retinal disease and if clinically indicated. 
Section(s) also containing this change or similar changes: 
 
Table 1, Schedule of Assessments, footnote q 
Purpose: Updated description of statistical analysis to align with currently planned analytic approach. 
The primary change occurs in Section 10.2.3 Efficacy Analyses 
Now reads: 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the subset of patients 
that have previously received placebo in the parent study, comparisons for the various efficacy assessments will be 
made between rates of change pre- and post-administration of patisiran, and relative to the treatment group in the 
parent study.  Additional analyses will compare rates of change with rates estimated from previous studies, 
including cross-sectional, natural history, and interventional studies of other drugs.  Associations between PD 
(serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the mNIS +7 composite 
score.  Summaries will also be provided for the components of the composite score (ie, the NIS weakness and reflex 
scores, the 5 NCS, and QST values).  The NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS 
will be summarized also.  Values of the individual components of the mNIS weakness and reflex scores will be 
depicted graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Section(s) also containing this change or similar changes: 
 
Synopsis, Statistical Methods 
 
Section 10.2.5 Healthcare Utilization Assessments 
 
Section 10.2.6 Interim Analysis 
Purpose: Added blood sampling for long-term storage in order to permit future exploratory investigations. 
The primary change occurs in Table 1 Schedule of Assessments 
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Added text: 
Added row to Schedule of Assessments indicating a blood sample for long-term storage is to be collected at each 
clinic visit. 
Section(s) also containing this change or similar changes: 
 
Section 8.1.17 Blood Sample for Long-term Storage (section added) 
Purpose: Clarified procedures for efficacy assessments, adding the location at which to conduct assessments, and removing specified duration. 
The primary change occurs in Section 8.1 Efficacy Parameters 
Now reads: 
Efficacy assessments will occur for all patients at the 52-week visit, which will take place over 2 daysat the CAS. 
Purpose: To remove reference to magnetic resonance neurography as this will not be performed in Brazil. 
The primary change occurs in Section 8.1.4 Magnetic Resonance Neurography (removed section) 
Deleted Section: 
8.1.4 Magnetic Resonance Neurography 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional images for the 
evaluation of peripheral nerve disorders.i  This procedure produces detailed images of nerve morphology to 
evaluate degeneration and regeneration.  Nerves in the lumbar plexus and lower extremity will be imaged for 
patients who have previously had MR neurography in the parent study and may be imaged for consenting 
patients who did not have MR neurography previously in the parent study.  A central reader will be used for 
MR neurography. 
Section(s) also containing this change or similar changes: 
 
Synopsis, Criteria for evaluation, Efficacy 
 
Table 1 Schedule of Assessments, MR neurography row (deleted) 
 
Table 1 Schedule of Assessments, footnote u (deleted) 
 
Section 8.1 Efficacy parameters 
Purpose: Removed language indicating that anti-drug antibodies would only be analyzed if clinically indicated. 
The primary change occurs in Section 8.1.16 Anti-drug Antibodies 
Deleted text: 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may be analyzed, if 
clinically indicated. 
Section(s) also containing this change or similar changes: 
 
Table 1, Schedule of Assessments, footnote u 
 
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344
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Clinical Protocol 
ALN-TTR02-006 
Version 2.1-Brazil 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 2.1-Brazil (Incorporating Amendment 1) 
15 September 2015 
117395 
2014-003 877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Signature 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
Alnylam Pharmaceuticals 
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PPD
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 
08 September 2015 
Incorporating Global Amendment 1 
2.1 
15 September 2015 
Incorporating Brazil-Specific Amendment 
 
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SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior 
Clinical Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate 
dosing in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to 
this timing may be allowed for medical or regulatory considerations only after consultation with the 
Medical Monitor.  The last testing visit in the parent study will serve as the baseline for this study, 
unless more than 45 days have elapsed, in which case the baseline tests will need to be repeated on 
Day 0.  Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days, or 
receive the patisiran infusions at home by a healthcare professional trained on the protocol and 
delivery of premedications and patisiran.  Patients who are receiving patisiran infusions at home will 
have a phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the 
clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
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Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN are 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing 
in this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation and 
for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit 
or prevent the expression of his will”), decided by a court 
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Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
• 
Intravenous dexamethasone (10 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or 
cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
• 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
• 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
• 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
• 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
• 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk 
test, and grip strength test 
• 
Polyneuropathy disability (PND) score and FAP stage 
• 
Nutritional status using modified body mass index (mBMI) 
• 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
• 
Magnetic resonance (MR) neurography  
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• 
Cardiac structure and function through echocardiograms and serum levels of terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
• 
New York Heart Association (NYHA) classification of heart failure 
• 
Serum TTR 
• 
Vitamin A 
• 
Thyroid Stimulating Hormone 
• 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical 
laboratory tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; 
measurement of anti-drug antibodies (if clinically indicated); vital signs; physical examinations; and 
ophthalmology examinations. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Efficacy analyses will examine between- and within-subject rates of change over time.  For the subset 
of patients that have previously received placebo in the parent study, comparisons for the various 
efficacy assessments will be made between rates of change pre- and post-administration of patisiran, 
and relative to the treatment group in the parent study.  Additional exploratory analyses will compare 
rates of change with rates estimated from previous studies, including cross-sectional, natural history, 
and interventional studies of other drugs.  Associations between pharmacodynamic and efficacy data 
will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to 
each on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
[X]f 
[X]f 
Vital Signsg 
X  
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test 
Xk 
Xk (Prior to each dose) 
X 
X 
TTR Protein (ELISA) 
X 
 
X 
X 
X 
X 
X 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
mNIS+7l 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS+7m 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS only 
 
 
 
 
Xn 
Xn,p 
Xn,p 
Grip Strength Testq 
Xd 
 
 
X 
 
[X]f 
[X]f 
10-Meter Walk Testr 
Xd 
 
 
X 
 
[X]f 
[X]f 
Ophthalmology Examinations 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) t 
 
 
 
X 
X 
Xo 
Xo 
MR Neurographyu 
 
 
 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNv 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
[X]f 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
[X]f 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,w 
 
 
X 
 
[X]f 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
[X]f 
[X]f 
Anti-Drug Antibody Testingx 
 
 
X 
X 
X 
X 
X 
Premedication / Patisiran Administration 
Xy 
Xy 
 
 
Phone Contact 
 
Xz 
 
 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
 
Table 1 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = 
familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified body mass index; mNIS = Modified Neuropathy 
Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; 
NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; R-ODS = Rasch-built Overall 
Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = transthyretin 
a Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may occur 
within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with the 
Medical Monitor. 
b Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c Assessment does not need to be repeated.  Information will be obtained from parent study. 
d Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f Assessment/procedure required only if patient withdraws before the 52-week visit. 
g Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
k A urine-based pregnancy test will be performed on all females of child-bearing potential prior to dosing at all visits.   In cases where a positive urine pregnancy 
test result is observed, a serum pregnancy test will be administered and the dose will be held.  No dose will be administered until a negative pregnancy test 
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is observed. Pregnancy test on  the Day 0 Visit does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the 
first dose.   
l The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (Σ5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after 
the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who performed the 
assessments for the patient in the patisiran study in which they were previously enrolled.   
m The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
n One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
o Assessment does not need to be repeated if done within the previous 26 weeks. 
p Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the previous 
26 weeks. 
q Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
r The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed on separate 
days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after the first 
assessment. 
s Examination will include visual acuity, visual fields, and slit-lamp evaluation. 
t Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin biopsies 
in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies taken from the 
distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
u Required only for patients who had MR neurography in the parent study and may be imaged for consenting patients who did not have MR neurography 
previously in their parent study.   
v Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to complete 
this assessment. 
w Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
x Serum samples for anti-drug antibodies will be collected as specified.  Samples may be analyzed, if clinically indicated. 
y Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study within the 21 (±3) days 
timeframe.  Doses may be administered at the clinical site or at home by a healthcare professional trained in the protocol. 
z Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 30 (±5) days for assessment of adverse events 
and concomitant medication use. 
 
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TABLE OF CONTENTS 
 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 
6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
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6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration.........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Magnetic Resonance Neurography .............................................................................37 
8.1.5. 
Modified Body Mass Index ........................................................................................38 
8.1.6. 
Timed 10-meter Walk Test .........................................................................................38 
8.1.7. 
Grip Strength Test .......................................................................................................38 
8.1.8. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.10. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.11. 
Rasch-built Overall Disability Scale ..........................................................................39 
8.1.12. 
Pharmacoeconomics Questionnaire ............................................................................39 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.14. 
Transthyretin ...............................................................................................................39 
8.1.15. 
Thyroid-Stimulating Hormone ...................................................................................39 
8.1.16. 
Vitamin A ...................................................................................................................39 
8.1.17. 
Anti-Drug Antibodies .................................................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................40 
9.1. 
Safety Parameters .......................................................................................................40 
9.1.1. 
Demographic and Medical History .............................................................................40 
9.1.2. 
Vital Signs ..................................................................................................................40 
9.1.3. 
Weight and Height ......................................................................................................40 
9.1.4. 
Physical Examination .................................................................................................40 
9.1.5. 
Laboratory Assessments .............................................................................................40 
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9.1.6. 
Ophthalmology Examination ......................................................................................42 
9.2. 
Adverse Events and Serious Adverse Events .............................................................42 
9.2.1. 
Definition of Adverse Events .....................................................................................42 
9.3. 
Relationship to Study Drug ........................................................................................43 
9.4. 
Recording Adverse Events .........................................................................................43 
9.5. 
Reporting Adverse Events ..........................................................................................44 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................44 
9.5.2. 
Pregnancy Reporting ..................................................................................................46 
10. 
STATISTICS ..............................................................................................................47 
10.1. 
Sample Size ................................................................................................................47 
10.2. 
Statistical Methodology ..............................................................................................47 
10.2.1. 
Populations to be Analyzed ........................................................................................47 
10.2.2. 
Baseline Evaluations ...................................................................................................47 
10.2.3. 
Efficacy Analyses .......................................................................................................47 
10.2.4. 
Safety Analyses ..........................................................................................................48 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................48 
10.2.6. 
Interim Analysis ..........................................................................................................48 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................49 
11.1. 
Study Monitoring ........................................................................................................49 
11.2. 
Audits and Inspections ................................................................................................49 
11.3. 
Institutional Review Board .........................................................................................49 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................50 
13. 
ETHICS ......................................................................................................................51 
13.1. 
Ethics Review .............................................................................................................51 
13.2. 
Ethical Conduct of the Study ......................................................................................51 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................51 
13.3. 
Written Informed Consent ..........................................................................................51 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................53 
14.1. 
Case Report Forms .....................................................................................................53 
14.2. 
Confidentiality ............................................................................................................53 
14.3. 
Inspection of Records .................................................................................................53 
14.4. 
Retention of Records ..................................................................................................54 
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15. 
PUBLICATION POLICY ..........................................................................................55 
16. 
LIST OF REFERENCES ............................................................................................56 
17. 
APPENDICES ............................................................................................................57 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
Σ5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WHO 
World Health Organization 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
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serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran IB. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
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nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
• Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an 
IRR with patisiran, all patients in this study will be premedicated prior to dosing with 
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a 
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing 
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
• Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in 
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the end of 
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical 
studies to date, there have been no clinically significant changes in liver function tests in 
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver 
function via serial laboratory assessments. 
• Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of 
circulating vitamin A levels.  Preclinical and clinical data have shown that the lowering of 
circulating vitamin A associated with suppression of RBP does not result in severe vitamin A 
deficiency.  Furthermore, there are individuals with RBP/TTR mutations who have life-long 
low levels of circulating vitamin A and are essentially in good health, suggesting that there 
are compensatory transport mechanisms for vitamin A that are yet undescribed.13  This has 
also been confirmed in TTR knockout mice, which do not exhibit any manifestations of 
vitamin A deficiency, with vitamin A uptake by most tissues continuing in the absence of 
RBP.14  Provided there is adequate vitamin A in the diet, tissue stores of vitamin A should 
not be affected by the lowering of TTR and RBP.  However, as the vitamin A content of the 
diet may vary between different countries and different individuals within a country, all 
patients on the study will be asked to take a daily supplement containing the recommended 
daily allowance of vitamin A.  Patients should have started vitamin A supplementation by the 
time they start his/her first dose of patisiran. 
• Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone 
mineralization.  If there are no medical contraindications, and per investigator judgment and 
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local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the IB. 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days, or receive the patisiran infusions at home by a healthcare professional trained on 
the protocol and delivery of premedications and patisiran.  Patients who are receiving patisiran 
infusions at home will have a phone contact with the site at least every 30 (±5) days.  Patients 
will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly 
thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
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which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or its 
representative, and the Investigators, Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) and Regulatory Authorities will be promptly informed of the termination and the 
reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on 
anticoagulant therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
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6. Is under legal protection (defined as “any person who becomes incapable of protecting
his/her interests due to a medically diagnosed impairment of his/her mental faculties that
may limit or prevent the expression of his will”), decided by a court
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
•
Is in violation of the protocol
•
Experiences a serious or intolerable AE
•
Becomes pregnant
•
Requires a prohibited medication (see Section 5.2)
•
Requests to be withdrawn from the study
•
Is found to be considerably noncompliant with the protocol-required patisiran dosing
visits
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not known 
whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients who are 
male or who are women of child bearing potential will affect reproduction.  Histopathological 
evaluations of all of the reproductive organs have been conducted in the rat and non-human 
primate (NHP) toxicology studies including a chronic NHP study in sexually mature animals, 
where there were no adverse effects in males (including sperm analyses and spermatogenic 
staging) or females.  In a dose range-finding rat embryo/fetal development study conducted with 
patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
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or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
• Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
• Placement of an intrauterine device (IUD) 
• Placement of an intrauterine system (IUS) 
• Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
• 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); 
• Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
• Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
• IUD in conjunction with condom or diaphragm and spermicide 
• Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
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CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
• Any investigational agent other than patisiran 
• Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
• Tafamidis 
• Diflunisal 
• Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take an oral daily supplement containing the 
recommended daily allowance of vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 
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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff or trained home healthcare professionals.  A dose will be considered 
completed if 80% or more of the total volume of the IV solution was administered to the patient.  
Patients will be permitted to miss an occasional dose of patisiran; however, if a patient misses 
3 consecutive doses, the Investigator, in consultation with the Medical Monitor, will discuss 
whether the patient will be able to continue on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 
• Intravenous dexamethasone (10 mg) or equivalent 
• Oral paracetamol/acetaminophen (500 mg) or equivalent 
• Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the clinical site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) 
or cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 
• If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.  
• If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid 
premedication will be lowered, then the following steps must be followed: 
1) If the current steroid dosage is 10 mg or less of intravenous dexamethasone or 
equivalent, then the patient may be lowered in increments no greater than 2.5 mg 
intravenous dexamethasone or equivalent. 
2) After each incremental lowering of intravenous dexamethasone or equivalent, the patient 
must receive three consecutive intravenous doses of patisiran without IRR and continued 
signs or symptoms of steroid intolerance before further reductions in steroid 
premedications.   
3) The premedication steroid dosage should not be reduced below 5 mg intravenous 
dexamethasone or equivalent. 
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone or 
equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
Patients who have received at least 3 doses of patisiran on this study at the clinical site with no 
evidence of IRRs or other adverse effects may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be done 
according to a site-specific plan by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran. 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 
• If the patient experiences an IRR the infusion time may be extended up to 3 hours in the 
event of a mild or moderate IRR. 
1) If the patient experiences a mild or moderate IRR that resolves by slowing the infusion 
rate then no further premedication changes are recommended. 
2) If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).   
• If the infusion time for a patient was already extended on the parent study due to an IRR, that 
modified infusion duration may be continued on this study for that particular patient.  
Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
• For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following 
completion of dosing. 
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A in an oral supplement. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
• In the event of an IRR, the infusion of patisiran may be stopped and the patient closely 
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and 
permit resumption of patisiran administration include, but are not limited to: 
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids. 
• Following resolution of a mild or moderate IRR that required interruption of the patisiran 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of 
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patisiran.  If the infusion is delayed, the administration of the infusion should be completed 
no more than 6 hours from the initial start of the infusion.   
• Patisiran 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place over 2 days.  Patients will not receive study drug at this 
visit.  A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
• Clinical exam-based NIS (weakness and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− Nerve conduction studies (NCS) 5 attributes (Σ5) 
− Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
• Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
• Full NIS (including weakness, sensation, and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− NCS Σ5 
− Vibration detection threshold (VDT) 
• Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Magnetic Resonance Neurography 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional 
images for the evaluation of peripheral nerve disorders.16  This procedure produces detailed 
images of nerve morphology to evaluate degeneration and regeneration.  Nerves in the lumbar 
plexus and lower extremity will be imaged for patients who have previously had MR 
neurography in the parent study and may be imaged for consenting patients who did not have 
MR neurography previously in the parent study.  A central reader will be used for MR 
neurography. 
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8.1.5. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.6. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.7. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.8. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.10. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
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8.1.11. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.12. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.14. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.15. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.16. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A supplementation. 
8.1.17. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may 
be analyzed, if clinically indicated. 
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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran administration, the test should be repeated and followed up at the discretion of the 
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Investigator until it has returned to the normal range or stabilized, and/or a diagnosis is made to 
adequately explain the abnormality. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
• Aspartate transaminase (AST) 
• Alkaline phosphatase 
• Alanine transaminase (ALT) 
• Bilirubin (total and direct) 
• Sodium 
• Glucose 
• Potassium 
• Phosphate 
• Blood urea nitrogen (BUN) 
• Albumin 
• Creatinine 
• Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
• Visual inspection for color and appearance 
• Leukocytes 
• pH 
• Bilirubin 
• Specific gravity 
• Nitrite 
• Ketones 
• Urobilinogen 
• Protein 
• Microscopic inspection of sediment 
• Glucose 
 
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9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Testing 
A urine-based pregnancy test will be performed on all females of child-bearing potential prior to 
dosing at all visits, as specified in Table 1.   In cases where a positive urine pregnancy test result 
is observed, a serum pregnancy test will be administered and the dose will be held.  No dose will 
be administered until a negative pregnancy test is observed. Pregnancy test on  the Day 0 Visit 
does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 
14 days of the first dose. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2. 
Serious Adverse Event 
A serious AE (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) 
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• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
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Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
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). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 causality
Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
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listed below (country-specific phone number will be provided in the Study Manual), and fax the 
completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
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9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
• Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
• Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the 
subset of patients that have previously received placebo in the parent study, comparisons for the 
various efficacy assessments will be made between rates of change pre- and post-administration 
of patisiran, and relative to the treatment group in the parent study.  Additional analyses will 
compare rates of change with rates estimated from previous studies, including cross-sectional, 
natural history, and interventional studies of other drugs.  Associations between PD (serum TTR) 
and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the Σ5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.  
Values of the individual components of the mNIS weakness and reflex scores will be depicted 
graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
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Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
The observed values and changes from baseline in healthcare utilization will be evaluated and 
summarized using descriptive statistics. 
10.2.6. 
Interim Analysis 
There is no formal interim analysis planned for this study.  Interim data examinations may be 
performed, but these will be of a descriptive nature and will not involve any formal hypothesis 
testing. 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB and/or 
Regulatory Authorities, providing direct access to source data/documents.  The study may be 
subject to audit by the Sponsor or its representatives or by regulatory authorities.  If such an audit 
occurs, the Investigator must agree to allow access to the required patient records.  In the event 
of an audit, the Investigator agrees to allow the Sponsor, representatives from the Sponsor, or 
regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Health Organization (WHO) Declaration of 
Helsinki, the ICH of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other 
applicable medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
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requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 
14.3. 
Inspection of Records 
The Sponsor 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 
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drug storage area, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2  
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3  
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4  
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5  
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6  
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7  
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8  
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9  
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10  
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11  
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13  
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14  
Episkopou, V., 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. 90: p. 2375-2379. 
15
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy and 
in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
16  
Kollmer J, Hund E, Hornung B, Schönland S, et al. MR-neurography: In-vivo detection of nerve 
injury in systemic light chain (AL) amyloidosis. XIVth International Symposium on 
Amyloidosis, 2014. 
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17. 
APPENDICES 
 
Appendix 1: Karnofsky Scale 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
 
 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 
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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
• 
Weakness (192) 
• 
Sensation (32) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (18.6)a 
• 
Sural SNAP, tibial motor n. distal latency, peroneal 
SNAP/motor n. conduction velocity/motor n. distal 
latency 
• 
Vibration detection threshold (3.7) 
• 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
• 
Weakness (192) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (10)a 
• 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
• 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
• 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 
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Version 2.1-Brazil  Summary of Changes 
 
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Country-Specific Amendment Summary of Changes for Brazil 
Protocol Version 2.1-Brazil, dated 15 September 2015, compared to Protocol Version 2.0 
(Amendment 1.0), dated 08 September 2015 
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who 
Have Completed a Prior Clinical Study with Patisiran 
 
Rationale for Version 2.1-Brazil 
Consistent with Brazil-specific protocol ALN-TTR02-004, pregnancy testing for women of 
child-bearing potential prior to each dose of patisiran has been included in Brazil-specific 
protocol ALN-TTR02-006. 
 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 
 
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Table 1: 
Version 2.1-Brazil Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in this amendment 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:   
Add pregnancy testing for women of child-bearing potential be performed prior to each dose of patisiran. 
Primary change: 
Section 9.1.5.5 Pregnancy Testing (formerly Pregnancy Screen) 
Formerly read: 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing of the tests is 
specified in in Table 1; additional testing may be done any time pregnancy is suspected. 
Now reads: 
A urine-based pregnancy test will be performed on all females of child-bearing potential prior to dosing at all 
visits, as specified in Table 1.   In cases where a positive urine pregnancy test result is observed, a serum 
pregnancy test will be administered and the dose will be held.  No dose will be administered until a negative 
pregnancy test is observed. Pregnancy test on the Day 0 Visit does not need to be repeated if the patient had a 
negative pregnancy test (urine or serum) within 14 days of the first dose. 
Section(s) also 
containing this 
change: 
• 
Table 1 Schedule of Assessments 
 
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 Amendment 2 Summary of Changes_05 January 2017 
 
ALN-TTR02-006 Protocol Amendment 2 
Summary of Changes (dated 05 January 2017)  
compared to Protocol Version 2.1 France and Germany (dated 17 December 2015) 
A Multicenter, Open-label, Extension Study to Evaluate the Long-Term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy who have 
Completed a Prior Clinical Study with Patisiran 
 
Rationale for Protocol Amendment 
The primary purpose of this amendment is to add the Columbia-Suicide Severity Rating Scale 
(C-SSRS) to the study assessments, which was inadvertently left out of previous versions of the 
protocol. The inclusion of the C-SSRS addresses a regulatory requirement to prospectively 
assess suicidality in clinical trials involving all drugs for neurological indications.  Overall, this 
amendment includes the following changes: 
• The Columbia-Suicide Severity Rating Scale has been added as an assessment of suicidal 
ideation and behavior. 
• Country-specific versions of the protocol have been integrated in order to increase 
consistency in the execution of the clinical study globally 
• Electroretinograms are now recommended to be performed in the case of suspected 
retinal disease. 
• The premedication regimen has been updated to align with commercially available doses. 
• Blood samples for long-term storage have been added in order to permit future 
exploratory investigations. 
• During scheduled phone contact, clinical sites may now ask patients who are receiving 
home infusions about their general experience receiving these infusions 
A detailed summary of the above changes, in addition to changes made for clarity, is provided in 
Table 1.  Corrections to abbreviations, typographical errors and formatting are not detailed. 
 
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Amendment 2 Summary of Changes_05 January 2017 
Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment 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: Added Columbia-Suicide Severity Rating Scale to the study assessments 
The primary change occurs in Table 1 Schedule of Assessments 
Added text: 
Added row to Schedule of Assessments indicating that the Columbia-Suicide Severity Rating Scale is to be 
collected at 26 weeks and 52 weeks after baseline and annually thereafter, as well as at the End of Study and Early 
Withdrawal visits. 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Criteria for Evaluation, Safety 
• 
Section 9.1.7 Columbia-Suicide Severity Rating Scale (section added) 
Purpose: As part of global protocol integration, specified that home infusions are allowed only where applicable country and local regulations 
allow. 
The primary change occurs in Section 3.1 Overall Study Design 
Added text: 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 21 (±3) days, or. 
Where applicable country and local regulations allow, patients may receive the patisiran infusions at home by a 
healthcare professional trained on the protocol and delivery of premedications and patisiran. 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Methodology 
• 
Table 1, Schedule of Assessments 
• 
Section 5.3 Treatment Compliance 
• 
Section 6.4.2 Study Drug Administration 
Purpose: As part of global protocol integration, specified that MR neurography is only to be conducted in Germany and France 
The primary change occurs in Table 1 Schedule of Assessments, footnote s 
Now reads: 
MR neurography will only be conducted at sites in Germany and France. In these countries, neurography may be 
conducted for patients who had MR neurography in the parent study and may be performed for a subset of patients providing 
informed consent who did not have MR neurography previously in their parent study. Imaging at baseline (Patients who had 
imaging in the parent study should have Day 0 visit imaging if they did not required for patients who underwent undergo 
MR neurography in the parent study within the past 3 months 
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Amendment 2 Summary of Changes_05 January 2017 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Criteria for evaluation, Efficacy 
• 
Section 8.1 Efficacy Parameters 
• 
Section 8.1.4 Magnetic Resonance Neurography (Germany and France Only) 
Purpose: As part of global protocol integration, specified which studies patients may roll in from, and that the ALN-TTR02-003 study is not being 
conducted in Japan. 
The primary change occurs in Section 3.1 Overall Study Design 
Added text: 
Patients in this study will have completed “parent” study ALN-TTR02-003 or ALN-TTR02-004.  Note that 
Study ALN-TTR02-003 is not being conducted in Japan. 
Purpose: As part of global protocol integration, added Japan-specific recommendations regarding contraception. 
The primary change occurs in Section 4.4 Pregnancy and Breastfeeding Restrictions / Contraception Requirements 
Added text: 
In Japan it is recommended that the Investigators select appropriate contraception methods, as available. 
Purpose: As part of global protocol integration, added Japan-specific instructions regarding duties related to study drug accountability. 
The primary change occurs in Section 6.5 Study Drug Accountability 
Added text: 
The Investigator or designee (or in Japan, the responsible pharmacist designated according to the Japan local 
regulations) will maintain accurate records of receipt and the condition of the patisiran supplied for this study, 
including dates of receipt. 
Purpose: As part of global protocol integration, added statement on compensation for health damages as per local regulations. 
The primary change occurs in Section 13.4 Compensation for Health Damages (section added) 
Added text: 
13.4    Compensation for Health Damages 
 
A copy of the certificate of insurance as a measure to compensation for health damages will be submitted to 
the IRB/IEC if required per local regulations 
Purpose: To update premedication regimen so that it aligns with commercially available doses. 
The primary change occurs in Section 6.4.1 Premedication 
Now reads: 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker available at the clinical site).  
Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or fexofenadine 30 mg or 60 mg PO or cetirizine 10 mg 
PO may be substituted for any patient who does not tolerate IV diphenhydramine or other IV H1 blocker. 
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Amendment 2 Summary of Changes_05 January 2017 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Investigational product, dosage and mode of administration 
Purpose: Added recommendation to collect an electroretinogram in the case of suspected retinal injury 
The primary change occurs in Section 9.1.6 Ophthalmology Examination 
Added text: 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to determine if there 
is damage to rods and cones.  ERG testing should be performed if visual changes raise the suspicion for this 
sort of retinal disease and if clinically indicated. 
Section(s) also containing this change or similar changes: 
• 
Table 1, Schedule of Assessments 
Purpose: Updated description of statistical analysis to align with currently planned analytic approach. 
The primary change occurs in Section 10.2.3 Efficacy Analyses 
Now reads: 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the subset of patients 
that have previously received placebo in the parent study, comparisons for the various efficacy assessments will be 
made between rates of change pre- and post-administration of patisiran, and relative to the treatment group in the 
parent study.  Additional analyses will compare rates of change with rates estimated from previous studies, 
including cross-sectional, natural history, and interventional studies of other drugs.  Associations between PD 
(serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the mNIS +7 composite 
score.  Summaries will also be provided for the components of the composite score (ie, the NIS weakness and reflex 
scores, the Σ5 NCS, and QST values).  The NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS 
will be summarized also.  Values of the individual components of the mNIS weakness and reflex scores will be 
depicted graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Statistical Methods 
• 
Section 10.2.5 Healthcare Utilization Assessments 
• 
Section 10.2.6 Interim Analysis 
Purpose: Added blood sampling for long-term storage in order to permit future exploratory investigations. 
The primary change occurs in Table 1 Schedule of Assessments 
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Amendment 2 Summary of Changes_05 January 2017 
Added text: 
Added row to Schedule of Assessments indicating a blood sample for long-term storage is to be collected at each 
clinic visit. 
Section(s) also containing this change or similar changes: 
• 
Section 8.1.18 Blood Sample for Long-term Storage (section added) 
Purpose: Added questionnaire regarding experience of home infusions to scheduled phone contact for home infusion patients. 
The primary change occurs in Table 1 Schedule of Assessments, footnote x 
Added text: 
x. Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 
30 (±5) days for assessment of adverse events and concomitant medication use. During phone contact, patients 
may also be asked additional questions about their general experience receiving infusions at home. 
Purpose: Added a definition of “woman of child-bearing potential”. 
The primary change occurs in Section 4.4 Pregnancy and Breastfeeding Restrictions / Contraception Requirements 
Added text: 
Women of child-bearing potential are defined as any woman or adolescent who has begun menstruation. A 
post-menopausal woman is defined as a woman who has 12 months of spontaneous amenorrhea or 6 months 
of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks postsurgical bilateral 
oophorectomy with or without hysterectomy. 
Purpose: Clarified language on Vitamin A dosing and added Japan-specific instructions. 
The primary change occurs in Section 5.2 Concomitant Medications 
Now reads: 
All patients will be asked to continue to take an oral daily supplement containing the recommended daily allowance 
of vitamin A. Patients will receive this daily dose for the duration of their participation in the study while 
being administered patisiran. In Japan, the clinical sites will provide patients with a prescription for vitamin 
A. 
Section(s) also containing this change or similar changes: 
• 
Section 6.4.2 Study Drug Administration 
• 
Section 8.1.16 Vitamin A 
Purpose: Clarified procedures for efficacy assessments, adding the location at which to conduct assessments, and removing specified duration. 
The primary change occurs in Section 8.1 Efficacy Parameters 
Now reads: 
Efficacy assessments will occur for all patients at the 52-week visit, which will take place over 2 daysat the CAS. 
Purpose: Removed language indicating that anti-drug antibodies would only be analyzed if clinically indicated. 
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Amendment 2 Summary of Changes_05 January 2017 
The primary change occurs in Section 8.1.17 Efficacy Parameters 
Deleted text: 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may be analyzed, if 
clinically indicated. 
Section(s) also containing this change or similar changes: 
• 
Table 1, Schedule of Assessments 
Purpose: Clarified that no study procedures may occur until approval is granted by all appropriate parties. 
The primary change occurs in Section 13.1 Ethics Review 
Added text: 
The Investigator should not start any study procedure with the patient until documentation of the approval 
by the IEC/IRB and written notification of the approval from the head of the study site to the Investigator 
and Alnylam Pharmaceuticals, Inc. 
 
 
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414
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Clinical Protocol 
ALN-TTR02-006 
Version 2.1 (Amendment 1- France and Germany) 17 December 2015 
P ATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 2.1 (Incorporating Amendment 1) - France 
and Germany 
17 December 2015 
117395 
2014-003 877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
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ALN-TTR02-006 
Clinical Protocol                                       Version 2.1 (Amendment 1 - France and Germany) 17 December 2015 
 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 
08 September 2015 
Incorporating Global Amendment 1 
2.1 
17 December 2015 
Incorporating French and German Specific Update 
 
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Clinical Protocol                                       Version 2.1 (Amendment 1 - France and Germany) 17 December 2015 
 
SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate dosing 
in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to this timing 
may be allowed for medical or regulatory considerations only after consultation with the Medical 
Monitor.  The last testing visit in the parent study will serve as the baseline for this study, unless more 
than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.  
Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days, or 
receive the patisiran infusions at home by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran.  Patients who are receiving patisiran infusions at home will have a 
phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the clinical site 
at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 
occur if deemed necessary by the study personnel. 
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Clinical Protocol                                       Version 2.1 (Amendment 1 - France and Germany) 17 December 2015 
 
Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) and, 
in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN are 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court 
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ALN-TTR02-006 
Clinical Protocol                                       Version 2.1 (Amendment 1 - France and Germany) 17 December 2015 
 
Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
• 
Intravenous dexamethasone (10 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or 
cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
• 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
• 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
• 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
• 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
• 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test 
• 
Polyneuropathy disability (PND) score and FAP stage 
• 
Nutritional status using modified body mass index (mBMI) 
• 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
• 
Magnetic resonance (MR) neurography  
• 
Cardiac structure and function through echocardiograms and serum levels of terminal 
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prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
• 
New York Heart Association (NYHA) classification of heart failure 
• 
Serum TTR 
• 
Vitamin A 
• 
Thyroid Stimulating Hormone 
• 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; and ophthalmology 
examinations. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Efficacy analyses will examine between- and within-subject rates of change over time.  For the subset 
of patients that have previously received placebo in the parent study, comparisons for the various 
efficacy assessments will be made between rates of change pre- and post-administration of patisiran, 
and relative to the treatment group in the parent study.  Additional exploratory analyses will compare 
rates of change with rates estimated from previous studies, including cross-sectional, natural history, 
and interventional studies of other drugs.  Associations between pharmacodynamic and efficacy data 
will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
[X]f 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test (urine) 
Xk 
 
X 
X 
X 
X 
X 
TTR Protein (ELISA) 
X 
 
X 
X 
X 
X 
X 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
mNIS+7l 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS+7m 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS only 
 
 
 
 
Xn 
Xn,p 
Xn,p 
Grip Strength Testq 
Xd 
 
 
X 
 
[X]f 
[X]f 
10-Meter Walk Testr 
Xd 
 
 
X 
 
[X]f 
[X]f 
Ophthalmology Examinations 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) t 
 
 
 
X 
X 
Xo 
Xo 
MR Neurographyu 
X 
 
X 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNv 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
[X]f 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
[X]f 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,w 
 
 
X 
 
[X]f 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
[X]f 
[X]f 
Anti-Drug Antibody Testingx 
 
 
X 
X 
X 
X 
X 
Premedication / Patisiran Administration 
Xy 
Xy 
 
 
Phone Contact 
 
Xz 
 
 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
 
Table 1 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = 
familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified body mass index; mNIS = Modified Neuropathy 
Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; 
NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; R-ODS = Rasch-built Overall 
Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = transthyretin 
a Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may occur 
within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with the 
Medical Monitor. 
b Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c Assessment does not need to be repeated.  Information will be obtained from parent study. 
d Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f Assessment/procedure required only if patient withdraws before the 52-week visit. 
g Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
k Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the first dose. 
l The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (Σ5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
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separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after 
the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who performed the 
assessments for the patient in the patisiran study in which they were previously enrolled.   
m The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
n One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
o Assessment does not need to be repeated if done within the previous 26 weeks. 
p Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the previous 
26 weeks. 
q Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
r The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed on separate 
days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after the first 
assessment. 
s Examination will include visual acuity, visual fields, and slit-lamp evaluation. 
t Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin biopsies 
in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies taken from the 
distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
u Required for patients who had MR neurography in the parent study and may be performed for a subset of patients providing informed consent who did not have 
MR neurography previously in their parent study.  Imaging at baseline (Day 0 visit) is not required for patients who underwent MR neurography in the parent 
study within the past 3 months. 
v Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to complete 
this assessment. 
w Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
x Serum samples for anti-drug antibodies will be collected as specified.  Samples may be analyzed, if clinically indicated. 
y Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study within the 21 (±3) days 
timeframe.  Doses may be administered at the clinical site or at home by a healthcare professional trained in the protocol. 
z Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 30 (±5) days for assessment of adverse events 
and concomitant medication use. 
 
