Clinical trial NCT01617967
Conditions: TTR-mediated Amyloidosis
Keywords: RNAi therapeutic
Sponsor: Alnylam Pharmaceuticals
Start date: 2012-05-01; Completion date: 2014-01-01
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a multiple dose, dose escalation study designed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of patisiran (ALN-TTR02) in participants with transthyretin (TTR) mediated amyloidosis (ATTR).

Detailed description:

Arms: arm 1: Two administrations of patisiran will be administered once every 4 weeks \[Q4W\]) in 4 sequential cohorts with escalating doses followed by optional cohorts with an alternative dosing regimen (once every 3 weeks \[Q3W\]), and an alternative premedication regimen.
Interventions: intervention 1: Patisiran
Intervention descriptions: intervention 1: Participants received a single dose of patisiran as an intravenous (IV) infusion on Day 0 and Day 28 (Q4W). Optional cohorts received an alternative dosing regimen (once every 3 weeks \[Q3W\]: Day 0 and Day 21) and an alternative premedication regimen.

Protocol documents:
Prot_001.pdf: 
 
 
Official Title:  
A Phase 2, Open‐Label, Multi‐Dose, Dose Escalation Trial to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
Intravenous Infusions of ALN‐TTR02 in Patients with TTR Amyloidosis 
 
NCT Number:    
NCT01617967 
 
Document Date:   
Clinical Study Protocol, Version 2.1, 16 January 2013 


 
CLINICAL STUDY PROTOCOL – CONFIDENTIAL 
ALN-TTR02-002 
A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Infusions of 
ALN-TTR02 in Patients with TTR Amyloidosis 
Original Protocol 
03 February 2012 
Amendment 1: 
19 June 2012 
Amendment 1.1: 
24 September 2012 
Amendment 2: 
16 January 2013 
Amendment 2.1: 
16 January 2013 
EudraCT Number: 
2012-000467-24 
Sponsor: 
Alnylam Pharmaceuticals, Inc 
300 Third Street 
Cambridge, MA  02142  USA 
Sponsor Contact: 
 
 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without expressed 
written authorization of Alnylam Pharmaceuticals, Inc. 
The study will be completed according to guidelines of Good Clinical Practice.  
Compliance with this practice provides public assurance that the rights, safety, and 
well-being of trial patients are protected consistent with the principles that have their 
origin in the Declaration of Helsinki. 
 
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CONTACT INFORMATION 
Alnylam Clinical Research 
 
  
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
 
 
 
Alnylam Medical Monitor 
 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
 
 
Alnylam Clinical Operations 
 
 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
 
 
Contract Research Organization (CRO) 
Medpace 
 
 
 