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TABLE OF CONTENTS 
 
SYNOPSIS 3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 
6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
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6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration.........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................36 
8.1.1.2. 
Neurological Impairment Score ..................................................................................37 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Magnetic Resonance Neurography .............................................................................37 
8.1.5. 
Modified Body Mass Index ........................................................................................38 
8.1.6. 
Timed 10-meter Walk Test .........................................................................................38 
8.1.7. 
Grip Strength Test .......................................................................................................38 
8.1.8. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.10. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.11. 
Rasch-built Overall Disability Scale ..........................................................................39 
8.1.12. 
Pharmacoeconomics Questionnaire ............................................................................39 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.14. 
Transthyretin ...............................................................................................................39 
8.1.15. 
Thyroid-Stimulating Hormone ...................................................................................39 
8.1.16. 
Vitamin A ...................................................................................................................39 
8.1.17. 
Anti-Drug Antibodies .................................................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................40 
9.1. 
Safety Parameters .......................................................................................................40 
9.1.1. 
Demographic and Medical History .............................................................................40 
9.1.2. 
Vital Signs ..................................................................................................................40 
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9.1.3. 
Weight and Height ......................................................................................................40 
9.1.4. 
Physical Examination .................................................................................................40 
9.1.5. 
Laboratory Assessments .............................................................................................40 
9.1.5.1. 
Hematology .................................................................................................................41 
9.1.5.2. 
Blood Chemistry .........................................................................................................41 
9.1.5.3. 
Urinalysis ....................................................................................................................41 
9.1.5.4. 
Coagulation .................................................................................................................41 
9.1.5.5. 
Pregnancy Screen ........................................................................................................42 
9.1.6. 
Ophthalmology Examination ......................................................................................42 
9.2. 
Adverse Events and Serious Adverse Events .............................................................42 
9.2.1. 
Definition of Adverse Events .....................................................................................42 
9.2.1.1. 
Adverse Event .............................................................................................................42 
9.2.1.2. 
Serious Adverse Event ................................................................................................42 
9.3. 
Relationship to Study Drug ........................................................................................43 
9.4. 
Recording Adverse Events .........................................................................................43 
9.5. 
Reporting Adverse Events ..........................................................................................44 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................44 
9.5.2. 
Pregnancy Reporting ..................................................................................................45 
10. 
STATISTICS ..............................................................................................................47 
10.1. 
Sample Size ................................................................................................................47 
10.2. 
Statistical Methodology ..............................................................................................47 
10.2.1. 
Populations to be Analyzed ........................................................................................47 
10.2.2. 
Baseline Evaluations ...................................................................................................47 
10.2.3. 
Efficacy Analyses .......................................................................................................47 
10.2.4. 
Safety Analyses ..........................................................................................................48 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................48 
10.2.6. 
Interim Analysis ..........................................................................................................48 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................49 
11.1. 
Study Monitoring ........................................................................................................49 
11.2. 
Audits and Inspections ................................................................................................49 
11.3. 
Institutional Review Board .........................................................................................49 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................50 
13. 
ETHICS ......................................................................................................................51 
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13.1. 
Ethics Review .............................................................................................................51 
13.2. 
Ethical Conduct of the Study ......................................................................................51 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................51 
13.3. 
Written Informed Consent ..........................................................................................51 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................53 
14.1. 
Case Report Forms .....................................................................................................53 
14.2. 
Confidentiality ............................................................................................................53 
14.3. 
Inspection of Records .................................................................................................54 
14.4. 
Retention of Records ..................................................................................................54 
15. 
PUBLICATION POLICY ..........................................................................................55 
16. 
LIST OF REFERENCES ............................................................................................56 
17. 
APPENDICES ............................................................................................................57 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
Σ5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WHO 
World Health Organization 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran IB. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
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circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
• Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain 
biological agents such as liposomes or monoclonal antibodies.  In order to reduce the 
potential for an IRR with patisiran, all patients in this study will be premedicated prior to 
dosing with patisiran.  The step-wise infusion regimen over approximately 70 minutes 
(starting with a slower infusion rate of approximately 1 mL/minute for the first 15 
minutes before increasing to 3 mL/minute for the remainder of the infusion), may further 
reduce the risk of an IRR. 
• Liver function test abnormalities 
In preclinical studies, patisiran-related increased serum liver markers and histopathology 
in the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the 
end of the 60-90 day dose free period, indicating that the toxicities were reversible.  In 
clinical studies to date, there have been no clinically significant changes in liver function 
tests in either the single-dose or multiple-dose studies. Patients in the study are monitored 
for liver function via serial laboratory assessments. 
• Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of 
circulating vitamin A levels.  Preclinical and clinical data have shown that the lowering 
of circulating vitamin A associated with suppression of RBP does not result in severe 
vitamin A deficiency.  Furthermore, there are individuals with RBP/TTR mutations who 
have life-long low levels of circulating vitamin A and are essentially in good health, 
suggesting that there are compensatory transport mechanisms for vitamin A that are yet 
undescribed.13  This has also been confirmed in TTR knockout mice, which do not 
exhibit any manifestations of vitamin A deficiency, with vitamin A uptake by most 
tissues continuing in the absence of RBP.14  Provided there is adequate vitamin A in the 
diet, tissue stores of vitamin A should not be affected by the lowering of TTR and RBP.  
However, as the vitamin A content of the diet may vary between different countries and 
different individuals within a country, all patients on the study will be asked to take a 
daily supplement containing the recommended daily allowance of vitamin A.  Patients 
should have started vitamin A supplementation by the time they start his/her first dose of 
patisiran. 
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• Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the 
premedication regimen administered prior to patisiran dosing every three weeks, FAP 
patients participating in this study are given glucocorticoids, a drug known to have the 
potential to reduce bone mineralization.  If there are no medical contraindications, and 
per investigator judgment and local standard of care, study participants should, if 
appropriate, receive therapy for the prevention and early treatment of osteoporosis such 
as: calcium and vitamin D supplementation, bisphosphonates, calcitonin, parathyroid 
hormone, estrogen agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the IB. 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days, or receive the patisiran infusions at home by a healthcare professional trained on 
the protocol and delivery of premedications and patisiran.  Patients who are receiving patisiran 
infusions at home will have a phone contact with the site at least every 30 (±5) days.  Patients 
will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly 
thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
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which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or its 
representative, and the Investigators, Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) and Regulatory Authorities will be promptly informed of the termination and the 
reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on 
anticoagulant therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 
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5. Is unable to take the required premedications, unless modifications to the premedication
regimen were previously allowed per the parent study
6. Is under legal protection (defined as “any person who becomes incapable of protecting
his/her interests due to a medically diagnosed impairment of his/her mental faculties that
may limit or prevent the expression of his will”), decided by a court
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
•
Is in violation of the protocol
•
Experiences a serious or intolerable AE
•
Becomes pregnant
•
Requires a prohibited medication (see Section 5.2)
•
Requests to be withdrawn from the study
•
Is found to be considerably noncompliant with the protocol-required patisiran dosing
visits
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.  It is not known 
whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients who are 
male or who are women of child bearing potential will affect reproduction.  Histopathological 
evaluations of all of the reproductive organs have been conducted in the rat and non-human 
primate (NHP) toxicology studies including a chronic NHP study in sexually mature animals, 
where there were no adverse effects in males (including sperm analyses and spermatogenic 
staging) or females.  In a dose range-finding rat embryo/fetal development study conducted with 
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patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, or fetal 
development despite reductions (-88% from baseline) in serum vitamin A in the dams dosed with 
the rat-specific TTR surrogate siRNA. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
• Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
• Placement of an intrauterine device (IUD) 
• Placement of an intrauterine system (IUS) 
• Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
• 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); 
• Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
• Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
• IUD in conjunction with condom or diaphragm and spermicide 
• Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
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CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
• Any investigational agent other than patisiran 
• Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
• Tafamidis 
• Diflunisal 
• Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take an oral daily supplement containing the 
recommended daily allowance of vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 
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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff or trained home healthcare professionals.  A dose will be considered 
completed if 80% or more of the total volume of the IV solution was administered to the patient.  
Patients will be permitted to miss an occasional dose of patisiran; however, if a patient misses 
3 consecutive doses, the Investigator, in consultation with the Medical Monitor, will discuss 
whether the patient will be able to continue on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 
• Intravenous dexamethasone (10 mg) or equivalent 
• Oral paracetamol/acetaminophen (500 mg) or equivalent 
• Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the clinical site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) 
or cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 
• If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.  
• If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid 
premedication will be lowered, then the following steps must be followed: 
1) If the current steroid dosage is 10 mg or less of intravenous dexamethasone or 
equivalent, then the patient may be lowered in increments no greater than 2.5 mg 
intravenous dexamethasone or equivalent. 
2) After each incremental lowering of intravenous dexamethasone or equivalent, the patient 
must receive three consecutive intravenous doses of patisiran without IRR and continued 
signs or symptoms of steroid intolerance before further reductions in steroid 
premedications.   
3) The premedication steroid dosage should not be reduced below 5 mg intravenous 
dexamethasone or equivalent. 
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone or 
equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
Patients who have received at least 3 doses of patisiran on this study at the clinical site with no 
evidence of IRRs or other adverse effects may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be done 
according to a site-specific plan by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran. 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 
• If the patient experiences an IRR the infusion time may be extended up to 3 hours in the 
event of a mild or moderate IRR. 
1) If the patient experiences a mild or moderate IRR that resolves by slowing the infusion 
rate then no further premedication changes are recommended. 
2) If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).   
• If the infusion time for a patient was already extended on the parent study due to an IRR, that 
modified infusion duration may be continued on this study for that particular patient.  
Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
• For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following 
completion of dosing. 
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A in an oral supplement. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
• In the event of an IRR, the infusion of patisiran may be stopped and the patient closely 
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and 
permit resumption of patisiran administration include, but are not limited to: 
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids. 
• Following resolution of a mild or moderate IRR that required interruption of the patisiran 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of 
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patisiran.  If the infusion is delayed, the administration of the infusion should be completed 
no more than 6 hours from the initial start of the infusion.   
• Patisiran 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place over 2 days.  Patients will not receive study drug at this 
visit.  A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
• Clinical exam-based NIS (weakness and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− Nerve conduction studies (NCS) 5 attributes (Σ5) 
− Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
• Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
• Full NIS (including weakness, sensation, and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− NCS Σ5 
− Vibration detection threshold (VDT) 
• Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Magnetic Resonance Neurography 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional 
images for the evaluation of peripheral nerve disorders.16  This procedure produces detailed 
images of nerve morphology to evaluate degeneration and regeneration.  Nerves in the lumbar 
plexus and lower extremity will be imaged for patients who have previously had MR 
neurography in the parent study and may be imaged for a subset of patients providing informed 
consent who did not have MR neurography previously in the parent study.  A central reader will 
be used for MR neurography.  This assessment will be performed serially at 6-month intervals 
for the first year and then yearly thereafter. 
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8.1.5. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.6. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.7. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.8. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.10. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
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8.1.11. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.12. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.14. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.15. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.16. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A supplementation. 
8.1.17. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may 
be analyzed, if clinically indicated. 
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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
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In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
• Aspartate transaminase (AST) 
• Alkaline phosphatase 
• Alanine transaminase (ALT) 
• Bilirubin (total and direct) 
• Sodium 
• Glucose 
• Potassium 
• Phosphate 
• Blood urea nitrogen (BUN) 
• Albumin 
• Creatinine 
• Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
• Visual inspection for color and appearance 
• Leukocytes 
• pH 
• Bilirubin 
• Specific gravity 
• Nitrite 
• Ketones 
• Urobilinogen 
• Protein 
• Microscopic inspection of sediment 
• Glucose 
 
9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
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9.1.5.5. 
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
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prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
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 
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should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 causality
Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
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24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
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discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
• Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
• Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the 
subset of patients that have previously received placebo in the parent study, comparisons for the 
various efficacy assessments will be made between rates of change pre- and post-administration 
of patisiran, and relative to the treatment group in the parent study.  Additional analyses will 
compare rates of change with rates estimated from previous studies, including cross-sectional, 
natural history, and interventional studies of other drugs.  Associations between PD (serum TTR) 
and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the Σ5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.  
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Values of the individual components of the mNIS weakness and reflex scores will be depicted 
graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
The observed values and changes from baseline in healthcare utilization will be evaluated and 
summarized using descriptive statistics. 
10.2.6. 
Interim Analysis 
There is no formal interim analysis planned for this study.  Interim data examinations may be 
performed, but these will be of a descriptive nature and will not involve any formal hypothesis 
testing. 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB and/or 
Regulatory Authorities, providing direct access to source data/documents.  The study may be 
subject to audit by the Sponsor or its representatives or by regulatory authorities.  If such an audit 
occurs, the Investigator must agree to allow access to the required patient records.  In the event 
of an audit, the Investigator agrees to allow the Sponsor, representatives from the Sponsor, or 
regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Health Organization (WHO) Declaration of 
Helsinki, the ICH of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other 
applicable medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
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the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 
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14.3. 
Inspection of Records 
The Sponsor 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, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2  
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3  
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4  
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5  
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6  
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7  
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8  
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9  
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10  
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11  
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13  
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14  
Episkopou, V., 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. 90: p. 2375-2379. 
15
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy and 
in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
16  
Kollmer J, Hund E, Hornung B, Schönland S, et al. MR-neurography: In-vivo detection of nerve 
injury in systemic light chain (AL) amyloidosis. XIVth International Symposium on 
Amyloidosis, 2014. 
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17. 
APPENDICES 
 
Appendix 1: Karnofsky Scale 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
 
 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 
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Clinical Protocol                                       Version 2.1 (Amendment 1 - France and Germany) 17 December 2015 
Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
• 
Weakness (192) 
• 
Sensation (32) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (18.6)a 
• 
Sural SNAP, tibial motor n. distal latency, peroneal 
SNAP/motor n. conduction velocity/motor n. distal 
latency 
• 
Vibration detection threshold (3.7) 
• 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
• 
Weakness (192) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (10)a 
• 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
• 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
• 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol                                       Version 2.1 (Amendment 1 - France and Germany) 17 December 2015 
Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
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Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol                                       Version 2.1 (Amendment 1 - France and Germany) 17 December 2015 
Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 
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ALN-TTR02-006 (patisiran)  
 
Clinical Study Protocol ALN-TTR02-006 
 
Protocol Version 2.1 – France and Germany  Summary of Changes_17 December 2015 
 
ALN-TTR02-006 Protocol Version 2.1 – France and Germany  
Summary of Changes 
Protocol Version 2.1 – France and Germany (Incorporating French and German-specific 
update), dated 17 December 2015, compared to Protocol Version 2.0 (Amendment 1), dated 
08 September 2015 
 
A Multicenter, Open-Label, Extension Study to Evaluate the Long-Term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy who have 
Completed a Prior Clinical Study with Patisiran 
 
Rationale for Protocol Amendment 
The primary purpose for this country-specific (France and Germany) protocol amendment is to 
add two additional MR neurography assessment time points to the schedule of assessments.  
These additional time points will permit exploration of the effect of patisiran on lower limb 
nerve injury at 6-month intervals for the first year and then yearly thereafter in patients who 
elected to undergo serial MR neurography on the parent study or in a subset of patients who 
provide informed consent to participate for the first time in this assessment on the ALN-TTR02-
006 study.   
A detailed summary of changes is provided in Table 1.  The addition of new reference(s), 
corrections to typographical errors, punctuation, grammar, abbreviations, and formatting are not 
detailed. 
 
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ALN-TTR02-006 (patisiran) 
Clinical Study Protocol ALN-TTR02-006 
 
Protocol Version 2.1 – Germany  Summary of Changes_17 December 2015 
Table 1: 
Protocol Amendment 6.1 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 2.1 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:  Addition of timepoints at the Day 0 Visit and at the 26 Week Visit for the MR neurography assessment 
The primary change occurs in Table 1, Schedule of Assessments.  
Added text: 
In the table, “X,” was added to the row labeled, “MR Neurography,” in the corresponding Day 0 and 26 Week 
columns. 
Purpose:  To expand information provided in the Table 1 footnote for the MR neurography assessment 
The primary change occurs in footnote “u” of Table 1, Schedule of Assessments. 
Added text: 
Required only for patients who had MR neurography in the parent study and may be imaged performed for a subset 
of consenting patients providing informed consent who did not have MR neurography previously in their parent 
study.  Imaging at baseline (Day 0 visit) not required for patients who underwent MR neurography on the 
parent study within the past 3 months. 
Purpose:  New text to note the 6-month intervals applied to the MR neurography assessment. 
The primary change occurs in Section 8.1.4, Magnetic Resonance Neurography.  
Added text: 
Nerves in the lumbar plexus and lower extremity will be imaged for patients who have previously had MR 
neurography in the parent study and may be imaged for consenting a subset of patients providing informed consent 
who did not have MR neurography previously in the parent study.  A central reader will be used for MR neurography.  
This assessment will be performed serially at 6-month intervals for the first year and then yearly thereafter. 
Purpose:  Addition of new references, correct typographical errors, punctuation, grammar, abbreviations, and formatting. 
These changes are not listed individually.   
 
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ALN-TTR02  
 
Clinical Study Protocol ALN-TTR02-006 
 
 Amendment 2 Summary of Changes_05 January 2017 
 
 
ALN-TTR02-006 Protocol Amendment 2 
Summary of Changes (dated 05 January 2017)  
compared to Protocol Version 2.2 - Japan (dated 14 March 2016) 
A Multicenter, Open-label, Extension Study to Evaluate the Long-Term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy who have 
Completed a Prior Clinical Study with Patisiran 
 
Rationale for Protocol Amendment 
The primary purpose of this amendment is to add the Columbia-Suicide Severity Rating Scale 
(C-SSRS) to the study assessments, which was inadvertently left out of previous versions of the 
protocol. The inclusion of the C-SSRS addresses a regulatory requirement to prospectively 
assess suicidality in clinical trials involving all drugs for neurological indications.  Overall, this 
amendment includes the following changes: 
• The Columbia-Suicide Severity Rating Scale has been added as an assessment of suicidal 
ideation and behavior. 
• Country-specific versions of the protocol have been integrated in order to increase 
consistency in the execution of the clinical study globally 
• Electroretinograms are now recommended to be performed in the case of suspected 
retinal disease. 
• The premedication regimen has been updated to align with commercially available doses. 
• Blood samples for long-term storage have been added in order to permit future 
exploratory investigations. 
• During scheduled phone contact, clinical sites may now ask patients who are receiving 
home infusions about their general experience receiving these infusions 
A detailed summary of the above changes, in addition to changes made for clarity, is provided in 
Table 1.  Corrections to abbreviations, typographical errors and formatting are not detailed. 
 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment 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: As part of global protocol integration, replaced “APOLLO” study with “parent” study, and specified that ALN-TTR02-003 is not being 
conducted in Japan.   
The primary change occurs in Section 3.1 Overall Study Design 
Added text: 
Patients in this study will have completed “parent” study ALN-TTR02-003 or ALN-TTR02-004.  Note that 
Study ALN-TTR02-003 is not being conducted in Japan. 
Section(s) also containing this change or similar changes: 
• 
Throughout protocol wherever “APOLLO” appeared  
Purpose: As part of global protocol integration, added magnetic resonance neurography to the protocol as a safety assessment, specifying it is 
only applicable for patients in Germany and France 
The primary change occurs in Table 1 Schedule of Assessments, footnote s 
Added text: 
s. MR neurography will only be conducted at sites in Germany and France. In these countries, neurography may be 
conductedfor patients who had MR neurography in the parent study and for a subset of patients providing informed 
consent who did not have MR neurography previously in their parent study. Patients who had imaging in the parent 
study should have Day 0 imaging if they did not undergo MR neurography within the past 3 months. 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Criteria for evaluation, Efficacy 
• 
Section 8.1 Efficacy Parameters 
• 
Section 8.1.4 Magnetic Resonance Neurography (Germany and France Only) (Section has been added) 
Purpose: Added Columbia-Suicide Severity Rating Scale to the study assessments 
The primary change occurs in Table 1 Schedule of Assessments 
Added text: 
Added row to Schedule of Assessments indicating that the Columbia-Suicide Severity Rating Scale is to be 
collected at 26 weeks and 52 weeks after baseline and annually thereafter, as well as at the End of Study and Early 
Withdrawal visits. 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Criteria for Evaluation, Safety 
• 
Section 9.1.7 Columbia-Suicide Severity Rating Scale (section added) 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
Purpose: As part of global protocol integration, added the option for home infusions, specifying they may occur only where applicable country 
and local regulations allow. 
The primary change occurs in Section 3.1 Overall Study Design 
Added text: 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 21 (±3) days.  Where 
applicable country and local regulations allow,  patients may receive the patisiran infusions at home by a 
healthcare professional trained on the protocol and delivery of premedications and patisiran.  Patients who 
are receiving patisiran infusions at home will have a phone contact with the site at least every 30 (±5) days.  
Patients will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Methodology 
• 
Table 1, Schedule of Assessments 
• 
Section 5.3 Treatment Compliance 
• 
Section 6.4.2 Study Drug Administration 
Purpose: As part of global protocol integration, added that study will be conducted in accordance with HIPAA in the US . 
The primary change occurs in Section 13.2 Ethical Conduct of the Study 
Added text: 
This study will be performed in accordance with the clinical trial agreement, the protocol, all applicable government 
laws, regulations, and guidances where the study is being conducted including policies with foundations in the 
World Medical Association Declaration of Helsinki, the ICH of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, the Health Insurance Portability and Accountability Act of 1996 (HIPAA) in 
the US, and all other applicable medical privacy laws and regulations. 
Purpose: To update premedication regimen so that it aligns with commercially available doses. 
The primary change occurs in Section 6.4.1 Premedication 
Now reads: 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker available at the clinical site).  
Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or fexofenadine 30 mg or 60 mg PO or cetirizine 10 mg 
PO may be substituted for any patient who does not tolerate IV diphenhydramine or other IV H1 blocker. 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Investigational product, dosage and mode of administration 
Purpose: Added recommendation to collect an electroretinogram in the case of suspected retinal injury 
The primary change occurs in Section 9.1.6 Ophthalmology Examination 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
Added text: 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to determine if there 
is damage to rods and cones.  ERG testing should be performed if visual changes raise the suspicion for this 
sort of retinal disease and if clinically indicated. 
Section(s) also containing this change or similar changes: 
• 
Table 1, Schedule of Assessments 
Purpose: Updated description of statistical analysis to align with currently planned analytic approach. 
The primary change occurs in Section 10.2.3 Efficacy Analyses 
Now reads: 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the subset of patients 
that have previously received placebo in the parent study, comparisons for the various efficacy assessments will be 
made between rates of change pre- and post-administration of patisiran, and relative to the treatment group in the 
parent study.  Additional analyses will compare rates of change with rates estimated from previous studies, 
including cross-sectional, natural history, and interventional studies of other drugs.  Associations between PD 
(serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the mNIS +7 composite 
score.  Summaries will also be provided for the components of the composite score (ie, the NIS weakness and reflex 
scores, the Σ5 NCS, and QST values).  The NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS 
will be summarized also.  Values of the individual components of the mNIS weakness and reflex scores will be 
depicted graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Section(s) also containing this change or similar changes: 
• 
Synopsis, Statistical Methods 
• 
Section 10.2.5 Healthcare Utilization Assessments 
• 
Section 10.2.6 Interim Analysis 
Purpose: Added blood sampling for long-term storage in order to permit future exploratory investigations. 
The primary change occurs in Table 1 Schedule of Assessments 
Added text: 
Added row to Schedule of Assessments indicating a blood sample for long-term storage is to be collected at each 
clinic visit. 
Section(s) also containing this change or similar changes: 
• 
Section 8.1.18 Blood Sample for Long-term Storage (section added) 
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ALN-TTR02 
Clinical Study Protocol ALN-TTR02-006 
 
Amendment 2 Summary of Changes_05 January 2017 
Purpose: Added questionnaire regarding experience of home infusions to scheduled phone contact for home infusion patients. 
The primary change occurs in Table 1 Schedule of Assessments, footnote x 
Added text: 
x. Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 
30 (±5) days for assessment of adverse events and concomitant medication use. During phone contact, patients 
may also be asked additional questions about their general experience receiving infusions at home. 
Purpose: Clarified procedures for efficacy assessments, adding the location at which to conduct assessments, and removing specified duration. 
The primary change occurs in Section 8.1 Efficacy Parameters 
Now reads: 
Efficacy assessments will occur for all patients at the 52-week visit, which will take place over 2 daysat the CAS. 
Purpose: Removed language indicating that anti-drug antibodies would only be analyzed if clinically indicated. 
The primary change occurs in Section 8.1.17 Efficacy Parameters 
Deleted text: 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may be analyzed, if 
clinically indicated. 
Section(s) also containing this change or similar changes: 
• 
Table 1, Schedule of Assessments 
 
 
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483
Patisiran (ALN-TTR02) 
Clinical Protocol 
ALN-TTR02-006 
Version 2.2-Japan 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 2.2-Japan (Incorporating Amendment 1) 
14 March 2016 
117395 
2014-003 877-40 
Alnylam Pharmaceuticals, Inc 
3 00 Third Street 
Cambridge, MA 02142 USA 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
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PPD


Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
Version 2.2-Japan 
 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 
08 September 2015 
Incorporating Global Amendment 1 
2.1 
14 October 2015 
Incorporating Japan-Specific Amendment 
2.2 
14 March 2016 
Incorporating Japan-Specific Amendment 
 
 
 
 
 
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Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
Version 2.2-Japan 
 
SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label, extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every-21-day dosing 
schedule from the prior clinical study (APOLLO study), patients are expected to have their first visit 
(Day 0) in this study 3 weeks after their last dose visit in the APOLLO study.  However, if necessary, a 
patient may initiate dosing in this study up to 45 days from the time of the last dose in the APOLLO 
study.  Exceptions to this timing may be allowed for medical or regulatory considerations only after 
consultation with the Medical Monitor.  The last testing visit in the APOLLO study will serve as the 
baseline for this study, unless more than 45 days have elapsed, in which case the baseline tests will 
need to be repeated on Day 0.  Eligibility for this study will be confirmed before administration of the 
first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days.  Patients 
will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
APOLLO study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 
occur if deemed necessary by the study personnel. 
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Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
Version 2.2-Japan 
 
Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the APOLLO study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤ 2.0 (patients on anticoagulant 
therapy with an INR of ≤ 3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN are 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤ 2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the APOLLO study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the APOLLO study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court 
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Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
Version 2.2-Japan 
 
Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
• 
Intravenous dexamethasone (10 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or 
cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
• 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS+7) composite score, and NIS+7  
• 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
• 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
• 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
• 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test 
• 
Polyneuropathy disability (PND) score and FAP stage 
• 
Nutritional status using modified body mass index (mBMI) 
• 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the APOLLO study) 
• 
Cardiac structure and function through echocardiograms and serum levels of terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
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Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
Version 2.2-Japan 
 
• 
New York Heart Association (NYHA) classification of heart failure 
• 
Serum TTR 
• 
Vitamin A 
• 
Thyroid Stimulating Hormone 
• 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; and ophthalmology 
examinations. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Efficacy analyses will examine between- and within-subject rates of change over time.  For the subset 
of patients that have previously received placebo in the APOLLO study, comparisons for the various 
efficacy assessments will be made between rates of change pre- and post-administration of patisiran, 
and relative to the treatment group in the APOLLO study.  Additional exploratory analyses will 
compare rates of change with rates estimated from previous studies, including cross-sectional, natural 
history, and interventional studies of other drugs.  Associations between pharmacodynamic and 
efficacy data will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
Version 2.2-Japan 
 
Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
[X]f 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test (urine) 
Xk 
 
X 
X 
X 
X 
X 
TTR Protein (ELISA) 
X 
 
X 
X 
X 
X 
X 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
mNIS+7l 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS+7m 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS only 
 
 
 
 
Xn 
Xn,p 
Xn,p 
Grip Strength Testq 
Xd 
 
 
X 
 
[X]f 
[X]f 
10-Meter Walk Testr 
Xd 
 
 
X 
 
[X]f 
[X]f 
Ophthalmology Examinations 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) t 
 
 
 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNu 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
[X]f 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
[X]f 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,w 
 
 
X 
 
[X]f 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
[X]f 
[X]f 
Anti-Drug Antibody Testingw 
 
 
X 
X 
X 
X 
X 
Premedication / Patisiran Administration 
Xx 
Xx 
 
 
Adverse Events 
Xb 
Continuous Monitoring 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Concomitant Medications 
Xb 
Continuous Monitoring 
 
Table 1 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = 
familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified body mass index; mNIS = Modified Neuropathy 
Impairment Score; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; NYHA = New York Heart 
Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; R-ODS = Rasch-built Overall Disability Scale; 
SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = transthyretin 
 
a Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the APOLLO study.  However, the Day 0 visit may 
occur within 45 days after the last dose in the APOLLO study.  Exceptions may be made for medical or regulatory considerations only after consultation with 
the Medical Monitor. 
b Medical history includes TTR genotype.  Ongoing AEs from the APOLLO study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the APOLLO study will be entered into the database. 
c Assessment does not need to be repeated.  Information will be obtained from APOLLO study. 
d Assessment/procedure does not need to be repeated if performed during the APOLLO study within 45 days of first dose in this study. 
e mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f Assessment/procedure required only if patient withdraws before the 52-week visit. 
g Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
k Assessment does not need to be repeated if the patient had a negative pregnancy test (urine) within 14 days of the first dose. 
l The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (Σ5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
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separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after 
the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who performed the 
assessments for the patient in the patisiran study in which they were previously enrolled.   
m The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
n One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
o Assessment does not need to be repeated if done within the previous 26 weeks. 
p Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the previous 
26 weeks. 
q Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
r The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed on separate 
days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after the first 
assessment. 
s Examination will include visual acuity, visual fields, and slit-lamp evaluation. 
t Optional skin biopsies will only be obtained if the patient had skin biopsies in the APOLLO study and has provided separate informed consent for the skin 
biopsies in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies taken 
from the distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
u Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to complete 
this assessment. 
v Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
w Serum samples for anti-drug antibodies will be collected as specified.  Samples may be analyzed, if clinically indicated. 
x Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the APOLLO study within the 21 (±3) days 
timeframe.  Doses will be administered at the clinical site. 
 
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TABLE OF CONTENTS 
 
SYNOPSIS 3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................21 
3. 
INVESTIGATIONAL PLAN .....................................................................................21 
3.1. 
Overall Study Design ..................................................................................................21 
3.2. 
Number of Patients .....................................................................................................22 
3.3. 
Treatment Assignment ................................................................................................22 
3.4. 
Criteria for Study Termination ...................................................................................22 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................23 
4.1. 
Patient Inclusion Criteria ............................................................................................23 
4.2. 
Patient Exclusion Criteria ...........................................................................................23 
4.3. 
Patient Withdrawal Criteria ........................................................................................24 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................24 
5. 
TREATMENT OF PATIENTS ..................................................................................27 
5.1. 
Description of Study Drug ..........................................................................................27 
5.2. 
Concomitant Medications ...........................................................................................27 
5.3. 
Treatment Compliance ................................................................................................28 
5.4. 
Randomization and Blinding ......................................................................................28 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................28 
6.1. 
Study Drug Packaging and Labeling ..........................................................................28 
6.2. 
Study Drug Storage .....................................................................................................28 
6.3. 
Study Drug Preparation ..............................................................................................29 
6.4. 
Administration ............................................................................................................29 
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6.4.1. 
Premedication .............................................................................................................29 
6.4.2. 
Study Drug Administration.........................................................................................30 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................31 
6.5. 
Study Drug Accountability .........................................................................................31 
6.6. 
Study Drug Handling and Disposal ............................................................................32 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................32 
8. 
ASSESSMENT OF EFFICACY ................................................................................32 
8.1. 
Efficacy Parameters ....................................................................................................32 
8.1.1. 
Neurological Testing ..................................................................................................32 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................33 
8.1.1.2. 
Neurological Impairment Score ..................................................................................33 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................33 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............34 
8.1.4. 
Modified Body Mass Index ........................................................................................34 
8.1.5. 
Timed 10-meter Walk Test .........................................................................................34 
8.1.6. 
Grip Strength Test .......................................................................................................34 
8.1.7. 
Composite Autonomic Symptom Score .....................................................................34 
8.1.8. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................35 
8.1.9. 
EuroQoL Quality of Life Questionnaire .....................................................................35 
8.1.10. 
Rasch-built Overall Disability Scale ..........................................................................35 
8.1.11. 
Pharmacoeconomics Questionnaire ............................................................................35 
8.1.12. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................35 
8.1.13. 
Transthyretin ...............................................................................................................35 
8.1.14. 
Thyroid-Stimulating Hormone ...................................................................................35 
8.1.15. 
Vitamin A ...................................................................................................................36 
8.1.16. 
Anti-Drug Antibodies .................................................................................................36 
9. 
ASSESSMENT OF SAFETY .....................................................................................36 
9.1. 
Safety Parameters .......................................................................................................36 
9.1.1. 
Demographic and Medical History .............................................................................36 
9.1.2. 
Vital Signs ..................................................................................................................36 
9.1.3. 
Weight and Height ......................................................................................................36 
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9.1.4. 
Physical Examination .................................................................................................36 
9.1.5. 
Laboratory Assessments .............................................................................................37 
9.1.5.1. 
Hematology .................................................................................................................37 
9.1.5.2. 
Blood Chemistry .........................................................................................................37 
9.1.5.3. 
Urinalysis ....................................................................................................................37 
9.1.5.4. 
Coagulation .................................................................................................................38 
9.1.5.5. 
Pregnancy Screen ........................................................................................................38 
9.1.6. 
Ophthalmology Examination ......................................................................................38 
9.2. 
Adverse Events and Serious Adverse Events .............................................................38 
9.2.1. 
Definition of Adverse Events .....................................................................................38 
9.2.1.1. 
Adverse Event .............................................................................................................38 
9.2.1.2. 
Serious Adverse Event ................................................................................................38 
9.3. 
Relationship to Study Drug ........................................................................................39 
9.4. 
Recording Adverse Events .........................................................................................39 
9.5. 
Reporting Adverse Events ..........................................................................................40 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................40 
9.5.2. 
Pregnancy Reporting ..................................................................................................42 
10. 
STATISTICS ..............................................................................................................42 
10.1. 
Sample Size ................................................................................................................42 
10.2. 
Statistical Methodology ..............................................................................................42 
10.2.1. 
Populations to be Analyzed ........................................................................................42 
10.2.2. 
Baseline Evaluations ...................................................................................................43 
10.2.3. 
Efficacy Analyses .......................................................................................................43 
10.2.4. 
Safety Analyses ..........................................................................................................43 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................44 
10.2.6. 
Interim Analysis ..........................................................................................................44 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................44 
11.1. 
Study Monitoring ........................................................................................................44 
11.2. 
Audits and Inspections ................................................................................................44 
11.3. 
Institutional Review Board .........................................................................................44 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................45 
13. 
ETHICS ......................................................................................................................45 
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13.1. 
Ethics Review .............................................................................................................45 
13.2. 
Ethical Conduct of the Study ......................................................................................46 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................46 
13.3. 
Written Informed Consent ..........................................................................................46 
13.4. 
Compensation for Health Damages ............................................................................47 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................47 
14.1. 
Case Report Forms .....................................................................................................47 
14.2. 
Confidentiality ............................................................................................................47 
14.3. 
Inspection of Records .................................................................................................48 
14.4. 
Retention of Records ..................................................................................................48 
15. 
PUBLICATION POLICY ..........................................................................................48 
16. 
LIST OF REFERENCES ............................................................................................49 
17. 
APPENDICES ............................................................................................................50 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
APOLLO 
Study name given to the Phase 3 study ALN-TTR02-004 
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
Σ5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
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Abbreviation 
Definition 
HRdb 
heart rate response to deep breathing 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WHO 
World Health Organization 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (> 80% 
reduction from pretreatment baseline) was observed at doses ≥ 0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of > 80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of > 80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran IB. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
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circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
• Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an 
IRR with patisiran, all patients in this study will be premedicated prior to dosing with 
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a 
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing 
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
• Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in 
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the end of 
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical 
studies to date, there have been no clinically significant changes in liver function tests in 
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver 
function via serial laboratory assessments. 
• Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of 
circulating vitamin A levels.  Preclinical and clinical data have shown that the lowering of 
circulating vitamin A associated with suppression of RBP does not result in severe vitamin A 
deficiency.  Furthermore, there are individuals with RBP/TTR mutations who have life-long 
low levels of circulating vitamin A and are essentially in good health, suggesting that there 
are compensatory transport mechanisms for vitamin A that are yet undescribed.13  This has 
also been confirmed in TTR knockout mice, which do not exhibit any manifestations of 
vitamin A deficiency, with vitamin A uptake by most tissues continuing in the absence of 
RBP.14  Provided there is adequate vitamin A in the diet, tissue stores of vitamin A should 
not be affected by the lowering of TTR and RBP.  However, as the vitamin A content of the 
diet may vary among different countries and among different individuals within a country, all 
patients on the study will be asked to take a daily supplement that contains the recommended 
daily allowance of vitamin A. Patients should have started an adequate daily intake of 
vitamin A by the time they start his/her first dose of patisiran. 
• Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone 
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mineralization.  If there are no medical contraindications, and per investigator judgment and 
local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the IB. 
2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the  prior clinical study (APOLLO 
study), patients are expected to have their first visit (Day 0) on this study 3 weeks after their last 
dose visit on the APOLLO study.  However, if necessary, a patient may initiate dosing in this 
study up to 45 days from the time of the last dose in the APOLLO study.  Exceptions to this 
timing may be allowed for medical or regulatory considerations only after consultation with the 
Medical Monitor.  The last testing visit in the APOLLO study will serve as the baseline for this 
study, unless more than 45 days have elapsed, in which case the baseline tests will need to be 
repeated on Day 0.  Eligibility for this study will be confirmed before administration of the first 
dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the APOLLO study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days.  Patients will also have visits at the clinical site at approximately 12, 26 and 52 
weeks, and yearly thereafter. 
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A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients(“Patient Care Sites [PCS]”), while sending the patients to the nearest CAS 
for their 52-week efficacy assessments. Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the APOLLO study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria. The patient will then be assigned a patient number that corresponds to their 
current patient number on APOLLO  study. A combination of the center number, APOLLO 
study number, enrollment number, and patient initials will create the unique patient identifier. In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by Alnylam Pharmaceuticals, Inc. 
Alnylam Pharmaceuticals, Inc. reserves the right to discontinue the study for clinical or 
administrative reasons at any time.  Should the study be terminated and/or the site closed for 
whatever reason, all documentation and patisiran supplied for the study must be returned to 
Alnylam Pharmaceuticals, Inc. or the CRO, and the Investigators, Independent Ethics Committee 
(IEC) / Institutional Review Board (IRB) and Regulatory Authorities will be promptly informed 
of the termination and the reason for the decision.  The Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the APOLLO 
study) and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤ 2.0 (patients on 
anticoagulant therapy with an INR of ≤ 3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤ 2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the APOLLO study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the APOLLO study 
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6. Is under legal protection (defined as “any person who becomes incapable of protecting
his/her interests due to a medically diagnosed impairment of his/her mental faculties that
may limit or prevent the expression of his will”), decided by a court
4.3.
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
•
Is in violation of the protocol
•
Experiences a serious or intolerable AE
•
Becomes pregnant
•
Requires a prohibited medication (see Section 5.2)
•
Requests to be withdrawn from the study
•
Is found to be considerably noncompliant with the protocol-required patisiran dosing
visits
The Investigator will withdraw patients from the study upon the request of Alnylam 
Pharmaceuticals, Inc., including if Alnylam Pharmaceuticals, Inc. terminates the study.  Upon 
occurrence of a serious or intolerable AE, the Investigator will confer with Alnylam 
Pharmaceuticals, Inc. before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4.
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not known 
whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients who are 
male or who are women of child bearing potential will affect reproduction.  Histopathological 
evaluations of all of the reproductive organs have been conducted in the rat and non-human 
primate (NHP) toxicology studies including a chronic NHP study in sexually mature animals, 
where there were no adverse effects in males (including sperm analyses and spermatogenic 
staging) or females.  In a dose range-finding rat embryo/fetal development study conducted with 
patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
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or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
Women of child-bearing potential are defined as any woman or adolescent who has begun 
menstruation. A post-menopausal woman is defined as a woman who has 12 months of 
spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 
40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
• Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
• Placement of an intrauterine device (IUD) 
• Placement of an intrauterine system (IUS) 
• Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
• 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); 
• Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
• Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
• IUD in conjunction with condom or diaphragm and spermicide 
• Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
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dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
It is recommended that the Investigators select appropriate contraception method in Japan as 
available. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
• Any investigational agent other than patisiran 
• Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is < 20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥ 20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the APOLLO study in accordance with the rules of that study 
protocol.  For patients who did not take these medications while on the APOLLO study, use of 
these medications is permitted, if necessary, only after the patient has completed the 52-week 
visit. 
• Tafamidis 
• Diflunisal 
• Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take the recommended daily allowance of vitamin A. 
Patients will receive this daily dose for the duration of their participation in the study while being 
administered patisiran. The Japan clinical sites will provide the subjects with a prescription for 
vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
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Similarly, concomitant medications that continue from the APOLLO study will be entered into 
the database. 
5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the study site 
for scheduled assessment visits.  Compliance with patisiran administration will be verified 
through observation by study staff.  A dose will be considered completed if 80% or more of the 
total volume of the IV solution was administered to the patient.  Patients will be permitted to 
miss an occasional dose of patisiran; however, if a patient misses 3 consecutive doses, the 
Investigator, in consultation with the Medical Monitor, will discuss whether the patient will be 
able to continue on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or Alnylam 
Pharmaceuticals, Inc. and use of the patisiran halted until authorization for its continued use has 
been given by Alnylam Pharmaceuticals, Inc. or its designee. 
No special procedures for the safe handling of patisiran are required.  An Alnylam 
Pharmaceuticals, Inc. representative or designee will be permitted, upon request, to audit the 
supplies, storage, dispensing procedures, and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
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6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (±3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 
• Intravenous dexamethasone (10 mg) or equivalent 
• Oral paracetamol/acetaminophen (500 mg) or equivalent 
• Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the clinical site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) 
or cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 
• If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.  
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• If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid 
premedication will be lowered, then the following steps must be followed: 
1) If the current steroid dosage is 10 mg or less of intravenous dexamethasone or 
equivalent, then the patient may be lowered in increments no greater than 2.5 mg 
intravenous dexamethasone or equivalent. 
2) After each incremental lowering of intravenous dexamethasone or equivalent, the patient 
must receive three consecutive intravenous doses of patisiran without IRR and continued 
signs or symptoms of steroid intolerance before further reductions in steroid 
premedications.   
3) The premedication steroid dosage should not be reduced below 5 mg intravenous 
dexamethasone or equivalent. 
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone or 
equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days. 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 
• If the patient experiences an IRR the infusion time may be extended up to 3 hours in the 
event of a mild or moderate IRR. 
1) If the patient experiences a mild or moderate IRR that resolves by slowing the infusion 
rate then no further premedication changes are recommended. 
2) If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).   
• If the infusion time for a patient was already extended on the APOLLO study due to an IRR, 
that modified infusion duration may be continued on this study for that particular patient.  
Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
• For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following 
completion of dosing. 
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
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In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A.  Patients will receive this daily dose for the duration of their participation in the study 
while being administered patisiran.  The Japan clinical sites will provide the subjects with a 
prescription for vitamin A. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
• In the event of an IRR, the infusion of patisiran may be stopped and the patient closely 
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and 
permit resumption of patisiran administration include, but are not limited to: 
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids. 
• Following resolution of a mild or moderate IRR that required interruption of the patisiran 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of 
patisiran.  If the infusion is delayed, the administration of the infusion should be completed 
no more than 6 hours from the initial start of the infusion.   
• Patisiran 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The investigator or the responsible pharmacist for study drug (designated according to the Japan 
local regulations) will maintain accurate records of the receipt and condition of patisiran supplied 
for this study, including dates of receipt.  In addition, accurate records will be kept of the weight 
used to calculate each dispensed patisiran dose, and when and how much patisiran is dispensed 
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and used by each patient in the study.  Any reasons for departure from the protocol dispensing 
regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by Alnylam 
Pharmaceuticals, Inc. or its designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to Alnylam 
Pharmaceuticals, Inc. or its designee/depot or destroyed at the site according to applicable 
regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the APOLLO study 
within 45 days of the first dose in this study.  Efficacy assessments will occur for all patients at 
the 52-week visit, which will take place over 2 days.  Patients will not receive study drug at this 
visit.  A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
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8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
• Clinical exam-based NIS (weakness and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− Nerve conduction studies (NCS) 5 attributes (Σ5) 
− Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
• Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
• Full NIS (including weakness, sensation, and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− NCS Σ5 
− Vibration detection threshold (VDT) 
• Heart rate response to deep breathing (HRdb) 
The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
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8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the APOLLO study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.5. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.6. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.7. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
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8.1.8. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.9. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
8.1.10. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.11. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire. This assessment will be performed at the location of the 
patient’s scheduled visit. 
8.1.12. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.13. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.14. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
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8.1.15. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A. 
8.1.16. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may 
be analyzed, if clinically indicated. 
9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the APOLLO study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the APOLLO study that are ongoing on Day 0 will be considered as part of the medical 
history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the APOLLO study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
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head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
• Aspartate transaminase (AST) 
• Alkaline phosphatase 
• Alanine transaminase (ALT) 
• Bilirubin (total and direct) 
• Sodium 
• Glucose 
• Potassium 
• Phosphate 
• Blood urea nitrogen (BUN) 
• Albumin 
• Creatinine 
• Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
• Visual inspection for color and appearance 
• Leukocytes 
• pH 
• Bilirubin 
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• Specific gravity 
• Nitrite 
• Ketones 
• Urobilinogen 
• Protein 
• Microscopic inspection of sediment 
• Glucose 
 
9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
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• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
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Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
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). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 causality 
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Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
Alnylam Pharmaceuticals, Inc. or the CRO will be responsible for the reporting of all relevant 
events to the concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after Alnylam Pharmaceuticals, Inc. or the CRO has first knowledge of the 
minimum criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be 
reported no later than 15 calendar days after Alnylam Pharmaceuticals, Inc. or the CRO has first 
knowledge of them. 
The Investigator may be informed by Alnylam Pharmaceuticals, Inc. or the CRO of SAEs from 
other Investigators or clinical studies which may have relevance to this clinical study.  These 
SAEs should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
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should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to Alnylam 
Pharmaceuticals, Inc. as part of the trial master file on study completion. 
9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
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• Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
• Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the APOLLO 
study will be summarized.  Data to be tabulated will include sex, age, and race, as well as 
disease-specific information. 
10.2.3. 
Efficacy Analyses 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the 
subset of patients that have previously received placebo in the APOLLO study, comparisons for 
the various efficacy assessments will be made between rates of change pre- and post-
administration of patisiran, and relative to the treatment group in the APOLLO study.  Additional 
analyses will compare rates of change with rates estimated from previous studies, including 
cross-sectional, natural history, and interventional studies of other drugs.  Associations between 
PD (serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS+7 composite score.  Summaries will also be provided for the components of the composite 
score (ie, the NIS weakness and reflex scores, the Σ5 NCS, and QST values).  The NIS+7 score 
(including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.  Values of 
the individual components of the mNIS weakness and reflex scores will be depicted graphically 
by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
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Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
The observed values and changes from baseline in healthcare utilization will be evaluated and 
summarized using descriptive statistics. 
10.2.6. 
Interim Analysis 
There is no formal interim analysis planned for this study.  Interim data examinations may be 
performed, but these will be of a descriptive nature and will not involve any formal hypothesis 
testing. 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of Alnylam Pharmaceuticals, Inc., has an obligation to 
follow the study closely.  In doing so, the Monitor will visit the Investigators and sites 
periodically and maintain frequent telephone and written contact.  The Monitor will maintain 
current personal knowledge of the study through observation, review of study records and source 
documentation and discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by Alnylam Pharmaceuticals, Inc. or its 
designee for compliance with applicable government regulations in respect to Good Clinical 
Practice (GCP) and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator and the study site will permit study-related monitoring, audits, and review by 
the IEC or IRB or Regulatory Authorities, providing direct access to source data/documents.  
The study may be subject to audit by Alnylam Pharmaceuticals, Inc. or the CRO or by regulatory 
authorities.  If such an audit occurs, the Investigator must agree to allow access to the required 
patient records.  In the event of an audit, the Investigator agrees to allow Alnylam 
Pharmaceuticals, Inc., the CRO, or regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, Alnylam may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to Alnylam Pharmaceuticals, Inc. or its designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by Alnylam Pharmaceuticals, Inc. and the IRB or 
IEC that approved the study.  Amendments to the protocol must be submitted in writing to the 
Investigator’s IRB or IEC and the Regulatory Authority for approval before patients are enrolled 
under the amended protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
The Investigator should not start any study procedure with the patient until documentation of the 
approval by the IEC/IRB and written notification of the approval from the head of the study site 
to the Investigator and Alnylam Pharmaceuticals, Inc. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by Alnylam Pharmaceuticals, Inc. or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply Alnylam 
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Pharmaceuticals, Inc. with written documentation of the approval of the continued clinical 
research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Health Organization (WHO) Declaration of 
Helsinki, the ICH of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, and all other applicable medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
Alnylam Pharmaceuticals, Inc. or the CRO designee will provide an ICF template to the 
Investigator for use in developing a site-specific ICF.  Prior to submission of the site-specific 
ICF to the IRB or IEC, the site-specific ICF must be reviewed and approved by Alnylam 
Pharmaceuticals, Inc. or its designee.  Any changes requested by the IRB or IEC must also be 
agreed upon.  The final IRB/IEC approved ICF must be provided to Alnylam Pharmaceuticals, 
Inc.  Revisions to the ICF required during the study must be agreed upon, and a copy of the 
revised ICF provided to Alnylam Pharmaceuticals, Inc. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
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13.4. 
Compensation for Health Damages 
A copy of the certificate of insurance as a measure to compensation for health damages will be 
submitted to the IRB/IEC if required. 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
Alnylam Pharmaceuticals, Inc. will supply CRFs for each patient.  Case report forms must be 
completed only by persons designated by the Investigator.  Corrections must be made so as not 
to obliterate original data and must be identified and dated by the person who made the 
correction.  All data entered into the CRF must also be available in the source documents.  The 
Investigator will allow the CRO and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by Alnylam Pharmaceuticals, Inc.  
A copy of the CRF will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to Alnylam Pharmaceuticals, Inc. or designees, patients should not be 
identified by their names, but by the assigned patient number and initials.  If patient names are 
included on copies of documents submitted to Alnylam Pharmaceuticals, Inc. or designees, the 
names (except for initials) will be obliterated and the assigned patient number added to the 
document.  Documents not for submission to Alnylam Pharmaceuticals, Inc. (eg, signed ICFs) 
should be maintained by the Investigator in strict confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and Alnylam Pharmaceuticals, Inc., thereby allowing no unwarranted access to the 
information.  The numbering code will also be held for samples in storage until marketing 
approval of patisiran in the countries where this study was conducted, or until clinical 
development of patisiran is halted.  Throughout sample collection, storage (limited, staff only 
access area containing locked sample storage, and limited access sample tracking) and 
processing, the samples will only be handled by appropriate personnel per the laboratory’s 
standard operating procedures. 
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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.  Alnylam Pharmaceuticals, 
Inc. must approve any transfer of information not directly involved in the study. 
14.3. 
Inspection of Records 
Alnylam Pharmaceuticals, Inc. 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, drug stocks, drug accountability records, patient charts 
and study source documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing Alnylam Pharmaceuticals, 
Inc. in writing and giving Alnylam Pharmaceuticals, Inc. the opportunity to store the records for 
a longer period of time at Alnylam Pharmaceuticals, Inc.’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at Alnylam Pharmaceuticals, Inc. at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by Alnylam Pharmaceuticals, Inc., or the study has been terminated 
at all centers.  A separate, individual publication of the results of the study will be delayed until 
initial publication of the results of the multicenter study, or a decision not to publish is made.  If 
an initial draft is not produced within 18 months of completion of the study at all centers, or the 
timeframe for publication is not satisfactory, the Investigator may disclose the results after 
providing a copy and Alnylam Pharmaceuticals, Inc. confirms receipt of the manuscript 30 days 
before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by Alnylam Pharmaceuticals, Inc. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2  
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3  
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4  
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5  
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6  
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7  
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8  
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9  
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10  
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11  
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13  
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14  
Episkopou, V., 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. 90: p. 2375-2379. 
15 
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy 
and in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
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17. 
APPENDICES 
 
Appendix 1: Karnofsky Scale 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
 
 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 
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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7 
 
270 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
• 
Weakness (192) 
• 
Sensation (32) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (18.6)a 
• 
Sural SNAP, tibial motor n. distal latency, peroneal 
SNAP/motor n. conduction velocity/motor n. distal 
latency 
• 
Vibration detection threshold (3.7) 
• 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
• 
Weakness (192) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (10)a 
• 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
• 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
• 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 
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Version 2.2-Japan Summary of Changes 14 March 2016 
 
ALN-TTR02-006 Protocol Version 2.2 - Japan 
Summary of Changes  
Protocol Version 2.2-Japan (Incorporating Japan-specific update), dated 14 March 2016, 
compared to Protocol Version 2.1-Japan, dated 14 October 2015 
 
 
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have 
Completed a Prior Clinical Study with Patisiran 
 
Rationale for the Japan Country-specific Protocol Amendment 
• The primary purpose of the Japan country-specific protocol amendment is to remove 
home infusion references and MR neurography scanning as these practices are not 
applicable in Japan, and to update the vitamin A dispensing requirments to better align 
with country-specific pharmacy practices. 
The following additional change was incorporated: 
• Changed reference from “parent study” to “APOLLO study”; this change is being 
implemented because only Japanese subjects from the APOLLO study (ALN-TTR02-
004) will be rolling into this extension study ALN-TTR02-006; none of the subjects 
participating in the other patisiran parent study (ALN-TTR02-003) are from Japan. 
• The name of the Sponsor was added in-text as Alnylam Pharmaceuticals. 
• Deleted from Section 13.2, text describing the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA) that is only applicable in the United States of 
America. 
• New Section 13.4 was added to describe Compensation for Health Damages according to 
local regulations. 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting (including administrative changes between 
protocol amendments 2.1 and 2.2) are not detailed. 
 
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Table 1: 
Protocol Amendment 3 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in this amendment 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:  Removal of text describing or referencing home infusion  
The primary change occurs in Section 3.1, Overall Study Design, paragraph 5. 
Deleted text: 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days, or receive the patisiran 
infusions at home by a healthcare professional trained on the protocol and delivery of premedications and patisiran.  
Patients who are receiving patisiran infusions at home will have a phone contact with the site at least every 30 (±5) days.  
Patients will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
Sections also containing this change:   
• 
Synopsis, Methodology, paragraph 3 
• 
Table 1, Schedule of Assessment to remove the Phone Contact row and corresponding footnote. 
• 
Section 5.3, Treatment Compliance 
• 
Section 6.4.2, Study Drug Administration 
Purpose:  Removal of text describing MR neurography scanning assessment 
The primary change occurs in Section 8.1, Efficacy Parameters, second paragraph 
Deleted text: 
For the 52-week time point, a central neurologic testing core facility will review the data derived from the various 
neuropathy measures at each participating site to ensure compliance with testing procedures and quality of the data.  A 
central echocardiography core lab will analyze the echocardiogram data.  A core lab will be responsible for processing 
and analyzing skin punch biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Sections also containing this change:   
• 
Synopsis, Criteria for evaluation, Efficacy, removal of MR neurography bullet 
• 
Table 1, Schedule of Assessment to remove the MR neurography scanning assessment row and corresponding footnote. 
• 
Section 8.1.4, Magnetic Resonance Neu  rography – subsection deleted entirely. 
Purpose:  Update the vitamin A dispensing requirments 
The primary change occurs in Section 5.2, Concomitant Medications, paragraph 4 
Deleted text: All patients will be asked to continue to take an oral daily supplement containing the recommended daily allowance of vitamin A.    
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Version 2.2 - Japan Summary of Changes 14 March 2016 
Patients will receive this daily dose for the duration of their participation in the study while being administered patisiran.  The Japan clinical sites 
will provide the subjects with a prescription for vitamin A. 
Sections also containing this change: 
• 
Section 6.2.4, Study Drug Administration last paragraph 
Purpose:  Changed reference from “parent study” to “APOLLO study 
The primary change occurs in Section 3.1, Overall Study Design, paragraph 2 
Changed Text:  
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once every 21 days for the duration of the 
study.  All dosing visits have a window of ± 3 days.  In order to maintain the every 21-day dosing schedule from the parent prior 
clinical study (APOLLO study), patients are expected to have their first visit (Day 0) on this study 3 weeks after their last dose 
visit on the parentAPOLLO study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the time 
of the last dose in the parentAPOLLO study.  Exceptions to this timing may be allowed for medical or regulatory considerations 
only after consultation with the Medical Monitor.  The last testing visit in the parentAPOLLO study will serve as the baseline for 
this study, unless more than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility 
for this study will be confirmed before administration of the first dose on Day 0. 
Sections also containing this change: 
• 
Synopsis, Methodology, Diagnosis and eligibility criteria , Criteria for (efficacy) evaluation, and Statistical methods sections 
• 
Table 1, Schedule of Assessment footnotes 
• 
Section 3.3, Treatment Assignment 
• 
Section 4.1, Patient Inclusion Criteria 
• 
Section 4.2, Patient Exclusion Criteria 
• 
Section 5.2, Concomitant Medications 
• 
Section 6.4.2, Study Drug Administration 
• 
Section 8.1, Efficacy Parameters 
• 
Section 9.1, Safety Parameters 
• 
Section 10, Statistics 
Purpose:  The name of the Sponsor was added in-text as Alnylam Pharmaceuticals 
The primary change occurs in Section 3.4, Criteria for Study Termination 
Changed text:   
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Clinical Study Protocol ALN-TTR02-006 
 
Version 2.2 - Japan Summary of Changes 14 March 2016 
The study may be terminated if patisiran does not obtain marketing approval or the development of patisiran is no longer being 
pursued by the SponsorAlnylam Pharmaceuticals, Inc. 
The SponsorAlnylam Pharmaceuticals, Inc. reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all documentation and patisiran supplied for 
the study must be returned to the Sponsor or its representativeAlnylam Pharmaceuticals, Inc. or the CRO, and the Investigators, 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) and Regulatory Authorities will be promptly informed of 
the termination and the reason for the decision.  The Investigator should promptly inform the patients and assure appropriate 
therapy and follow-up. 
Sections also containing this change: 
• 
Synopsis, Methodology, Diagnosis and eligibility 
• 
Section 4.3, Patient Withdrawal Criteria 
• 
Section 6.2, Study Drug Storage 
• 
Section 6.5, 6.5. Study Drug Accountability 
• 
Section 9.5.1, 9.5.1. Serious Adverse Event Reporting 
• 
Section 11, Direct Access to Source Data/Documents 
• 
Section 12, Quality Control and Quality Assurance 
• 
Section 13, Ethics 
• 
Section 14, Data Handling and Record Keeping 
• 
Section 15, Publication Policy 
Purpose:  Deleted text referring to the HIPAA that is only applicable in the United States of America. 
The change occurs in Section 13.2, Ethical Conduct of the Study 
Deleted text:  
This study will be performed in accordance with the clinical trial agreement, the protocol, all applicable government laws, 
regulations, and guidances where the study is being conducted including policies with foundations in the World Health 
Organization (WHO) Declaration of Helsinki, the ICH of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other applicable medical privacy laws and 
regulations 
Purpose:  Provided clarification that written notification of the approval from the IEC/IRB from the head of the study site to the Investigator and 
Alnylam Pharmaceuticals, Inc.should be provided before the start of study procedures. 
The change occurs in Section 13.1, Ethics Review 
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Added text: 
The Investigator should not start any study procedure with the patient until documentation of the approval by the IEC/IRB and written 
notification of the approval from the head of the study site to the Investigator and Alnylam Pharmaceuticals, Inc. 
Purpose:  New Section 13.4 was added to describe Compensation for Health Damages according to local regulations 
The change occurs in newly added Section 13.4, Compensation for Health Damages 
Added text:  
13.4. Compensation for Health Damages 
A copy of the certificate of insurance as a measure to compensation for health damages will be submitted to the IRB/IEC if 
required. 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting[, including administrative changes, if appropriate] 
These changes are not listed individually. 
 
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543
Patisiran (ALN-TTR02) 
Clinical Protocol 
ALN-TTR02-006 
Version 2.1-Japan 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 2.1-Japan (Incorporating Amendment 1) 
14 October 2015 
117395 
2014-003 877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Signature 
(y 
i) 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
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PPD
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Patisiran (ALN-TTR02) 
 
ALN-TTR02-006 
Clinical Protocol 
 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 
08 September 2015 
Incorporating Global Amendment 1 
2.1 
14 October 2015 
Incorporating Japan-Specific Amendment 
 
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SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate dosing 
in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to this timing 
may be allowed for medical or regulatory considerations only after consultation with the Medical 
Monitor.  The last testing visit in the parent study will serve as the baseline for this study, unless more 
than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.  
Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days, or 
receive the patisiran infusions at home by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran.  Patients who are receiving patisiran infusions at home will have a 
phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the clinical site 
at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 
occur if deemed necessary by the study personnel. 
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Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) and, 
in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN are 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court 
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Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
• 
Intravenous dexamethasone (10 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or 
cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
• 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
• 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
• 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
• 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
• 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test 
• 
Polyneuropathy disability (PND) score and FAP stage 
• 
Nutritional status using modified body mass index (mBMI) 
• 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
• 
Magnetic resonance (MR) neurography  
• 
Cardiac structure and function through echocardiograms and serum levels of terminal 
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prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
• 
New York Heart Association (NYHA) classification of heart failure 
• 
Serum TTR 
• 
Vitamin A 
• 
Thyroid Stimulating Hormone 
• 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; and ophthalmology 
examinations. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Efficacy analyses will examine between- and within-subject rates of change over time.  For the subset 
of patients that have previously received placebo in the parent study, comparisons for the various 
efficacy assessments will be made between rates of change pre- and post-administration of patisiran, 
and relative to the treatment group in the parent study.  Additional exploratory analyses will compare 
rates of change with rates estimated from previous studies, including cross-sectional, natural history, 
and interventional studies of other drugs.  Associations between pharmacodynamic and efficacy data 
will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
[X]f 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test (urine) 
Xk 
 
X 
X 
X 
X 
X 
TTR Protein (ELISA) 
X 
 
X 
X 
X 
X 
X 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
mNIS+7l 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS+7m 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS only 
 
 
 
 
Xn 
Xn,p 
Xn,p 
Grip Strength Testq 
Xd 
 
 
X 
 
[X]f 
[X]f 
10-Meter Walk Testr 
Xd 
 
 
X 
 
[X]f 
[X]f 
Ophthalmology Examinations 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) t 
 
 
 
X 
X 
Xo 
Xo 
MR Neurographyu 
 
 
 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNv 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
[X]f 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
[X]f 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,w 
 
 
X 
 
[X]f 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
[X]f 
[X]f 
Anti-Drug Antibody Testingx 
 
 
X 
X 
X 
X 
X 
Premedication / Patisiran Administration 
Xy 
Xy 
 
 
Phone Contact 
 
Xz 
 
 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
 
Table 1 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = 
familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified body mass index; mNIS = Modified Neuropathy 
Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; 
NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; R-ODS = Rasch-built Overall 
Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = transthyretin 
a Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may occur 
within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with the 
Medical Monitor. 
b Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c Assessment does not need to be repeated.  Information will be obtained from parent study. 
d Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f Assessment/procedure required only if patient withdraws before the 52-week visit. 
g Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
k Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the first dose. 
l The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (Σ5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
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separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after 
the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who performed the 
assessments for the patient in the patisiran study in which they were previously enrolled.   
m The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
n One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
o Assessment does not need to be repeated if done within the previous 26 weeks. 
p Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the previous 
26 weeks. 
q Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
r The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed on separate 
days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after the first 
assessment. 
s Examination will include visual acuity, visual fields, and slit-lamp evaluation. 
t Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin biopsies 
in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies taken from the 
distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
u Required only for patients who had MR neurography in the parent study and may be imaged for consenting patients who did not have MR neurography 
previously in their parent study.   
v Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to complete 
this assessment. 
w Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
x Serum samples for anti-drug antibodies will be collected as specified.  Samples may be analyzed, if clinically indicated. 
y Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study within the 21 (±3) days 
timeframe.  Doses may be administered at the clinical site or at home by a healthcare professional trained in the protocol. 
z Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 30 (±5) days for assessment of adverse events 
and concomitant medication use. 
 
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TABLE OF CONTENTS 
 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 
6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
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6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration .........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................36 
8.1.1.2. 
Neurological Impairment Score ..................................................................................37 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Magnetic Resonance Neurography .............................................................................37 
8.1.5. 
Modified Body Mass Index ........................................................................................38 
8.1.6. 
Timed 10-meter Walk Test .........................................................................................38 
8.1.7. 
Grip Strength Test .......................................................................................................38 
8.1.8. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.10. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.11. 
Rasch-built Overall Disability Scale ..........................................................................39 
8.1.12. 
Pharmacoeconomics Questionnaire ............................................................................39 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.14. 
Transthyretin ...............................................................................................................39 
8.1.15. 
Thyroid-Stimulating Hormone ...................................................................................39 
8.1.16. 
Vitamin A ...................................................................................................................39 
8.1.17. 
Anti-Drug Antibodies .................................................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................40 
9.1. 
Safety Parameters .......................................................................................................40 
9.1.1. 
Demographic and Medical History .............................................................................40 
9.1.2. 
Vital Signs ..................................................................................................................40 
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9.1.3. 
Weight and Height ......................................................................................................40 
9.1.4. 
Physical Examination .................................................................................................40 
9.1.5. 
Laboratory Assessments .............................................................................................40 
9.1.5.1. 
Hematology .................................................................................................................41 
9.1.5.2. 
Blood Chemistry .........................................................................................................41 
9.1.5.3. 
Urinalysis ....................................................................................................................41 
9.1.5.4. 
Coagulation .................................................................................................................42 
A sample for INR assessment will be collected.............................................................................42 
9.1.5.5. 
Pregnancy Screen ........................................................................................................42 
9.1.6. 
Ophthalmology Examination ......................................................................................42 
9.2. 
Adverse Events and Serious Adverse Events .............................................................42 
9.2.1. 
Definition of Adverse Events .....................................................................................42 
9.2.1.1. 
Adverse Event .............................................................................................................42 
9.2.1.2. 
Serious Adverse Event ................................................................................................42 
9.3. 
Relationship to Study Drug ........................................................................................43 
9.4. 
Recording Adverse Events .........................................................................................43 
9.5. 
Reporting Adverse Events ..........................................................................................44 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................44 
9.5.2. 
Pregnancy Reporting ..................................................................................................46 
10. 
STATISTICS ..............................................................................................................47 
10.1. 
Sample Size ................................................................................................................47 
10.2. 
Statistical Methodology ..............................................................................................47 
10.2.1. 
Populations to be Analyzed ........................................................................................47 
10.2.2. 
Baseline Evaluations ...................................................................................................47 
10.2.3. 
Efficacy Analyses .......................................................................................................47 
10.2.4. 
Safety Analyses ..........................................................................................................48 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................48 
10.2.6. 
Interim Analysis ..........................................................................................................48 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................49 
11.1. 
Study Monitoring ........................................................................................................49 
11.2. 
Audits and Inspections ................................................................................................49 
11.3. 
Institutional Review Board .........................................................................................49 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................50 
13. 
ETHICS ......................................................................................................................51 
13.1. 
Ethics Review .............................................................................................................51 
13.2. 
Ethical Conduct of the Study ......................................................................................51 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................51 
13.3. 
Written Informed Consent ..........................................................................................51 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................53 
14.1. 
Case Report Forms .....................................................................................................53 
14.2. 
Confidentiality ............................................................................................................53 
14.3. 
Inspection of Records .................................................................................................54 
14.4. 
Retention of Records ..................................................................................................54 
15. 
PUBLICATION POLICY ..........................................................................................55 
16. 
LIST OF REFERENCES ............................................................................................56 
17. 
APPENDICES ............................................................................................................57 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
Σ5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WHO 
World Health Organization 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran IB. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
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circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
• Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an 
IRR with patisiran, all patients in this study will be premedicated prior to dosing with 
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a 
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing 
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
• Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in 
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the end of 
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical 
studies to date, there have been no clinically significant changes in liver function tests in 
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver 
function via serial laboratory assessments. 
• Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of 
circulating vitamin A levels.  Preclinical and clinical data have shown that the lowering of 
circulating vitamin A associated with suppression of RBP does not result in severe vitamin A 
deficiency.  Furthermore, there are individuals with RBP/TTR mutations who have life-long 
low levels of circulating vitamin A and are essentially in good health, suggesting that there 
are compensatory transport mechanisms for vitamin A that are yet undescribed.13  This has 
also been confirmed in TTR knockout mice, which do not exhibit any manifestations of 
vitamin A deficiency, with vitamin A uptake by most tissues continuing in the absence of 
RBP.14  Provided there is adequate vitamin A in the diet, tissue stores of vitamin A should 
not be affected by the lowering of TTR and RBP.  However, as the vitamin A content of the 
diet may vary between different countries and different individuals within a country, all 
patients on the study will be asked to take a daily supplement containing the recommended 
daily allowance of vitamin A.  Patients should have started vitamin A supplementation by the 
time they start his/her first dose of patisiran. 
• Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone 
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mineralization.  If there are no medical contraindications, and per investigator judgment and 
local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the IB. 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days, or receive the patisiran infusions at home by a healthcare professional trained on 
the protocol and delivery of premedications and patisiran.  Patients who are receiving patisiran 
infusions at home will have a phone contact with the site at least every 30 (±5) days.  Patients 
will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly 
thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
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which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or its 
representative, and the Investigators, Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) and Regulatory Authorities will be promptly informed of the termination and the 
reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on 
anticoagulant therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 
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5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting 
his/her interests due to a medically diagnosed impairment of his/her mental faculties that 
may limit or prevent the expression of his will”), decided by a court 
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
• Is in violation of the protocol 
• Experiences a serious or intolerable AE 
• Becomes pregnant 
• Requires a prohibited medication (see Section 5.2) 
• Requests to be withdrawn from the study 
• Is found to be considerably noncompliant with the protocol-required patisiran dosing 
visits 
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not 
known whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients 
who are male or who are women of child bearing potential will affect reproduction.  
Histopathological evaluations of all of the reproductive organs have been conducted in the rat 
and non-human primate (NHP) toxicology studies including a chronic NHP study in sexually 
mature animals, where there were no adverse effects in males (including sperm analyses and 
spermatogenic staging) or females.  In a dose range-finding rat embryo/fetal development study 
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conducted with patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
Women of child-bearing potential are defined as any woman or adolescent who has begun 
menstruation. A post-menopausal woman is defined as a woman who has 12 months of 
spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels 
>40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
• Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
• Placement of an intrauterine device (IUD) 
• Placement of an intrauterine system (IUS) 
• Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
• 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); 
• Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
• Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
• IUD in conjunction with condom or diaphragm and spermicide 
• Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
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Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
It is recommended that the Investigators select appropriate contraception method in Japan as 
available. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
• Any investigational agent other than patisiran 
• Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
• Tafamidis 
• Diflunisal 
• Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take an oral daily supplement containing the 
recommended daily allowance of vitamin A.    Patients will receive this daily dose for the 
duration of their participation in the study while being administered patisiran. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 
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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff or trained home healthcare professionals.  A dose will be considered 
completed if 80% or more of the total volume of the IV solution was administered to the patient.  
Patients will be permitted to miss an occasional dose of patisiran; however, if a patient misses 
3 consecutive doses, the Investigator, in consultation with the Medical Monitor, will discuss 
whether the patient will be able to continue on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 
• Intravenous dexamethasone (10 mg) or equivalent 
• Oral paracetamol/acetaminophen (500 mg) or equivalent 
• Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the clinical site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) 
or cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 
• If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.  
• If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid 
premedication will be lowered, then the following steps must be followed: 
1) If the current steroid dosage is 10 mg or less of intravenous dexamethasone or 
equivalent, then the patient may be lowered in increments no greater than 2.5 mg 
intravenous dexamethasone or equivalent. 
2) After each incremental lowering of intravenous dexamethasone or equivalent, the patient 
must receive three consecutive intravenous doses of patisiran without IRR and continued 
signs or symptoms of steroid intolerance before further reductions in steroid 
premedications.   
3) The premedication steroid dosage should not be reduced below 5 mg intravenous 
dexamethasone or equivalent. 
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone or 
equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
Patients who have received at least 3 doses of patisiran on this study at the clinical site with no 
evidence of IRRs or other adverse effects may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be done 
according to a site-specific plan by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran. 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 
• If the patient experiences an IRR the infusion time may be extended up to 3 hours in the 
event of a mild or moderate IRR. 
1) If the patient experiences a mild or moderate IRR that resolves by slowing the infusion 
rate then no further premedication changes are recommended. 
2) If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).   
• If the infusion time for a patient was already extended on the parent study due to an IRR, that 
modified infusion duration may be continued on this study for that particular patient.  
Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
• For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following 
completion of dosing. 
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A in an oral supplement.  Patients will receive this daily dose for the duration of their 
participation in the study while being administered patisiran. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
• In the event of an IRR, the infusion of patisiran may be stopped and the patient closely 
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and 
permit resumption of patisiran administration include, but are not limited to: 
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids. 
• Following resolution of a mild or moderate IRR that required interruption of the patisiran 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
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infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of 
patisiran.  If the infusion is delayed, the administration of the infusion should be completed 
no more than 6 hours from the initial start of the infusion.   
• Patisiran 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place over 2 days.  Patients will not receive study drug at this 
visit.  A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
• Clinical exam-based NIS (weakness and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− Nerve conduction studies (NCS) 5 attributes (Σ5) 
− Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
• Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
• Full NIS (including weakness, sensation, and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− NCS Σ5 
− Vibration detection threshold (VDT) 
• Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Magnetic Resonance Neurography 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional 
images for the evaluation of peripheral nerve disorders.16  This procedure produces detailed 
images of nerve morphology to evaluate degeneration and regeneration.  Nerves in the lumbar 
plexus and lower extremity will be imaged for patients who have previously had MR 
neurography in the parent study and may be imaged for consenting patients who did not have 
MR neurography previously in the parent study.  A central reader will be used for MR 
neurography. 
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8.1.5. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.6. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.7. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.8. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.10. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
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8.1.11. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.12. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.14. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.15. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.16. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A supplementation. 
8.1.17. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may 
be analyzed, if clinically indicated. 
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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
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In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
• Aspartate transaminase (AST) 
• Alkaline phosphatase 
• Alanine transaminase (ALT) 
• Bilirubin (total and direct) 
• Sodium 
• Glucose 
• Potassium 
• Phosphate 
• Blood urea nitrogen (BUN) 
• Albumin 
• Creatinine 
• Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
• Visual inspection for color and appearance 
• Leukocytes 
• pH 
• Bilirubin 
• Specific gravity 
• Nitrite 
• Ketones 
• Urobilinogen 
• Protein 
• Microscopic inspection of sediment 
• Glucose 
 
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9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
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• Is a congenital anomaly or birth defect 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
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Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 causality
Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
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completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
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9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
• Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
• Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the 
subset of patients that have previously received placebo in the parent study, comparisons for the 
various efficacy assessments will be made between rates of change pre- and post-administration 
of patisiran, and relative to the treatment group in the parent study.  Additional analyses will 
compare rates of change with rates estimated from previous studies, including cross-sectional, 
natural history, and interventional studies of other drugs.  Associations between PD (serum TTR) 
and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the Σ5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.  
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Values of the individual components of the mNIS weakness and reflex scores will be depicted 
graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
The observed values and changes from baseline in healthcare utilization will be evaluated and 
summarized using descriptive statistics. 
10.2.6. 
Interim Analysis 
There is no formal interim analysis planned for this study.  Interim data examinations may be 
performed, but these will be of a descriptive nature and will not involve any formal hypothesis 
testing. 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB and/or 
Regulatory Authorities, providing direct access to source data/documents.  The study may be 
subject to audit by the Sponsor or its representatives or by regulatory authorities.  If such an audit 
occurs, the Investigator must agree to allow access to the required patient records.  In the event 
of an audit, the Investigator agrees to allow the Sponsor, representatives from the Sponsor, or 
regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Health Organization (WHO) Declaration of 
Helsinki, the ICH of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other 
applicable medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
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The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 
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14.3. 
Inspection of Records 
The Sponsor 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, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2 
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3 
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4 
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5 
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6 
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7 
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8 
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9 
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10 
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11 
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13 
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14 
Episkopou, V., 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. 90: p. 2375-2379. 
15
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy and 
in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
16 
Kollmer J, Hund E, Hornung B, Schönland S, et al. MR-neurography: In-vivo detection of nerve 
injury in systemic light chain (AL) amyloidosis. XIVth International Symposium on 
Amyloidosis, 2014. 
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17.
APPENDICES
Appendix 1: Karnofsky Scale 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
 
 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 
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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
• 
Weakness (192) 
• 
Sensation (32) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (18.6)a 
• 
Sural SNAP, tibial motor n. distal latency, peroneal 
SNAP/motor n. conduction velocity/motor n. distal 
latency 
• 
Vibration detection threshold (3.7) 
• 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
• 
Weakness (192) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (10)a 
• 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
• 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
• 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 
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Country-Specific Amendment Summary of Changes for Japan 
Protocol Version 2.1-Japan dated 14 October 2015, compared to Protocol Version 2.0 
(Amendment 1.0), dated 08 September 2015 
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who 
Have Completed a Prior Clinical Study with Patisiran 
 
Rationale for Version 2.1-Japan 
Consistent with Japan-specific protocol ALN-TTR02-004, the following changes have been 
made to the ALN-TTR02-006 Japan-specific protocol: 
• Added the definitions for women of childbearing potential and a post-menopausal women 
• Recommended that the Investigators select appropriate contraception method in Japan, as 
available 
• Clarified that patients will receive daily vitamin A supplementation for the duration of 
their participation in the study while being administered study drug 
 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 
 
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Table 1: 
Version 2.1-Japan Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in this amendment 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:   
Added the definitions for women of childbearing potential and a post-menopausal women 
Primary change: 
Section 4.4 Pregnancy and Breastfeeding Restrictions/Contraception Requirements 
Added text: 
Women of child-bearing potential are defined as any woman or adolescent who has begun menstruation. A post-
menopausal woman is defined as a woman who has 12 months of spontaneous amenorrhea or 6 months of 
spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with 
or without hysterectomy. 
Purpose:   
Recommended that the Investigators select appropriate contraception method in Japan, as available 
Primary change: 
Section 4.4 Pregnancy and Breastfeeding Restrictions/Contraception Requirements 
Added text: 
It is recommended that the Investigators select appropriate contraception method in Japan as available. 
Purpose:   
Clarified that patients will receive daily vitamin A supplementation for the duration of their participation in 
the study while being administered study drug 
Primary change: 
Section 6.4.2 Study Drug Administration 
Added text: 
In addition to study treatment, patients will receive the recommended daily allowance of vitamin A in an oral supplement.  
Patients will receive this daily dose for the duration of their participation in the study while being administered 
patisiran. 
Section(s) also 
containing this 
change: 
• 
Section 5.2 Concomitant Medications 
 
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Version 2.1-Taiwan 10 December 2015 
P A TIS IRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 2.1-Taiwan (Incorporating Amendment 1) 
10 December 2015 
117395 
2014-003877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Date 
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. 
The study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
Alnylam Pharmaceuticals 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 
08 September 2015 
Incorporating Global Amendment 1 
2.1-Taiwan 
10 Decmeber 2015 
Incorporating Global Amendment 1 and 
Taiwan-specific change 
 
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SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate dosing 
in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to this timing 
may be allowed for medical or regulatory considerations only after consultation with the Medical 
Monitor.  The last testing visit in the parent study will serve as the baseline for this study, unless more 
than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.  
Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days, or 
receive the patisiran infusions at home by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran.  Patients who are receiving patisiran infusions at home will have a 
phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the clinical site 
at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 
occur if deemed necessary by the study personnel. 
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Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) and, 
in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN are 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court 
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Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
• 
Intravenous dexamethasone (10 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or 
cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
• 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
• 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
• 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
• 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
• 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test 
• 
Polyneuropathy disability (PND) score and FAP stage 
• 
Nutritional status using modified body mass index (mBMI) 
• 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
• 
Magnetic resonance (MR) neurography  
• 
Cardiac structure and function through echocardiograms and serum levels of terminal 
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prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
• 
New York Heart Association (NYHA) classification of heart failure 
• 
Serum TTR 
• 
Vitamin A 
• 
Thyroid Stimulating Hormone 
• 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; and ophthalmology 
examinations. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Efficacy analyses will examine between- and within-subject rates of change over time.  For the subset 
of patients that have previously received placebo in the parent study, comparisons for the various 
efficacy assessments will be made between rates of change pre- and post-administration of patisiran, 
and relative to the treatment group in the parent study.  Additional exploratory analyses will compare 
rates of change with rates estimated from previous studies, including cross-sectional, natural history, 
and interventional studies of other drugs.  Associations between pharmacodynamic and efficacy data 
will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
[X]f 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test (urine) 
Xk 
 
X 
X 
X 
X 
X 
TTR Protein (ELISA) 
X 
 
X 
X 
X 
X 
X 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
mNIS+7l 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS+7m 
Xd 
 
 
X 
 
[X]f 
[X]f 
NIS only 
 
 
 
 
Xn 
Xn,p 
Xn,p 
Grip Strength Testq 
Xd 
 
 
X 
 
[X]f 
[X]f 
10-Meter Walk Testr 
Xd 
 
 
X 
 
[X]f 
[X]f 
Ophthalmology Examinations 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) t 
 
 
 
X 
X 
Xo 
Xo 
MR Neurographyu 
 
 
 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNv 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
[X]f 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
[X]f 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,w 
 
 
X 
 
[X]f 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
[X]f 
[X]f 
Anti-Drug Antibody Testingx 
 
 
X 
X 
X 
X 
X 
Premedication / Patisiran Administration 
Xy 
Xy 
 
 
Phone Contact 
 
Xz 
 
 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
 
Table 1 Footnotes: 
Abbreviations:  COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = 
familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified body mass index; mNIS = Modified Neuropathy 
Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; 
NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-Diabetic Neuropathy; R-ODS = Rasch-built Overall 
Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = transthyretin 
a Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may occur 
within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with the 
Medical Monitor. 
b Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c Assessment does not need to be repeated.  Information will be obtained from parent study. 
d Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f Assessment/procedure required only if patient withdraws before the 52-week visit. 
g Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
k Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the first dose. 
l The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (Σ5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
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separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after 
the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who performed the 
assessments for the patient in the patisiran study in which they were previously enrolled.   
m The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
n One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
o Assessment does not need to be repeated if done within the previous 26 weeks. 
p Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the previous 
26 weeks. 
q Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second (repeat) 
assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
r The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and walkers 
are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed on separate 
days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days after the first 
assessment. 
s Examination will include visual acuity, visual fields, and slit-lamp evaluation. 
t Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin biopsies 
in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies taken from the 
distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
u Required only for patients who had MR neurography in the parent study and may be imaged for consenting patients who did not have MR neurography 
previously in their parent study.   
v Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to complete 
this assessment. 
w Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
x Serum samples for anti-drug antibodies will be collected as specified.  Samples may be analyzed, if clinically indicated. 
y Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study within the 21 (±3) days 
timeframe.  Doses may be administered at the clinical site or at home by a healthcare professional trained in the protocol. 
z Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 30 (±5) days for assessment of adverse events 
and concomitant medication use. 
 