CRO Medical Monitor 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
Contact Information ..........................................................................................................3 
Table of Contents ...............................................................................................................4 
List of Tables ......................................................................................................................7 
List of Figures .....................................................................................................................7 
Protocol Synopsis ...............................................................................................................8 
Abbreviations ...................................................................................................................21 
1 
Introduction ..........................................................................................................26 
1.1 
Background and Rationale ........................................................................ 26 
1.1.1 Transthyretin Biology and Impact of Transthyretin Lowering ..... 26 
1.1.2 Disease Overview ......................................................................... 27 
1.1.3 RNA interference .......................................................................... 28 
1.1.4 ALN-TTR02 ................................................................................. 29 
1.2 
Summary of ALN-TTR02 Non-Clinical Data .......................................... 30 
1.3 
Summary of Clinical Data with siRNA-LNPs .......................................... 32 
1.4 
Study Hypothesis and Rationale ............................................................... 33 
1.5 
Dose Selection and Rationale ................................................................... 33 
1.6 
Risk-Benefit Assessment .......................................................................... 35 
1.6.1 Infusion-Related Reactions ........................................................... 35 
1.6.2 Hepatotoxicity ............................................................................... 36 
2 
Study Objectives...................................................................................................37 
2.1 
Primary Objective ..................................................................................... 37 
2.2 
Secondary Objectives ................................................................................ 37 
3 
Study Plan .............................................................................................................38 
3.1 
Overall Design .......................................................................................... 38 
3.2 
Safety Assessments ................................................................................... 40 
3.3 
Pharmacodynamic Assessments ............................................................... 40 
3.4 
Pharmacokinetic Assessments .................................................................. 40 
3.5 
Other Assessments .................................................................................... 41 
4 
Patient Population ................................................................................................42 
4.1 
Eligibility of Patients ................................................................................ 42 
4.2 
Inclusion Criteria ...................................................................................... 42 
4.3 
Exclusion Criteria ..................................................................................... 43 
4.4 
Assignment to Dose Cohort/Patient Number ............................................ 44 
4.4.1 Assignment to Dose Cohort .......................................................... 44 
4.4.2 Blinding Procedures ...................................................................... 44 
4.5 
Early Patient Withdrawal .......................................................................... 44 
4.5.1 Reasons for Withdrawal ................................................................ 44 
4.5.2 Handling of Withdrawals .............................................................. 45 
4.5.3 Patient Replacement ...................................................................... 45 
5 
Study Medication .................................................................................................47 
5.1 
Presentation of Study Drug ....................................................................... 47 
5.2 
Preparation of Study Drug ........................................................................ 47 
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5.3 
Storage of Study Drug .............................................................................. 47 
5.4 
Labeling and Packaging of Study Drug .................................................... 48 
5.5 
Premedication Plan ................................................................................... 48 
5.6 
Dose, Route, and Schedule of Study Drug Administration ...................... 49 
5.7 
Criteria for Dose Escalation, Dose Modification or Discontinuation of 
Study Drug ................................................................................................ 51 
5.7.1 Dose Escalation Procedures .......................................................... 51 
5.7.2 Optional Cohorts ........................................................................... 55 
5.7.3 Dose-limiting Toxicity .................................................................. 55 
5.7.4 Stopping Criteria ........................................................................... 55 
5.8 
Measurement of Patient Compliance ........................................................ 56 
5.9 
Study Drug Accountability ....................................................................... 56 
5.10 
Concomitant Medication / Treatment ....................................................... 56 
5.11 
Suggested Guidelines for Management of Infusion Reactions ................. 57 
6 
Study Visits ...........................................................................................................59 
6.1 
Screening Visit (Day -45 to -3) ................................................................. 60 
6.2 
Pre-Dosing (Day -1 or Day 27); Day -1 or Day 20 for optional cohorts 
dosed once every 3 weeks ......................................................................... 61 
6.3 
Treatment Visits ........................................................................................ 61 
6.3.1 Day 0 or Day 28 (+2 days); Day 0 or Day 21 for optional cohorts 
dosed once every 3 weeks ............................................................. 61 
6.3.2 Day 1 or Day 29; Day 1 or Day 22 for optional cohorts dosed once 
every 3 weeks ................................................................................ 65 
6.3.3 Day 2 or Day 30; Day 2 or Day 23 for optional cohorts dosed once 
every 3 weeks ................................................................................ 66 
6.3.4 Day 7 or Day 35 ±1 day; or Day 7 or Day 28 for optional cohorts 
dosed once every 3 weeks) ........................................................... 66 
6.3.5 Day 10 or Day 38 ±2 days; or Day 10 or Day 31 for optional 
cohorts dosed once every 3 weeks ................................................ 67 
6.3.6 Day 14 or Day 42 ±3 days; or Day 14 and Day 35 for optional 
cohorts dosed once every 3 weeks ................................................ 67 
6.3.7 Day 21 or Day 49 ±3 days; or Day 21 and Day 42 for optional 
cohorts dosed once every 3 weeks ................................................ 68 
6.3.8 Day 56 (±3 days; End of Study) ................................................... 68 
6.3.9 Day 112 (±10 days) ....................................................................... 69 
6.3.10 Day 208 (±2 weeks) ...................................................................... 69 
6.4 
Early Termination ..................................................................................... 69 
6.5 
Unscheduled Visits ................................................................................... 69 
6.6 
Participation in an Open-label Extension Study ....................................... 70 
7 
Study Assessments ...............................................................................................71 
7.1 
Demographic Data and Medical History .................................................. 71 
7.2 
Safety Assessments ................................................................................... 71 
7.2.1 Physical Examination.................................................................... 71 
7.2.2 Vital Signs ..................................................................................... 71 
7.2.3 Echocardiogram ............................................................................ 72 
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7.2.4 Electrocardiogram ......................................................................... 72 
7.2.5 Pulse Oximetry.............................................................................. 73 
7.2.6 Cardiac Monitoring ....................................................................... 73 
7.2.7 Clinical Laboratory Tests .............................................................. 73 
7.3 
Pharmacodynamic Assessments ............................................................... 77 
7.3.1 Transthyretin Protein .................................................................... 77 
7.3.2 Transthyretin mRNA .................................................................... 78 
7.4 
Pharmacokinetic Evaluations .................................................................... 79 
7.4.1 Plasma Pharmacokinetics .............................................................. 79 
7.4.2 Urine Pharmacokinetics ................................................................ 81 
7.4.3 Banking of Serum for Future Studies ........................................... 82 
8 
Reporting Adverse Events ...................................................................................83 
8.1 
Adverse Event Definition ......................................................................... 83 
8.2 
Serious Adverse Event Definition ............................................................ 83 
8.3 
Eliciting Adverse Event Information ........................................................ 83 
8.4 
Adverse Event Reporting .......................................................................... 84 
8.5 
Adverse Event Reporting Period .............................................................. 84 
8.6 
Assessment of Causality ........................................................................... 84 
8.7 
Assessment of Severity ............................................................................. 85 
8.8 
Action Taken for Adverse Event .............................................................. 86 
8.9 
Outcome of Adverse Event ....................................................................... 86 
8.10 
Coding of Adverse Events ........................................................................ 86 
8.11 
Serious Adverse Event Reporting ............................................................. 86 
8.12 
Pregnancy Reporting ................................................................................. 88 
9 
Statistical Methods ...............................................................................................89 
9.1 
Sample Size ............................................................................................... 89 
9.2 
Statistical Methodology ............................................................................ 89 
9.2.1 Populations to be Analyzed .......................................................... 89 
9.2.2 Baseline Evaluations ..................................................................... 90 
9.2.3 Safety Analyses ............................................................................. 90 
9.2.4 Pharmacodynamics ....................................................................... 90 
9.2.5 Pharmacokinetics .......................................................................... 90 
9.2.6 Summary of Pharmacodynamic and Pharmacokinetic Analyses .. 91 
9.2.7 Interim Analysis ............................................................................ 91 
10 
Study Management ..............................................................................................92 
10.1 
Data Handling and Quality Assurance ...................................................... 92 
10.1.1 Case Report Forms ........................................................................ 92 
10.1.2 Monitoring .................................................................................... 92 
10.1.3 Inspections .................................................................................... 92 
10.2 
Regulatory Guidelines .............................................................................. 93 
10.2.1 Independent Ethics Committee ..................................................... 93 
10.2.2 Regulatory Authorities .................................................................. 93 
10.2.3 Modification of the Protocol ......................................................... 94 
10.2.4 Informed Consent Form ................................................................ 94 
10.2.5 Study Reporting Requirements ..................................................... 94 
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10.2.6 Financial Disclosure Reporting Obligations ................................. 95 
10.3 
Study Committees ..................................................................................... 95 
10.4 
Ancillary Research .................................................................................... 96 
10.5 
Study Record Retention ............................................................................ 96 
10.6 
Discontinuation of the Study by Alnylam ................................................ 96 
10.7 
Study Documentation................................................................................ 96 
10.8 
Confidentiality .......................................................................................... 97 
10.9 
Publications/Reports ................................................................................. 98 
11 
References .............................................................................................................99 
12 
Appendices ..........................................................................................................102 
 
LIST OF TABLES 
Table 1-1: 
Schedule of Assessments for Cohorts Administered ALN-TTR02 Once 
Every Four Weeks ............................................................................................................. 17 
Table 5-1: 
Planned Dose Cohorts and Enrollment ..................................................... 51 
Table 12-1: 
Schedule of Assessment for Optional Cohorts Administered ALN-TTR02 
Once Every Three Weeks ............................................................................................... 107 
 
LIST OF FIGURES 
Figure 5-1: 
Scheme for Patient Enrollment and SRC Review Within and Between 
Each Patient Cohort .......................................................................................................... 54 
 
LIST OF APPENDICES 
Appendix
 
 1: 
Guidelines for Acute Infusion-Related Reactions .................................. 103
Appendix
 
 2: 
Guidelines for Delayed Infusion-Related Reactions ............................... 104
Appendix
 
 3: 
Karnofsky Scale ...................................................................................... 105
Appendix
 
 4: 
Schedule of Assessments for Optional Cohorts Administered ALN-TTR02 
Once Every Three Weeks ............................................................................................... 106
Appendix
 
 5: 
New York Heart Association Classification of Heart Failure ................ 111
Appendix
 
 6: 
World Medical Association Declaration of Helsinki .............................. 112
 
 
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PROTOCOL SYNOPSIS 
 
Protocol Title: 
A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of Intravenous Infusions of ALN-TTR02  
in Patients with TTR Amyloidosis 
Indication: 
Treatment of patients with transthyretin (TTR)-mediated 
amyloidosis (ATTR) 
Protocol Number: 
ALN-TTR02-002 
Phase of 
Development: 
2 
Design: 
Multi-center, multi-national, open-label, multi-dose, dose 
escalation study. 
Consented patients meeting the eligibility criteria will be 
enrolled into sequential cohorts of increasing doses of 
ALN-TTR02, the investigational drug.  Each cohort will 
comprise 3 patients, who are to receive 2 intravenous (IV) 
infusions of ALN-TTR02, 4 weeks apart. 
A Safety Review Committee (SRC) will evaluate safety in the 
study and determine if it remains acceptable to continue 
dosing per their safety review charter.  To ensure timely 
safety information exchange across the participating study 
centers, the SRC will be comprised of all Principal 
Investigators (PIs) participating in the study or their designee, 
the Alnylam Medical Monitor, and the Contract Research 
Organization (CRO) Medical Monitor. 
The dosing of cohorts will be as follows: 
• Dosing within a cohort: The first patient will receive 
their first dose and if the dose is well tolerated, per 
Section 5.7.3 (Dose-limiting Toxicity), Patients 2 and 
3 will receive their first dose at that same dose level no 
sooner than 48 hours apart, with Patient 2 receiving a 
dose of study drug no sooner than 48 hours after the 
dosing of Patient 1.  Similar to the first dose, the 
second dose will be administered to patients 4 weeks 
after the first dose in a sequential manner with at least 
48 hours separating dosing of each patient.   
• Dosing of the next cohort: Collective cohort safety and 
tolerability data on Patients 1 to 3 through at least 
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96 hours post-first dose will be reviewed by the SRC; 
if the administered dose is found to be safe and well 
tolerated, dosing for the next cohort will begin no 
sooner than 96 hours after Patient 3 had safely 
received dose 1 from the previous cohort.  Patients in 
the cohort would be dosed and reviewed for safety and 
tolerability following the same procedures as used for 
other cohorts (as stated above).   
For patients on all dose levels other than the starting 
dose level of 10 µg/kg, prior to receiving the second 
dose, the SRC will review the cumulative safety and 
tolerability data of at least 2 patients from the previous 
dose level(s) with at least 96 hours of follow-up after 
receiving a second dose of study drug. 
The SRC will also be convened in the event of any potential 
dose-limiting toxicity (DLT) to determine whether stopping 
rules have been met. 
Study Sites 
This study is planned to be conducted at up to 10 study 
centers worldwide. 
Investigational Drug: 
ALN-TTR02 is comprised of drug substance ALN-18328 
(small interfering ribonucleic acid [siRNA] targeting wild 
type TTR messenger ribonucleic acid [mRNA] as well as all 
TTR mutations) formulated in a lipid nanoparticle (LNP) 
containing the following lipid excipients: DLin-MC3-DMA, 
PEG2000-C-DMG, DSPC, and cholesterol. 
Control Drug: 
Not applicable. 
Dosage, Route of 
Administration and 
Duration of 
Treatment of 
Investigational Drug: 
Four cohorts are planned to be enrolled to evaluate 
2 consecutive doses, 4 weeks apart of the following dose 
levels: 10, 50, 150, and 300 µg/kg ALN-TTR02.  Based on 
the interim evaluation of safety data, it may also be decided 
by the SRC that an optional cohort may be utilized which will 
include 3 additional patients.  Dosing in these optional cohorts 
may occur at a previously tested dose that was found to be 
safe and where stopping rules were not met or at an 
intermediate dose level.  Patients in the optional cohort would 
be dosed and reviewed for safety and tolerability following 
the same procedures as used for other cohorts.  Optional 
cohort(s) would be included to further confirm the safety 
and/or pharmacodynamic (PD) effect of previously evaluated 
dose levels, which may include evaluation of the original 
dosing regimen (once every 4 weeks), an alternative dosing 
regimen (once every 3 weeks), and/or an alternative 
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premedication regimen and infusion rate.  The dosing regimen 
for the first optional cohort will be once every 4 weeks, and 
the dosing regimen for the remaining 4 optional cohorts will 
be once every 3 or 4 weeks.  It is anticipated that the first 
2 optional cohorts will use the original premedication 
regimen, and the remaining 3 optional cohorts may be used to 
explore the alternative premedication regimen and infusion 
rate.   
The SRC will review all available safety data and make 
recommendations on dosing and premedication regimens 
prior to dosing of any of the optional cohorts.  
The Independent Ethics Committees (IECs) will be informed 
of the implementation of optional cohorts.  Up to 5 optional 
cohorts are permitted in this study. 
Patients receiving the original premedication regimen will be 
administered the following prior to each dose of ALN-
TTR02: 
• Oral (PO) dexamethasone (8 mg) or equivalent 
administered the evening before dosing and 20 mg 30 
to 60 minutes prior to start of infusion of ALN-
TTR02; 
• Oral paracetamol (500 mg) or equivalent the evening 
before dosing and 30 to 60 minutes prior to the start of 
infusion of ALN-TTR02; 
• Oral H2 blocker (e.g., ranitidine 150 mg or famotidine 
20 mg or equivalent other H2 blocker dose) the 
evening before dosing and 30 to 60 minutes prior to 
start of infusion of ALN-TTR02; and 
• Oral H1 blocker, 10 mg cetirizine or equivalent 
(hydroxyzine 25 mg or fexofenadine may be 
substituted if patient does not tolerate cetirizine) the 
evening before dosing and 30 to 60 minutes prior to 
start of infusion of ALN-TTR02. 
The alternative premedication regimen that can be used in 
select optional cohorts, as agreed upon by the SRC, will be 
administered prior to each dose of ALN-TTR02 and includes 
the following: 
• Intravenous (IV) dexamethasone (10 mg) or 
equivalent, administered at least 60 minutes prior to 
the start of infusion of ALN-TTR02; 
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• Oral paracetamol (500 mg) or equivalent at least 
60 minutes prior to the start of infusion of ALN-
TTR02; 
• Intravenous H2 blocker (e.g., ranitidine 50 mg, 
famotidine 20 mg, or equivalent other H2 blocker 
dose) at least 60 minutes prior to start of infusion of 
ALN-TTR02; and 
• Intravenous H1 blocker: diphenhydramine 50 mg IV 
(or equivalent other IV H1 blocker available at the 
study site) at least 60 minutes prior to start of infusion 
of ALN-TTR02.  Hydroxyzine or fexofenadine 25 mg 
PO or cetirizine 10 mg PO may be substituted for any 
patient who does not tolerate IV diphenhydramine or 
other IV H1 blocker. 
For patients receiving the original premedication regimen and 
infusion rate, doses of ALN-TTR02 will be administered IV 
over 60 minutes by a controlled infusion device at a flow rate 
of approximately 3.3 mL/min.   
For patients enrolled in the optional cohorts evaluating the 
alternative premedication regimen and infusion rate, the flow 
rate of ALN-TTR02 will be approximately 1.1 mL/min during 
the first 15 minutes (1/3rd the original flow rate) with the 
remainder of the infusion administered at a flow rate of 
3.3 mL/min for a total infusion time of approximately 
70 minutes. 
The infusion time may be extended up to 3 hours in the event 
of a mild or moderate infusion reaction (study drug 
administration will not be resumed for any patient following a 
severe infusion reaction).   
Patients will remain hospitalized at the study site for at least 
24 hours following completion of dosing on Days 0 and 28, 
for safety assessments and pharmacokinetic (PK) sampling.   