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TABLE OF CONTENTS 
 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 
6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
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6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration.........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................36 
8.1.1.2. 
Neurological Impairment Score ..................................................................................37 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Magnetic Resonance Neurography .............................................................................37 
8.1.5. 
Modified Body Mass Index ........................................................................................38 
8.1.6. 
Timed 10-meter Walk Test .........................................................................................38 
8.1.7. 
Grip Strength Test .......................................................................................................38 
8.1.8. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.10. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.11. 
Rasch-built Overall Disability Scale ..........................................................................39 
8.1.12. 
Pharmacoeconomics Questionnaire ............................................................................39 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.14. 
Transthyretin ...............................................................................................................39 
8.1.15. 
Thyroid-Stimulating Hormone ...................................................................................39 
8.1.16. 
Vitamin A ...................................................................................................................39 
8.1.17. 
Anti-Drug Antibodies .................................................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................40 
9.1. 
Safety Parameters .......................................................................................................40 
9.1.1. 
Demographic and Medical History .............................................................................40 
9.1.2. 
Vital Signs ..................................................................................................................40 
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9.1.3. 
Weight and Height ......................................................................................................40 
9.1.4. 
Physical Examination .................................................................................................40 
9.1.5. 
Laboratory Assessments .............................................................................................40 
9.1.5.1. 
Hematology .................................................................................................................41 
9.1.5.2. 
Blood Chemistry .........................................................................................................41 
9.1.5.3. 
Urinalysis ....................................................................................................................41 
9.1.5.4. 
Coagulation .................................................................................................................42 
9.1.5.5. 
Pregnancy Screen ........................................................................................................42 
9.1.6. 
Ophthalmology Examination ......................................................................................42 
9.2. 
Adverse Events and Serious Adverse Events .............................................................42 
9.2.1. 
Definition of Adverse Events .....................................................................................42 
9.2.1.1. 
Adverse Event .............................................................................................................42 
9.2.1.2. 
Serious Adverse Event ................................................................................................42 
9.3. 
Relationship to Study Drug ........................................................................................43 
9.4. 
Recording Adverse Events .........................................................................................43 
9.5. 
Reporting Adverse Events ..........................................................................................44 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................44 
9.5.2. 
Pregnancy Reporting ..................................................................................................46 
10. 
STATISTICS ..............................................................................................................47 
10.1. 
Sample Size ................................................................................................................47 
10.2. 
Statistical Methodology ..............................................................................................47 
10.2.1. 
Populations to be Analyzed ........................................................................................47 
10.2.2. 
Baseline Evaluations ...................................................................................................47 
10.2.3. 
Efficacy Analyses .......................................................................................................47 
10.2.4. 
Safety Analyses ..........................................................................................................48 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................48 
10.2.6. 
Interim Analysis ..........................................................................................................48 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................49 
11.1. 
Study Monitoring ........................................................................................................49 
11.2. 
Audits and Inspections ................................................................................................49 
11.3. 
Institutional Review Board .........................................................................................49 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................50 
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13. 
ETHICS ......................................................................................................................51 
13.1. 
Ethics Review .............................................................................................................51 
13.2. 
Ethical Conduct of the Study ......................................................................................51 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................51 
13.3. 
Written Informed Consent ..........................................................................................51 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................53 
14.1. 
Case Report Forms .....................................................................................................53 
14.2. 
Confidentiality ............................................................................................................53 
14.3. 
Inspection of Records .................................................................................................54 
14.4. 
Retention of Records ..................................................................................................54 
15. 
PUBLICATION POLICY ..........................................................................................55 
16. 
LIST OF REFERENCES ............................................................................................56 
17. 
APPENDICES ............................................................................................................57 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
Σ5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WHO 
World Health Organization 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran IB. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
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circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
• Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an 
IRR with patisiran, all patients in this study will be premedicated prior to dosing with 
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a 
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing 
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
• Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in 
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the end of 
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical 
studies to date, there have been no clinically significant changes in liver function tests in 
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver 
function via serial laboratory assessments. 
• Vitamin A Lowering 
The suppression of serum levels of TTR and RBP is expected to result in the lowering of 
circulating vitamin A levels.  Preclinical and clinical data have shown that the lowering of 
circulating vitamin A associated with suppression of RBP does not result in severe vitamin A 
deficiency.  Furthermore, there are individuals with RBP/TTR mutations who have life-long 
low levels of circulating vitamin A and are essentially in good health, suggesting that there 
are compensatory transport mechanisms for vitamin A that are yet undescribed.13  This has 
also been confirmed in TTR knockout mice, which do not exhibit any manifestations of 
vitamin A deficiency, with vitamin A uptake by most tissues continuing in the absence of 
RBP.14  Provided there is adequate vitamin A in the diet, tissue stores of vitamin A should 
not be affected by the lowering of TTR and RBP.  However, as the vitamin A content of the 
diet may vary between different countries and different individuals within a country, all 
patients on the study will be asked to take a daily supplement containing the recommended 
daily allowance of vitamin A.  Patients should have started vitamin A supplementation by the 
time they start his/her first dose of patisiran. 
• Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone 
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mineralization.  If there are no medical contraindications, and per investigator judgment and 
local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the IB. 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days, or receive the patisiran infusions at home by a healthcare professional trained on 
the protocol and delivery of premedications and patisiran.  Patients who are receiving patisiran 
infusions at home will have a phone contact with the site at least every 30 (±5) days.  Patients 
will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and yearly 
thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
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which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor. 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or its 
representative, and the Investigators, Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) and Regulatory Authorities will be promptly informed of the termination and the 
reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on 
anticoagulant therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing at the Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 
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5. Is unable to take the required premedications, unless modifications to the premedication
regimen were previously allowed per the parent study
6. Is under legal protection (defined as “any person who becomes incapable of protecting
his/her interests due to a medically diagnosed impairment of his/her mental faculties that
may limit or prevent the expression of his will”), decided by a court
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
•
Is in violation of the protocol
•
Experiences a serious or intolerable AE
•
Becomes pregnant
•
Requires a prohibited medication (see Section 5.2)
•
Requests to be withdrawn from the study
•
Is found to be considerably noncompliant with the protocol-required patisiran dosing
visits
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not 
known whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients 
who are male or who are women of child bearing potential will affect reproduction.  
Histopathological evaluations of all of the reproductive organs have been conducted in the rat 
and non-human primate (NHP) toxicology studies including a chronic NHP study in sexually 
mature animals, where there were no adverse effects in males (including sperm analyses and 
spermatogenic staging) or females.  In a dose range-finding rat embryo/fetal development study 
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conducted with patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
• Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
• Placement of an intrauterine device (IUD) 
• Placement of an intrauterine system (IUS) 
• Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
• 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); 
• Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
• Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
• IUD in conjunction with condom or diaphragm and spermicide 
• Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
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CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
• Any investigational agent other than patisiran 
• Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
• Tafamidis 
• Diflunisal 
• Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take an oral daily supplement containing the 
recommended daily allowance of vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 
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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff or trained home healthcare professionals.  A dose will be considered 
completed if 80% or more of the total volume of the IV solution was administered to the patient.  
Patients will be permitted to miss an occasional dose of patisiran; however, if a patient misses 
3 consecutive doses, the Investigator, in consultation with the Medical Monitor, will discuss 
whether the patient will be able to continue on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 
• Intravenous dexamethasone (10 mg) or equivalent 
• Oral paracetamol/acetaminophen (500 mg) or equivalent 
• Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the clinical site).  Hydroxyzine or fexofenadine 25 mg per os (PO, orally) 
or cetirizine 10 mg PO may be substituted for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blocker. 
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 
• If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.  
• If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid 
premedication will be lowered, then the following steps must be followed: 
1) If the current steroid dosage is 10 mg or less of intravenous dexamethasone or 
equivalent, then the patient may be lowered in increments no greater than 2.5 mg 
intravenous dexamethasone or equivalent. 
2) After each incremental lowering of intravenous dexamethasone or equivalent, the patient 
must receive three consecutive intravenous doses of patisiran without IRR and continued 
signs or symptoms of steroid intolerance before further reductions in steroid 
premedications.   
3) The premedication steroid dosage should not be reduced below 5 mg intravenous 
dexamethasone or equivalent. 
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone or 
equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
Patients who have received at least 3 doses of patisiran on this study at the clinical site with no 
evidence of IRRs or other adverse effects may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be done 
according to a site-specific plan by a healthcare professional trained on the protocol and delivery 
of premedications and patisiran. 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 
• If the patient experiences an IRR the infusion time may be extended up to 3 hours in the 
event of a mild or moderate IRR. 
1) If the patient experiences a mild or moderate IRR that resolves by slowing the infusion 
rate then no further premedication changes are recommended. 
2) If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).   
• If the infusion time for a patient was already extended on the parent study due to an IRR, that 
modified infusion duration may be continued on this study for that particular patient.  
Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
• For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following 
completion of dosing. 
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A in an oral supplement. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
• In the event of an IRR, the infusion of patisiran may be stopped and the patient closely 
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and 
permit resumption of patisiran administration include, but are not limited to: 
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids. 
• Following resolution of a mild or moderate IRR that required interruption of the patisiran 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of 
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patisiran.  If the infusion is delayed, the administration of the infusion should be completed 
no more than 6 hours from the initial start of the infusion.   
• Patisiran 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place over 2 days.  Patients will not receive study drug at this 
visit.  A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
• Clinical exam-based NIS (weakness and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− Nerve conduction studies (NCS) 5 attributes (Σ5) 
− Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
• Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
• Full NIS (including weakness, sensation, and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− NCS Σ5 
− Vibration detection threshold (VDT) 
• Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Magnetic Resonance Neurography 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional 
images for the evaluation of peripheral nerve disorders.16  This procedure produces detailed 
images of nerve morphology to evaluate degeneration and regeneration.  Nerves in the lumbar 
plexus and lower extremity will be imaged for patients who have previously had MR 
neurography in the parent study and may be imaged for consenting patients who did not have 
MR neurography previously in the parent study.  A central reader will be used for MR 
neurography. 
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8.1.5. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.6. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.7. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.8. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.10. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
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8.1.11. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.12. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.14. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.15. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.16. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A supplementation. 
8.1.17. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may 
be analyzed, if clinically indicated. 
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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
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In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
• Aspartate transaminase (AST) 
• Alkaline phosphatase 
• Alanine transaminase (ALT) 
• Bilirubin (total and direct) 
• Sodium 
• Glucose 
• Potassium 
• Phosphate 
• Blood urea nitrogen (BUN) 
• Albumin 
• Creatinine 
• Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
• Visual inspection for color and appearance 
• Leukocytes 
• pH 
• Bilirubin 
• Specific gravity 
• Nitrite 
• Ketones 
• Urobilinogen 
• Protein 
• Microscopic inspection of sediment 
• Glucose 
 
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9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
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• Is a congenital anomaly or birth defect 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
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Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
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 causality
Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
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completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
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9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
• Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
• Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the 
subset of patients that have previously received placebo in the parent study, comparisons for the 
various efficacy assessments will be made between rates of change pre- and post-administration 
of patisiran, and relative to the treatment group in the parent study.  Additional analyses will 
compare rates of change with rates estimated from previous studies, including cross-sectional, 
natural history, and interventional studies of other drugs.  Associations between PD (serum TTR) 
and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the Σ5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.  
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Values of the individual components of the mNIS weakness and reflex scores will be depicted 
graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
The observed values and changes from baseline in healthcare utilization will be evaluated and 
summarized using descriptive statistics. 
10.2.6. 
Interim Analysis 
There is no formal interim analysis planned for this study.  Interim data examinations may be 
performed, but these will be of a descriptive nature and will not involve any formal hypothesis 
testing. 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC or IRB and/or 
Regulatory Authorities, providing direct access to source data/documents.  The study may be 
subject to audit by the Sponsor or its representatives or by regulatory authorities.  If such an audit 
occurs, the Investigator must agree to allow access to the required patient records.  In the event 
of an audit, the Investigator agrees to allow the Sponsor, representatives from the Sponsor, or 
regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Health Organization (WHO) Declaration of 
Helsinki, the ICH of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and all other 
applicable medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
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The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 
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14.3. 
Inspection of Records 
The Sponsor 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, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2  
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3  
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4  
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5  
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6  
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7  
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8  
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9  
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10  
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11  
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13  
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14  
Episkopou, V., 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. 90: p. 2375-2379. 
15
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy and 
in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
16  
Kollmer J, Hund E, Hornung B, Schönland S, et al. MR-neurography: In-vivo detection of nerve 
injury in systemic light chain (AL) amyloidosis. XIVth International Symposium on 
Amyloidosis, 2014. 
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17. 
APPENDICES 
 
Appendix 1: Karnofsky Scale 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
 
 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 
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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
• 
Weakness (192) 
• 
Sensation (32) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (18.6)a 
• 
Sural SNAP, tibial motor n. distal latency, peroneal 
SNAP/motor n. conduction velocity/motor n. distal 
latency 
• 
Vibration detection threshold (3.7) 
• 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
• 
Weakness (192) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (10)a 
• 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
• 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
• 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 
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Clinical Study Protocol ALN-TTR02-006 
 
 Amendment 2 Summary of Changes_05 January 2017 
 
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ALN-TTR02-006 Protocol Amendment 2 
Summary of Changes (dated 05 January 2017)  
compared to Protocol Version 2.1 Taiwan (dated 10 December 2015) 
A Multicenter, Open-label, Extension Study to Evaluate the Long-Term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy who have 
Completed a Prior Clinical Study with Patisiran 
 
Rationale for Protocol Amendment 
The primary purpose of this amendment is to add the Columbia-Suicide Severity Rating Scale 
(C-SSRS) to the study assessments, which was inadvertently left out of previous versions of the 
protocol. The inclusion of the C-SSRS addresses a regulatory requirement to prospectively 
assess suicidality in clinical trials involving all drugs for neurological indications.  Overall, this 
amendment includes the following changes: 
 The Columbia-Suicide Severity Rating Scale has been added as an assessment of suicidal 
ideation and behavior. 
 Country-specific versions of the protocol have been integrated in order to increase 
consistency in the execution of the clinical study globally 
 Electroretinograms are now recommended to be performed in the case of suspected 
retinal disease. 
 The premedication regimen has been updated to align with commercially available doses. 
 Blood samples for long-term storage have been added in order to permit future 
exploratory investigations. 
 During scheduled phone contact, clinical sites may now ask patients who are receiving 
home infusions about their general experience receiving these infusions 
A detailed summary of the above changes, in addition to changes made for clarity, is provided in 
Table 1.  Corrections to abbreviations, typographical errors and formatting are not detailed. 
 
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Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment 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: Added Columbia-Suicide Severity Rating Scale to the study assessments 
The primary change occurs in Table 1 Schedule of Assessments 
Added text: 
Added row to Schedule of Assessments indicating that the Columbia-Suicide Severity Rating Scale is to be 
collected at 26 weeks and 52 weeks after baseline and annually thereafter, as well as at the End of Study and Early 
Withdrawal visits. 
Section(s) also containing this change or similar changes: 
 
Synopsis, Criteria for Evaluation, Safety 
 
Section 9.1.7 Columbia-Suicide Severity Rating Scale (section added) 
Purpose: As part of global protocol integration, specified that home infusions are allowed only where applicable country and local regulations 
allow. 
The primary change occurs in Section 3.1 Overall Study Design 
Added text: 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 21 (±3) days, or. 
Where applicable country and local regulations allow, patients may receive the patisiran infusions at home by a 
healthcare professional trained on the protocol and delivery of premedications and patisiran. 
Section(s) also containing this change or similar changes: 
 
Synopsis, Methodology 
 
Table 1, Schedule of Assessments 
 
Section 5.3 Treatment Compliance 
 
Section 6.4.2 Study Drug Administration 
Purpose: As part of global protocol integration, specified that MR neurography is only to be conducted in Germany and France 
The primary change occurs in Table 1 Schedule of Assessments, footnote s 
Now reads: 
Required only forMR neurography will only be conducted at sites in Germany and France. In these countries, 
neurography may be conducted for patients who had MR neurography in the parent study and may be imaged for 
consentingfor a subset of patients providing informed consent who did not have MR neurography previously in 
their parent study.  Patients who had imaging in the parent study should have Day 0 imaging if they did not 
undergo MR neurography within the past 3 months. 
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Section(s) also containing this change or similar changes: 
 
Synopsis, Criteria for evaluation, Efficacy 
 
Section 8.1 Efficacy Parameters 
 
Section 8.1.4 Magnetic Resonance Neurography (Germany and France Only) (Section has been added) 
Purpose: As part of global protocol integration, specified which studies patients may roll in from, and that the ALN-TTR02-003 study is not being 
conducted in Japan. 
The primary change occurs in Section 3.1 Overall Study Design 
Added text: 
Patients in this study will have completed “parent” study ALN-TTR02-003 or ALN-TTR02-004.  Note that 
Study ALN-TTR02-003 is not being conducted in Japan. 
Purpose: As part of global protocol integration, added Japan-specific recommendations regarding contraception. 
The primary change occurs in Section 4.4 Pregnancy and Breastfeeding Restrictions / Contraception Requirements 
Added text: 
In Japan it is recommended that the Investigators select appropriate contraception methods, as available. 
Purpose: As part of global protocol integration, added Japan-specific instructions regarding duties related to study drug accountability. 
The primary change occurs in Section 6.5 Study Drug Accountability 
Added text: 
The Investigator or designee (or in Japan, the responsible pharmacist designated according to the Japan local 
regulations) will maintain accurate records of receipt and the condition of the patisiran supplied for this study, 
including dates of receipt. 
Purpose: As part of global protocol integration, added statement on compensation for health damages as per local regulations. 
The primary change occurs in Section 13.4 Compensation for Health Damages (section added) 
Added text: 
13.4    Compensation for Health Damages 
 
A copy of the certificate of insurance as a measure to compensation for health damages will be submitted to 
the IRB/IEC if required per local regulations 
Purpose: To update premedication regimen so that it aligns with commercially available doses. 
The primary change occurs in Section 6.4.1 Premedication 
Now reads: 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker available at the clinical site).  
Hydroxyzine or fexofenadine 25 mg per os (PO, orally) or fexofenadine 30 mg or 60 mg PO or cetirizine 10 mg 
PO may be substituted for any patient who does not tolerate IV diphenhydramine or other IV H1 blocker. 
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Section(s) also containing this change or similar changes: 
 
Synopsis, Investigational product, dosage and mode of administration 
Purpose: Added recommendation to collect an electroretinogram in the case of suspected retinal injury 
The primary change occurs in Section 9.1.6 Ophthalmology Examination 
Added text: 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to determine if there 
is damage to rods and cones.  ERG testing should be performed if visual changes raise the suspicion for this 
sort of retinal disease and if clinically indicated. 
Section(s) also containing this change or similar changes: 
 
Table 1, Schedule of Assessments 
Purpose: Updated description of statistical analysis to align with currently planned analytic approach. 
The primary change occurs in Section 10.2.3 Efficacy Analyses 
Now reads: 
Efficacy analyses will examine between- and within-patient rates of change over time.  For the subset of patients 
that have previously received placebo in the parent study, comparisons for the various efficacy assessments will be 
made between rates of change pre- and post-administration of patisiran, and relative to the treatment group in the 
parent study.  Additional analyses will compare rates of change with rates estimated from previous studies, 
including cross-sectional, natural history, and interventional studies of other drugs.  Associations between PD 
(serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the mNIS +7 composite 
score.  Summaries will also be provided for the components of the composite score (ie, the NIS weakness and reflex 
scores, the 5 NCS, and QST values).  The NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS 
will be summarized also.  Values of the individual components of the mNIS weakness and reflex scores will be 
depicted graphically by presenting the mean (±SE) values over time for each location (hip, knee, etc.). 
Section(s) also containing this change or similar changes: 
 
Synopsis, Statistical Methods 
 
Section 10.2.5 Healthcare Utilization Assessments 
 
Section 10.2.6 Interim Analysis 
Purpose: Added blood sampling for long-term storage in order to permit future exploratory investigations. 
The primary change occurs in Table 1 Schedule of Assessments 
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Added text: 
Added row to Schedule of Assessments indicating a blood sample for long-term storage is to be collected at each 
clinic visit. 
Section(s) also containing this change or similar changes: 
 
Section 8.1.18 Blood Sample for Long-term Storage (section added) 
Purpose: Added questionnaire regarding experience of home infusions to scheduled phone contact for home infusion patients. 
The primary change occurs in Table 1 Schedule of Assessments, footnote x 
Added text: 
x. Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 
30 (±5) days for assessment of adverse events and concomitant medication use. During phone contact, patients 
may also be asked additional questions about their general experience receiving infusions at home. 
Purpose: Added a definition of “woman of child-bearing potential”. 
The primary change occurs in Section 4.4 Pregnancy and Breastfeeding Restrictions / Contraception Requirements 
Added text: 
Women of child-bearing potential are defined as any woman or adolescent who has begun menstruation. A 
post-menopausal woman is defined as a woman who has 12 months of spontaneous amenorrhea or 6 months 
of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks postsurgical bilateral 
oophorectomy with or without hysterectomy. 
Purpose: Clarified language on Vitamin A dosing and added Japan-specific instructions. 
The primary change occurs in Section 5.2 Concomitant Medications 
Now reads: 
All patients will be asked to continue to take an oral daily supplement containing the recommended daily allowance 
of vitamin A. Patients will receive this daily dose for the duration of their participation in the study while 
being administered patisiran. In Japan, the clinical sites will provide patients with a prescription for vitamin 
A. 
Section(s) also containing this change or similar changes: 
 
Section 6.4.2 Study Drug Administration 
 
Section 8.1.16 Vitamin A 
Purpose: Clarified procedures for efficacy assessments, adding the location at which to conduct assessments, and removing specified duration. 
The primary change occurs in Section 8.1 Efficacy Parameters 
Now reads: 
Efficacy assessments will occur for all patients at the 52-week visit, which will take place over 2 daysat the CAS. 
Purpose: Removed language indicating that anti-drug antibodies would only be analyzed if clinically indicated. 
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The primary change occurs in Section 8.1.17 Efficacy Parameters 
Deleted text: 
Serum samples for anti-drug antibodies will be collected as specified in Table 1.  Samples may be analyzed, if 
clinically indicated. 
Section(s) also containing this change or similar changes: 
 
Table 1, Schedule of Assessments 
Purpose: Clarified that no study procedures may occur until approval is granted by all appropriate parties. 
The primary change occurs in Section 13.1 Ethics Review 
Added text: 
The Investigator should not start any study procedure with the patient until documentation of the approval 
by the IEC/IRB and written notification of the approval from the head of the study site to the Investigator 
and Alnylam Pharmaceuticals, Inc. 
 
 
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Clinical Protocol 
ALN-TTR02-006 
Version 3.1-United Kingdom 11 May 2017 
PATISIRAN (ALN-TTR02) 
ALN-TTR02-006 
A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF PATISIRAN IN 
PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY 
WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH 
PATISIRAN 
Protocol Version: 
Protocol Date 
INDNumber: 
EUDRACT Number 
Sponsor: 
Sponsor Contact: 
Version 3 .1 - United Kingdom (Incorporating 
country-specific request) 
11 May2017 
117395 
2014-003877-40 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA 02142 USA 
Date 
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. 
study will be completed according to guidelines of Good Clinical Practice (GCP). Compliance with 
this practice provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
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Clinical Protocol 
Version 3.1-United Kingdom 11 May 2017 
 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-006 protocol and agree to conduct the study as outlined.  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 
 
 
Version History: 
Version Number 
Date 
Comment 
1.0 (Original) 
06 November 2014 
Initial Release 
2.0 – Global 
08 September 2015 
Incorporating Global Amendment 1 
2.1 – Japan 
14 October 2015 
Incorporating Japan-specific Amendment 1 
2.1 – Taiwan 
10 December 2015 
Incorporating Taiwan-specific Amendment 1 
2.1 – France/Germany 
17 December 2015 
Incorporating France/Germany-specific 
Amendment 1 
2.1 – Brazil 
16 September 2015 
Incorporating Brazil-specific Amendment 1 
2.2 – Japan 
14 March 2016 
Incorporating Japan-specific Amendment 2 
3.0 - Global 
05 January 2017 
Incorporating Global Amendment 2 (including 
Japan-, Taiwan- and France/Germany-specific 
changes) 
3.1 – Brazil 
20 January 2017 
Incorporating Global Amendment 2 (including 
Japan-, Taiwan- and France/Germany-specific 
changes) 
3.1 – Argentina 
20 January 2017 
Incorporating Global Amendment 2 (including 
Japan-, Taiwan- and France/Germany-specific 
changes) 
3.1 – United Kingdom 
11 May 2017 
Incorporating country-specific request 
 
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SYNOPSIS 
Name of Sponsor/Company: 
Alnylam Pharmaceuticals, Inc 
Name of Investigational Product: 
Patisiran 
Title of Study:  
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of 
Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical 
Study with Patisiran 
Study Centers: 
This study will be conducted at multiple sites worldwide that have enrolled patients in a previous 
patisiran study. 
Objectives: 
To assess the safety and efficacy of long-term dosing with patisiran in transthyretin-mediated 
amyloidosis (ATTR) patients with familial amyloidotic polyneuropathy (FAP). 
Methodology:  
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran intravenously (IV) 
once every 21 (±3) days for the duration of the study.  In order to maintain the every 21-day dosing 
schedule from the parent study, patients are expected to have their first visit (Day 0) in this study 3 
weeks after their last dose visit in the parent study.  However, if necessary, a patient may initiate dosing 
in this study up to 45 days from the time of the last dose in the parent study.  Exceptions to this timing 
may be allowed for medical or regulatory considerations only after consultation with the Medical 
Monitor.  The last testing visit in the parent study will serve as the baseline for this study, unless more 
than 45 days have elapsed, in which case the baseline tests will need to be repeated on Day 0.  
Eligibility for this study will be confirmed before administration of the first dose on Day 0. 
After the Day 0 visit, patients should return to the site for patisiran dosing once every 21 days. Where 
applicable country and local regulations allow, patients may receive the patisiran infusions at home by 
a healthcare professional trained on the protocol and delivery of premedications and patisiran.  Patients 
who are receiving patisiran infusions at home will have a phone contact with the site at least every 30 
(±5) days.  Patients will also have visits at the clinical site at approximately 12, 26 and 52 weeks, and 
yearly thereafter. 
A complete set of efficacy assessments will be done at 52 weeks, followed by more limited efficacy 
assessments yearly thereafter.  In order to decrease the variability in the efficacy assessment testing at 
the 52-week visit, there will be a limited number of sites within any one territory that conduct these 
efficacy assessments (referred to as “Central Assessment Sites [CAS]”); these sites can also dose and 
manage patients.  There will also be sites that can dose and manage the patients (“Patient Care Sites 
[PCS])”, while sending the patients to the nearest CAS for their 52-week efficacy assessments.  Every 
effort should be made for the patient to return to the same CAS center that the patient went to in the 
parent study.  Yearly efficacy assessments after the 52-week visit may be done at a PCS. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be continually 
assessed throughout the study for adverse events (AEs).  Unscheduled visits for study assessments may 
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occur if deemed necessary by the study personnel. 
Number of patients (planned):  
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
Diagnosis and eligibility criteria:  
To be enrolled in the study, patients must meet the following criteria before administration of patisiran 
on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) and, 
in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the upper 
limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on anticoagulant 
therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤2 x ULN is eligible 
if the elevation is secondary to documented Gilbert’s syndrome (elevation of unconjugated 
bilirubin with normal conjugated bilirubin) and the patient has ALT and AST levels within 
normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing in 
this study and agree to use 2 highly effective methods of contraception throughout study 
participation and for 75 days after last dose of patisiran in this study. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method (eg, condom) 
and 1 additional method (eg, spermicide) of contraception throughout study participation and 
for 75 days after the last dose of patisiran in this study; males must also abstain from sperm 
donation after the first dose of patisiran through study participation and for 75 days after last 
dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit requirements 
and provide written informed consent 
A patient will be excluded if they meet any of the following criteria before dosing on Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid (TUDCA), 
unless previously allowed per the parent study 
5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting his/her 
interests due to a medically diagnosed impairment of his/her mental faculties that may limit or 
prevent the expression of his will”), decided by a court 
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Investigational product, dosage and mode of administration:  
Patisiran (comprising a small interfering ribonucleic acid [siRNA] targeting mutant and wild type 
transthyretin [TTR] messenger RNA [mRNA], in a lipid nanoparticle formulation for IV 
administration), 0.3 mg/kg once every 21 (±3) days administered as an IV infusion over 70 minutes 
(approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the 
remainder of the infusion) by a controlled infusion device. 
Patients will receive the following premedications at least 60 minutes before the start of the patisiran 
infusion: 
• 
Intravenous dexamethasone (10 mg) or equivalent 
• 
Oral paracetamol/acetaminophen (500 mg) or equivalent 
• 
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
• 
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine 25 mg per os (PO, orally) or fexofenadine 30 mg 
or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who does not 
tolerate IV diphenhydramine or other IV H1 blocker. 
Duration of treatment:  
The duration of the study has been determined to allow the collection of long-term safety, tolerability 
and efficacy data of patisiran in patients with FAP who have completed a prior study with patisiran.  
The estimated duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
The efficacy of patisiran will be assessed by the following evaluations: 
• 
Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score, and NIS+7  
• 
Patient-reported quality of life (QOL) using the Norfolk Quality of Life-Diabetic 
Neuropathy (QOL-DN) and the EuroQOL (EQ-5D) questionnaires 
• 
Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS) 
• 
Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS 31) 
• 
Motor function assessments, including NIS-Weakness (NIS-W), timed 10-meter walk test, 
and grip strength test 
• 
Polyneuropathy disability (PND) score and FAP stage 
• 
Nutritional status using modified body mass index (mBMI) 
• 
Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3 mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study) 
• 
Magnetic resonance (MR) neurography (as regionally applicable) 
• 
Cardiac structure and function through echocardiograms and serum levels of terminal 
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prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I 
• 
New York Heart Association (NYHA) classification of heart failure 
• 
Serum TTR 
• 
Vitamin A 
• 
Thyroid stimulating hormone 
• 
Disease burden and healthcare utilization assessed using a patient-reported 
pharmacoeconomics questionnaire 
Safety: 
Safety assessments will include monitoring for AEs (including serious AEs [SAEs]); clinical laboratory 
tests, including hematology, clinical chemistry, urinalysis, and pregnancy testing; measurement of anti-
drug antibodies (if clinically indicated); vital signs; physical examinations; ophthalmology 
examinations; and assessment of suicidal ideation and behavior. 
Statistical methods: 
This is an open-label extension study enrolling patients who have previously completed a patisiran 
study; the size of the study is not determined via power analysis of particular hypotheses tests. 
Associations between pharmacodynamic and efficacy data will be explored via correlation. 
Descriptive statistics will be provided for clinical efficacy data, clinical laboratory data, vital signs 
data, and ECG interval data, presented as both actual values and changes from baseline relative to each 
on-study evaluation.  Laboratory shift tables from baseline to worst values will be presented. 
 
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Table 1 
Schedule of Assessments 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
Demographics 
Xc 
 
 
 
 
 
 
Physical Examination 
Xd 
 
 
X 
X 
Xo 
Xo 
Weight 
X 
Prior to Each Dose 
Xo 
Xo 
mBMIe 
Xd 
 
 
X 
X 
Xo 
Xo 
Height 
Xc 
 
 
 
 
 
 
FAP Stage and PND Score 
Xd 
 
 
X 
X 
Xo 
Xo 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
 
 
[X]f 
Vital Signsg 
X 
Prior to Each Dose 
 
 
Safety Laboratory Assessmentsh 
Xd 
X 
X 
X 
X 
X 
X 
INR 
X 
 
 
 
 
 
 
Pregnancy Test (urine) 
Xi 
 
X 
X 
X 
X 
X 
C-SSRS Questionnaire 
 
 
X 
X 
X 
X 
X 
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Version 3.1-United Kingdom 11 May 2017 
 
Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
TTR Protein (ELISA) 
Xd 
 
X 
X 
X 
X 
X 
TSH and Vitamin A 
 
 
 
X 
X 
Xo 
Xo 
Blood Sample for Long-term Storage 
X 
X 
X 
X 
X 
X 
X 
mNIS+7j 
Xd 
 
 
X 
 
 
[X]f 
NIS+7k 
Xd 
 
 
X 
 
 
[X]f 
NIS only 
 
 
 
 
Xl 
Xm 
Xm 
Grip Strength Testn 
Xd 
 
 
X 
 
 
[X]f 
10-Meter Walk Testp 
Xd 
 
 
X 
 
 
[X]f 
Ophthalmology Examinationq 
Xd 
 
 
X 
X 
Xo 
Xo 
Skin Punch Biopsy (IENFD and SGNFD) r 
 
 
 
X 
X 
Xo 
Xo 
MR Neurographys (Germany & France only) 
X 
 
X 
X 
X 
Xo 
Xo 
Pharmacoeconomics Questionnaire 
X 
 
 
X 
X 
Xo 
Xo 
Norfolk QOL-DNt 
Xd 
 
 
X 
X 
Xo 
Xo 
COMPASS 31 Questionnaire 
Xd 
 
 
X 
 
 
[X]f 
R-ODS Disability 
Xd 
 
 
X 
 
 
[X]f 
EQ-5D QOL 
Xd 
 
 
X 
X 
Xo 
Xo 
Echocardiogram 
Xd,u 
 
 
X 
 
 
[X]f 
Troponin I and NT-proBNP 
Xd 
 
 
X 
 
 
[X]f 
Anti-Drug Antibody Testingv 
 
 
X 
X 
X 
X 
X 
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Window 
Day 0 Visit 
12 Week 
Visit 
26 Week 
Visit 
52 Week 
Visit 
Annual 
Visit 
End of 
Study 
Early 
Withdrawal 
Visit 
≤45 Days from 
Last Dosea 
±4 Weeks 
±4 Weeks 
±4 
Weeks 
±6 
Weeks 
4 (+1) 
Weeks 
from 
Last 
Dose 
4 (+1) 
Weeks 
from Last 
Dose 
Procedure 
 
 
 
 
 
 
 
Premedication / Patisiran Administrationw 
X 
X 
 
 
Phone Contactx (In applicable regions only) 
 
X 
 
 
Adverse Events 
Xb 
Continuous Monitoring 
Concomitant Medications 
Xb 
Continuous Monitoring 
Table 1 Footnotes: 
Abbreviations:  C-SSRS = Columbia-Suicide Severity Rating Scale; COMPASS 31 = Composite Autonomic Symptom Score; ELISA = enzyme linked 
immunosorbent assay; EQ-5D QOL = EuroQOL; FAP = familial amyloidotic polyneuropathy; IENFD = intraepidermal nerve fiber density; mBMI = modified 
body mass index; mNIS = Modified Neuropathy Impairment Score; MR = magnetic resonance; NIS = Neuropathy Impairment Score; NT-proBNP = N-
terminal prohormone of B-type natriuretic peptide; NYHA = New York Heart Association; PND = polyneuropathy disability; QOL-DN = Quality of Life-
Diabetic Neuropathy; R-ODS = Rasch-built Overall Disability Scale; SGNFD = sweat gland nerve fiber density; TSH = thyroid stimulating hormone; TTR = 
transthyretin 
a. 
Every effort should be made to perform Day 0 visit 3 weeks (±3 days) from the last dose of study drug in the parent study.  However, the Day 0 visit may 
occur within 45 days after the last dose in the parent study.  Exceptions may be made for medical or regulatory considerations only after consultation with 
the Medical Monitor. 
b. Medical history includes TTR genotype.  Ongoing AEs from the parent study will be captured as Medical History on the case report form (CRF). Similarly 
concomitant medications that continue from the parent study will be entered into the database. 
c. 
Assessment does not need to be repeated.  Information will be obtained from parent study. 
d. Assessment/procedure does not need to be repeated if performed during the parent study within 45 days of first dose in this study. 
e. 
mBMI will be calculated within the clinical database; this calculation does not need to be performed at the study center. 
f. 
Assessment/procedure required only if patient withdraws before the 52-week visit. 
g. Vital signs include blood pressure, heart rate, body temperature, and respiratory rate.  Collected supine using an automated instrument after patient rests for 
10 minutes.  Must be performed pre-dose. 
h. Includes serum chemistry, hematology, and urinalysis.  Refer to Section 9.1.5 for specific laboratory assessments. 
i. 
Assessment does not need to be repeated if the patient had a negative pregnancy test (urine or serum) within 14 days of the first dose. 
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j. 
The mNIS+7 consists of the modified NIS tool (weakness and reflexes), nerve conduction studies (NCS) 5 attributes (Σ5), quantitative sensory testing (QST) 
by body surface area including touch pressure (TP) and heat pain (HP), and postural blood pressure.  Two assessments of the mNIS+7 will be performed on 
separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days 
after the first assessment. Each site will make every effort to have these assessments at the Week 52 visit performed by the same study personnel who 
performed the assessments for the patient in the patisiran study in which they were previously enrolled.   
k. The NIS+7 consists of the NIS tool (weakness, sensation, and reflexes), NCS Σ5, vibration detection threshold (VDT), and heart rate response to deep 
breathing (HRdB).  Two assessments of the NIS+7 will be performed on separate days (1 assessment on each day).  The second (repeat) assessment must be 
conducted at least 24 hours (approximately) but not more than 7 days after the first assessment. Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the patient in the patisiran study in which they were previously 
enrolled.   
l. 
One assessment of the NIS will be performed at each specified visit and must be performed by a neurologist. 
m. Assessment of NIS only does not need to be repeated if done as part of the NIS+7 at the End of Study or Early Withdrawal visit or if done within the 
previous 26 weeks. 
n. Grip strength will be measured in triplicate using a dynamometer held in the dominant hand.  Every effort will be made to use the same device for a patient 
throughout the duration of the study.  Two assessments of the grip strength will be performed on separate days (1 assessment on each day).  The second 
(repeat) assessment must be conducted at least 24 hours (approximately) after the first assessment, but not more than 7 days apart. 
o. Assessment does not need to be repeated if done within the previous 26 weeks. 
p. The patient will be asked to walk 10 meters.  The walk must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded.  Two assessments of the 10-meter walk test will be performed 
on separate days (1 assessment on each day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but not more than 7 days 
after the first assessment. 
q. Examination will include visual acuity, visual fields, and slit-lamp evaluation. An electroretinogram may also be performed, as described in Section 9.1.6  
r. 
Optional skin biopsies will only be obtained if the patient had skin biopsies in the parent study and has provided separate informed consent for the skin 
biopsies in this study.  Each skin biopsy assessment will include 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total), including 1 set of biopsies 
taken from the distal lower leg, when a patient’s clinical status allows, and 1 set from the distal thigh. 
s. 
MR neurography will only be conducted at sites in Germany and France. In these countries, neurography may be conductedfor patients who had MR 
neurography in the parent study and for a subset of patients providing informed consent who did not have MR neurography previously in their parent study. 
Patients who had imaging in the parent study should have Day 0 imaging if they did not undergo MR neurography within the past 3 months. 
t. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN questionnaire (eg, ALN-TTR02-003) do not have to 
complete this assessment. 
u. Patients entering this study from study ALN-TTR02-003, who were not previously participating in the cardiac subgroup, will be required to have an 
echocardiogram before dosing on Day 0. 
v. Serum samples for anti-drug antibodies will be collected as specified. 
w. Patisiran will be administered once every 21 (±3) days.  Every effort should be made to continue dosing from the parent study in the 21 (±3) day timeframe.  
Doses may be administered at the clinical site or, where applicable country and local regulations allow, at home by a healthcare professional trained in the 
protocol. 
x. Patients who are receiving patisiran infusions at home must be contacted by the clinical site a minimum of every 30 (±5) days for assessment of adverse 
events and concomitant medication use. During phone contact, patients may also be asked additional questions about their general experience receiving 
infusions at home. 
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TABLE OF CONTENTS 
 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Disease Overview .......................................................................................................18 
1.2. 
Patisiran ......................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................19 
1.4. 
Risk-Benefit Assessment ............................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Overall Study Design ..................................................................................................23 
3.2. 
Number of Patients .....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Criteria for Study Termination ...................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
4.1. 
Patient Inclusion Criteria ............................................................................................25 
4.2. 
Patient Exclusion Criteria ...........................................................................................25 
4.3. 
Patient Withdrawal Criteria ........................................................................................26 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception Requirements ................26 
5. 
TREATMENT OF PATIENTS ..................................................................................29 
5.1. 
Description of Study Drug ..........................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................29 
5.3. 
Treatment Compliance ................................................................................................30 
5.4. 
Randomization and Blinding ......................................................................................30 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31 
6.1. 
Study Drug Packaging and Labeling ..........................................................................31 
6.2. 
Study Drug Storage .....................................................................................................31 
6.3. 
Study Drug Preparation ..............................................................................................31 
6.4. 
Administration ............................................................................................................32 
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6.4.1. 
Premedication .............................................................................................................32 
6.4.2. 
Study Drug Administration.........................................................................................33 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................33 
6.5. 
Study Drug Accountability .........................................................................................34 
6.6. 
Study Drug Handling and Disposal ............................................................................34 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................35 
8. 
ASSESSMENT OF EFFICACY ................................................................................36 
8.1. 
Efficacy Parameters ....................................................................................................36 
8.1.1. 
Neurological Testing ..................................................................................................36 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 ......................................................................................................................36 
8.1.1.2. 
Neurological Impairment Score ..................................................................................37 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density .............37 
8.1.4. 
Magnetic Resonance Neurography (Germany and France Only) ...............................37 
8.1.5. 
Modified Body Mass Index ........................................................................................38 
8.1.6. 
Timed 10-meter Walk Test .........................................................................................38 
8.1.7. 
Grip Strength Test .......................................................................................................38 
8.1.8. 
Composite Autonomic Symptom Score .....................................................................38 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................38 
8.1.10. 
EuroQoL Quality of Life Questionnaire .....................................................................38 
8.1.11. 
Rasch-built Overall Disability Scale ..........................................................................39 
8.1.12. 
Pharmacoeconomics Questionnaire ............................................................................39 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................39 
8.1.14. 
Transthyretin ...............................................................................................................39 
8.1.15. 
Thyroid-Stimulating Hormone ...................................................................................39 
8.1.16. 
Vitamin A ...................................................................................................................39 
8.1.17. 
Anti-Drug Antibodies .................................................................................................39 
8.1.18. 
Blood Sample for Long-term Storage .........................................................................39 
9. 
ASSESSMENT OF SAFETY .....................................................................................41 
9.1. 
Safety Parameters .......................................................................................................41 
9.1.1. 
Demographic and Medical History .............................................................................41 
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9.1.2. 
Vital Signs ..................................................................................................................41 
9.1.3. 
Weight and Height ......................................................................................................41 
9.1.4. 
Physical Examination .................................................................................................41 
9.1.5. 
Laboratory Assessments .............................................................................................41 
9.1.5.1. 
Hematology .................................................................................................................42 
9.1.5.2. 
Blood Chemistry .........................................................................................................42 
9.1.5.3. 
Urinalysis ....................................................................................................................42 
9.1.5.4. 
Coagulation .................................................................................................................43 
9.1.5.5. 
Pregnancy Screen ........................................................................................................43 
9.1.6. 
Ophthalmology Examination ......................................................................................43 
9.1.7. 
Columbia-Suicide Severity Rating Scale ....................................................................43 
9.2. 
Adverse Events and Serious Adverse Events .............................................................43 
9.2.1. 
Definition of Adverse Events .....................................................................................43 
9.2.1.1. 
Adverse Event .............................................................................................................43 
9.2.1.2. 
Serious Adverse Event ................................................................................................44 
9.3. 
Relationship to Study Drug ........................................................................................44 
9.4. 
Recording Adverse Events .........................................................................................44 
9.5. 
Reporting Adverse Events ..........................................................................................45 
9.5.1. 
Serious Adverse Event Reporting ...............................................................................45 
9.5.2. 
Pregnancy Reporting ..................................................................................................47 
10. 
STATISTICS ..............................................................................................................48 
10.1. 
Sample Size ................................................................................................................48 
10.2. 
Statistical Methodology ..............................................................................................48 
10.2.1. 
Populations to be Analyzed ........................................................................................48 
10.2.2. 
Baseline Evaluations ...................................................................................................48 
10.2.3. 
Efficacy Analyses .......................................................................................................48 
10.2.4. 
Safety Analyses ..........................................................................................................49 
10.2.5. 
Healthcare Utilization Assessments ...........................................................................49 
10.2.6. 
Interim Analysis ..........................................................................................................49 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................50 
11.1. 
Study Monitoring ........................................................................................................50 
11.2. 
Audits and Inspections ................................................................................................50 
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11.3. 
Institutional Review Board .........................................................................................50 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................51 
13. 
ETHICS ......................................................................................................................52 
13.1. 
Ethics Review .............................................................................................................52 
13.2. 
Ethical Conduct of the Study ......................................................................................52 
13.2.1. 
Financial Disclosure Reporting Obligations ...............................................................52 
13.3. 
Written Informed Consent ..........................................................................................53 
13.4. 
Compensation for Health Damages ............................................................................53 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................54 
14.1. 
Case Report Forms .....................................................................................................54 
14.2. 
Confidentiality ............................................................................................................54 
14.3. 
Inspection of Records .................................................................................................55 
14.4. 
Retention of Records ..................................................................................................55 
15. 
PUBLICATION POLICY ..........................................................................................56 
16. 
LIST OF REFERENCES ............................................................................................57 
17. 
APPENDICES ............................................................................................................58 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..............................................................................................7 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
aspartate transaminase 
ATTR 
transthyretin-mediated amyloidosis 
BUN 
blood urea nitrogen 
CAS 
Central Assessment Sites 
CFR 
Code of Federal Regulations 
COMPASS 31 
Composite Autonomic Symptom Score 
CRF 
case report form 
CRO 
clinical research organization  
CYP 
cytochrome P450 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DN 
diabetic neuropathy 
DSPC 
1,2-Distearoyl-sn-glycero-3-phosphocholine 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EP 
European Pharmacopoeia 
EQ-5D 
EuroQOL 
EU 
European Union 
Σ5 
5 attributes 
FAC 
familial amyloidotic cardiomyopathy 
FAP 
familial amyloidotic polyneuropathy 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
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Abbreviation 
Definition 
IB 
Investigators Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRS 
interactive response system 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LNP 
lipid nanoparticle 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS 
Modified Neuropathy Impairment Score 
mRNA 
messenger RNA 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NHP 
non-human primate 
NIS 
Neuropathy Impairment Score 
NIS-W 
Neuropathy Impairment Score- Weakness 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PCS 
Patient Care Sites 
PD 
pharmacodynamic 
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Abbreviation 
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PO 
per os (orally) 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
RBC 
red blood cell 
RBP 
retinol binding protein 
RNAi 
ribonucleic acid interference 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP 
touch pressure 
TSH  
thyroid stimulating hormone 
TTR 
transthyretin 
TUDCA 
tauroursodeoxycholic acid 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WBC 
white blood cell 
WT 
wild type 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Transthyretin-mediated amyloidosis (ATTR) is a hereditary, autosomal dominant, systemic 
disease caused by a mutation in the transthyretin (TTR) gene leading to the extracellular 
deposition of amyloid fibrils containing both mutant and wild type (WT) TTR.1,2 The particular 
TTR mutation and site of amyloid deposition determines the clinical manifestations of the 
disease, which include sensory and motor neuropathy, autonomic neuropathy, and/or 
cardiomyopathy.  ATTR is a progressive disease associated with severe morbidity, with a life 
expectancy limited to 5 to 15 years from symptom onset.3 There are over 100 reported TTR 
mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy 
(FAP) and familial amyloidotic cardiomyopathy (FAC).4,5,6 The estimated worldwide prevalence 
of FAP is 5,000 to 10,000, with the majority of cases in Portugal, Sweden, France, Japan, Brazil, 
and the United States.7,8 The most common causative mutation of FAP is TTR Val30Met 
(V30M), with the onset of symptoms typically occurring between 30 and 55 years of age.9 
Reduction of circulating amyloidogenic TTR improves outcomes in patients with FAP.  
Orthotopic liver transplantation, which eliminates mutant TTR from the circulation, has 
improved survival in early stage FAP patients.10  The TTR tetramer stabilizer tafamidis 
(Vyndaqel®) was approved in the European Union (EU) for the treatment of stage 1 FAP based 
on evidence that it may slow neuropathy progression in these patients, but has not been approved 
for use in other regions of the world.  Diflunisal, a generic, nonsteroidal anti-inflammatory drug 
(NSAID) that is also a tetramer stabilizer, exhibits slowing of neuropathy progression in FAP 
patients, but is not standardly used among practitioners.  Thus, there remains an unmet medical 
need for a potent and effective therapy for FAP that will have an impact on patients across a 
broad range of neurologic impairment, regardless of their mutation. 
1.2. 
Patisiran 
Patisiran (the International Nonproprietary Name [INN] name for the drug product also referred 
to as ALN-TTR02) is a novel investigational agent being developed for the treatment of ATTR 
patients with symptomatic FAP.  Patisiran comprises a small interfering ribonucleic acid 
(siRNA) which is specific for TTR, and is formulated in a hepatotropic lipid nanoparticle (LNP) 
for intravenous (IV) administration.11 It 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 FAP. 
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.  A summary of the nonclinical data can be found in the patisiran Investigators Brochure 
(IB). 
In a Phase 1 study of patisiran in healthy volunteers (Study ALN-TTR02-001), patisiran was 
generally well tolerated.  Significant pharmacology in terms of TTR protein lowering (>80% 
reduction from pretreatment baseline) was observed at doses ≥0.15 mg/kg.  TTR levels showed 
evidence of recovery at Day 28 and return to baseline by Day 70.  A Phase 1 study in healthy 
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subjects of Japanese origin (Study ALN-TTR02-005) also showed dose dependent reduction in 
serum TTR, similar to that observed in Study ALN-TTR02-001 in Caucasian subjects; patisiran 
was safe and well tolerated up to 0.3 mg/kg.  An open-label Phase 2 multiple ascending dose 
study of patisiran in ATTR patients with FAP (Study ALN-TTR02-002) was conducted to 
determine the safety and tolerability, PK, and pharmacodynamics (PD) of a 60 or 70 minute IV 
infusion of patisiran administered once every 3 or 4 weeks for 2 doses.  The top dose of 
0.3 mg/kg administered every 3 or 4 weeks was found to be generally safe and well tolerated, 
with maximum TTR knockdown of ~90% and sustained TTR suppression of >80% most 
consistently observed with every 3 week dosing.  Twenty seven of the 29 patients treated on the 
Phase 2 trial enrolled in an open-label extension study (ALN-TTR02-003) to evaluate safety and 
tolerability of long-term dosing with patisiran for approximately 2 years.  Multiple doses of 
patisiran have been generally safe and well-tolerated on the -003 study, with preliminary data 
indicating no changes in liver function tests, renal function, or hematologic parameters, and no 
treatment-related discontinuations.  Sustained suppression of serum TTR of >80% has been 
observed in the open-label extension study, and preliminary clinical data at 6 months showed 
evidence for disease stabilization.12  A randomized, double-blind, placebo-controlled Phase 3 
study of patisiran (ALN-TTR02-004; APOLLO) is ongoing worldwide.  The main objectives of 
the study are to demonstrate the clinical efficacy of patisiran and to establish the safety of 
chronic dosing in ATTR patients with FAP.  Further details on the clinical studies of patisiran 
can be found in the patisiran Investigator’s Brochure. 
1.3. 
Study Design Rationale 
This is a multicenter, open-label extension study designed to evaluate the long-term safety and 
efficacy of patisiran in patients with FAP who have completed a prior study with patisiran. 
The nonclinical data and clinical experience with patisiran support the continuation of patisiran 
treatment in this long-term extension study for ATTR patients with FAP.  All patients will 
receive patisiran at 0.3 mg/kg administered IV every 3 weeks, which is the dose and regimen 
employed in the ongoing Phase 3 study with patisiran.  Various clinical evaluations will be 
performed periodically as outlined in Table 1 to continue to assess the effect of patisiran beyond 
the duration of the ongoing clinical studies, and will enable all patients who have completed a 
prior study with patisiran (provided they meet the eligibility criteria of this study), including 
those previously on placebo, to receive open-label patisiran.  Patients coming on to this open-
label study from a blinded study will remain blinded to their previous treatment assignment until 
at least database lock has occurred in that study.  The duration of the study has been determined 
to allow the collection of long-term safety, tolerability and efficacy data of patisiran in patients 
with FAP who have completed a prior study with patisiran.  The estimated duration of the study 
is 5 years. 
1.4. 
Risk-Benefit Assessment 
Patisiran is a novel investigational agent intended for the treatment of FAP, a serious and life-
threatening orphan disease with limited treatment options. The therapeutic hypothesis that systemic 
amyloidoses can be managed by reducing circulating levels of amyloidogenic protein has been 
established in other acquired and hereditary amyloidoses.  The experience from these systemic 
amyloidotic disorders, as well as the liver transplant data in FAP, suggest that lowering of the 
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circulating amyloidogenic protein could impact the clinical course of the disease.  Based on 
nonclinical and clinical data that showed suppression in levels of WT and mutant TTR upon 
administration of 0.3 mg/kg patisiran once every 21 days, it is possible that long term treatment with 
patisiran may have a clinical benefit in FAP patients with mild to moderate polyneuropathy and that 
further study is warranted.  
In completed and ongoing clinical studies (ALN-TTR02-001, ALN-TTR02-002 and ALN-
TTR02-003), single and multiple doses of patisiran have been generally well tolerated.  Potential 
risks of patisiran include the following: 
• Infusion-Related Reactions 
Infusion-related reactions (IRRs) can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  In order to reduce the potential for an 
IRR with patisiran, all patients in this study will be premedicated prior to dosing with 
patisiran.  The step-wise infusion regimen over approximately 70 minutes (starting with a 
slower infusion rate of approximately 1 mL/minute for the first 15 minutes before increasing 
to 3 mL/minute for the remainder of the infusion), may further reduce the risk of an IRR. 
• Liver function test abnormalities   
In preclinical studies, patisiran-related increased serum liver markers and histopathology in 
the liver were observed at dosages > 0.1 mg/kg in rats and > 1.0 mg/kg in monkeys.  In 
general, all of the findings were not observed or were observed at lower severity at the end of 
the 60-90 day dose free period, indicating that the toxicities were reversible.  In clinical 
studies to date, there have been no clinically significant changes in liver function tests in 
either the single-dose or multiple-dose studies. Patients in the study are monitored for liver 
function via serial laboratory assessments. 
• Vitamin A Lowering 
The suppression of serum levels of TTR and retinol binding protein (RBP) is expected to 
result in the lowering of circulating vitamin A levels.  Preclinical and clinical data have 
shown that the lowering of circulating vitamin A associated with suppression of RBP does 
not result in severe vitamin A deficiency.  Furthermore, there are individuals with RBP/TTR 
mutations who have life-long low levels of circulating vitamin A and are essentially in good 
health, suggesting that there are compensatory transport mechanisms for vitamin A that are 
yet undescribed.13  This has also been confirmed in TTR knockout mice, which do not 
exhibit any manifestations of vitamin A deficiency, with vitamin A uptake by most tissues 
continuing in the absence of RBP.14  Provided there is adequate vitamin A in the diet, tissue 
stores of vitamin A should not be affected by the lowering of TTR and RBP.  However, as 
the vitamin A content of the diet may vary between different countries and different 
individuals within a country, all patients on the study will be asked to take a daily 
supplement containing the recommended daily allowance of vitamin A.  Patients should have 
started vitamin A supplementation by the time they start his/her first dose of patisiran. 
• Osteoporosis 
Patients with FAP may be at risk for osteoporosis.15 In addition, as part of the premedication 
regimen administered prior to patisiran dosing every three weeks, FAP patients participating 
in this study are given glucocorticoids, a drug known to have the potential to reduce bone 
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mineralization.  If there are no medical contraindications, and per investigator judgment and 
local standard of care, study participants should, if appropriate, receive therapy for the 
prevention and early treatment of osteoporosis such as: calcium and vitamin D 
supplementation, bisphosphonates, calcitonin, parathyroid hormone, estrogen 
agonist/antagonist or combination therapies. 
Further guidance to the investigator can be found in the Investigator’s Brochure. 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in ATTR patients with FAP. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with FAP who have previously completed a patisiran study. 
Patients in this study will have completed “parent” study ALN-TTR02-003 or ALN-TTR02-004.  
Note that Study ALN-TTR02-003 is not being conducted in Japan.  
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study.  All dosing visits have a window of ± 3 days.  In 
order to maintain the every 21-day dosing schedule from the parent study, patients are expected 
to have their first visit (Day 0) on this study 3 weeks after their last dose visit on the parent 
study.  However, if necessary, a patient may initiate dosing in this study up to 45 days from the 
time of the last dose in the parent study.  Exceptions to this timing may be allowed for medical or 
regulatory considerations only after consultation with the Medical Monitor.  The last testing visit 
in the parent study will serve as the baseline for this study, unless more than 45 days have 
elapsed, in which case the baseline tests will need to be repeated on Day 0.  Eligibility for this 
study will be confirmed before administration of the first dose on Day 0. 
The duration of the study has been determined to allow the collection of long-term safety, 
tolerability and efficacy data of patisiran in patients with FAP who have completed a prior study 
with patisiran.  The estimated duration of the study is 5 years. 
In order to reduce the potential for an IRR with patisiran, all patients on this study will receive 
premedications at least 60 minutes before the start of the patisiran infusion.  Patisiran will be 
administered as a 70-minute IV infusion (approximately 1 mL/minute for the first 15-minutes 
followed by approximately 3 mL/minute for the remainder of the infusion).  If the infusion 
duration for a patient was lengthened beyond 70 minutes due to the occurrence of an IRR while 
on the parent study, that infusion duration may be continued on this study for that particular 
patient.  Returning the patient’s infusion duration to 70 minutes will require a discussion with the 
Medical Monitor. 
After the Day 0 visit, patients should return to the clinical site for patisiran dosing once every 
21 (±3) days.  Where applicable country and local regulations allow,  patients may receive the 
patisiran infusions at home by a healthcare professional trained on the protocol and delivery of 
premedications and patisiran.  Patients who are receiving patisiran infusions at home will have a 
phone contact with the site at least every 30 (±5) days.  Patients will also have visits at the 
clinical site at approximately 12, 26 and 52 weeks, and yearly thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks, followed by more limited 
efficacy assessments yearly thereafter.  In order to decrease the variability in the efficacy 
assessment testing at the 52-week visit, there will be a limited number of sites within any one 
territory that conduct these efficacy assessments (referred to as “Central Assessment Sites 
[CAS]”); these sites can dose and manage patients.  There will also be sites that can dose and 
manage the patients (“Patient Care Sites [PCS])”, while sending the patients to the nearest CAS 
for their 52-week efficacy assessments.  Every effort should be made for the patient to return to 
the same CAS center that the patient went to in the parent study.  Yearly efficacy assessments 
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after the 52-week visit may be done at a PCS.  Prior to starting the study, the CAS and PCS will 
create a delegation of responsibilities document that clearly details which site is responsible for 
which efficacy tests and safety parameters to ensure adherence to the protocol.  This document 
will become part of the study site specific documentation. 
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at 12, 26 and 52 weeks during the first year and yearly thereafter.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
3.2. 
Number of Patients 
All patients who have previously completed a patisiran study may be enrolled if they meet the 
eligibility criteria for this study. 
3.3. 
Treatment Assignment 
All patients enrolled in this study will receive open-label patisiran at 0.3 mg/kg administered IV 
once every 21 (±3) days. 
The Investigator or his/her delegate will contact the interactive response system (IRS) (via phone 
or web) after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria.  The patient will then be assigned a patient number that corresponds to their 
current patient number on the parent study.  A combination of the center number, parent study 
number, enrollment number, and patient initials will create the unique patient identifier.  In 
countries with regulations prohibiting the use of patient initials, a strategy consistent with local 
regulations will be used to generate replacement values for the patient initials. 
3.4. 
Criteria for Study Termination 
The study may be terminated if patisiran does not obtain marketing approval or the development 
of patisiran is no longer being pursued by the Sponsor (Alnylam Pharmaceuticals, Inc). 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  Should the study be terminated and/or the site closed for whatever reason, all 
documentation and patisiran supplied for the study must be returned to the Sponsor or Medpace, 
and the Investigators, Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
and Regulatory Authorities will be promptly informed of the termination and the reason for the 
decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Patient Inclusion Criteria 
To be enrolled in the study, patients must meet the following criteria before administration of 
patisiran on Day 0: 
1. Have completed a patisiran study (ie, completed the last efficacy visit in the parent study) 
and, in the opinion of the investigator, tolerated study drug 
2. Be considered fit for the study by the Investigator 
3. Have aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 × the 
upper limit of normal (ULN), international normalized ratio (INR) ≤2.0 (patients on 
anticoagulant therapy with an INR of ≤3.5 will be allowed) 
4. Have a total bilirubin within normal limits.  A patient with total bilirubin ≤ 2 X ULN is 
eligible if the elevation is secondary to documented Gilbert’s syndrome (elevation of 
unconjugated bilirubin with normal conjugated bilirubin) and the patient has ALT and AST 
levels within normal ranges. 
5. Have a serum creatinine ≤2 × ULN 
6. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to 
dosing in this study and agree to use 2 highly effective methods of contraception 
throughout study participation and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control are defined in Section 4.4. 
7. Males with partners of child-bearing potential must agree to use 1 barrier method 
(eg, condom) and 1 additional method (eg, spermicide) of contraception throughout study 
participation and for 75 days after the last dose of patisiran in this study; males must also 
abstain from sperm donation after the first dose of patisiran through study participation 
and for 75 days after last dose of patisiran in this study 
8. Be willing and able to comply with the protocol-required visit schedule and visit 
requirements and provide written informed consent 
4.2. 
Patient Exclusion Criteria 
A patient will be excluded if they meet any of the following criteria before dosing on Day 0: 
1. Has an active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed before the first dose of patisiran administration 
2. Has poorly controlled diabetes mellitus 
3. Has uncontrolled cardiac arrhythmia or unstable angina 
4. Is currently taking tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid 
(TUDCA), unless previously allowed per the parent study 
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5. Is unable to take the required premedications, unless modifications to the premedication 
regimen were previously allowed per the parent study 
6. Is under legal protection (defined as “any person who becomes incapable of protecting 
his/her interests due to a medically diagnosed impairment of his/her mental faculties that 
may limit or prevent the expression of his will”), decided by a court 
4.3. 
Patient Withdrawal Criteria 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care.  For those patients who withdraw, every effort will be made to 
determine their reason for dropping out, and to complete the Early Withdrawal visit. 
The Investigator may withdraw a patient from the study if the patient: 
• Is in violation of the protocol 
• Experiences a serious or intolerable AE 
• Becomes pregnant 
• Requires a prohibited medication (see Section 5.2) 
• Requests to be withdrawn from the study 
• Is found to be considerably noncompliant with the protocol-required patisiran dosing 
visits 
The Investigator will withdraw patients from the study upon the request of the Sponsor, 
including if the Sponsor terminates the study.  Upon occurrence of a serious or intolerable AE, 
the Investigator will confer with the Sponsor before discontinuing the patient. 
Missing an occasional dose of patisiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses 3 consecutive doses of patisiran, the Investigator at 
the clinical site and the Medical Monitor will determine whether the patient should be withdrawn 
from the study.  If the patient is withdrawn from the study, the reason will be noted in the patient 
medical record and on the case report form (CRF). 
In the event a patient is withdrawn from the study, the clinical research organization (CRO) 
Medical Monitor must be informed immediately. 
4.4. 
Pregnancy and Breastfeeding Restrictions / Contraception 
Requirements 
TTR transports vitamin A in plasma; therefore, reductions in circulating vitamin A levels 
accompany reductions in TTR caused by patisiran.  Vitamin A deficiency has known effects on 
both male and female reproductive performance and embryo/fetal development.14  It is not 
known whether decreased levels of vitamin A at efficacious patisiran doses in ATTR patients 
who are male or who are women of child bearing potential will affect reproduction.  
Histopathological evaluations of all of the reproductive organs have been conducted in the rat 
and non-human primate (NHP) toxicology studies including a chronic NHP study in sexually 
mature animals, where there were no adverse effects in males (including sperm analyses and 
spermatogenic staging) or females.  In a dose range-finding rat embryo/fetal development study 
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conducted with patisiran, there were no effects on mating, fertility, ovarian or uterine parameters, 
or fetal development despite reductions (-88% from baseline) in serum vitamin A in the dams 
dosed with the rat-specific TTR surrogate siRNA. 
Women of child-bearing potential are defined as any woman or adolescent who has begun 
menstruation. A post-menopausal woman is defined as a woman who has 12 months of 
spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels 
>40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. 
In this study, women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and must be using 2 highly effective methods of contraception prior to dosing on 
Day 0, throughout study participation, and for 75 days after last dose of patisiran in this study.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
• Hormonal:  established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception 
• Placement of an intrauterine device (IUD) 
• Placement of an intrauterine system (IUS) 
• Mechanical/barrier method of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or 
suppository) 
Note:  Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection.  However, spermicides 
alone are inefficient at preventing pregnancy when the whole ejaculate is spilled.  
Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 
• 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); 
• Sexual true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Patients should be instructed to use 2 different forms of effective contraception from the list 
above.  Examples of 2 forms of highly effective contraception are as follows:  
• Oral, implantable, injectable, or transdermal contraceptives in conjunction with 
condom or diaphragm and spermicide 
• IUD in conjunction with condom or diaphragm and spermicide 
• Surgical sterilization of partner in conjunction with condom or diaphragm and 
spermicide 
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Interaction between patisiran and hormonal contraceptives is not anticipated.  The patisiran drug 
substance ALN-18328 (siRNA), and the 2 novel lipid excipients 1,2-Dilinoleyloxy-N,N-
dimethylpropylamine (DLin-MC3-DMA) and (R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-
sn-glyceride (PEG-2000-C-DMG), were evaluated by in vitro human microsomal incubations to 
determine if any had inhibitory effects on cytochrome P450 (CYP) activity.  None of the 
components displayed an inhibitory effect on any of the CYPs investigated (CYP1A2, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5).  In addition, there was no induction of CYP1A2, 
CYP2B6, or CYP3A4 at any of the concentrations studied.  These data suggest a low likelihood 
of patisiran to interfere with the metabolism of hormonal contraceptives. 
Males (including men who have had vasectomies) with partners of child-bearing potential, must 
agree to use 1 barrier method (eg, condom) and 1 additional method (eg, spermicidal foam, gel, 
film, cream, or suppository) of contraception throughout study participation and for 75 days 
(ie, a whole spermatogenic cycle) after the last dose of patisiran in this study.  Males must also 
abstain from sperm donation after the first dose of patisiran through study participation and for 
75 days after last dose of patisiran in this study. 
In Japan it is recommended that the Investigators select appropriate contraception methods, as 
available. 
Pregnancy reporting guidelines are provided in Section 9.5.2. 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
Patisiran Solution for Injection is a ribonucleic acid interference (RNAi) therapeutic consisting 
of an siRNA targeting TTR messenger RNA (mRNA) formulated in a LNP.  The patisiran drug 
product is a sterile formulation of ALN-18328, an siRNA targeting TTR, formulated as LNPs 
siRNA with lipid excipients (DLin-MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine 
[DSPC], cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.  Patisiran 
Solution for Injection contains 2 mg/mL of the TTR siRNA drug substance. 
5.2. 
Concomitant Medications 
Use of the following medications/treatments is prohibited during study participation: 
• Any investigational agent other than patisiran 
• Corticosteroids other than those administered as premedications prior to the dose of 
patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids.  
However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid 
arthritis), systemically administered steroids may be permitted provided that: 1) the 
dose is <20 mg/day prednisone or equivalent if administered chronically, or 2) for 
doses ≥20 mg/day, administration is limited to no more than 5 consecutive days. 
Use of the medications/treatments listed below is permitted in patients who were already taking 
such medications while on the parent study in accordance with the rules of that study protocol.  
For patients who did not take these medications while on the parent study, use of these 
medications is permitted, if necessary, only after the patient has completed the 52-week visit. 
• Tafamidis 
• Diflunisal 
• Doxycycline/TUDCA 
Medications and treatments other than those specified above, including palliative and supportive 
care approved by the Investigator for disease-related symptoms, are permitted during the study. 
All patients will be asked to continue to take the recommended daily allowance of vitamin A. 
Patients will receive this daily dose for the duration of their participation in the study while being 
administered patisiran. In Japan, the clinical sites will provide patients with a prescription for 
vitamin A. 
Any concomitant medication or treatment that is required for the patient’s welfare may be given 
by the Investigator.  Use of all concomitant medications and treatments will be recorded on the 
patient’s CRF through the end of the patient’s participation in the study.  This will include all 
prescription drugs, herbal preparations, over-the-counter (OTC) medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the CRF. 
Similarly, concomitant medications that continue from the parent study will be entered into the 
database. 
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5.3. 
Treatment Compliance 
Compliance with patisiran administration is dependent on the proper preparation and 
administration of IV infusions by trained personnel and attendance by the patient at the clinic for 
scheduled assessment visits.  Compliance with patisiran administration will be verified through 
observation by study staff or (in applicable regions) trained home healthcare professionals.  A 
dose will be considered completed if 80% or more of the total volume of the IV solution was 
administered to the patient.  Patients will be permitted to miss an occasional dose of patisiran; 
however, if a patient misses 3 consecutive doses, the Investigator, in consultation with the 
Medical Monitor, will discuss whether the patient will be able to continue on the study. 
5.4. 
Randomization and Blinding 
This is an open-label study; however, patients rolling over into this study from a previously 
blinded study will remain blind to their previous treatment assignment until database lock has 
occurred in that study. 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug Packaging and Labeling 
All packaging, labeling, and the preparation of patisiran will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in the Manufacture of Investigational 
Medicinal Products Volume 4 Annex 13, and any other or local applicable regulations. 
Patisiran labels will include all appropriate local labeling requirements on the vial and external 
label.  Sample labels will be submitted to health authorities, per local country submission 
requirements. 
The patisiran drug product is packaged in 10 mL glass vials with a fill volume of 5.5 mL.  The 
container closure system consists of a United States Pharmacopeia/European Pharmacopoeia 
(USP/EP) Type I borosilicate glass vial, a Teflon-faced butyl rubber stopper, and an aluminium 
flip-off cap. 
6.2. 
Study Drug Storage 
Patisiran will be stored upright and refrigerated at approximately 5 ± 3oC.  Any deviation from 
the recommended storage conditions must be reported to the CRO and/or the Sponsor and use of 
the patisiran halted until authorization for its continued use has been given by the Sponsor or 
designee. 
No special procedures for the safe handling of patisiran are required.  A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Patisiran supplied for this study may not be administered to any person not enrolled in the study. 
6.3. 
Study Drug Preparation 
Staff at each clinical site or the healthcare professional administering patisiran will be 
responsible for preparation of patisiran doses, according to procedures detailed in the Pharmacy 
Manual. 
All patients in this study will receive 0.3 mg/kg patisiran once every 21 days (± 3 days).  The 
amount (mg) of patisiran to be administered will be based on the patient’s body weight (kg).  For 
each dose administered, the weight obtained during the previous dosing visit will be used to 
calculate the dose of patisiran.  In the event that the weight obtained on the previous dosing day 
is not available, the weight obtained pre-dose on the current dosing day can be used for dose 
calculation.  Patients who weigh 105 kg or more will receive patisiran dosing based on an 
assumption of a body weight of 104 kg. 
Patisiran will be prepared under aseptic conditions.  The total amount to be infused into each 
patient at each dosing visit will be 200 mL.  Sterile normal saline (0.9% NaCl) will be added to a 
sterile infusion bag, and the calculated volume of patisiran will be withdrawn from the vials and 
injected into the infusion bag. 
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6.4. 
Administration 
6.4.1. 
Premedication 
Prior to each dose of patisiran, patients will receive the following premedications in order to 
reduce the risk of experiencing an IRR at least 60 minutes before the infusion: 
•
Intravenous dexamethasone (10 mg) or equivalent
•
Oral paracetamol/acetaminophen (500 mg) or equivalent
•
Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2
blocker dose)
•
Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker
available at the clinical site).  Hydroxyzine 25 mg per os (PO, orally) or fexofenadine
30 mg or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who
does not tolerate IV diphenhydramine or other IV H1 blocker.
Further details (including a table of equivalent premedications) can be found in the patisiran 
Pharmacy Manual. 
Patients will be started on the above premedication regimen.  However, modifications may be 
made to the premedication regimen after consultation with the medical monitor either due to a 
patient’s inability to tolerate one or more of the premedications or to the occurrence of IRRs 
unresponsive to slowing of the infusion rate. 
•
If a patient is having difficulty tolerating the steroid premedication regimen (e.g., 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.
•
If after consultation with the medical monitor, it is agreed that an individual patient’s  steroid
premedication will be lowered, then the following steps must be followed:
1)
If the current steroid dosage is 10 mg or less of intravenous dexamethasone or
equivalent, then the patient may be lowered in increments no greater than 2.5 mg
intravenous dexamethasone or equivalent.
2)
After each incremental lowering of intravenous dexamethasone or equivalent, the patient
must receive three consecutive intravenous doses of patisiran without IRR and continued
signs or symptoms of steroid intolerance before further reductions in steroid
premedications.
3)
The premedication steroid dosage should not be reduced below 5 mg intravenous
dexamethasone or equivalent.
Alternatively if a patient experiences an IRR when 10 mg or less of IV dexamethasone or 
equivalent is used as the steroid premedication, then proceed to Section 6.4.3. 
If a patient’s premedication regimen was modified prior to enrollment in Study TTR02-006, the 
patient may continue on that modified premedication regimen. 
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6.4.2. 
Study Drug Administration 
Patisiran will be administered under the supervision of the site personnel every 21 (±3) days.  
Patients who have received at least 3 doses of patisiran on this study at the clinical site with no 
evidence of IRRs or other adverse effects may have patisiran administered at home, where 
applicable country and local regulations allow.  Home administration of patisiran will be done by 
a healthcare professional trained on the protocol and delivery of premedications and patisiran. 
On all dosing days, patisiran will be administered as a 70-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion). 
•
If the patient experiences an IRR the infusion time may be extended up to 3 hours in the
event of a mild or moderate IRR.
1)
If the patient experiences a mild or moderate IRR that resolves by slowing the infusion
rate then no further premedication changes are recommended.
2)
If the patient experiences a severe IRR, then patisiran administration will not be resumed 
until the case is discussed with the Medical Monitor (see Section 6.4.3).
•
If the infusion time for a patient was already extended on the parent study due to an IRR, that
modified infusion duration may be continued on this study for that particular patient.
Returning the patient’s infusion duration to 70 minutes will require a discussion with the
Medical Monitor.
•
For the first 3 infusions of patisiran on this study, 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, and the patient will remain at the clinical site for 1 hour following
completion of dosing.
If a patient does not receive a dose of patisiran within the dosing window (±3 days), the dose will 
be considered missed and not administered. 
Additional details can be found in the patisiran Pharmacy Manual. 
In addition to study treatment, patients will receive the recommended daily allowance of 
vitamin A .  Patients will receive this daily dose for the duration of their participation in the 
study while being administered patisiran.  In Japan the clinical sites will provide the subjects 
with a prescription for vitamin A.. 
6.4.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
Criteria for categorizing IRRs are provided in Appendix 3. 
•
In the event of an IRR, the infusion of patisiran may be stopped and the patient closely
monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution and
permit resumption of patisiran administration include, but are not limited to:
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids.
•
Following resolution of a mild or moderate IRR that required interruption of the patisiran
infusion, resumption of administration may occur at the Investigator’s discretion at a slower
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infusion rate (but not to exceed 3 hours) for that dose and for all subsequent doses of 
patisiran.  If the infusion is delayed, the administration of the infusion should be completed 
no more than 6 hours from the initial start of the infusion.   
• Patisiran 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 intravenous 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 intravenous 
dexamethasone or equivalent at least 60 minutes before the infusion and/or 5 mg oral 
dexamethasone or equivalent the night before the intravenous infusion.  
2) Increased dose of premedication steroids should NOT exceed the combination of 20 mg 
intravenous 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 intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous 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. 
6.5. 
Study Drug Accountability 
The Investigator or designee (or in Japan, the responsible pharmacist designated according to the 
Japan local regulations) will maintain accurate records of receipt and the condition of the 
patisiran supplied for this study, including dates of receipt.  In addition, accurate records will be 
kept of the weight used to calculate each dispensed patisiran dose, and when and how much 
patisiran is dispensed and used by each patient in the study.  Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. 
Further instructions about drug accountability are detailed in the patisiran Pharmacy Manual. 
6.6. 
Study Drug Handling and Disposal 
All used, partially used, and unused vials of patisiran will be returned to the Sponsor or its 
specified designee/depot or destroyed at the site according to applicable regulations. 
Patisiran supplied for this study must not be used for any purpose other than the present study.  
Drug that has been dispensed for a patient and returned unused must not be redispensed. 
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7. 
PHARMACOKINETIC ASSESSMENTS 
No PK assessments will be performed in this study. 
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8. 
ASSESSMENT OF EFFICACY 
8.1. 
Efficacy Parameters 
Efficacy assessments may be performed at Day 0 if not performed during the parent study within 
45 days of the first dose in this study.  Efficacy assessments will occur for all patients at the 
52-week visit, which will take place at the CAS.  Patients will not receive study drug at this visit.  
A subset of the efficacy assessments performed at 52 weeks will be performed annually 
thereafter.  The specific timing for each assessment is presented in Table 1. 
For the 52-week time point, a central neurologic testing core facility will review the data derived 
from the various neuropathy measures at each participating site to ensure compliance with 
testing procedures and quality of the data.  A central echocardiography core lab will analyze the 
echocardiogram data.  A core lab will be responsible for processing and analyzing skin punch 
biopsy samples.  Magnetic resonance (MR) neurography data (when performed) will also be 
centrally read. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual. 
8.1.1. 
Neurological Testing 
Neurological testing will be performed and the results of these tests will be used to calculate the 
Neuropathy Impairment Score (NIS), modified NIS (mNIS+7), and NIS+7, at the time points 
specified in Table 1. 
8.1.1.1. 
Modified Neurological Impairment Score +7 and Neurological Impairment 
Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
• Clinical exam-based NIS (weakness and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− Nerve conduction studies (NCS) 5 attributes (Σ5) 
− Quantitative sensory testing (QST) by body surface area including touch pressure 
(TP) and heat pain (HP) 
• Autonomic function (postural blood pressure) 
Neurologic impairment will also be assessed by NIS+7.  The NIS+7 consists of the following 
measures: 
• Full NIS (including weakness, sensation, and reflexes) 
• Electrophysiologic measures of small and large nerve fiber function (+7) including: 
− NCS Σ5 
− Vibration detection threshold (VDT) 
• Heart rate response to deep breathing (HRdb) 
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The scoring and components of the mNIS+7 and NIS+7 are summarized in Appendix 4.  
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be 
performed once at each assessment. 
Every effort will be made to use the same devices for NCS, QST, and VDT for a patient 
throughout the duration of the study. 
For each patient, 2 independent assessments of the mNIS+7 and NIS+7 will be performed at 
each time point at a CAS.  Assessments are to be performed at least 24 hours (approximately) 
apart from each other but no greater than 7 days apart.  In order to limit potential intra-operator 
bias, results of any of the prior assessments will not be available to the examiner when 
performing the second assessment.  Each site will make every effort to have these assessments at 
the Week 52 visit performed by the same study personnel who performed the assessments for the 
patient in the patisiran study in which they were previously enrolled.  Assessments of the NIS 
during the annual visit (after the Week 52 visit) must be performed by a neurologist. 
8.1.1.2. 
Neurological Impairment Score 
At each time point when only the full NIS is required, 1 assessment of the NIS will be performed 
at a CAS or PCS. 
8.1.2. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
FAP stage (see Appendix 5 and Appendix 6, respectively). 
8.1.3. 
Intraepidermal Nerve Fiber Density and Sweat Gland Nerve Fiber Density 
Quantification of nerve fibers in skin will be assessed via intraepidermal nerve fiber density 
(IENFD) and sweat gland nerve fiber density (SGNFD).  For patients who had skin biopsies on 
the parent study and who have provided additional voluntary consent for skin biopsy on this 
study, 2 sets of tandem 3-mm skin punch biopsies (4 biopsies total) for IENFD and SGNFD will 
be obtained at each time point.  One set of biopsies will be taken from the distal lower leg, when 
a patient’s clinical status allows, and 1 set from the distal thigh. 
Details on sample collection, processing, and storage will be provided in the Study Laboratory 
Manual. 
Skin biopsies will be performed at a CAS or PCS. 
8.1.4. 
Magnetic Resonance Neurography (Germany and France Only) 
Magnetic resonance (MR) neurography will only be performed at sites in Germany and France. 
Magnetic resonance neurography enables direct high-resolution longitudinal and cross-sectional 
images for the evaluation of peripheral nerve disorders.16  This procedure produces detailed 
images of nerve morphology to evaluate degeneration and regeneration.  Nerves in the lumbar 
plexus and lower extremity may be imaged for patients in Germany and France who have 
previously had MR neurography in the parent study and for  a subset of patients providing 
informed consent who did not have MR neurography previously in the parent study.  A central 
reader will be used for MR neurography. 
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8.1.5. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI) will be calculated (BMI × albumin) programmatically in the clinical database and 
does not need to be performed at the study center. 
8.1.6. 
Timed 10-meter Walk Test 
To perform the timed 10-meter walk test, the patient will be asked to walk 10 meters.  The walk 
must be completed without assistance from another person; ambulatory aids such as canes and 
walkers are permitted.  The time required for the patient to walk 10 meters will be recorded. 
Two assessments of the 10-meter walk test are to be conducted on separate days (1 assessment 
on each day).  The second (repeat) assessment must be conducted at least 24 hours 
(approximately) but not more than 7 days after the first assessment.  Each site will make every 
effort to have this assessment performed by the same Investigator. 
8.1.7. 
Grip Strength Test 
Hand grip strength is to be measured by dynamometer.  Sites will be trained on dynamometer 
and testing for the study.  When performing the test, patients will stand, holding the 
dynamometer in their dominant hand, with their arm parallel to the body without squeezing the 
arm against the body.  Tests will be performed in triplicate for each assessment.  Two 
assessments of the grip strength test are to be conducted on separate days (1 assessment on each 
day).  The second (repeat) assessment must be conducted at least 24 hours (approximately) but 
not more than 7 days after the first assessment. 
Every effort will be made to use the same dynamometer for a patient on both assessment days. 
8.1.8. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
8.1.9. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life - Diabetic Neuropathy 
(QOL-DN) questionnaire, a standardized 47-item patient-reported outcomes measure that is 
sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and 
autonomic nerve function. 
Patients who are entering this study from a protocol that does not include the Norfolk QOL-DN 
questionnaire (eg, ALN-TTR02-003) will not complete this assessment. 
8.1.10. 
EuroQoL Quality of Life Questionnaire 
Quality of life will also be assessed through the use of the EuroQOL (EQ-5D) questionnaire, a 
standardized 5 question instrument for use as a measure of health outcomes. 
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8.1.11. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS).  The R-ODS consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
8.1.12. 
Pharmacoeconomics Questionnaire 
The burden of disease and healthcare utilization will be assessed using a patient-reported 
pharmacoeconomics questionnaire.  This assessment will be performed at the location of the 
patient’s scheduled visit. 
8.1.13. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) and troponin I. 
Echocardiograms will be performed and interpreted at a central echocardiography core 
laboratory.  Patients entering this study from Study ALN-TTR02-003 who were not previously 
participating in the cardiac subgroup study will also be required to have an echocardiogram 
performed before dosing on Day 0.  Image acquisition, storage, and transfer guidelines will be 
provided in a Study Manual. 
Blood samples will be drawn to measure levels of NT-proBNP and troponin I.  Details on sample 
collection, processing, and storage will be provided in a Study Laboratory Manual. 
8.1.14. 
Transthyretin 
Blood for serum TTR levels will be collected at scheduled time points before the administration 
of patisiran.  Serum TTR will be assessed using enzyme linked immunosorbent assay (ELISA). 
8.1.15. 
Thyroid-Stimulating Hormone 
Blood for TSH levels will be collected at scheduled visits. 
8.1.16. 
Vitamin A 
Blood for serum vitamin A levels will be collected at scheduled visits before the administration 
of vitamin A. 
8.1.17. 
Anti-Drug Antibodies 
Serum samples for anti-drug antibodies will be collected as specified in Table 1. 
8.1.18. 
Blood Sample for Long-term Storage 
To permit exploratory investigations and the application of novel approaches to bioanalysis that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action and/or efficacy of patisiran, blood samples will be collected for 
long-term storage. These samples will be securely stored in a central biorepository for up to 10 
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years following the last patient last visit in this clinical study. After 10 years have elapsed, 
samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of samples will be provided in 
the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
All study participants will be advised during the informed consent process of these biobanking 
details and the potential for exploratory investigation of their samples. Those who do not wish to 
contribute specimens to the biorepository will be asked to sign an “opt out” form. Moreover, 
patients who subsequently decide to withdraw consent for the utilization of such stored samples 
will be able to do so, with the understanding that any data arising from samples already analyzed 
will be the property of Alnylam Pharmaceuticals. 
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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
All safety assessment measures will be recorded in the patient’s medical record and CRF.  Refer 
to Table 1 for the timing of each safety assessment. 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained from the parent study. 
The Investigator will assess all patients according to the Karnofsky Scale (see Appendix 1) and 
the New York Heart Association Classification of Heart Failure (NYHA; see Appendix 2). 
For all patients, a complete medical history will be obtained, including TTR genotype.  Any AEs 
from the parent study that are ongoing on Day 0 will be considered as part of the medical history. 
9.1.2. 
Vital Signs 
Vital signs will be measured pre-dose on all dosing days.  Vital signs include systolic/diastolic 
blood pressure, heart rate, respiratory rate, and body temperature, and will be measured in the 
supine position using an automated instrument after the patient has rested comfortably for 
10 minutes.  Each patient’s blood pressure should be taken using the same arm.  Temperature 
will be recorded in Celsius or Fahrenheit.  Heart rate will be counted for a full minute and 
recorded in beats per minute.  Respirations will be counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
9.1.3. 
Weight and Height 
Body weight will be measured on all dosing days to inform the next infusion dosing calculation.  
The rules for using body weight to calculate dose are described in Section 6.4.2. 
Height will be measured only if it was not obtained in the parent study. 
9.1.4. 
Physical Examination 
A physical examination will be performed by a physician before dosing at scheduled time points.  
The physical examinations will include the examination of the following: general appearance; 
head, ears, eyes, nose, and throat; cardiovascular; dermatologic; abdominal; genito-urinary; 
lymph nodes; hepatic; musculoskeletal; respiratory; and neurological. 
9.1.5. 
Laboratory Assessments 
Blood samples for clinical laboratory testing will be collected before patisiran dosing at the time 
points listed in Table 1.  All samples will be sent to a central laboratory for analysis.  Details on 
sample collection, processing, and shipping will be provided in a Laboratory Manual. 
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In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
patisiran 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. 
9.1.5.1. 
Hematology 
Blood samples will be collected for evaluation of the following hematology parameters: 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
9.1.5.2. 
Blood Chemistry 
Blood samples will be collected for evaluation of the following chemistry parameters: 
• Aspartate transaminase (AST) 
• Alkaline phosphatase 
• Alanine transaminase (ALT) 
• Bilirubin (total and direct) 
• Sodium 
• Glucose 
• Potassium 
• Phosphate 
• Blood urea nitrogen (BUN) 
• Albumin 
• Creatinine 
• Calcium 
9.1.5.3. 
Urinalysis 
Urine samples will be collected for evaluation of the following urinalysis parameters: 
• Visual inspection for color and appearance 
• Leukocytes 
• pH 
• Bilirubin 
• Specific gravity 
• Nitrite 
• Ketones 
• Urobilinogen 
• Protein 
• Microscopic inspection of sediment 
• Glucose 
 