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Time on Study 
The duration of patient participation in this study is 
approximately 36 weeks (screening [up to 45 days prior to 
study drug administration] through Day 208). 
An open-label extension study at the recommended Phase 3 
dose and regimen (as derived from Study ALN-TTR02-002) 
is planned, which will enable the patients who enrolled in 
Study ALN-TTR02-002 to receive additional, long-term 
dosing and safety follow-up.  For some of the patients, this 
may preclude the completion of all of the follow-up period 
assessments of Study ALN-TTR02-002 if they are deemed 
eligible to participate in the extension study prior to 
completion of the full follow up through Day 208.  Such 
patients will be followed up for a minimum of 28 days after 
their last dose in the current ALN-TTR02-002 study prior to 
being enrolled in the extension study.  The extension study 
will be implemented only after dose escalation is completed in 
Study ALN-TTR02-002, with post second dose follow-up 
through Day 208 in at least 1 cohort at the highest dose. 
Note: A patient will be followed every 2 weeks after Day 56 
until TTR levels have recovered to at least 80% of baseline. 
Evaluations will be performed as indicated in the schedule of 
assessments. 
Primary Objective: 
• To evaluate the safety and tolerability of multiple doses of 
ALN-TTR02. 
Secondary 
Objectives: 
• To characterize the plasma and urine PK of ALN-TTR02. 
• To assess preliminary evidence of the PD effect of 
ALN-TTR02 on serum total TTR levels. 
Sample Size: 
Based on the entry criteria and the proposed dose escalation 
scheme, up to 27 patients are expected to be enrolled.  Three 
patients are to be enrolled at each dose level and up to 
5 optional cohorts of 3 patients each will be permitted. 
Inclusion and 
Exclusion Criteria: 
Each patient must meet the following criteria to be enrolled: 
1. Male or female aged 18 years or older. 
2. Patients has a biopsy-proven diagnosis of TTR 
amyloidosis with documented signs/symptoms of the 
disease (e.g., sensory, motor, or autonomic neuropathy) 
that are at least mild to moderate in severity. 
3. Body mass index (BMI) of 17–33 kg/m2. 
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4. Karnofsky performance status of 60% or greater. 
5. Absolute neutrophil count (ANC) ≥1500 cells/mm³, 
platelet count ≥100,000 cells/mm³, and hemoglobin 
≥10 g/dL. 
6. Adequate liver function, demonstrated by an aspartate 
transaminase (AST) and alanine transaminase (ALT) 
≤2.5 × the upper limit of normal (ULN), total bilirubin 
within normal limits, albumin >3 g/dL, international 
normalized ratio (INR) ≤1.2. 
7. Adequate renal function: serum creatinine ≤1.5 × ULN. 
8. Seronegative for hepatitis B virus (HBV) and hepatitis C 
virus (HCV). 
9. Women of child-bearing potential must have a negative 
pregnancy test, cannot be breast feeding, and must be 
using two highly effective methods of contraception 
prior to screening, throughout study participation, and 
for 1 month after ending study participation.  Highly 
effective methods of birth control are defined as: 
hormonal - oral, implantable, injectable, or transdermal 
contraceptives in conjunction with spermicide, condom, 
or diaphragm; mechanical - spermicide in conjunction 
with a barrier such as a condom or diaphragm; 
intrauterine device (IUD) in conjunction with spermicide 
or condom; or surgical sterilization of partner in 
conjunction with spermicide, condom, or diaphragm. 
10. Males agree to use appropriate contraception throughout 
study participation and for 1 month after ending study 
participation. 
11. Patient is willing and able to comply with protocol-
required visit schedule and visit requirements and 
provide written informed consent. 
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12. Patients will be excluded if they meet any of the 
following criteria: 
13. Pregnant or nursing. 
14. Has had a liver transplant. 
15. Has a known surgery planned during any point of the 
study period. 
16. Has known human immunodeficiency virus (HIV) 
positive status. 
17. Has a known or suspected systemic bacterial, viral, 
parasitic, or fungal infection. 
18. Received an investigational agent, other than tafamidis 
or diflunisal, within 30 days prior to study drug 
administration. 
19. Has a New York Heart Association heart failure 
classification >2. 
20. Has unstable angina. 
21. Has uncontrolled clinically significant cardiac 
arrhythmia. 
22. Is considered unfit for the study by the Principal 
Investigator. 
23. Had a prior severe reaction to a liposomal product. 
24. Has known hypersensitivity to oligonucleotides. 
25. Is an employee or family member of Alnylam or the 
clinical study site personnel. 
Pharmacodynamic 
Assessments: 
The PD evaluation will include assessment of effects of 
ALN-TTR02 on serum total TTR levels.  
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Pharmacokinetic 
Assessments: 
The PK evaluation will include plasma-concentration time 
profiles for ALN-18328 and the novel lipid components 
DLin-MC3-DMA and polyethylene glycol (PEG)2000-C-
DMG.  ALN-18328 concentration will be determined at 
specified time points post-dose.  DLin-MC3-DMA and 
PEG2000-C-DMG concentrations will be determined at 
specified time points up to 180 days post- second dose.  An 
assessment of plasma concentrations of free and encapsulated 
siRNA will be determined at specified time points. 
If the infusion of study drug is stopped and the site is 
considering restarting, a PK blood sample will be taken when 
the infusion is stopped. 
Urine will be collected to determine ALN-18328 excreted in 
urine and renal clearance (CLR) of ALN-18328 after dosing 
with ALN-TTR02.  In addition urine samples will be 
collected to quantify analytes that may include DLin-MC3-
DMA and/or its metabolites at specified time points. 
Safety Assessments: 
26. Safety evaluations will include assessment of adverse 
events (AEs), electrocardiograms (ECGs), cardiac 
monitoring (telemetry), arterial oxygen saturation (SaO2) 
using pulse oximetry, vital signs (blood pressure, pulse 
rate, oral body temperature, and respiration rate), clinical 
laboratory safety tests (hematology, serum chemistry, 
liver function tests, thyroid function parameters, 
serology, coagulation parameters, urinalysis, cytokines, 
C-reactive protein, complement factors), and physical 
examinations. 
Other Assessments: 
27. Exploratory effects of ALN-TTR02 will be evaluated by: 
28. Serial measurement of circulating mutant and wild type 
TTR levels 
29. Serial measurement of circulating vitamin A and retinol 
binding protein (RBP) levels 
• Blood collections to explore the expression of hepatocyte 
derived proteins to further characterize the biological 
effects of siRNA LNPs.  
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Dose-Limiting 
Toxicities and 
Stopping Criteria: 
Dose-limiting toxicities will include any of the following: 
1. Any life-threatening toxicity. 
2. ALT and AST ≥5 × ULN or total bilirubin >2.0 mg/dL. 
3. An infusion reaction that requires hospitalization, despite 
premedication. 
4. Any other toxicity which in the opinion of the SRC 
precludes further dosing. 
Stopping Rules: 
For any DLT, accrual to that dose level will stop, all dosing 
will be discontinued, and dose escalation will end, pending 
further evaluation of all available safety data by the SRC. 
Statistical Methods: 
Statistical analyses will be primarily descriptive in nature.  
Adverse event summaries will include tabulations of all 
treatment-emergent AEs, treatment-related AEs, serious 
adverse events (SAEs), discontinuations due to AEs, and AEs 
of various grading severity.  By-patient listings will be 
provided for deaths, SAEs, and AEs leading to 
discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory 
data, vital signs data, and ECG interval data, presented as both 
actual values and changes from baseline relative to each on-
study evaluation.  Laboratory shift tables from baseline to 
worst values will be presented. 
Pharmacokinetic analyses will be conducted using non-
compartmental and/or compartmental evaluation of ALN-
18328 (siRNA), DLin-MC3-DMA (lipid) and PEG2000-C-
DMG (lipid) plasma concentration-time data to determine PK 
parameter estimates using a validated software program, 
.  
PK and PD data will be assessed descriptively whenever 
possible and by exploratory statistical comparisons. 
 