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9.1.5.4. 
Coagulation 
A sample for INR assessment will be collected. 
9.1.5.5. 
Pregnancy Screen 
Urine pregnancy tests are to be performed for all women of child-bearing potential.  The timing 
of the tests is specified in in Table 1; additional testing may be done any time pregnancy is 
suspected. 
9.1.6. 
Ophthalmology Examination 
Ophthalmology examinations will include assessment of visual acuity, visual fields, and slit-
lamp evaluation.  Visual acuity should be evaluated at the beginning of each specified visit in the 
study (ie, prior to slit-lamp examination).  Manifest refraction will be performed at each 
specified visit before visual acuity testing and will be used to obtain a correction for visual acuity 
evaluations.  Visual acuity testing should be done with best (most recent) correction. 
An electroretinogram (ERG) is a test to evaluate the retinal response to light.  It is done to 
determine if there is damage to rods and cones.  ERG testing should be performed if visual 
changes raise the suspicion for this sort of retinal disease and if clinically indicated.  
Further details regarding the ophthalmology examinations will be provided in the Study 
Reference Manual.  
9.1.7. 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to assess each patient's 
mental status as it relates to suicidal ideation and behavior.  If a patient’s C-SSRS raises concern 
of suicidal ideation or behavior, the Investigator must ensure prompt and appropriate mental 
health interventions in accordance with standard of care. 
9.2. 
Adverse Events and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Disease progression (including worsening of neuropathy impairment) will not be considered an 
AE. 
All IRRs will be recorded as AEs. 
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9.2.1.2. 
Serious Adverse Event 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred; it does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, such events 
include allergic bronchospasm, blood dyscrasias or convulsions, or the development 
of drug dependency or abuse) 
9.3. 
Relationship to Study Drug 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to the medication administration, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on the drug withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology. 
9.4. 
Recording Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC). 
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In addition to patient observations, AEs will be documented from any clinically relevant 
laboratory findings, physical examination findings, or other findings. 
Adverse events are to be graded according to the categories detailed below. 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
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). 
9.5. 
Reporting Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported after the first 
dose of patisiran regardless of their relationship to patisiran administration through the end of the 
study. 
Any medical condition that is present when the patient enters this extension study and does not 
deteriorate should not be reported as an AE.  However, if it does deteriorate at any time during 
the study, it should be reported as an AE. 
All AEs must be fully recorded in the site’s source records and in the patients’ CRF, whether or 
not they are considered to be drug-related.  Each AE should be described in detail: onset time 
and date, description of event, severity, relationship to investigational product, action taken, and 
outcome (including time and date of resolution, if applicable). 
Adverse events should be followed through the end of study visit or until recovery to the normal 
state has been achieved, whichever occurs first.  In the event of a patient not returning to the 
clinical unit, the outcome of this event will be recorded as lost to follow-up. 
For patients who withdraw from the study early, ongoing AEs will be followed until resolution 
or 28 days from last dose, whichever occurs first.  SAEs will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable. 
9.5.1. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the above seriousness criteria (Section 9.2.1.2) must be 
reported immediately to the CRO, always within 24 hours from the time that site personnel first 
learn of the event.  All SAEs must be reported regardless of the relationship to patisiran. 
The initial report should include at least the following information: 
• Patient’s study number 
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•
Description and date of onset of the event
•
Criterion for serious
•
Preliminary assignment of causality
Serious AE reporting will be via electronic data capture (EDC). 
To report the SAE, complete the SAE form electronically in the EDC system for the study.  If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at 
 or call the Medpace SAE hotline 
listed below (country-specific phone number will be provided in the Study Manual), and fax the 
completed back-up paper SAE form to Medpace (country-specific fax number will be provided 
in the Study Manual) within 24 hours of awareness.  When the form is completed, Medpace 
Safety personnel will be notified electronically and will retrieve the form.  When the EDC 
system becomes available, the SAE information must be entered into the EDC system within 
24 hours of the system becoming available.  Medpace Safety personnel will be available for SAE 
reporting on a 24 hour basis.  Incoming reports will be reviewed during normal business hours. 
Medpace SAE hotline – USA: 
Telephone: 
 ext. 
 or 
 ext. 
 
Facsimile: 
 or 
 
Medpace SAE hotline – Europe: 
Telephone: 
 
Facsimile: 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Safety personnel via fax or e-
mail.  If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
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 causality, 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. 
The Investigator will be responsible for reporting all SAEs to the local IEC or IRB when 
required by national regulations. 
The Sponsor or its representative will be responsible for the reporting of all relevant events to the 
concerned regulatory authorities according to all applicable regulations. 
In Europe, in accordance with the Directive 2001/20/EC, the Competent Authorities and the 
Ethics Committees in the concerned Member States will be notified of fatal and life-threatening 
Suspected Unexpected Serious Adverse Reactions (SUSARs) as soon as possible but no later 
than 7 calendar days after the Sponsor or its representative has first knowledge of the minimum 
criteria for expedited reporting.  Non-fatal and non-life-threatening SUSARs should be reported 
no later than 15 calendar days after the Sponsor or its representative has first knowledge of them. 
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The Investigator may be informed by the Sponsor or its representative of SAEs from other 
Investigators or clinical studies which may have relevance to this clinical study.  These SAEs 
should also be reported promptly to the IEC/IRB that approved the study.  All SAE reports 
should be transmitted to the IEC/IRB with a cover letter or transmittal form, and a copy of that 
transmittal should be maintained in the Investigator’s files and forwarded to the Sponsor as part 
of the trial master file on study completion. 
9.5.2. 
Pregnancy Reporting 
A female patient must have a negative pregnancy test within 14 days before the first dose of 
patisiran on this study.  If a female patient is found to be pregnant during the course of the study 
or during the first month after receiving the last dose of patisiran, the Investigator should report 
the pregnancy to the CRO within 24 hours of being notified of the pregnancy.  Details of the 
pregnancy will be recorded on the pregnancy reporting form.  Treatment with patisiran will be 
discontinued in any patient who is found to be pregnant during the study.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy meets the criteria for an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should follow the 
procedures for reporting an SAE outlined above. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the Investigator, who will then report this to the CRO and follow to outcome as described 
above. 
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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran study; the size of the study is not determined via power analysis of particular 
hypotheses tests. 
10.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All data will be provided in by-patient listings. 
10.2.1. 
Populations to be Analyzed 
The following patient populations (ie, analysis sets) may be evaluated and used for presentation 
of the data: 
• Full Analysis Set:  All patients who were enrolled will be included in the full analysis 
set.  The full analysis set will be the primary set for the analysis of efficacy data. 
• Safety Analysis Set:  All patients in the full analysis set who received patisiran.  The 
safety analysis set will be used for the analysis of safety assessments. 
10.2.2. 
Baseline Evaluations 
Demographic information and baseline disease characteristic data collected in the parent study 
will be summarized.  Data to be tabulated will include sex, age, and race, as well as disease-
specific information. 
10.2.3. 
Efficacy Analyses 
Associations between PD (serum TTR) and efficacy data will be explored via correlation. 
Summary statistics of observed values and changes from baseline will be provided for the 
mNIS +7 composite score.  Summaries will also be provided for the components of the 
composite score (ie, the NIS weakness and reflex scores, the Σ5 NCS, and QST values).  The 
NIS+7 score (including full NIS, NCS, VDT, and HRdb), and full NIS will be summarized also.   
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
EQ5D and R-ODS.  Summary statistics will be provided for observed values and changes from 
baseline.  Patient reported autonomic neuropathy symptoms will be assessed by descriptive 
statistics for the COMPASS 31. 
Descriptive statistics will also be provided for observed values and changes from baseline in 
motor function (10-meter walk test and test of grip strength), nutritional status (mBMI), sensory 
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and autonomic innervation (IENFD and SGNFD), VDT, and ambulation (FAP stage and PND 
score). 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study. 
Descriptive statistics will be provided for actual values and changes from baseline in serum 
levels of troponin I and NT-proBNP in the subset of patients with evidence of pre-existing 
cardiac amyloid involvement.  Results of echocardiograms will be summarized. 
10.2.4. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, and the 
proportions of patients with modifications in the durations of infusions will be produced. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term.  Separate tabulations will be produced for all 
treatment emergent AEs, treatment-related AEs (those considered by the Investigator as at least 
possibly drug related), SAEs, and discontinuations due to AEs, and AEs by severity.  By-patient 
listings will be provided for deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented. 
10.2.5. 
Healthcare Utilization Assessments 
A listing of healthcare utilization data will be  presented. 
10.2.6. 
Interim Analysis 
Interim data examinations may be performed, but these will be of a descriptive nature and will 
not involve any formal hypothesis testing. 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The Clinical Monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the Monitor will visit the Investigators and sites periodically and maintain 
frequent telephone and written contact.  The Monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation and 
discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice (GCP) 
and current standard operating procedures. 
11.2. 
Audits and Inspections 
The Investigator and the site will permit study-related monitoring, audits and review by the IEC 
or IRB and/or Regulatory Authorities, providing direct access to source data/documents.  The 
study may be subject to audit by the Sponsor or its representatives or by regulatory authorities.  
If such an audit occurs, the Investigator must agree to allow access to the required patient 
records.  In the event of an audit, the Investigator agrees to allow the Sponsor, representatives 
from the Sponsor, or regulatory agencies access to all study records. 
11.3. 
Institutional Review Board 
The Investigator must obtain IRB or IEC approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements.  To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 
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13. 
ETHICS 
13.1. 
Ethics Review 
National regulations and International Conference on Harmonization (ICH) require that approval 
be obtained from an IRB or an IEC prior to participation of patients in research studies.  Prior to 
the study onset, the protocol, any protocol amendments, informed consent forms (ICFs), and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (eg, name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the 
clinical research. 
The Investigator should not start any study procedure with the patient until documentation of the 
approval by the IEC/IRB and written notification of the approval from the head of the study site 
to the Investigator and Alnylam Pharmaceuticals, Inc. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC.  The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
13.2. 
Ethical Conduct of the Study 
This study will be performed in accordance with the clinical trial agreement, the protocol, all 
applicable government laws, regulations, and guidances where the study is being conducted 
including policies with foundations in the World Medical Association Declaration of Helsinki, 
the ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use, the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) in the US, and all other 
applicable medical privacy laws and regulations. 
13.2.1. 
Financial Disclosure Reporting Obligations 
Each Investigator (including Principal and any Sub Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information 
according to all applicable legal requirements.  In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of one year after the completion of the study. 
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13.3. 
Written Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and 
ICH will be obtained from each patient before undergoing any protocol-specific tests or 
procedures that are not part of routine care. 
The Sponsor or the CRO designee will provide an ICF template to the Investigator for use in 
developing a site-specific ICF.  Prior to submission of the site-specific ICF to the IRB or IEC, 
the site-specific ICF must be reviewed and approved by the Sponsor or designee.  Any changes 
requested by the IRB or IEC must also be agreed upon.  The final IRB/IEC approved ICF must 
be provided to the Sponsor.  Revisions to the ICF required during the study must be agreed upon, 
and a copy of the revised ICF provided to the Sponsor. 
At the time of recruitment, each prospective patient (or legal guardian) will be given a full 
explanation of the study and be allowed to read the ICF.  Once the Investigator is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF.  A copy of the fully signed and 
dated ICF will be given to the patient.  The original ICF will be maintained in the patient’s 
medical record at the site.  All active patients will sign an updated ICF if revisions are made to 
the ICF during the course of the study. 
Prior to dosing in this study, the patient will sign and date the ICF and receive a copy of the 
signed ICF.  No study procedures should be performed before informed consent is obtained.  The 
Investigator or another person authorized by the Investigator will also sign and date the informed 
consent before giving a copy to the patient.  The ICF will be filed in the patient’s medical record. 
13.4. 
Compensation for Health Damages 
A copy of the certificate of insurance as a measure to compensation for health damages will be 
submitted to the IRB/IEC if required per local regulations. 
 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source documentation as 
part of these case histories.  Source documents are the originals of any documents used by the 
Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
The Sponsor will supply CRFs for each patient.  Case report forms must be completed only by 
persons designated by the Investigator.  Corrections must be made so as not to obliterate original 
data and must be identified and dated by the person who made the correction.  All data entered 
into the CRF must also be available in the source documents.  The Investigator will allow 
designated Sponsor representatives and regulatory bodies to have direct access to the source 
documents to verify the data reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a timely 
manner.  The completed CRF will be the records maintained by the Sponsor.  A copy of the CRF 
will remain in the Investigator’s files. 
14.2. 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the CRFs or 
other documents submitted to the Sponsor or designees, patients should not be identified by their 
names, but by the assigned patient number and initials.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
Following the principles of the GCP, if local regulations specify a patient’s number and initials 
will be used to identify the patient on their study records.  Laboratory samples may be labeled 
with an independent numbering code, and the label will not contain any other personal 
identification information.  The numbering code associated with these labels will be held by the 
study CRO and the Sponsor, thereby allowing no unwarranted access to the information.  The 
numbering code will also be held for samples in storage until marketing approval of patisiran in 
the countries where this study was conducted, or until clinical development of patisiran is halted.  
Throughout sample collection, storage (limited, staff only access area containing locked sample 
storage, and limited access sample tracking) and processing, the samples will only be handled by 
appropriate personnel per the laboratory’s standard operating procedures. 
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. 
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14.3. 
Inspection of Records 
The Sponsor 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, drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
14.4. 
Retention of Records 
Essential documents should be retained for the period of time required by applicable local law.  
The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated curricula vitae of the Investigators, copies of the 
completed CRFs, signed ICFs, IEC/IRB approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the 
Sponsor’s expense. 
The ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
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15. 
PUBLICATION POLICY 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting.  A copy of the manuscript must be provided and 
confirmed received at the Sponsor at least 30 days before its submission. 
No submission of a manuscript may be made until the results from all of the clinical sites have 
been received and analyzed by the Sponsor, or the study has been terminated at all centers.  A 
separate, individual publication of the results of the study will be delayed until initial publication 
of the results of the multicenter study, or a decision not to publish is made.  If an initial draft is 
not produced within 18 months of completion of the study at all centers, or the timeframe for 
publication is not satisfactory, the Investigator may disclose the results after providing a copy 
and the Sponsor confirms receipt of the manuscript 30 days before submission. 
Research ancillary to this main protocol may not be performed by individual sites without prior 
discussion and approval by the Sponsor. 
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16.
LIST OF REFERENCES
1 
Yazaki M., Tokuda T, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy 
consists of abundant wild-type transthyretin. Biochem Biophys Res Commun.  2000; 274(3):702-
706. 
2 
Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol.  2006. 2(5):263-70. 
3 
Suhr OB, Herlenius G, et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver 
Transpl. 2000;6(3): 263-276. 
4 
Benson MD. Familial amyloidotic polyneuropathy. Trends Neurosci. 1989;12(3):88-92. 
5 
Connors LH, Yamashita T, et al. A rare transthyretin mutation (Asp18Glu) associated with 
cardiomyopathy. Amyloid. 2004;11(1):61-66. 
6 
Buxbaum JN. (2007). Transthyretin and the Transthyretin Amyloidoses. Protein Reviews: Protein 
Misfolding, Aggregation, and Conformational Diseases. V. N. a. F. Uversky, A. New York, 
Springer US. 7: 259-283. 
7 
Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' 
symptoms and complications. Amyloid. 2003;10 (Suppl 1):77-83. 
8 
Ando Y, Nakamura M, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-1062. 
9 
Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic Targeting 
Transthyretin (TTR) for TTR Amyloidosis. NEJM.  2013, accepted for publication. 
10 
Stangou AJ and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid 
polyneuropathy. Current Opinion in Neurology. 2004;17(5):615-620. 
11 
Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of RNAi 
therapeutics. Nat Biotechnol. 2008;26(5):561-569. 
12 
Adams D, Suhr O, Coelho T, et al.  Phase 2 open-label extension study of patisiran, an RNAi 
therapeutic for the treatment of familial amyloidotic polyneuropathy.  Presented at:  Annual 
Meeting of the American Neurological Association; 2014 Oct 12; Baltimore, MD. 
13 
Biesalski, H.K., et al., Biochemical but not clinical vitamin A deficiency results from mutations 
in the gene for retinol binding protein. Am J Clin Nutr, 1999. 69(5): p. 931-6. 
14 
Episkopou, V., 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. 90: p. 2375-2379. 
15
Conceiciao IM, Miranda LC, et al.  Bone mineral density in familial amyloid polyneuropathy and 
in other neuromuscular disorders. Eur J Neurol. 2005;12(6):480-2. 
16 
Kollmer J, Hund E, Hornung B, Schönland S, et al. MR-neurography: In-vivo detection of nerve 
injury in systemic light chain (AL) amyloidosis. XIVth International Symposium on 
Amyloidosis, 2014. 
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17.
APPENDICES
Appendix 1: Karnofsky Scale 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
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Appendix 2: New York Heart Association Classification of Heart Failure 
 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
 
 
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Appendix 3: Categorization of Infusion-Related Reactions 
 
Signs and symptoms of an infusion-related reaction (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, 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, nonsteroidal anti-inflammatory drug 
[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. 
 
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Appendix 4: Neuropathy Scores and Their Components 
 
Assessment Tool 
Total 
Points 
Components (points) 
NIS+7  
 
270 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (NISa) 
• 
Weakness (192) 
• 
Sensation (32) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (18.6)a 
• 
Sural SNAP, tibial motor n. distal latency, peroneal 
CMAP/motor n. conduction velocity/motor n. distal 
latency 
• 
Vibration detection threshold (3.7) 
• 
Heart rate response to deep breathing (3.7) 
Modified NIS+7 
304 
• 
Neurologic exam of lower limbs, upper limbs and cranial 
nerves (mNISa) 
• 
Weakness (192) 
• 
Reflexes (20) 
• 
Nerve conduction studies ∑5 (10)a 
• 
Ulnar CMAP and SNAP, sural SNAP, tibial CMAP, 
peroneal CMAP 
• 
Quantitative sensory testing: QST-BSATP+HP5 (80) 
• 
Postural blood pressure (2) 
a 
Components that are shared between the mNIS+7 and NIS+7 (including NIS and NCS) will be performed once at each 
assessment. 
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Appendix 5: Polyneuropathy Disability Score 
 
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
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Appendix 6: Familial Amyloidotic Polyneuropathy Stage 
 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 
 
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Version 3.1-United Kingdom Summary of Changes_11 May 2017 
 
ALN-TTR02-006 Protocol Version 3.1 United Kingdom 
Summary of Changes (dated 11 May 2017)  
compared to Protocol Version 3.0 (dated 05 January 2017) 
A Multicenter, Open-label, Extension Study to Evaluate the Long-Term Safety and 
Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy who have 
Completed a Prior Clinical Study with Patisiran 
 
Rationale for Protocol Amendment 
The purpose of this country-specific protocol amendment is to address comments (dated 
28 February 2017) from the United Kingdom’s National Health Service Ethics Committee 
   Text has been added to the 
protocol detailing that if a patient’s Columbia-Suicide Severity Rating Scale (C-SSRS) score 
raises concern of suicidal ideation or behavior, the Investigator must ensure prompt and 
appropriate mental health interventions in accordance with standard of care.  
A detailed summary of changes is provided in Table 1.   
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Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment 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: Added text that if a patient’s Columbia-Suicide Severity Rating Scale (C-SSRS) score raises concern of suicidal ideation or behavior, the 
Investigator must ensure prompt and appropriate mental health interventions in accordance with standard of care  
The primary change occurs in Section 9.1.7, Columbia-Suicide Severity Rating Scale 
Added text: 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to assess each patient's mental status 
as it relates to suicidal ideation and behavior.  If a patient’s C-SSRS raises concern of suicidal ideation 
or behavior, the Investigator must ensure prompt and appropriate mental health interventions in 
accordance with standard of care. 
 
 
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SAP_001.pdf: 
 
 
Official Title:  A MULTICENTER, OPEN-LABEL, EXTENSION STUDY TO EVALUATE THE LONG-TERM 
SAFETY AND EFFICACY OF PATISIRAN IN PATIENTS WITH FAMILIAL AMYLOIDOTIC 
POLYNEUROPATHY WHO HAVE COMPLETED A PRIOR CLINICAL STUDY WITH PATISIRAN 
 
NCT Number:   
NCT02510261 
 
Document Date:   
Statistical Analysis Plan, Version 1.0, 12 July 2017  


 
 
STATISTICAL ANALYSIS PLAN: PROTOCOL ALN-TTR-006 
 
A Multicenter, Open-Label, Extension Study to Evaluate the Long-Term 
Safety and Efficacy of Patisiran in Patients with Familial Amyloidotic 
Polyneuropathy Who Have Completed a Prior Clinical Study with Patisiran 
 
Protocol Number: 
Protocol Version and Date: 
ALN-TTR02-006 
Amendment 2: 05 January 2017 
Amendment 1: 08 September 2015 
Original: 06 November 2014 
Name of Test Drug: 
Patisiran (ALN-TTR02) 
Phase: 
Phase 3 
Methodology: 
Multicenter, open label study 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
Tel: 
 
Fax: 
 
Sponsor Representative: 
 
 
Analysis Plan Version and Date: 
Final Version 1.0: 12 July 2017 
 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary  
property of Alnylam Pharmaceuticals, Inc. and any unauthorized use or  
disclosure of such information without the prior written authorization  
of Alnylam Pharmaceuticals, Inc. is expressly prohibited. 
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Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-1TR02-006 
12 July 2017, Final Version 1.0 
APPROVAL SIGNATURE PAGE 
Protocol Title: 
Sponsor: 
Protocol Number: 
Document Date I Version: 
Veristat, LLC Author: 
Veristat, LLC 
118 Turnpike Road 
Southborough, MA 01772 USA 
Sponsor Approval 
A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy ofPatisiran in Patients with 
Familial Amyloidotic Polyneuropathy Who Have Completed 
a Prior Clinical Study with Patisiran 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
ALN-1TR02-006 
12July2017 /Final Version 1.0 
Signatille:
oate: 
/3. 
do IT 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a 
he 
planned analyses Will be descnbed m the chru
 
Signature: _
4 --{" 
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Date: 
\. 
7 
Alnylam Pharmaceuticals, Inc. 
Alnylam Pharmaceuticals, Inc. 
2 
CONFIDEN11AL 
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Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-006 
12 July 2017, Final Version 1.0 
 
CONFIDENTIAL 
3 
TABLE OF CONTENTS 
Section 
Page 
1. 
INFORMATION FROM THE STUDY PROTOCOL ...................................................... 7 
1.1. 
Introduction and Objectives ................................................................................... 7 
1.1.1. 
Introduction ............................................................................................. 7 
1.1.2. 
Document and Study Objectives............................................................. 7 
1.2. 
Study Design .......................................................................................................... 7 
1.2.1. 
Synopsis of Study Design ....................................................................... 7 
1.2.2. 
Study Procedures .................................................................................... 8 
1.2.3. 
Efficacy, Pharmacodynamic, Safety, and Other 
Assessments ............................................................................................ 8 
2. 
PATIENT POPULATION ............................................................................................... 10 
2.1. 
Population Definitions ......................................................................................... 10 
2.2. 
Protocol Deviations .............................................................................................. 10 
3. 
GENERAL STATISTICAL METHODS ........................................................................ 11 
3.1. 
Sample Size Justification ..................................................................................... 11 
3.2. 
General Methods .................................................................................................. 11 
3.3. 
Computing Environment ...................................................................................... 11 
3.4. 
Baseline Definitions ............................................................................................. 11 
3.5. 
Study Group ......................................................................................................... 12 
3.6. 
Adjustments for Covariates.................................................................................. 12 
3.7. 
Multiple Comparisons/Multiplicity ..................................................................... 12 
3.8. 
Subpopulations ..................................................................................................... 12 
3.9. 
Withdrawals, Dropouts, and Loss to Follow-up .................................................. 12 
3.10. Missing Data ........................................................................................................ 12 
3.10.1. 
Partially Missing Efficacy Endpoints ................................................... 12 
3.10.2. 
Other Missing Data ............................................................................... 13 
3.11. Visit Windows ..................................................................................................... 13 
3.12. Interim Analyses .................................................................................................. 13 
4. 
STUDY ANALYSES ...................................................................................................... 14 
4.1. 
Patient Disposition ............................................................................................... 14 
4.2. 
Demographics and Baseline Characteristics ........................................................ 14 


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Section 
Page 
4.3. 
Pharmacokinetic Evaluations ............................................................................... 14 
4.4. 
Pharmacodynamic Analyses ................................................................................ 15 
4.5. 
Efficacy Analyses ................................................................................................ 15 
4.6. 
Healthcare Utilization Assessments ..................................................................... 16 
4.7. 
Safety Analyses .................................................................................................... 16 
4.7.1. 
Study Drug Exposure ............................................................................ 16 
4.7.2. 
Adverse Events ..................................................................................... 16 
4.7.3. 
Laboratory Data .................................................................................... 18 
4.7.4. 
Vital Signs and Physical Examination .................................................. 18 
4.7.5. 
Ophthalmology Examinations .............................................................. 19 
4.7.6. 
Premedications ...................................................................................... 19 
4.7.7. 
Concomitant Medications ..................................................................... 20 
4.7.8. 
Suicide Questionnaire ........................................................................... 20 
4.8. 
Anti-Drug Antibody ............................................................................................. 20 
5. 
CHANGES TO PLANNED ANALYSES ....................................................................... 21 
6. 
REFERENCES ................................................................................................................ 22 
7. 
QUESTIONNAIRE/SCORING APPENDICES ............................................................. 23 
7.1. 
Modified Neuropathy Impairment Score + 7 (mNIS+7) and 
Neuropathy Impairment Score + 7 (NIS+7) ........................................................ 23 
7.1.1. 
Modified Neuropathy Impairment Score + 7 (mNIS+7) ...................... 24 
7.1.2. 
Neuropathy Impairment Score + 7 (NIS+7) ......................................... 25 
7.1.3. 
NIS Total Score .................................................................................... 26 
7.1.4. 
Algorithms for Setting Normal Deviates and Points ............................ 26 
7.2. 
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) .................... 32 
7.3. 
EuroQOL-5-Dimension 5-Level (EQ-5D-5L) ..................................................... 32 
7.4. 
Rasch-Built Overall Disability Scale (R-ODS) ................................................... 33 
7.5. 
Composite Autonomic Symptom Score-31 (COMPASS-31) ............................. 33 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
5 
sum of 5 nerve conduction attributes 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
anatomic therapeutic class 
BMI 
body mass index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
clinical study report 
COMPASS-31 
Composite Autonomic Symptom Score 
eCRF 
electronic case report form 
CRO 
contract research organization  
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme linked immunosorbent assay 
EQ-5D-5L 
EuroQoL five dimensions, five-level scale 
EQ-VAS 
EuroQoL visual analog scale 
EW 
early withdrawal 
FAP 
familial amyloidotic polyneuropathy 
hATTR 
hereditary transthyretin-mediated amyloidosis 
HLT 
high level term 
HP 
heat pain 
HRdb 
heart rate response to deep breathing 
ICH 
International Conference on Harmonisation 
IENFD 
intraepidermal nerve fiber density 
INN 
International Nonproprietary Name 
IRR 
infusion-related reaction 
IV 
intravenous 
KPS 
Karnofsky performance status 
LOCF 
last observation carried forward 
mBMI 
modified body mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mNIS+7 
Modified Neuropathy Impairment Score 


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Abbreviation 
Definition 
MR 
magnetic resonance 
NCS 
nerve conduction studies 
NIS 
Neuropathy Impairment Score 
NIS+7 
Neuropathy Impairment Score + sum of 7 nerve tests 
NIS-W 
Neuropathy Impairment Score - Weakness 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
PBP 
postural blood pressure 
PD 
pharmacodynamic 
PND 
polyneuropathy disability 
PT 
preferred term 
QOL 
quality of life 
QOL-DN 
Quality of Life-Diabetic Neuropathy 
QST 
quantitative sensory testing 
R-ODS 
Rasch-built Overall Disability Scale 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SGNFD 
sweat gland nerve fiber density 
siRNA 
small interfering ribonucleic acid 
SMQ 
Standardized MedDRA query 
SOC 
system organ class 
TP 
touch pressure 
TTR 
transthyretin 
ULN 
upper limit of normal 
V30M 
Val30Met 
VDT 
vibration detection threshold 
WHO 
World Health Organization 
WT 
wild type 
 


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Statistical Analysis Plan, Protocol ALN-TTR02-006 
12 July 2017, Final Version 1.0 
 
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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction  
Patisiran (the International Nonproprietary Name [INN] for the drug product also referred to as 
ALN-TTR02) is a novel investigational agent being developed for the treatment of 
polyneuropathy in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. 
Patisiran comprises a small interfering ribonucleic acid (siRNA) which is specific for 
transthyretin (TTR), and is formulated in a hepatotropic lipid nanoparticle (LNP) for 
intravenous (IV) administration.[1] It is designed to significantly suppress liver production of 
both wild type (WT) and all mutant forms of TTR, thereby having the potential to reduce 
amyloid formation and provide clinical benefit to patients with hATTR amyloidosis. 
ALN-TTR02-006 (hereinafter referred to as study 006) is a multicenter, open-label extension 
study designed to evaluate the long-term safety and efficacy of patisiran in patients with hATTR 
amyloidosis with polyneuropathy who have completed a prior study with patisiran (ALN-
TTR02-003 or ALN-TTR02-004, hereinafter referred to as Studies 003 and 004, respectively). 
1.1.2. 
Document and Study Objectives 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to address the study objectives of Study 006. Populations for analysis, 
data handling rules, statistical methods, and formats for data presentation are provided. The 
statistical analyses and summary tabulations described in this SAP will provide the basis for the 
results sections of the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol and will be used to guide the interim and final analyses of 
the study. 
The objective of this study is to assess the safety and efficacy of long-term dosing with patisiran 
in patients with hATTR amyloidosis with polyneuropathy. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This is a multicenter, multinational, open-label extension study to evaluate the long-term safety 
and efficacy of patisiran in patients with hATTR amyloidosis with polyneuropathy who have 
previously completed a patisiran study. 
Consented eligible patients will enroll in this study and receive 0.3 mg/kg patisiran IV once 
every 21 days for the duration of the study. The study inclusion and exclusion criteria are listed 
in Sections 4.1 and 4.2 of the study protocol. All dosing visits have a window of ± 3 days. In 
order to maintain the 21-day dosing schedule from the parent study, patients are expected to 
have their first visit (Day 1) on this study 3 weeks after their last dosing visit on the parent 
study. However, a patient may initiate dosing in this study up to 45 days from the time of the 
last dose in the parent study. The last testing visit in the parent study will serve as the baseline 
for this study, unless more than 45 days have elapsed, in which case the baseline tests will be 
repeated prior to the first dose of patisiran on Day 1. Eligibility for this study will be confirmed 
before administration of the first dose on Day 1. 


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12 July 2017, Final Version 1.0 
 
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After the Day 1 visit, patients will either return to the clinical site for the patisiran infusions or 
will receive the patisiran infusions at home once every 21 (±3) days. Patients who are receiving 
patisiran infusions at home will have phone contact with the site at least every 30 (±5) days. 
Patients will also have visits at the clinical site at approximately 26 and 52 weeks, and yearly 
thereafter. 
A complete set of efficacy assessments will be performed at 52 weeks (+/-4 weeks), followed by 
more limited efficacy assessments yearly thereafter. 
Safety will be assessed throughout the study. Patients will return to the clinical site for safety 
evaluations at 26 and 52 weeks during the first year and yearly thereafter. Patients will be 
continually assessed throughout the study for adverse events (AEs). Unscheduled visits for 
study assessments may occur if deemed necessary by the study personnel. 
Patients rolling over into this open-label study from a previously blinded study will remain 
blinded to their previous treatment assignment until after database lock has occurred in that 
parent study. 
1.2.2. 
Study Procedures 
The schedule of assessments is presented in Table 1 of the study protocol. 
1.2.3. 
Efficacy, Pharmacodynamic, Safety, and Other Assessments 
1.2.3.1. 
Efficacy Assessments 
The efficacy of patisiran will be evaluated using the following assessments: 
 Neurological impairment assessed using the Neuropathy Impairment Score (NIS), 
Modified NIS (mNIS +7) composite score and NIS+7. 
 Patient reported quality of life (QOL) using the EuroQoL five dimensions, five-level 
scale (EQ-5D-5L) questionnaire and the Norfolk Quality of Life –Diabetic Neuropathy 
(QOL-DN) questionnaire; patients from Study 003 do not have to complete the Norfolk 
QOL-DN questionnaire. 
 Overall health using the EuroQoL visual analog scale (EQ-VAS). 
 Disability reported by patients using the Rasch-built Overall Disability Scale (R-ODS). 
 Autonomic symptoms assessed using the Composite Autonomic Symptom Score 
(COMPASS-31). 
 Motor function assessments, including timed 10-meter walk test and grip strength test. 
 Polyneuropathy disability (PND) score and familial amyloidotic polyneuropathy (FAP) 
stage. 
 Nutritional status using modified body mass index (mBMI). 
 Pathologic evaluation of sensory and autonomic innervation evaluated by intraepidermal 
nerve fiber density (IENFD) analysis and quantitation of dermal sweat gland nerve fibers 
(SGNFD) via tandem 3mm skin punch biopsies taken from the leg (only for patients 
having this assessment in the parent study). 
 Dermal amyloid content (% Congo Red staining) using the same skin punch biopsy 
specimens analyzed for nerve fiber density. 


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 Magnetic resonance (MR) neurography (in Germany and France only). 
 Cardiac assessment with echocardiograms and serum levels of terminal prohormone of 
B-type natriuretic peptide (NT-proBNP) and troponin I. 
 New York Heart Association (NYHA) classification of heart failure. 
1.2.3.2. 
Pharmacodynamic Parameters and Pharmacology Parameters 
Pharmacodynamic (PD) markers include serum TTR assessed using enzyme linked 
immunosorbent assay (ELISA) and vitamin A. 
Blood will be collected to evaluate anti-drug antibodies (ADA). 
1.2.3.3. 
Safety Parameters 
Safety evaluations performed during the study include monitoring of AEs and concomitant 
medications, physical examinations, measurement of vital signs, clinical laboratory evaluations 
(including hematology, clinical chemistry [including liver function tests and thyroid stimulating 
hormone], urinalysis, and pregnancy testing), and ophthalmology examinations. 
Suicidal ideation and behavior will be assessed using the Columbia–Suicide Severity Rating 
Scale (C-SSRS) questionnaire. 
1.2.3.4. 
Other Parameters 
Disease burden and healthcare utilization will be assessed using a patient reported 
pharmacoeconomics questionnaire. 


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2. 
PATIENT POPULATION 
2.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
 Full Analysis Set: All patients who were enrolled will be included in the full analysis set. 
The full analysis set will be the primary set for the analysis of efficacy data. 
 Pharmacodynamic (PD) Analysis Set: All patients who received at least 1 dose of 
patisiran in this study and have both baseline and at least 1 post-baseline PD assessment 
(either TTR or Vitamin A). For a patient who received patisiran in the parent study, if 
more than 45 days elapsed between the last dose of patisiran in the parent study and the 
first dose of patisiran in this study, the patient will be excluded from the PD analysis set. 
 Safety Analysis Set: All patients who were enrolled and who received at least 1 dose of 
patisiran in this study. The safety analysis set will be used for the analysis of safety data. 
2.2. 
Protocol Deviations 
A deviation is considered any departure from the procedures set forth in the protocol. Protocol 
deviations will be classified into major and minor by medical review. A major deviation 
includes any deviation that may impact patient safety or efficacy interpretation. Deviations not 
designated as major will be considered minor. 
All protocol deviations and major protocol deviations will be presented in separate data listings. 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
This is an open-label extension study enrolling patients who have previously completed a 
patisiran clinical study (Study 004 or 003); the size of the study is not determined via power 
analysis of particular hypotheses tests. 
3.2. 
General Methods 
As this is an extension study, formal statistical hypothesis testing will not be performed. All 
summaries are descriptive. 
All data will be presented in by-patient data listings. The listings that contain an evaluation date 
will include 2 study days as described below: 
1) Extension study day: the study day relative to the first dose date of patisiran in this 
study. The first dose date is designated as Day 1. On-treatment study days will be 
calculated as evaluation date – first dose date +1 and pre-treatment days will be 
calculated as evaluation date – first dose date. For example, the day prior to the first dose 
of patisiran will be Day -1 and the day after the first dose of patisiran will be Day 2, etc. 
2) Parent study day: the study day relative to the day of the first dose of study drug in the 
parent study (Study 004 or 003). 
All output will be incorporated into Microsoft Word files, sorted and labeled according to the 
International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) of the parameter will be presented. For 
continuous variables, the number of patients, mean, median, standard deviation (SD), minimum, 
and maximum values will be presented. 
Laboratory data (including vitamin A) collected and recorded as below the limit of detection 
will be set equal to the lower limit of detection for the calculation of summary statistics. 
For assessments with planned repeat assessments at a given study visit (e.g., 10-meter walk 
tests), the average will be calculated unless otherwise noted. 
All data recorded on the eCRF will be included in data listings. 
3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.3 
(or later), unless otherwise noted. Medical history and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 18.0 (or later). Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary 
version March 2015 (or later). 
3.4. 
Baseline Definitions 
Unless noted otherwise, baseline will be defined as the last non-missing measurement on or 
prior to the first dose of patisiran in this study. For several procedures, the last testing visit in the 
parent study will serve as the baseline for this study, unless more than 45 days have elapsed, in 
which case the test will need to be repeated on Day 1 in this study; see Table 1 of the study 


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protocol for additional details. If more than 45 days have elapsed and the assessment is not 
repeated on Day 1, the last assessment from the parent study will serve as baseline for this 
study; any such occurrence will be identified as a protocol deviation. 
For the mNIS+7/NIS+7 individual components, total scores and related endpoints, grip strength 
test, and 10-meter walk test, baseline will be calculated as the average of 2 replicates. 
3.5. 
Study Group 
Data from all sites will be summarized together. Patients will be grouped into the following 3 
study groups: 
1) 004 Placebo: patients in Study 006 who previously received placebo in Study 004. 
2) 004 Patisiran: patients in Study 006 who previously received patisiran in Study 004. 
3) 003 Patisiran: patients in Study 006 who previously received patisiran in Study 003. 
Summary tables and figures will include presentations by study group and overall. 
3.6. 
Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned. 
3.7. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a descriptive interpretation. 
3.8. 
Subpopulations 
No analyses of patient subgroups are planned. 
3.9. 
Withdrawals, Dropouts, and Loss to Follow-up 
Patients are free to withdraw from the study at any time and for any reason, without penalty to 
their continuing medical care. Every effort should be made to complete the Early Withdrawal 
(EW) visit, if applicable. Patients who permanently discontinue treatment are to be withdrawn 
from the study. 
In the event a patient withdraws early from the study, the contract research organization (CRO) 
Medical Monitor must be informed immediately. If an AE is the reason for withdrawal, the 
patient will remain under the supervision of the Investigator for protocol-specified safety follow 
up procedures. 
When a patient withdraws from the study, the primary reason for withdrawal must be recorded 
in the appropriate section of the electronic case report form (eCRF) and all efforts will be made 
to complete and report the observations as thoroughly as possible. 
3.10. 
Missing Data 
3.10.1. 
Partially Missing Efficacy Endpoints 
Specific algorithms will be used to impute values and/or subcomponents of particular 
assessments when subcomponents are missing (mNIS+7, NIS+7, Norfolk QOL-DN, EQ-5D-5L, 
R-ODS, and COMPASS-31; see Section 7.1, Section 7.2, Section 7.3, Section 7.4, and 
Section 7.5). The result of the partial imputation (either a non-missing or missing value) will be 
used in all statistical analyses. 


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In general, there will be no imputation for missing data for other efficacy endpoints unless 
specified otherwise. All data recorded on the eCRF will be included in data listings that will 
accompany the CSR. 
3.10.2. 
Other Missing Data 
Conventions for determining whether an AE is treatment emergent are discussed in 
Section 4.7.2. For the calculation of duration (e.g., time in years since diagnosis with hATTR) in 
the presence of an incomplete date, the following conventions will be used: 
 Missing day: the first day of the month will be used; 
 Missing day and month: duration will be calculated as the simple difference in years 
(e.g., year of informed consent minus year of diagnosis with hATTR); 
 Missing day, month, and year: no duration will be calculated. 
3.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the eCRF even if the assessment is outside of 
the visit window. In data listings, the extension study day and parent study day will be 
presented.  
For efficacy assessments, if the scheduled 52-week or annual visits are not performed, any 
evaluable visit will be grouped with the 52-week or annual assessments if it is performed within 
3 months of the scheduled assessment. 
Unless otherwise specified above, data collected at unscheduled visits will be included in by-
patient data listings and figures, but no assignment to a study visit will be made for the purpose 
of by-visit summary tabulations. However, unscheduled visits will be considered for baseline 
values, as discussed in Section 3.4, and for inclusion in any categorical shift summaries (e.g., 
shift from baseline to “worst” post-baseline value). 
3.12. 
Interim Analyses 
Interim analyses will be performed to support regulatory activities and publications. These 
analyses will be of a descriptive nature and will not involve any formal hypothesis testing. 
For an interim analysis, as this study will be ongoing, a cut-off analysis approach will be 
implemented to ensure data quality. The interim analysis will include data on or prior to a pre-
specified cut-off date. For assessments with starting/ending dates (e.g., AEs, medications, 
medical history), the starting date will be compared with the pre-specified cut-off date. For any 
assessments consisting of multiple replicates associated with a single visit, the earliest of the 
dates will be compared to the cut-off; if this date is on or before the cutoff date, the replicates 
will be included in the analysis. In particular, for mNIS+7, NIS+7, and NIS, the date for the 
earliest replicate of NIS-W at the visit will be compared to the cut-off date. 


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4. 
STUDY ANALYSES 
4.1. 
Patient Disposition 
Patient disposition will be tabulated and will include the following parameters: the number of 
patients in each analysis population, the number of patients enrolled, the number of patients 
treated with patisiran, the number of patients who are ongoing, the number of patients who 
completed the study, and the number of patients who withdrew from the study and the primary 
reasons for withdrawal. 
A by-patient data listing of study completion information including the reason for premature 
study withdrawal will be presented. 
4.2. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics, baseline disease characteristics, baseline efficacy 
parameters, and medical history information will be summarized by study group and overall. No 
formal statistical comparisons will be performed. 
Age, height, weight, and body mass index (BMI) will be summarized using descriptive statistics 
(number of patients, mean, SD, median, minimum, and maximum). Sex, race, ethnicity, and 
region will be summarized by presenting the numbers and percentages of patients in each 
category. 
The following baseline disease characteristics will be summarized by presenting the numbers 
and percentages of patients in each category: 
 Genotype (V30M vs non-V30M) 
 Karnofsky Performance Status (KPS) 
 Concurrent Stabilizer Use at Study Entry (yes, no) 
Concurrent stabilizer use at study entry is defined as patients who were receiving TTR tetramer 
stabilizers (tafamidis or diflunisal) for at least 2 weeks within the first month following the first 
dose of patisiran in Study 006. 
Time in years since diagnosis with hATTR will be summarized using descriptive statistics. 
Baseline values of continuous efficacy parameters (mNIS+7, Norfolk QOL, NIS-W, mBMI, 
10-meter walk test, COMPASS-31, NIS, NIS+7, grip strength, EQ-5D-5L, EQ-VAS, R-ODS, 
IENFD distal thigh and distal leg, and SGNFD distal thigh and distal leg) will be summarized 
using descriptive summary statistics. The numbers and percentages of patients in each category 
for baseline PND score (I, II, IIIA, IIIB, IV), baseline FAP stage (0, I, II, III), and baseline 
NYHA class (I, II, III, IV) will also be summarized. 
All demographic and baseline data for each patient will be provided in data listings. 
Medical history will be summarized by MedDRA system organ class (SOC), high level term 
(HLT) and preferred term (PT). A patient contributes only once to the count for a given 
condition (overall, by SOC, by HLT, by PT). Medical history including prior surgeries and 
pregnancy test results will be presented in data listings. 
4.3. 
Pharmacokinetic Evaluations 
No pharmacokinetic evaluations will be done for this study. 


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4.4. 
Pharmacodynamic Analyses 
Pharmacodynamic analyses will be based on the PD analysis set. 
The PD parameters include serum TTR (ELISA) and vitamin A. All summary tables and figures 
will be based on assessments within 21 days of last dose of patisiran. Assessments more than 21 
days after last dose will be presented in listings and individual patient plots only. 
Summary tables will be provided for observed values, changes and percentage changes from 
baseline for each scheduled time point by study group and overall. Graphical displays will be 
provided for the observed values of TTR and vitamin A for each scheduled time point by study 
group. 
All PD data will be displayed in data listings. 
4.5. 
Efficacy Analyses 
Efficacy analyses will be based on the full analysis set. Summaries will be provided for each 
scheduled time point by study group and overall. 
Neurologic impairment will be assessed by mNIS+7, NIS+7, and NIS. The observed values and 
changes from baseline in the composite and component scores of mNIS+7, NIS+7, and NIS will 
be summarized. The mNIS+7 composite score consists of the NIS weakness (NIS-W) and reflex 
(NIS-R) domains, quantitative sensory testing (QST) by body surface area including touch 
pressure (TP) and heat pain (HP), 5 nerve conduction studies (Σ5 NCS), as well as autonomic 
assessment through postural blood pressure (PBP). The NIS+7 includes the NIS-W, NIS-R, NIS 
sensation (NIS-S), and Σ7 Nerve tests (including sum of 5 NCS which overlaps but is not 
identical to the Σ5 NCS calculated for mNIS+7 above, vibration detection threshold (VDT), and 
heart rate response to deep breathing [HRdb]). The total NIS score is the sum of NIS-W, NIS-R, 
and NIS-S. Scoring algorithms for mNIS+7, NIS+7, and NIS, including methods for handling 
missing components, are included in Section 7.1. 
Patient reported QOL will be assessed by the Norfolk QOL-DN total score (Study 003 patients 
do not have to complete this assessment) and by the EQ-5D-5L index value (using U.S. 
references to calculate the index). Overall health will be assessed by the EQ-VAS and disability 
will be assessed by the R-ODS. Patient reported autonomic neuropathy symptoms will be 
assessed by the COMPASS-31 total score. The observed values and changes from baseline in 
these measures will be summarized. Continuous summaries of each Norfolk QOL-DN and 
COMPASS-31 domain score, as well as categorical summaries of each EQ-5D-5L domain will 
also be provided. Scoring algorithms for the Norfolk QOL-DN, EQ-5D-5L, R-ODS, and 
COMPASS-31 are included in Section 7.2, Section 7.3, Section 7.4, and Section 7.5. 
Motor function assessments will include a timed 10-meter walk test and test of grip strength in 
the dominant arm, as well as an evaluation of ambulation using PND score and FAP stage. The 
observed values and changes from baseline in 10-meter walk test speed and grip strength will be 
summarized. Categorical summaries of FAP stage and PND score will also be provided. 
Pathologic evaluation of sensory and autonomic innervation will be evaluated by IENFD 
analysis and quantitation of SGNFD via tandem 3 mm skin punch biopsies taken from the distal 
leg and distal thigh. In addition, the evaluation of dermal amyloid content (% Congo Red 
staining) using the same skin punch biopsy specimens analyzed for nerve fiber density (SGNFD 
and IENFD) will also be assessed. Continuous summaries of the observed values and changes 


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from baseline in IENFD, SGNFD, and dermal amyloid content will be provided by site (i.e., 
distal thigh, distal leg). 
Nutritional status of patients will be evaluated using the mBMI, calculated as BMI (kg/m2) 
multiplied by albumin (g/L). The observed values and changes from baseline in mBMI will be 
summarized. 
A categorical summary of the observed values and changes from baseline in the NYHA 
classification of heart failure will be provided. 
Cardiac structure and function will be assessed through echocardiograms as well as 
measurement of serum levels of the cardiac biomarkers NTproBNP and troponin I. Descriptive 
statistics will be provided for actual values, changes, and percentage changes from baseline in 
echocardiogram parameters (including wall thickness, ejection fraction, and other echo 
parameters), serum levels of troponin I and NT-proBNP. 
Magnetic resonance (MR) neurography data will be presented in a by-patient data listing. 
4.6. 
Healthcare Utilization Assessments 
The patient-reported pharmacoeconomics questionnaire data will be presented in a data listing. 
4.7. 
Safety Analyses 
Safety analyses will be based on the safety analysis set. All safety summaries will be presented 
by study group and may include an overall column as specified. 
4.7.1. 
Study Drug Exposure 
The total duration of drug exposure will be defined as (the last dose of patisiran in this study – 
the first dose of patisiran in this study + 21)/30.44 months. Duration of drug exposure, the total 
number of doses received, duration of infusion (per infusion) and amount of patisiran received 
(per infusion and in total) will be summarized by descriptive statistics. Summaries of the 
numbers and percentages of patients with at least 1 missed dose, and the number of missed 
doses per patient will also be provided. The total amount of drug received and the total volume 
infused will also be summarized. The number of patients who experienced dose interruptions for 
any reason will be tabulated, as well as the number of patients with dose interruptions due to an 
infusion related reaction (IRR). 
A drug exposure table summarizing the treatment duration and interruptions under the 
“original” and “reduced” premedication regimens (see Section 4.7.6) will be also provided. A 
patient who switches from “original” to “reduced” regimen during treatment will be counted in 
both categories. For patients switching to the reduced regimen, the duration of exposure on the 
original regimen is defined as (the date of regimen change – the first dose of patisiran in this 
study)/30.44 months, and the duration of exposure on the reduced regimen is defined as (the last 
dose of patisiran in this study – the date of regimen change + 21)/30.44 months. 
Dosing information for each patient will be presented in a data listing. In addition, a listing will 
be provided to present the durations of study drug exposure under the original regimen and 
reduced regimen for each patient. 
4.7.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system (version 18.0 or later) and displayed 
in tables and data listings using SOC and PT. 


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Summaries of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined per protocol as any AE with onset during or after the first 
administration of patisiran in this study through 28 days after the last dose of patisiran. In 
addition, any event that was present at baseline but worsened in intensity or was subsequently 
considered drug-related by the Investigator through the end of the study will be considered 
treatment-emergent. Events with a fully or partially missing onset date will be assumed to be 
treatment emergent unless it can be unequivocally determined (from the partial onset date and/or 
a partial or complete stop date) that the event occurred prior to the first administration of 
patisiran. For an interim analysis where a cut-off approach is used, events with a partially 
missing onset date will be assumed to have started prior to the cut-off date unless it can be 
unequivocally determined (from the partial onset date) that the event occurred after the cut-off 
date; events with a fully missing onset date will be assumed to have started prior to the cut-off 
date. 
AEs will be summarized by the number and percentage of patients reporting a given AE. A 
patient contributes only once to the count for a given AE (overall, by SOC, by PT). Overall 
event counts and frequencies may also be summarized. 
An overall summary of AEs will include the numbers and percentages of patients with any AE, 
any AE assessed by the Investigator as related to treatment (definite or possible relationship), 
any severe AE, any severe AE related to treatment, any serious AE (SAE), any SAE related to 
treatment, any AE leading to study withdrawal, any study drug related AE leading to study 
withdrawal, and any deaths. 
Tabulations by SOC and PT will be produced for the following: all AEs; AEs related to 
treatment; severe AEs; AEs leading to study withdrawal, and SAEs. Separate tables will be 
provided summarizing signs and symptoms of IRRs and AEs related to premedication by SOC 
and PT. The incidence and frequency of AEs and IRRs over time will also be summarized by 
SOC and PT. AEs and AEs related to treatment will also be tabulated by PT in decreasing order 
of frequency over all patients. 
Separate tables will present AE incidence rates by maximum relationship to study drug and by 
maximum severity. If a patient experiences more than 1 event in a given SOC or PT, the patient 
is counted once for that SOC or PT according to the most related or the most severe occurrence, 
respectively. AEs with a missing relationship will be considered as definitely related to study 
drug, and AEs with a missing severity will be considered as severe. 
AEs identified by the Depression and Suicide/Self-injury standardized MedDRA query (SMQ) 
will be summarized by PT; these AEs will be tabulated by PT in decreasing order of frequency 
over all patients. AEs identified by the Drug Related Hepatic Disorder SMQ will be summarized 
by SOC and PT. AEs identified by the Malignant or Unspecified Tumors SMQ will be 
summarized by HLT and PT. Other SMQs or AE groupings may be evaluated. 
All AEs occurring on-study, including both treatment emergent and non-treatment emergent 
events, will be listed in patient data listings. A separate listing will be provided for IRRs. 
Listings will be provided for any AEs assessed by the Investigator as related to premedication or 
any study procedure. Non-treatment emergent AEs will also be listed separately. 
By-patient listings will also be provided for the following: all patient deaths, all SAEs, and AEs 
leading to study withdrawal. 


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4.7.3. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. 
Summary data for each laboratory parameter will be presented for each continuous clinical 
laboratory parameter (including hematology, serum chemistry, coagulation studies, thyroid, and 
liver function tests). Descriptive statistics will be presented for the actual values, change from 
baseline, and percent change from baseline by scheduled visit. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges. Shift tables will be employed to summarize the baseline 
category versus the “worst” post-baseline category, where the “worst” post-baseline category 
will be based on the maximum difference (in absolute value) from the upper or lower limits of 
the normal range. 
A listing will be produced for all patients with abnormal liver function tests defined as an ALT 
>3 ×ULN, AST >3 ×ULN, and/or total bilirubin >2 ×ULN at any time point. 
A table will be produced to summarize the number and percentage of patients in each of the 
below categories at any post-baseline time point. 
 AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20 ×ULN, 
 ALT or AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20 ×ULN, 
 ALP >1.5 ×ULN, 
 Total Bilirubin >1.5 & ≤2, >2 & ≤3, >3 & ≤5 and >5 ×ULN, 
 Total Bilirubin >2 ×ULN concurrent with ALT or AST >3 ×ULN. 
The peak total bilirubin (at any time post-baseline) will be plotted against the peak AST or ALT 
level at any time post-baseline. 
Laboratory test results will be graded according to the NCI CTCAE Version 4.0 or above, where 
applicable. A shift summary of baseline to maximum post-baseline CTCAE grade may be 
presented, as appropriate. 
The estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) will be categorized as follows: 
≥90; 60-89; 30-59; 15-29 and <15. A shift summary of baseline to worst post-baseline eGFR 
category will be presented. 
All laboratory data will be provided in data listings. Laboratory values outside of the normal 
ranges will additionally be listed separately. 
4.7.4. 
Vital Signs and Physical Examination 
The observed values and changes from baseline in weight and vital signs, including blood 
pressure, pulse rate, oral body temperature and respiration rate, will be summarized by 
scheduled visit. The frequency and percentage of patients with an abnormal change from 
baseline in pulse rate or blood pressure measures will also be presented. 
Vital sign measurements will be presented for each patient in a data listing. 
All abnormal physical examination findings will be presented in a by-patient data listing. 


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4.7.5. 
Ophthalmology Examinations 
Ophthalmology examinations include Visual Acuity, Slit Lamp Biomicroscopy, and Visual 
Field assessments. 
Visual Acuity and Visual Field Exam Results: The actual value and change from baseline 
results will be summarized by scheduled visit. 
Biomicroscopy (Slit Lamp) Exam Results: For the baseline results, the number and percentage 
of patients falling into each category of the examination status (normal, abnormal/not clinically 
significant, abnormal/clinically significant) will be summarized for each eye structure. For post-
baseline results, the number and percentage of patients falling into each category of the 
examination status (new findings/worsening of finding, no change, improvement of finding) will 
be summarized for each eye structure. 
Data for each of these assessments will be provided in a data listing. 
4.7.6. 
Premedications 
All patients will receive premedication prior to the dose of patisiran in order to reduce the 
potential of an IRR. The original premedication regimen as outlined below was used at the start 
of the study. A subset of patients experienced AEs suspected to be related to steroids (e.g., 
flushing) and were transitioned to a reduced premedication regimen, with a reduced dose of 
corticosteriod to mitigate these events, as sanctioned in the protocol. After observing that the 
subset of patients tolerated the lower corticosteroid dose with no increase in IRRs, the protocol 
was amended (Amendment 1.0) to transition the rest of the patients to the reduced 
premedication regimen (see below). 
The following original premedication regimen was used prior to protocol amendment 1.0: 
 Dexamethasone 8 mg PO or equivalent administered the evening before dosing and 
20 mg PO at least 60 minutes prior to the start of the infusion of patisiran; 
 Paracetamol 500 mg PO or equivalent administered the evening before dosing and at 
least 60 minutes prior to the start of the infusion of patisiran; 
 H2 blocker PO (e.g., ranitidine 150 mg or famotidine 20 mg or equivalent other H2 
blocker dose) administered the evening before dosing and at least 60 minutes prior to 
start of the infusion of patisiran; and 
 H1 blocker PO, 10 mg cetirizine or equivalent (hydroxyzine 25 mg or fexofenadine 
could be substituted if patient did not tolerate cetirizine) administered the evening before 
dosing and at least 60 minutes prior to start of the infusion of patisiran. 
The following reduced premedication regimen was instituted for all patients with protocol 
amendment 1.0: 
 Dexamethasone 10 mg IV or equivalent, administered at least 60 minutes prior to the 
start of the infusion of patisiran; 
 Paracetamol 500 mg PO or equivalent at least 60 minutes prior to the start of the 
infusion of patisiran; 
 H2 blocker IV (e.g., ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 blocker 
dose) at least 60 minutes prior to the start of the infusion of patisiran; and 


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 H1 blocker IV, diphenhydramine 50 mg (or equivalent other IV H1 blocker available at 
the study site) at least 60 minutes prior to the start of the infusion of patisiran. 
Hydroxyzine 25 mg PO or fexofenadine 30 or 60 mg PO or cetirizine 10 mg PO could 
be substituted for any patient who did not tolerate IV diphenhydramine or other IV H1 
blocker. 
Premedications will be coded using the WHO Drug Dictionary (March 2015 or later). Results 
will be tabulated by anatomic therapeutic class (ATC) and PT. Premedication data will be listed. 
4.7.7. 
Concomitant Medications 
Concomitant medications will be defined as those medications that were initiated after first 
patisiran administration in this extension study or those that were ongoing at the time of the first 
patisiran administration in this study. For medications with partial start or stop dates: the first 
day/month will be imputed for start date, and the last day/month will be imputed for stop date. 
For medications with a completely missing start date, the medications will be considered as 
started prior to the first dose of study drug; medications will be classified as prior, concomitant 
or both depending on the medication stop dates. For medications with a completely missing stop 
date, the earlier of the data cut-off date or the end of study date will be imputed. 
Concomitant medications will be coded using the WHO Drug Dictionary (March 2015 or later). 
Results will be tabulated by ATC and PT; patients will only count once for each ATC or PT in 
the event that they have multiple medications with the same ATC or PT. Medications taken as 
protocol-specified premedications will be summarized separately. 
Concomitant medications will be included in a by-patient data listing. 
4.7.8. 
Suicide Questionnaire 
The numbers and percentages of patients experiencing the suicidal ideation, suicidal behavior, 
or self-injurious behavior composite outcomes (and individual components thereof) during the 
treatment period will be summarized. A shift table will be employed to summarize the baseline 
C-SSRS category versus the worst post-baseline C-SSRS category; the categories are defined as 
1) no suicidal ideation or behavior, 2) suicidal ideation, and 3) suicidal behavior. Subjects 
experiencing both suicidal ideation and suicidal behavior are included in the suicidal behavior 
category. 
Data from the C-SSRS questionnaire will be provided in a data listing. 
4.8. 
Anti-Drug Antibody 
Anti-drug antibody data will be presented in a data listing. Patients with positive ADA results 
will be presented in a separate listing. 


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5. 
CHANGES TO PLANNED ANALYSES 
In the protocol, the first day of drug administration in this study was designated as Day 0. In the 
SAP and table/listing/figure outputs, the first dose day will be defined as Day 1, following 
CDISC convention. Each calculated study day after dosing is 1 day plus the reported study day 
following the protocol defined Schedule of Assessments. 
In addition to IENFD and SGNFD, skin punch biopsies will also be assessed for dermal amyloid 
content, which has been added as an efficacy parameter. 
 


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6. 
REFERENCES 
 
1  Akinc A, Zumbuehl A, et al. A combinatorial library of lipid-like materials for delivery of 
RNAi therapeutics. Nat Biotechnol. 2008;26(5):561-569. 


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7. 
QUESTIONNAIRE/SCORING APPENDICES 
In questionnaires, if multiple responses are provided to a single-response question, the question 
is deemed as missing. 
7.1. 
Modified Neuropathy Impairment Score + 7 (mNIS+7) and 
Neuropathy Impairment Score + 7 (NIS+7) 
Note: the mNIS+7 and NIS+7 measurements are conducted in duplicate per time point. The 
average of 2 complete duplicate values will be reported, except in cases of missing or partially 
missing data as described below. 
Assessment Tool 
Total 
Points 
Components (maximum points) 
mNIS+7 
304 
 
NIS-W: Weakness (192) 
 
NIS-R: Reflexes (20) 
 
Quantitative sensory testing by body surface area including touch 
pressure (TP) and heat as pain (HP): QST-BSATP+HP5 (80) 
 
∑5 nerve conduction studies (10) 
• 
Ulnar compound muscle action potential (ulnar CMAP) 
• 
Ulnar sensory nerve action potential (ulnar SNAP) 
• 
Sural sensory nerve action potential (sural SNAP) 
• 
Tibial compound muscle action potential (tibial CMAP) 
• 
Peroneal compound muscle action potential (peroneal CMAP) 
 
Postural blood pressure (BP) (2) 
NIS+7 
270 
 
NIS-W: Weakness (192) 
 
NIS-R: Reflexes (20) 
 
NIS-S: Sensation (32) 
 
∑7 Nerve tests 
 
5 Nerve conduction studies ∑5 (18.6) 
• 
Peroneal compound muscle action potential (peroneal CMAP) 
• 
Peroneal motor nerve conduction velocity (peroneal MNCV) 
• 
Peroneal motor nerve distal latency (peroneal MNDL) 
• 
Tibial motor DL 
• 
Sural sensory nerve action potential (sural SNAP) 
 
Vibration detection threshold (VDT) (3.72) 
 
Heart rate response to deep breathing (HRdb) (3.72) 


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7.1.1. 
Modified Neuropathy Impairment Score + 7 (mNIS+7) 
There are 5 components within mNIS+7 total score including NIS-W, NIS-R, QST, ∑5 NC, and 
postural BP, as described in detail below. 
1. NIS-W is the sum of the cranial nerve components (3rd nerve, 6th nerve, facial weakness, 
palate weakness, tongue weakness) and muscle weakness components (respiratory, neck 
flexion, shoulder abduction, elbow flexion, brachioradialis, elbow extension, wrist 
flexion, wrist extension, finger flexion, finger spread, thumb abduction, hip flexion, hip 
extension, knee flexion, knee extension, ankle dorsiflexors, ankle plantar flexors, toe 
extensors, toe flexors). Assessments are performed separately for the right- and left-hand 
side of the body. Scoring for each component is 0 (normal), 1 (25% weak), 2 (50% 
weak), 3 (75% weak), 3.25 (move against gravity), 3.5 (movement, gravity eliminated), 
3.75 (muscle flicker, no movement), and 4 (paralysis). The maximum total score for 
NIS-W is 192. 
2. NIS-R is the sum of the reflex components (biceps brachii, triceps brachii, 
brachioradialis, quadriceps femoris, and triceps surae). Assessments are performed 
separately for the right and left foot. Scoring for each component is 0 (normal), 1 
(decreased) and 2 (absent). Adjustments are made for the age of the patient (e.g., absent 
reflexes in a patient older than 60 is assessed as 0, or normal). The maximum total score 
for NIS-R is 20. 
3. QST measures HP and TP from among 10 distributed anatomical sites on one side of the 
body. Scoring is based on point abnormality (<95th = 0 point, ≥95th – <99th = 1 point and 
≥99th = 2 points). The test score is 2 times the total scores for QST of HP by body 
surface area (QST-BSAHP) and QST of TP by body surface area (QST-BSATP). The 
maximum total score for QST is 80. Missing values for QST-BSAHP and QST-BSATP 
will be imputed separately (see below), but only the total score will be summarized. 
4. ∑5 nerve conductions include ulnar CMAP, ulnar SNAP, sural SNAP, tibial CMAP, and 
peroneal CMAP. Their measured values were transformed to normal deviates from 
percentile values correcting for applicable variables of age, gender, height or weight as 
based on earlier studies of a large healthy patient reference cohort. Additionally, these 
percentile values were expressed as points from obtained percentile values (i.e., >5th = 0 
points; ≤5th – >1st = 1 point and ≤1st = 2 points (and similarly when abnormality is in the 
upper tail of the normal distribution). The total score is calculated as the mean point 
scores of the non-missing 5 nerve tests and multiply this value by 5. The maximum total 
score for ∑5 NC is 10. 
5. Postural BP test measures autonomic function to address risk of orthostasis. The points 
are assigned based on change in PBP (> -20 mmHg = 0 points; > -30 - ≤ -20 mmHg = 1 
point; and ≤ -30 mmHg = 2 points). 
If at least 1 value at a time point and (replicate) assessment is missing then do the following: 
 Missing items within the ∑5 NCs component (e.g., missing tibial CMAP) are handled in 
Step 4 above. 


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 If 1 of the following components or subcomponents of mNIS+7 (NIS-W, NIS-S, QST-
BSATP, QST-BSAHP, the entire ∑5 NCs, or postural BP) is missing from 1 of the 
assessments at a time point (“replicate A”), then impute via substituting the component 
from the other assessment at that time point (“replicate B”)  recover 2 complete 
replicate mNIS+7 measures A and B at that particular time point. 
 If both replicates A and B are incomplete at different components, insert replicate A 
components into replicate B and replicate B components into replicate A as necessary  
allow recovery of 2 complete replicate mNIS+7 measures A and B. 
 If NIS-W component is missing from both replicates A & B, mNIS+7 score is 
considered as missing. If 1 of the other mNIS+7 components or subcomponents (NIS-R, 
the entire ∑5 NCs, QST-BSATP, QST-BSAHP, or postural BP) is missing from both 
replicates A and B, impute this component as the average of the component using data 
from any of the patients who had non-missing data for that component at the time point. 
 If 1 entire mNIS+7 replicate is missing, do not impute the missing replicate; just use the 
singular (other) replicate rather than the average of the 2 in subsequent calculations. 
 If no single complete mNIS+7 measure can be found or recovered, mNIS+7 score is 
considered as missing. 
In 006, if the last mNIS+7 assessment in the parent study was done more than 45 days before 
the first dose in 006, mNIS+7 will be reassessed on Day 1 in 006. It is expected that very few 
patients will have this Day 1 assessment; therefore, the imputation algorithm for missing 
components in mNIS+7 will be slightly different from the general algorithm. If NIS-W is 
missing from both replicates, the mNIS+7 total score will be considered as missing, similar to 
the general algorithm. If any other component is missing from both replicates, the component 
score will be imputed by last observation carried forward (LOCF) using the imputed average 
component score from the last assessment in the parent study. 
7.1.2. 
Neuropathy Impairment Score + 7 (NIS+7) 
The components of NIS+7 include the following: 
1. NIS-W as described in previous section. 
2. NIS-R as described in previous section. 
3. NIS-S is the sum of the finger and toe sensation components (TP, pin-prick, vibration, 
joint position). Assessments are performed separately for the right- and left-hand side of 
the body. Scoring for the sensory assessment is 0 (normal), 1 (decreased) and 2 (absent). 
The maximum total score for NIS-S is 32. 
4. ∑7 nerve tests normal deviates include the following: 
 ∑5 nerve conductions: 
o For peroneal DL and tibial DL, using normal deviate. 
o For peroneal CMAP, peroneal CV and sural SNAP, using (-1) × normal 
deviate. 
 Vibration detection threshold (VDT): using normal deviate. 
 Heart rate response to deep breathing (HRdb): using (-1) × normal deviate. 