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Table 1-1: 
Schedule of Assessments for Cohorts Administered ALN-TTR02 Once Every Four Weeks 
Procedures 
Screening 
Pre-Dosing 
Dosing Cycles 
Follow-Up 
D -45 to  
D -3 
D -1 
D 0 
D 0 
D 1 
D 2 
D 7 
(±1 D) 
D 10 
(±2 D) 
D 14 
(±3 D) 
D 21 
(±3 D) 
D 56a 
(±3 D) 
D 112 
(±10 D) 
D 208a 
(±2 W) 
D 27 
D 28 
(+2 D) 
D 28 
(+2 D) 
D 29 
D 30 
D 35 
(±1 D) 
D 38 
(±2 D) 
D 42 
(±3 D) 
D 49 
(±3 D) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
Xb 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination, 
excluding weight 
X 
 
Xc 
 
Xc 
Xc 
 
 
Xc 
 
X 
 
 
Weight 
X 
 
Xd 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index (BMI) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signse 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Vital Signs (Serial)f 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Echocardiogramg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG (Serial)h 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Inpatient at Study Site 
 
 
X 
X 
Xi 
 
 
 
 
 
 
 
 
Cardiac Monitoring 
(Telemetry)j 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Pulse Oximetry (Serial)f 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
(females only) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine Pregnancy Test 
(females only)k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C Statusl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry, 
Hematology, Urinalysis 
X 
 
Xm 
 
X 
 
 
 
X 
 
X 
 
 
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Procedures 
Screening 
Pre-Dosing 
Dosing Cycles 
Follow-Up 
D -45 to  
D -3 
D -1 
D 0 
D 0 
D 1 
D 2 
D 7 
(±1 D) 
D 10 
(±2 D) 
D 14 
(±3 D) 
D 21 
(±3 D) 
D 56a 
(±3 D) 
D 112 
(±10 D) 
D 208a 
(±2 W) 
D 27 
D 28 
(+2 D) 
D 28 
(+2 D) 
D 29 
D 30 
D 35 
(±1 D) 
D 38 
(±2 D) 
D 42 
(±3 D) 
D 49 
(±3 D) 
Liver Function Testsn 
X 
 
Xm 
 
X 
X 
X 
 
X 
 
X 
 
 
Coagulation Studieso 
X 
 
Xm 
 
X 
 
 
 
 
 
 
 
 
Lipid Panelp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
TTR protein, Vitamin A, 
and RBP in serum 
X 
 
Xq 
 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
TTR mRNA in serum 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Thyroid Function Testss 
X 
 
Xm 
 
 
 
 
 
X 
 
X 
 
 
Complement Bbt 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
If infusion reaction:  
Tryptase and C3au 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Premedicationv 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Premedication reminderw 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Administration 
 
 
 
Xx 
 
 
 
 
 
 
 
 
 