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Each normal deviate ranges from -3.72 to +3.72. The total score is calculated as the 
mean normal deviates of the non-missing 7 nerve tests multiplied by 7. The total score 
ranges from -26 to +26. 
Missing values will be handled as follows: 
 Missing items within the 7 nerve tests are handled in Step 4 above. 
 If a component of NIS+7 (NIS-W, NIS-R, NIS-S, and 7 nerve tests) is missing from 
replicate A, then impute the component from replicate B  recover 2 complete replicate 
NIS+7 measures A and B. 
 If both replicates A and B are incomplete at different components, insert A components 
into B and B components into A as necessary  recover 2 complete replicate NIS+7 
measures A and B. 
 If NIS-W component is missing from both replicates A & B, NIS+7 score is considered 
as missing. If 1 of the other NIS+7 components (NIS-R, NIS-S, and 7 nerve tests) is 
missing from both replicates A and B, impute this component as the average of the other 
patients at this time point who had non-missing data. 
 If 1 entire NIS+7 replicate is missing, use the singular (other) replicate rather than the 
average of the 2 in subsequent calculations. 
 If no single complete NIS+7 measure can be found or recovered, NIS+7 score is 
considered as missing. 
In 006, if the last NIS+7 assessment in the parent study was done more than 45 days before the 
first dose in 006, NIS+7 will be reassessed on Day 1 in 006. It is expected that very few patients 
will have this Day 1 assessment; therefore, the imputation algorithm for missing components in 
NIS+7 will be slightly different from the general algorithm. If NIS-W is missing from both 
replicates, the NIS+7 total score will be considered as missing, similar to the general algorithm. 
If any other component is missing from both replicates, the component score will be imputed by 
LOCF using the imputed average component score from the last assessment in the parent study. 
7.1.3. 
NIS Total Score 
NIS total score is the sum of NIS-W, NIS-R, and NIS-S. The handling of missing data is similar 
as the steps described for mNIS+7. If NIS-W is missing from both replicates, NIS score is 
considered as missing. 
7.1.4. 
Algorithms for Setting Normal Deviates and Points 
For nerve conductions and HRdb tests, raw values are provided by the Mayo Clinic. Each raw 
value is first converted to a z-score which is then used to set either normal deviate or point 
score. 
Z-scores are calculated using the following equations provided by the Mayo Clinic: 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-006 
12 July 2017, Final Version 1.0 
 
CONFIDENTIAL 
27 
Parameter  
(abbreviation, units) 
Z-score Equation 
Heart Rate Response to Deep 
Breathing (HRdb, beats/min) 
HRdbz = HRdb - (28.87292939 + -0.24448047*age) 
Ulnar CMAP (UMAE, mV) 
UMAEz = UMAE - (12.34105776660360 + -0.04413566229394*age) 
Peroneal CMAP (PMAK, mV) 
PMAKz = PMAK - (7.26194271992764 + -0.04324792361150*age) 
Peroneal MNCV (PMCVK, 
m/sec) 
PMCVKz = PMCVK - (87.98055432974630 + 0.01685327077581*age +  
 -0.00134262390616*age2 + -0.21761114034235*height) 
Peroneal MNDL (PMLA, 
msec) 
PMLAz = PMLA - (4.97158112197395 + -0.36990514432031*sex) 
Tibial CMAP (TMAK, mV) 
TMAKz = TMAK - (11.91330602787780 + 0.79541113237729*age +  
 -0.01622568048284*age2 + 0.00008722708244*age3 +  
 -5.49838000227032*bsa) 
Tibial MNDL (TMLA, msec) 
TMLAz = TMLA - (4.00321823725368 + 0.00588241012995*age +  
 -0.25248993385258*sex) 
Sural SNAP (SSAB, uV) 
y = ln(1+SSAB) - (5.58389110852732 + 0.01546531508256*age +  
 -0.01693664229181*height + -0.00034198271691*age2) 
if y > 0 then SSABz = y/( 0.7001926549587 + -0.20662093194825*bsa) 
 else if y ≤ 0 then SSABz = y 
Wrist-Fifth Ulnar SNAP 
(USAW, uV) 
y = ln(1+USAW) - (3.38461614473185 + -0.01702085210501*age + 
 0.59463420483099*sex) 
if y > 0 then USAWz = y 
 else if y ≤ 0 then USAWz = y/(0.16695910921534 + 0.00291051555416*age) 
Notes:  
1) sex is coded 1 = male, 2 = female 
2) height is in cm 
3) weight is in kg 
4) bsa = body surface area (m2) = weight0.425 × height0.725 × 0.007184 
5) age is an integer rounded down to the nearest year 
For a given parameter, the calculated z-score is then compared to 2 lookup tables (see below) 
using the following procedure to assign the normal deviate score: 
1. If the calculated z-score value is less than the lower z-score value (ZLOWER) in the 
Extended Percentiles (EP) table, then the normal deviate value is the maximum of 
(-3.72, (z-score – ZLOWER + WLOWER)). 
2. If the calculated z-score value is greater than or equal to ZLOWER and less than the 
minimum z-score value in the All Percentiles (AP) table, then the normal deviate value 
= -2.75. 
3. If the calculated z-score value is greater than upper z-score value (ZUPPER) in the EP 
table, then the normal deviate value is the minimum of (3.72, (z-score – ZUPPER + 
WUPPER)). 
4. If the calculated z-score value is less than or equal to ZUPPER and greater than the 
maximum z-score value in the AP table, then the normal deviate value = 2.75. 


Alnylam Pharmaceuticals, Inc. 
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12 July 2017, Final Version 1.0 
 
CONFIDENTIAL 
28 
5. If the calculated z-score falls between 2 values in the AP table, select the z-score with 
the normal deviate value closer to 0 (i.e., the 50th percentile). The normal deviate value is 
the value from the Normal Deviate column corresponding to the selected z-score. For 
example, if PMLAZ = -0.8 then the PMLA normal deviate (PMLAND) value = -1.65. If 
PMLAZ = 2.2 then PMLAND = 2.37. 
6. If the calculated z-score is less than or equal to the z-score corresponding to the 50th 
percentile and exactly matches a z-score for that parameter in the AP table, then select 
the row with the next highest z-score value. The normal deviate value is the value from 
the Normal Deviate column corresponding to the selected z-score. For example, if 
PMLAZ = -0.9017 then PMLAND = -1.88. 
7. If the calculated z-score is greater than the z-score corresponding to the 50th percentile 
and exactly matches a z-score for that parameter in the AP table, then select the row with 
the next lowest z-score value. The normal deviate value is the value from the Normal 
Deviate column corresponding to the selected z-score. For example, if PMLAZ = 2.2682 
then PMLAND = 2.37. 
The points for the parameters are calculated as follows: 
1. For PMLA, TMLA, and VDT: z-scores <1.65 are assigned 0 points, z-scores ≥1.65 but 
<2.33 are assigned 1 point, and z-scores ≥2.33 are assigned 2 points. 
2. For HRdb, UMAE, PMAK, PMCVK, TMAK, SSAB, and USAW: z-scores > -1.65 are 
assigned 0 points, z-scores ≤ -1.65 but < -2.33 are assigned 1 point, and z-scores ≤ -2.33 
are assigned 2 points. 
 
 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-006 
12 July 2017, Final Version 1.0 
 
CONFIDENTIAL 
29 
All Percentiles Table 
Percentile 
Normal 
Deviate 
HRdb 
UMAE 
PMAK 
PMCVK 
PMLA 
TMAK 
TMLA 
USAW 
SSAB 
0.3 
-2.75 
-12.783 
-5.5287 
-4.6320 
-9.3076 
-1.0017 
-7.6549 
-0.9448 
-4.5129 
-2.3235 
0.4 
-2.65 
-12.4944 
-5.5287 
-4.6320 
-9.3076 
-1.0017 
-7.6549 
-0.9448 
-4.5129 
-2.3235 
0.5 
-2.58 
-12.4944 
-5.5287 
-4.6320 
-9.3076 
-1.0017 
-7.6549 
-0.9448 
-4.5129 
-2.3235 
0.6 
-2.51 
-12.4944 
-5.1192 
-4.3753 
-8.8001 
-1.0017 
-7.2749 
-0.9037 
-4.1808 
-2.2050 
0.7 
-2.46 
-12.2499 
-5.1192 
-4.3753 
-8.8001 
-1.0017 
-7.2749 
-0.9037 
-4.1808 
-2.2050 
0.8 
-2.41 
-12.2499 
-4.8488 
-4.3712 
-8.8001 
-1.0017 
-7.2270 
-0.8394 
-3.9289 
-2.1063 
0.9 
-2.37 
-12.2499 
-4.8488 
-4.3671 
-8.7164 
-0.9017 
-7.2270 
-0.8394 
-3.9289 
-2.1063 
1 
-2.33 
-11.4044 
-4.8488 
-4.3671 
-8.7164 
-0.9017 
-7.2270 
-0.8394 
-3.9289 
-2.1063 
2 
-2.05 
-10.6489 
-4.0722 
-3.8807 
-6.9587 
-0.9017 
-7.0107 
-0.7982 
-2.7648 
-1.0013 
3 
-1.88 
-10.2499 
-3.6577 
-3.1211 
-6.3385 
-0.8017 
-6.2660 
-0.7159 
-2.4600 
-0.9160 
4 
-1.75 
-10.0054 
-3.4371 
-3.0279 
-5.5293 
-0.8017 
-5.7380 
-0.6688 
-2.0958 
-0.7910 
5 
-1.65 
-9.7388 
-3.2846 
-2.9915 
-4.9611 
-0.7318 
-5.5688 
-0.6335 
-2.0534 
-0.7595 
6 
-1.56 
-9.3603 
-3.1142 
-2.9481 
-4.7403 
-0.7318 
-5.0376 
-0.5982 
-1.9855 
-0.7098 
7 
-1.48 
-9.2041 
-2.9929 
-2.8510 
-4.3695 
-0.7017 
-4.7452 
-0.5625 
-1.8139 
-0.6757 
8 
-1.41 
-8.3161 
-2.9192 
-2.7860 
-4.3445 
-0.6318 
-4.4486 
-0.5448 
-1.7251 
-0.6156 
9 
-1.34 
-7.8272 
-2.7729 
-2.6320 
-3.9685 
-0.6318 
-4.3632 
-0.5037 
-1.6250 
-0.5995 
10 
-1.28 
-7.2262 
-2.6901 
-2.4320 
-3.7034 
-0.6017 
-4.2040 
-0.4865 
-1.6014 
-0.5764 
11 
-1.23 
-7.0496 
-2.5750 
-2.3156 
-3.4907 
-0.6017 
-4.0853 
-0.4743 
-1.4781 
-0.5648 
12 
-1.18 
-6.9596 
-2.4377 
-2.2738 
-3.2399 
-0.6017 
-3.9092 
-0.4512 
-1.4231 
-0.5289 
13 
-1.13 
-6.783 
-2.3142 
-2.1563 
-2.9994 
-0.5318 
-3.8051 
-0.4394 
-1.3393 
-0.5133 
14 
-1.08 
-6.6489 
-2.1605 
-2.0428 
-2.9135 
-0.5318 
-3.6773 
-0.4277 
-1.2372 
-0.4995 
15 
-1.04 
-6.3603 
-2.0225 
-1.9645 
-2.8256 
-0.5318 
-3.5900 
-0.4100 
-1.1589 
-0.4773 
16 
-0.99 
-6.2041 
-1.9701 
-1.8968 
-2.7349 
-0.5318 
-3.4409 
-0.4037 
-1.1203 
-0.4555 
17 
-0.95 
-5.9833 
-1.9080 
-1.8590 
-2.6739 
-0.5318 
-3.2858 
-0.3865 
-1.0880 
-0.4279 
18 
-0.92 
-5.9596 
-1.8577 
-1.8346 
-2.4869 
-0.5017 
-3.1555 
-0.3860 
-1.0282 
-0.4215 
19 
-0.88 
-5.8713 
-1.7605 
-1.7293 
-2.3484 
-0.5017 
-3.0824 
-0.3684 
-0.9673 
-0.3858 
20 
-0.84 
-5.7593 
-1.7019 
-1.6495 
-2.2547 
-0.5017 
-2.9948 
-0.3512 
-0.9323 
-0.3752 
21 
-0.81 
-5.5827 
-1.6695 
-1.6238 
-2.1736 
-0.4318 
-2.8392 
-0.3448 
-0.9115 
-0.3611 
22 
-0.77 
-5.4707 
-1.6377 
-1.5266 
-2.1275 
-0.4318 
-2.6699 
-0.3394 
-0.8764 
-0.3578 
23 
-0.74 
-5.3382 
-1.5426 
-1.4375 
-2.0479 
-0.4017 
-2.6461 
-0.3218 
-0.8461 
-0.3288 
24 
-0.71 
-5.2703 
-1.4818 
-1.3954 
-1.9541 
-0.4017 
-2.5639 
-0.3213 
-0.8201 
-0.3198 
25 
-0.67 
-4.9817 
-1.3633 
-1.3401 
-1.8102 
-0.3318 
-2.4213 
-0.3159 
-0.8141 
-0.3080 
26 
-0.64 
-4.9596 
-1.3102 
-1.2428 
-1.6411 
-0.3318 
-2.3032 
-0.3037 
-0.7693 
-0.2923 
27 
-0.61 
-4.6268 
-1.2259 
-1.1266 
-1.5417 
-0.3318 
-2.2417 
-0.2978 
-0.7567 
-0.2861 
28 
-0.58 
-4.4486 
-1.1722 
-1.0847 
-1.4258 
-0.3318 
-2.1872 
-0.2688 
-0.7011 
-0.2745 
29 
-0.55 
-4.2041 
-1.0840 
-1.0103 
-1.3566 
-0.3017 
-2.0659 
-0.2453 
-0.6843 
-0.2657 
30 
-0.52 
-4.0937 
-1.0488 
-1.0021 
-1.2907 
-0.3017 
-2.0309 
-0.2335 
-0.6642 
-0.2466 
31 
-0.5 
-4.0038 
-1.0142 
-0.9508 
-1.2377 
-0.3017 
-1.9931 
-0.2277 
-0.6416 
-0.2374 
32 
-0.47 
-3.7814 
-0.9253 
-0.9198 
-1.0846 
-0.3017 
-1.9077 
-0.2218 
-0.5357 
-0.2242 
33 
-0.44 
-3.6268 
-0.8750 
-0.8671 
-0.9904 
-0.2318 
-1.7583 
-0.2159 
-0.5096 
-0.1981 
34 
-0.41 
-3.4707 
-0.7778 
-0.8158 
-0.9556 
-0.2318 
-1.6953 
-0.2096 
-0.4527 
-0.1894 


Alnylam Pharmaceuticals, Inc. 
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12 July 2017, Final Version 1.0 
 
CONFIDENTIAL 
30 
35 
-0.39 
-3.2924 
-0.7371 
-0.7618 
-0.8822 
-0.2318 
-1.6426 
-0.1924 
-0.3916 
-0.1858 
36 
-0.36 
-3.182 
-0.7074 
-0.7523 
-0.8417 
-0.2318 
-1.6022 
-0.1860 
-0.3633 
-0.1721 
37 
-0.33 
-3.0479 
-0.6701 
-0.6942 
-0.7822 
-0.2318 
-1.5846 
-0.1747 
-0.3306 
-0.1566 
38 
-0.31 
-3.0259 
-0.6287 
-0.6483 
-0.6634 
-0.2017 
-1.5418 
-0.1688 
-0.2903 
-0.1415 
39 
-0.28 
-2.9596 
-0.5661 
-0.6078 
-0.6256 
-0.2017 
-1.3820 
-0.1566 
-0.2631 
-0.1236 
40 
-0.25 
-2.8272 
-0.4846 
-0.5467 
-0.5417 
-0.2017 
-1.3434 
-0.1507 
-0.2465 
-0.1043 
41 
-0.23 
-2.7388 
-0.4074 
-0.5348 
-0.4421 
-0.1318 
-1.2323 
-0.1390 
-0.2363 
-0.0878 
42 
-0.2 
-2.671 
-0.3633 
-0.4346 
-0.3655 
-0.1318 
-1.2023 
-0.1277 
-0.2028 
-0.0774 
43 
-0.18 
-2.2041 
-0.2985 
-0.3995 
-0.3276 
-0.1318 
-1.0807 
-0.1213 
-0.1897 
-0.0668 
44 
-0.15 
-2.1599 
-0.2516 
-0.3077 
-0.2133 
-0.1318 
-0.8723 
-0.1154 
-0.1189 
-0.0559 
45 
-0.13 
-2.0038 
-0.1454 
-0.2103 
-0.1076 
-0.1017 
-0.8126 
-0.1096 
-0.0814 
-0.0369 
46 
-0.1 
-1.8713 
-0.1019 
-0.1778 
-0.0405 
-0.1017 
-0.7094 
-0.0924 
-0.0478 
-0.0225 
47 
-0.08 
-1.6489 
-0.0343 
-0.1373 
-0.0001 
-0.1017 
-0.5876 
-0.0801 
-0.0218 
-0.0129 
48 
-0.05 
-1.6047 
-0.0170 
-0.1143 
0.0387 
-0.1017 
-0.5527 
-0.0743 
0.0061 
-0.0013 
49 
-0.03 
-1.3382 
0.0160 
-0.1048 
0.0957 
-0.0318 
-0.4625 
-0.0629 
0.0136 
0.0217 
50 
0 
-1.0937 
0.0623 
-0.0618 
0.1549 
-0.0318 
-0.3295 
-0.0512 
0.0188 
0.0689 
51 
0.03 
-1.0275 
0.0830 
0.0032 
0.2071 
-0.0318 
-0.2915 
-0.0448 
0.0190 
0.1077 
52 
0.05 
-0.7814 
0.1278 
0.0654 
0.2973 
-0.0017 
-0.1557 
-0.0390 
0.0248 
0.1716 
53 
0.08 
-0.7593 
0.1602 
0.1059 
0.3555 
-0.0017 
-0.1220 
-0.0331 
0.0348 
0.1897 
54 
0.1 
-0.4944 
0.1802 
0.1572 
0.3712 
-0.0017 
-0.0486 
-0.0213 
0.0413 
0.2291 
55 
0.13 
-0.0937 
0.2484 
0.2032 
0.4167 
-0.0017 
0.1142 
-0.0096 
0.0479 
0.2536 
56 
0.15 
0.217 
0.2947 
0.2220 
0.4744 
0.0682 
0.2349 
-0.0041 
0.0566 
0.2940 
57 
0.18 
0.4173 
0.3299 
0.2490 
0.5896 
0.0682 
0.3547 
0.0253 
0.0679 
0.3011 
58 
0.2 
0.5735 
0.4133 
0.3410 
0.6710 
0.0682 
0.4620 
0.0316 
0.0888 
0.3257 
59 
0.23 
0.6618 
0.4568 
0.4220 
0.7195 
0.0682 
0.5717 
0.0547 
0.0932 
0.3661 
60 
0.25 
0.8842 
0.5222 
0.4734 
0.7472 
0.0682 
0.6988 
0.0665 
0.1035 
0.3965 
61 
0.28 
1.0404 
0.5747 
0.4950 
0.7809 
0.0682 
0.8750 
0.0669 
0.1171 
0.4216 
62 
0.31 
1.1949 
0.6574 
0.5681 
0.8423 
0.0682 
0.9640 
0.0782 
0.1228 
0.4373 
63 
0.33 
1.2612 
0.7423 
0.6625 
0.9056 
0.0983 
1.1068 
0.0841 
0.1330 
0.4770 
64 
0.36 
1.5293 
0.7830 
0.6869 
0.9563 
0.0983 
1.1252 
0.0963 
0.1398 
0.4957 
65 
0.39 
1.706 
0.8250 
0.7114 
1.0163 
0.0983 
1.2375 
0.1140 
0.1501 
0.5152 
66 
0.41 
1.8621 
0.8540 
0.7681 
1.0514 
0.0983 
1.2980 
0.1199 
0.1575 
0.5415 
67 
0.44 
1.9962 
0.8892 
0.8490 
1.1319 
0.1682 
1.5574 
0.1316 
0.1721 
0.5839 
68 
0.47 
2.1287 
0.9389 
0.9058 
1.2285 
0.1682 
1.6796 
0.1493 
0.1822 
0.6237 
69 
0.5 
2.2612 
1.0037 
0.9463 
1.3007 
0.1682 
1.8460 
0.1669 
0.1872 
0.6942 
70 
0.52 
2.7738 
1.0629 
0.9627 
1.4587 
0.1983 
1.8750 
0.1782 
0.1953 
0.7186 
71 
0.55 
3.3511 
1.1305 
1.0895 
1.5916 
0.1983 
1.9733 
0.1841 
0.2049 
0.7646 
72 
0.58 
3.706 
1.1484 
1.1613 
1.6512 
0.2682 
2.0584 
0.1904 
0.2115 
0.8278 
73 
0.61 
4.0167 
1.2271 
1.1922 
1.7069 
0.2682 
2.1753 
0.2194 
0.2320 
0.8722 
74 
0.64 
4.2407 
1.2808 
1.2355 
1.7460 
0.2682 
2.2577 
0.2257 
0.2492 
0.9115 
75 
0.67 
4.4836 
1.3802 
1.2762 
1.7924 
0.2983 
2.3567 
0.2434 
0.2622 
0.9370 
76 
0.71 
4.6839 
1.4719 
1.3398 
1.8449 
0.2983 
2.6142 
0.2665 
0.2779 
0.9709 
77 
0.74 
5.1508 
1.5133 
1.3922 
1.9352 
0.2983 
2.7013 
0.2846 
0.2955 
0.9916 
78 
0.77 
5.5514 
1.5747 
1.4815 
2.2061 
0.3682 
2.7523 
0.3081 
0.3004 
1.0341 
79 
0.81 
5.7297 
1.6099 
1.5627 
2.3972 
0.3682 
2.8504 
0.3199 
0.3205 
1.0512 


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31 
80 
0.84 
6.1066 
1.7065 
1.6491 
2.5217 
0.3682 
3.0249 
0.3312 
0.3330 
1.0760 
81 
0.88 
6.4173 
1.7802 
1.7247 
2.5986 
0.3983 
3.1374 
0.3434 
0.3382 
1.1249 
82 
0.92 
6.5293 
1.8802 
1.8599 
2.7346 
0.3983 
3.2372 
0.3547 
0.3524 
1.1720 
83 
0.95 
6.7076 
1.9395 
1.9140 
2.8123 
0.4682 
3.3970 
0.3846 
0.3572 
1.2310 
84 
0.99 
7.2391 
2.0244 
1.9801 
2.9923 
0.4983 
3.5065 
0.4199 
0.3732 
1.2883 
85 
1.04 
7.6177 
2.1450 
1.9924 
3.0338 
0.4983 
3.6598 
0.4547 
0.3822 
1.3203 
86 
1.08 
8.0845 
2.2395 
2.0627 
3.1704 
0.5682 
3.8320 
0.4782 
0.3962 
1.3679 
87 
1.13 
8.217 
2.3305 
2.1275 
3.2896 
0.5983 
3.8959 
0.4959 
0.4054 
1.3814 
88 
1.18 
8.5514 
2.5574 
2.1924 
3.4144 
0.5983 
4.2745 
0.5900 
0.4366 
1.5034 
89 
1.23 
9.0404 
2.6361 
2.2815 
3.5946 
0.6682 
4.4199 
0.6076 
0.4498 
1.5338 
90 
1.28 
9.1949 
2.7657 
2.3654 
3.7666 
0.6983 
4.4980 
0.6257 
0.4756 
1.6781 
91 
1.34 
9.5073 
2.9512 
2.4599 
3.8362 
0.7682 
4.7815 
0.6488 
0.4876 
1.7277 
92 
1.41 
9.7297 
3.0596 
2.5342 
3.9685 
0.8682 
4.9848 
0.6552 
0.4995 
1.7787 
93 
1.48 
9.9741 
3.2333 
2.7005 
4.1271 
0.9682 
5.3345 
0.6787 
0.5271 
1.8612 
94 
1.56 
10.9521 
3.4389 
2.7815 
4.3815 
0.9983 
5.5661 
0.7665 
0.5548 
1.9634 
95 
1.65 
11.728 
3.6568 
2.9652 
4.6629 
1.0682 
6.1351 
0.7963 
0.5886 
2.0163 
96 
1.75 
12.4836 
3.7333 
3.1627 
5.0363 
1.1682 
6.3302 
0.8199 
0.6115 
2.1509 
97 
1.88 
13.8401 
3.9250 
3.8382 
5.1400 
1.2983 
6.9363 
0.9140 
0.6422 
2.2184 
98 
2.05 
14.6618 
4.3540 
4.0519 
5.5861 
1.5983 
7.9601 
1.1959 
0.7477 
2.4046 
99 
2.33 
17.728 
5.1216 
4.3517 
7.3224 
1.8983 
9.8583 
1.3963 
0.8782 
2.8233 
99.1 
2.37 
20.0845 
5.1216 
4.3517 
7.3224 
1.8983 
9.8583 
1.3963 
0.8782 
2.8233 
99.2 
2.41 
20.0845 
5.1216 
4.4761 
7.4064 
2.2682 
9.8583 
1.3963 
0.8782 
2.8233 
99.3 
2.46 
20.0845 
5.1685 
4.6005 
7.4064 
2.2682 
10.0358 
1.4371 
0.8803 
2.9923 
99.4 
2.51 
21.1728 
5.1685 
4.6005 
7.4064 
2.2682 
10.0358 
1.4371 
0.8803 
2.9923 
99.5 
2.58 
21.1728 
7.4830 
6.2977 
7.6495 
2.5983 
10.3303 
1.6728 
0.8973 
3.0371 
99.6 
2.65 
21.1728 
7.4830 
6.2977 
7.6495 
2.5983 
10.3303 
1.6728 
0.8973 
3.0371 
99.7 
2.75 
25.7517 
7.4830 
6.2977 
7.6495 
2.5983 
10.3303 
1.6728 
0.8973 
3.0371 
 
Extended Percentiles Table 
Variable 
WLOWER 
WUPPER 
ZLOWER 
ZUPPER 
HRdb 
-2.65 
2.65 
-12.6387 
23.4623 
UMAE 
-2.75 
2.75 
-7.4715 
7.5668 
PMAK 
-2.75 
2.75 
-5.1036 
6.4342 
PMCVK 
-2.75 
2.75 
-9.3393 
8.1941 
PMLA 
-2.75 
2.75 
-1.0517 
3.0833 
TMAK 
-2.75 
2.75 
-7.7785 
10.6018 
TMLA 
-2.75 
2.75 
-0.9831 
3.414 
USAW 
-2.75 
2.75 
-6.5249 
0.9233 
SSAB 
-2.75 
2.75 
-2.3692 
3.2713 
 
 


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7.2. 
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) 
Norfolk QOL-DN is a tool for assessing patients’ perception of the effects of diabetes and 
diabetic neuropathy. There are 35 questions divided into 5 domains. The range of possible total 
scores is -4 to 136. 
Part I: Symptoms 
Items 1-7 (Part I) are a simple inventory of symptoms of neuropathy. The presence of the 
symptom is checked in whichever box applies, and an absence of a symptom is checked under 
“none.” Positive responses are scored as 1; and negative responses, as 0. 
Part II: Activities of Daily Life 
Items 8-35 (Part II) pertain to Activities of Daily Life, and most of these are scaled on a 5-point 
Likert scale ranging from 0 (“Not a problem”) to 4 (“Severe problem”). However, Questions 31 
and 32 are scored differently. In Question 31, “Good,” the middle item, is scored as 0. “Very 
Good” is scored as –1, Excellent” is scored as –2. “Fair is scored as 1, and “Poor” is scored as 2. 
In Question 32, “About the Same,” the middle item, is scored as 0. “Somewhat better” is scored 
as –1, “Much better” is scored as -2. “Somewhat worse” is scored as 1 and “Much worse” is 
scored as 2. 
Subscales and Scoring Algorithm 
The Total QOL and 5 domains should be summed as follows: 
 Total QOL (35 items)  
 
 
Σ(1-7, 8-35) 
 Physical Functioning/Large Fiber (15 items) Σ(8, 11, 13-15, 24, 27-35 ) 
 Activities of Daily Living (ADLs) (5 items) Σ(12, 22, 23, 25, 26) 
 Symptoms (8 items)  
 
 
Σ(1-7, 9) 
 Small Fiber (4 items)  
 
 
Σ(10, 16, 17, 18) 
 Autonomic (3 items)  
 
 
Σ(19, 20, 21) 
The total score and domain scores are calculated without weighting of any kind, and reported as 
the integer sum of the listed questionnaire items. 
If at least 50% of the items are non-missing, domain scores are calculated as the average scores 
of non-missing included items multiplied by the number of items in the domain, rounded to the 
nearest integer. A domain score is missing if more than 50% of the included items are missing. 
If the scores for all 5 domains are non-missing, then Total QOL is the sum of scores of the 5 
domains; however, if at least 1 of the domains is missing and at least 50% of the items (18 
items) are non-missing, then Total QOL is calculated as 35 times the mean of the non-missing 
items, rounded to the nearest integer. Otherwise, Total QOL is deemed as missing. 
7.3. 
EuroQOL-5-Dimension 5-Level (EQ-5D-5L) 
Each of the 5 dimensions (Mobility, Self-Care, Usual Activities, Pain/Discomfort, 
Anxiety/Depression) is scored on a 5-point Likert scale from 1 (“I have no 
problems/pain/anxiety”) to 5 (“I am unable to…”, “I have extreme anxiety/depression”). 
The 5 scores are concatenated together (in the order of Mobility, Self-Care, Usual Activities, 
Pain/Discomfort, Anxiety/Depression) to create an EQ-5D-5L profile (e.g., 11111, 55555). The 


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profile is then used to obtain an index value using the United States value set. The index values 
range from –0.109, associated with a profile of 55555, to 1.0, associated with a profile of 11111. 
Smaller index values indicate greater impairment. 
Missing values are handled as follows: 
 Missing items are coded as “9” in creating patient profiles. 
 The index value is deemed as missing when responses are missing for 1 or more of the 5 
dimensions. 
 If the entire instrument is missing, the EQ-5D-5L index value is considered as missing. 
7.4. 
Rasch-Built Overall Disability Scale (R-ODS) 
The R-ODS consists of 24 items scored on a scale of 0 (unable to perform), 1 (able to perform, 
but with difficulty) or 2 (able to perform without difficulty). A total score will be calculated as 
the average of all non-missing items multiplied by 24 if at least 90% of the items are non-
missing. The total score will be deemed as missing if more than 10% of the items (3 or more 
items) are missing. 
7.5. 
Composite Autonomic Symptom Score-31 (COMPASS-31) 
The COMPASS-31 questionnaire comprises 6 domains: Orthostatic intolerance, Vasomotor, 
Secretomotor, Gastrointestinal, Bladder, and Pupillomotor. Within each domain, individual 
questions are scored as follows: Simple yes or no questions are scored as 0 points for no and 1 
point for yes. Questions about a specific site of symptoms or symptoms under specific 
circumstances are scored as 0 if not present and as 1 if present for each site or circumstance. All 
questions regarding the frequency of symptoms are scored as 0 points for rarely or never, 1 
point for occasionally or sometimes, 2 points for frequently or “a lot of the time,” and 3 points 
for almost always or constantly. All questions regarding the severity of symptoms are scored as 
1 point for mild, 2 points for moderate, and 3 points for severe. Questions assessing the time 
course of a symptom are scored 0 points for responses such as “gotten somewhat better,” 
“gotten much better,” “completely gone,” and “I have not had any of these symptoms,” 1 point 
for “stayed about the same,” 2 points for “gotten somewhat worse,” and 3 points for “gotten 
much worse.” The scores for changes in bodily functions depend on the individual question 
asked. For example, “I get full a lot more quickly than I used to when eating a meal” is scored 2 
points and “I get full a lot less quickly than I used to” is scored 0 points, while the answer “I 
sweat much more than I used to” is given 1 point and “I sweat much less than I used to” is 
scored 2 points. 
The overall scoring proceeds as follows: 
 Sum the numerical values associated with responses in each domain 
 Apply the following weighting factors to the domain sums: 
o Orthostatic intolerance, 4.0 
o Vasomotor, 0.83333333 
o Secretomotor, 2.1428571 
o Gastrointestinal, 0.8928571 
o Bladder, 1.1111111 
o Pupillomotor, 0.3333333 


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
Sum the weighted domain scores to obtain a total weighted score (maximum of 100)
Within each domain, there are “gatekeeper” questions. For example, consider questions 5-7:
5. In the past year, have you ever noticed color changes in your skin, such as red, white, or purple?
1 
Yes  
2 
No (if you marked No, please skip to question 8) 
6. What parts of your body are affected by these color changes? (Check all that apply)
1 
Hands 
2 
Feet 
7. Are these changes in your skin color:
1 
Getting much worse  
2 
Getting somewhat worse 
3 
Staying about the same  
4 
Getting somewhat better  
5 
Getting much better  
6 
Completely gone  
Answering “No” to question 5 obviates questions 6-7. Similarly, answering “Yes” to question 5 
causes the responses to questions 6-7 to be summed in the resulting overall score. A failure to 
answer question 5 would render responses to questions 6-7 problematic. Question 5 is the 
gatekeeper question and question 6-7 will be referred as subsequent questions. 
The full list of gatekeeper questions is: 

Question 1: Gatekeeper to questions, 2, 3, 4

Question 5: Gatekeeper to question 7

Question 16: Gatekeeper to questions 17, 18, 19

Question 20: Gatekeeper to questions, 21, 22, 23

Question 27: Gatekeeper to question 28

Question 29: Gatekeeper to question 30
A domain score will be deemed as missing if: 
1) Answering “No” or “Never” to gatekeeper question but non-missing responses to any of
the subsequent questions.
2) Answering “Yes” to gatekeeper question but 1 or more missing responses to subsequent
questions.
3) Missing response to gatekeeper question and 1 or more missing responses to subsequent
questions.
4) Multiple responses to the same question within a domain, with the exception of question
6 that says “check all.”
5) Missing response to a question within a domain that is not part of a gatekeeper/
subsequent question set. These questions are: 8, 9, 10, 11, 12, 13, 14, 15, 24, 25, 26, 31.
The exception is when both questions 9 & 10 are answered as “No” and question 11 is
missing, the score will be 0.
When a gatekeeper question is missing response but all subsequent questions are non-missing, 
the gatekeeper question will be imputed as “Yes” or the max impairment (example: 


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“Constantly” for questions 27 and 29). For questions 9, 10, and 11, if both questions 9 and 10 
are missing responses and the response to question 11 is “1,” question 9 & 10 will be imputed as 
“No.” For all other responses, question 9 & 10 will be imputed as “Yes.” 
For each patient, if ≤2 domain scores are missing, the total score will be calculated by imputing 
the missing domain score by the average domain score using data from any of the patients who 
had non-missing score for that domain at the time point. If more than 2 domain scores are 
missing, the total score will be deemed as missing. 
The full text of the COMPASS-31 is below. 
1. In the past year, have you ever felt faint, dizzy, “goofy”, or had difficulty thinking soon after 
standing up from a sitting or lying position?  
1  
Yes  
2  
No (if you marked No, please skip to question 5)  
2. When standing up, how frequently do you get these feelings or symptoms?  
1  
Rarely  
2  
Occasionally  
3  
Frequently  
4  
Almost Always  
3. How would you rate the severity of these feelings or symptoms?  
1  
Mild  
2  
Moderate  
3  
Severe  
4. In the past year, have these feelings or symptoms that you have experienced:  
1  
Gotten much worse  
2  
Gotten somewhat worse  
3  
Stayed about the same  
4  
Gotten somewhat better  
5  
Gotten much better  
6  
Completely gone  
5. In the past year, have you ever noticed color changes in your skin, such as red, white, or purple?  
1  
Yes  
2  
No (if you marked No, please skip to question 8)  
6. What parts of your body are affected by these color changes? (Check all that apply)  
1  
Hands  
2  
Feet  
7. Are these changes in your skin color:  
1  
Getting much worse  
2  
Getting somewhat worse  
3  
Staying about the same  
4  
Getting somewhat better  
5  
Getting much better  
6  
Completely gone  


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8. In the past 5 years, what changes, if any, have occurred in your general body sweating?  
1  
I sweat much more than I used to  
2  
I sweat somewhat more than I used to  
3  
I haven’t noticed any changes in my sweating  
4  
I sweat somewhat less than I used to  
5  
I sweat much less than I used to  
9. Do your eyes feel excessively dry?  
1  
Yes  
2  
No  
10. Does your mouth feel excessively dry?  
1  
Yes  
2  
No  
11. For the symptom of dry eyes or dry mouth that you have had for the longest period of time, is this 
symptom:  
1  
I have not had any of these symptoms  
2  
Getting much worse  
3  
Getting somewhat worse  
4  
Staying about the same  
5  
Getting somewhat better  
6  
Getting much better  
7  
Completely gone  
12. In the past year, have you noticed any changes in how quickly you get full when eating a meal?  
1  
I get full a lot more quickly now than I used to  
2  
I get full more quickly now than I used to  
3  
I haven’t noticed any change  
4  
I get full less quickly now than I used to  
5  
I get full a lot less quickly now than I used to  
13. In the past year, have you felt excessively full or persistently full (bloated feeling) after a meal?  
1  
Never  
2  
Sometimes  
3  
A lot of the time  
14. In the past year, have you vomited after a meal?  
1  
Never  
2  
Sometimes  
3  
A lot of the time  
15. In the past year, have you had a cramping or colicky abdominal pain?  
1  
Never  
2  
Sometimes  
3  
A lot of the time  
16. In the past year, have you had any bouts of diarrhea?  
1  
Yes  
2  
No (if you marked No, please skip to question 20)  


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17. How frequently does this occur?  
1  
Rarely  
2  
Occasionally  
3  
Frequently ____________ times per month  
4  
Constantly  
18. How severe are these bouts of diarrhea?  
1  
Mild  
2  
Moderate  
3  
Severe  
19. Are your bouts of diarrhea getting:  
1  
Much worse  
2  
Somewhat worse  
3  
Staying the same  
4  
Somewhat better  
5  
Much better  
6  
Completely gone  
20. In the past year, have you been constipated?  
1  
Yes  
2  
No (if you marked No, please skip to question 24)  
21. How frequently are you constipated?  
1  
Rarely  
2  
Occasionally  
3  
Frequently ____________ times per month  
4  
Constantly  
22. How severe are these episodes of constipation?  
1  
Mild  
2  
Moderate  
3  
Severe  
23. Is your constipation getting:  
1  
Much worse  
2  
Somewhat worse  
3  
Staying the same  
4  
Somewhat better  
5  
Much better  
6  
Completely gone  
24. In the past year, have you ever lost control of your bladder function?  
1  
Never  
2  
Occasionally  
3  
Frequently ____________ times per month  
4  
Constantly  
25. In the past year, have you had difficulty passing urine?  
1  
Never  
2  
Occasionally  
3  
Frequently ____________ times per month  
4  
Constantly  


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26. In the past year, have you had trouble completely emptying your bladder?  
1  
Never  
2  
Occasionally  
3  
Frequently ____________ times per month  
4  
Constantly  
27. In the past year, without sunglasses or tinted glasses, has bright light bothered your eyes?  
1  
Never (if you marked Never, please skip to question 29)  
2  
Occasionally  
3  
Frequently  
4  
Constantly  
28. How severe is this sensitivity to bright light?  
1  
Mild  
2  
Moderate  
3  
Severe  
29. In the past year, have you had trouble focusing your eyes?  
1  
Never (if you marked Never, please skip to question 31)  
2  
Occasionally  
3  
Frequently  
4  
Constantly  
30. How severe is this focusing problem?  
1  
Mild  
2  
Moderate  
3  
Severe  
31. Is the most troublesome symptom with your eyes (i.e. sensitivity to bright light or trouble focusing) 
getting:  
1  
I have not had any of these symptoms  
2  
Much worse  
3  
Somewhat worse  
4  
Staying about the same  
5  
Somewhat better  
6  
Much better  
7  
Completely gone