Anti-PEG Antibody 
Testing (IgG, IgM) 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Cytokines and CRPy 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Plasma PK Samplingz 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urine PK Samplingaa 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Exploratory Biomarkers 
X 
 
Xbb 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant 
Medications 
X 
 
 
Continuous Monitoring 
 
 
Review/Record AEs 
 
 
 
 
 
Study Completion 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Footnotes on following pages. 
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Note: The schedule of assessments for optional cohorts administered ALN-TTR02 once every 3 weeks is provided in Appendix 4. 
a 
Early termination procedures: if a patient withdraws prior to Day 56, then the Days 56 and 208 visits should be performed.  If a patient is withdrawn/withdraws after Day 56 
and prior to Day 208, then the Day 208 visit should be performed. 
b 
Interval medical history. 
c 
Focused physical examination (includes head/ears/eyes/nose/throat [HEENT], cardiovascular, respiratory, abdominal, and hepatic assessments).  If the screening physical 
examination was performed within 72 hours of Day 0, then the pre-dose (Day 0) physical examination does not need to be repeated; however, the patient’s weight will be 
obtained. 
d 
Weight measured on Day 0 and Day 28 will be used for calculating first and second dose, respectively. 
e 
Vital signs to include: blood pressure, pulse rate, oral body temperature, and respiratory rate.  Parameters are to be measured in the supine position using an automated 
instrument after the patient has rested comfortably for 10 minutes. 
f 
Serial measures (vital signs and pulse oximetry) are to be measured within 30 minutes pre-dose; at the end of infusion (EOI); and 30 (±5) minutes; 1, 2, and 3 (±15 minutes) 
hours; 6, 12, and 18 (±30 minutes) hours; and 24 (+30 minutes) hours post-infusion. 
g 
Not needed if a normal echocardiogram has been obtained within the past 90 days. 
h 
Serial electrocardiograms (ECGs) will be collected in 3 replicates within 30 minutes pre-dose, EOI, and 30 (±5) minutes, 2 and 4 (±15 minutes) hours, and 24 (+30 minutes) 
hours post-infusion. 
i 
Patients will be hospitalized at the study site for at least 24 hours after the end of infusion of study drug.  Patients may be discharged upon completion of review by the 
Investigator of ECG, sodium, potassium, creatinine, albumin, calcium, glucose, phosphate, and LFTs results obtained at 24-hours post-infusion, if results are deemed not 
clinically significant.  Any clinically significant findings must be discussed with the medical monitor to determine whether patient can be discharged and to formulate plans 
for patient follow-up. 
j 
Continuous cardiac monitoring will be performed via telemetry starting no later than 30 minutes prior to dosing and continuing through 24 hours (+1 hour) post-dose. 
k 
Day 0 pre-dose only, not performed on Day 28. 
l 
Serologies include hepatitis B surface antibody (HbsAb), hepatitis B surface antigen (HbsAg), and anti–hepatitis C virus antibody (anti-HCV Ab). 
m 
If the parameter was assessed and meets eligibility requirements within 72 hours of Days 0 and 28, then it does not need to be repeated pre-dose (Days 0 and 28, respectively). 
n 
Liver function tests include aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and bilirubin (total and direct). 
o 
Coagulation studies include prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR). 
p 
Lipid panel (non-fasting) includes total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), and triglycerides 
will be collected on Day 0 only. 
q 
Pre-dose samples for TTR protein, vitamin A, and RBP measurements will be drawn immediately (within 10 minutes) prior to the premedications and immediately prior to 
dosing. 
r 
A patient will be followed approximately every 2 weeks after Day 56 if their TTR level continues to recover but is not found to have returned to within at least 80% of the 
baseline value.  If this occurs, the patient will be followed and discussed at each SRC meeting until the TTR level returns to within at least 80% of the baseline value. 
s 
Thyroid function tests include thyroid stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3). 
t 
A blood sample will be collected for the assessment of complement Bb immediately (within 10 minutes) pre-dose, and 30 (±5) minutes, and 2 (± 15 minutes) and 24 hours 
(±120 minutes) post infusion.  If the patient experiences an infusion reaction, a blood sample for analysis of complement factors should be obtained within 1 hour of the start 
of the reaction. 
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u 
A blood sample for the assessment of tryptase and C3a is to be collected only in the event of an acute infusion reaction: at time of event or as soon as possible after onset, 
1 hour, and 24 hours after the event. 
v 
Premedications include dexamethasone (8 mg, or equivalent), paracetamol (500 mg, or equivalent), H2 blocker (e.g., 150 mg ranitidine or 20 mg famotidine, or equivalent 
other H2 blocker dose), and H1 blocker (10 mg cetirizine, 25 mg hydroxyzine, fexofenadine or equivalent may be substituted) will be self-administered per os (PO) the 
evening before study drug administration.  Thirty to 60 minutes prior to the start of study drug infusion, dexamethasone (20 mg PO, or equivalent), paracetamol (500 mg PO, 
or equivalent), an H2 blocker (PO), and an H1 blocker (PO) will be administered by study site personnel.  Patients enrolled in an optional cohort evaluating the use of an 
alternative premedication regimen, as agreed upon by the SRC, will receive the following medications at least 60 minutes prior to the start of infusion of ALN-TTR02:  
dexamethasone (10 mg IV, or equivalent), paracetamol (PO 500 mg; or equivalent), IV H2 blocker (e.g. ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 blocker 
dose), and IV H1 blocker (e.g., diphenhydramine 50 mg or equivalent; hydroxyzine or fexofenadine 25 mg PO or cetirizine 10 mg PO may be substituted for any patient who 
does not tolerate IV diphenhydramine or other IV H1 blockers).  These patients will not receive any premedications the evening prior to ALN-TTR02 dosing. 
w 
Site personnel are to call patients the day before dosing to remind them to take premedications that evening (the day before dosing).  This reminder will not be needed for 
patients enrolled in optional cohorts evaluating the alternative premedication regimen. 
x 
The infusion site will be assessed for any localized reaction pre-dose, during infusion, and for 30 minutes after the infusion. 
y 
A blood sample for the assessment of cytokines and C-reactive protein (CRP) will be collected immediately (within 10 minutes) pre-dose, and 2 (±15 minutes), 6 (±15 
minutes), and 24 hours (±120 minutes) post infusion.  If the patient experiences an infusion reaction, a blood sample for analysis of cytokines should be obtained within 
1 hour of the start of the reaction. 
z 
For each dose, plasma PK samples (siRNA and lipids) will be collected pre-dose (within 1 hour of planned dosing start), EOI, and then 5, 10, and 30 minutes, and 1, 2, 4, 6, 
24 and 48 hours post infusion.  Samples will also be collected on Days 7, 14, 21, 35, 42, 49, 56, 112, and 208.  Plasma PK on Day 0 at EOI and then 2 hours post-infusion will 
be analyzed for both free and encapsulated siRNA for cohort 3 and onward, including any optional cohorts.  For each post dose PK blood draw, the following sampling 
windows are allowed: ±1 minute for the 5- and 10-minute draws; ±2 minutes for the 30-minute draws; ±5 minutes for the 1-, 2-, 4-, and 6-hour draws; and ±120 minutes for 
the 24- and 48-hour draws. 
aa 
For each dose, urine PK samples will be collected pre-dose (within 1 hour of planned dosing start), and from 0-6 hours post-infusion (pooled). Samples will also be collected 
on Days 7, 14, 21, 35, 42, 49, 56, 112, and 208.   
bb Pre-dose samples should be collected prior to infusion, but after premedications have been administered. 
 
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ABBREVIATIONS 
Abbreviation 
Definition 
λz 
Elimination rate constant 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
anti-HCV Ab 
Anti–hepatitis C virus antibody 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
ATTR 
Transthyretin-mediated amyloidosis 
AUC 
Area under the plasma concentration-time curve 
AUC0-∞ 
Area under the plasma concentration-time curve 
extrapolated to infinity 
AUC0-last 
Area under the plasma concentration-time curve from zero 
to the last measurable time point 
AUC0-t 
Area under the plasma concentration-time curve to the last 
measurable concentration 
AUCp 
Partial area under the plasma concentration-time curve 
Bb 
Activation fragment of complement fragment B 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
C3a 
Complement component 3a 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CL 
Systemic clearance 
CLR 
Renal clearance 
Cmax 
Observed maximum plasma concentration  
CPK 
Creatine phosphokinase 
CPK-MB 
Myocardial band of enzymes of creatine phosphokinase 
CRF 
Case Report Form 
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Abbreviation 
Definition 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CV 
Curriculum vitae 
DEHP 
di(2-ethylhexyl)phthalate 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DLT 
Dose-limiting toxicity 
EC50 
50% effective concentration 
ECG 
Electrocardiogram 
EOI 
End of infusion 
ET 
Early termination 
EU 
European Union 
FAC 
Familial amyloidotic cardiomyopathy 
FAP 
Familial amyloidotic polyneuropathy 
G-CSF 
Granulocyte-colony stimulating factor 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
H1/H2 blocker 
Histamine H1/H2 receptor antagonist 
HbsAb 
Hepatitis B surface antibody 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HEENT 
Head/ears/eyes/nose/throat 
HIPAA 
Health Insurance Portability and Accountability Act of 
1996 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IFN-α 
Interferon-alpha 
IFN-γ 
Interferon-gamma 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL-1β 
Interleukin-1 beta 
IL-1 RA 
IL-1 receptor antagonist 
IL-12 
Interleukin-12 
IL-6 
Interleukin-6 
INR 
International normalized ratio 
IP-10 
Interferon-inducible protein-10 
IRR 
Infusion-related reaction 
ITT 
Intent-to-treat 
IV 
Intravenous(ly) 
LC/MS/MS 
Liquid chromatography/mass spectrometry 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LFT 
Liver function test 
LNP 
Lipid nanoparticles 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
Messenger ribonucleic acid 
NHP 
Non-human primate (cynomolgus monkey) 
NOAEL 
No observed adverse effect limit 
NOEL 
No observable effect level 
OTC 
Over-the-counter 
PD 
Pharmacodynamic 
PEG2000-C-DMG 
3-N-[(ω-methoxy poly(ethylene glycol)2000) carbamoyl]-
1,2-dimyristyloxy-propylamine 
PI 
Principal Investigator 
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Abbreviation 
Definition 
PK 
Pharmacokinetic(s) 
PO 
Per os (orally) 
PP 
Per-protocol 
PT 
Prothrombin time 
PVC 
Polyvinyl chloride 
QTc 
QT interval corrected for heart rate 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RNAi 
RNA interference 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SaO2 
Arterial oxygen saturation 
siRNA 
Small interfering ribonucleic acid 
SNALP 
Stable nucleic acid lipid particles 
SRC 
Safety Review Committee 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Terminal elimination half-life 
t1/2α 
Alpha half-life 
t1/2β 
Beta half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBG 
Thyroxine-binding globulin 
tmax 
Time of observed maximum plasma concentration 
TNF-α 
Tumor necrosis factor-alpha 
TSH 
Thyroid stimulating hormone 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
US/USA 
United States 
USP/EP 
United States Pharmacopeia/European Pharmacopoeia 
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Abbreviation 
Definition 
VLDL 
Very low density lipoprotein 
Vss 
Volume of distribution at steady state 
Vz 
Volume of distribution based on the terminal phase 
WBC 
White blood cell 
WHO 
World Health Organization 
WT 
Wild type 
 
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1 
INTRODUCTION 
1.1 
Background and Rationale 
1.1.1 
Transthyretin Biology and Impact of Transthyretin Lowering 
Transthyretin (TTR), also known as prealbumin, is a tetramer protein produced 
predominantly by hepatocytes (>95% of TTR is liver-derived), with a small fraction 
produced in the choroid plexus and retina.1
In humans, approximately 15% of T4 circulating in the plasma is bound to TTR; the 
remainder is predominantly bound to thyroxine-binding globulin (TBG).  In the mouse, 
where TTR plays a greater role as a carrier for T4, the absence of TTR reduces 
circulating levels of T4 but does not adversely affect the concentration of the hormone in 
peripheral tissues.2,3   
  The primary physiological role of TTR is to 
serve as a carrier of retinol (also known as vitamin A); it also plays a minor role as a 
carrier for thyroxine (T4).   
Vitamin A circulates through the plasma primarily bound to retinol binding protein 
(RBP).1  The clearance of RBP from the circulation is greatly reduced through its binding 
to TTR.  Because vitamin A is lipid-soluble, it can diffuse across the membranes of cells 
and thus, most tissues receive adequate levels of vitamin A obtained normally from the 
diet without its being bound to RBP.  Studies performed in TTR-knockout mice have 
demonstrated that in the absence of TTR, circulating levels of both RBP and vitamin A 
are dramatically reduced (e.g., 5% of vitamin A seen in wild type [WT] mice); however, 
the concentration of vitamin A in the tissues is comparable with that seen in WT mice.4,5  
In addition, the TTR-knockout mice did not demonstrate any signs of vitamin A 
deficiency.  In humans, individuals with mutations in the RBP gene leading to complete 
loss of circulating RBP and very low concentrations of circulating vitamin A have not 
shown any significant signs of vitamin A deficiency other than modest retinal dystrophy 
and decrease in night vision.6  This confirmed the finding in mice that vitamin A uptake 
by most tissues continues in the absence of RBP.  In women with breast cancer treated 
for an average of at least 30 months with the retinoid fenretinide, which causes a 75% 
reduction in circulating vitamin A levels, there were no reports of night blindness or any 
other signs of vitamin A deficiency, and only subtle changes in retinal function were seen 
on electroretinograms in women older than 50 years of age who were on fenretinide for 
30 months or longer.7,8  The safety of lowering vitamin A through TTR suppression has 
now been further confirmed by the absence of AEs in TTR amyloidosis patients treated 
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with ALN-TTR01 who experienced substantial lowering of both TTR and vitamin A (see 
Section 1.3). 
1.1.2 
Disease Overview 
Mutations in the TTR gene can lead to destabilization of the tetrameric protein and 
disassociation of the TTR subunits into dimers and individual monomers.  These 
misfolded TTR monomers (both mutant and WT) can then self-assemble into amyloid 
fibrils.9  The amyloid fibrils are deposited into the extracellular space of various tissues 
where they form amyloid plaques, with the peripheral nervous system, gastrointestinal 
tract, and heart being major sites of deposition. 
There are over 100 reported TTR genetic mutations.  These mutations are phenotypically 
expressed as a spectrum of disease which is collectively referred to as TTR-mediated 
amyloidosis (ATTR).10  There is a range of clinical manifestations of ATTR; the most 
common manifestations include some form of cardiac and/or neurologic involvement 
(e.g., cardiomyopathy, autonomic neuropathy, and sensory and motor neuropathy) that 
depends, in part, upon the particular TTR mutation and the site of amyloid deposition.  
Transthyretin amyloidosis is associated with severe morbidity and mortality, with a life 
expectancy limited to approximately 5 to 15 years from symptom onset.11 
Two significant clinical syndromes of ATTR have been described: familial amyloidotic 
polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC), both of which 
are characterized by amyloid deposits of both mutant and WT TTR.12   
Familial amyloidotic polyneuropathy, caused predominantly by the V30M mutation, 
occurs primarily in families with heritage from Portugal, Sweden and Japan, has an 
earlier onset (age 30-50 years), and is characterized initially by peripheral neuropathy 
leading to sensory and motor deficits as well as profound autonomic dysfunction that 
produces disabling gastrointestinal pathology, orthostatic hypotension, and bladder 
dysfunction.13,14  Amyloid infiltration of the sinus node and atrioventricular conduction 
system in the heart is also common in FAP.  Sudden death is not uncommon in FAP, and 
is believed to result from heart block or tachyarrhythmias.15,16   
Familial amyloidotic cardiomyopathy, caused primarily by the TTR variant V122I, is a 
late-onset (age >60 years) syndrome in which amyloid deposition is largely restricted to 
the heart and manifests as conduction defects, arrhythmias, congestive heart failure, and 
death; neuropathy is uncommon.17  The V122I mutation is found in up to 4% of African 
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Americans and in over 5% of West African populations, although rates of disease 
penetrance are low.18   
It is estimated that 45,000 – 50,000 individuals have FAP or FAC.  In both FAP and 
FAC, quality of life is severely impacted following the onset of symptoms, and the 
disease proceeds inexorably to death.19,20 
Because the liver is the primary source of mutant TTR, liver transplantation has been 
used over the past 20 years in an attempt to treat ATTR.1  However, the procedure is only 
effective in halting or slowing the progression of disease in patients with an early age of 
onset,21 especially for those with the V30M mutation and short disease duration prior to 
transplant; consequently almost two-thirds of ATTR patients are not transplant-eligible.  
When performed early in the course of the disease, liver transplantation can stabilize and 
slow progression of neuropathy in patients with FAP due to V30M.  However, in FAC 
patients and FAP patients with evidence of cardiac involvement, liver transplantation is 
contraindicated since it does not halt the progression of cardiac disease in these 
patients,22,23,24,25 and may actually accelerate the course of cardiomyopathy due to further 
deposition of WT TTR (originating from the transplanted liver) in the heart.26 
Tafamidis, a TTR tetramer stabilizer, was approved (November 2011) in the European 
Union (EU) for the treatment of ATTR in adult patients with stage 1 symptomatic 
polyneuropathy to delay peripheral neurologic impairment.27  However, the large 
majority of ATTR patients do not qualify for either liver transplantation or tafamidis.  In 
these patients, the disease is primarily managed with palliative care.   
1.1.3 
RNA interference 
Ribonucleic interference (RNAi) is a naturally occurring cellular mechanism for 
regulating gene expression that is mediated by “small interfering ribonucleic acids” 
(siRNAs).28  Typically, synthetic siRNAs are 19 to 23 base pair double-stranded 
oligonucleotides in a staggered duplex with a 2-nucleotide overhang at one or both of the 
3' ends.  Such siRNAs can be designed to target an endogenous or virally-expressed gene.  
When introduced into cells, the net effect of an RNAi-based pharmacological approach is 
the binding of the siRNA to its complementary messenger ribonucleic acid (mRNA) 
sequence, cleavage of this target mRNA, and suppression of the target protein.29  The 
ability to selectively and potently degrade the mRNA encoding the TTR protein using an 
siRNA offers a potent and specific approach for the treatment of ATTR. 
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Unformulated siRNAs, and those without chemical modification, are rapidly degraded 
and eliminated upon systemic administration, and thus do not achieve significant tissue 
distribution.30  As a result, various formulations are used to target siRNA distribution to 
tissues, and to facilitate their uptake into the relevant cell type.  One approach that has 
been used successfully in vivo, including in rodents and non-human primates (NHPs), 
employs intravenous (IV) delivery of siRNAs in lipid nanoparticles (LNPs).,31,32,33,34  
These LNPs, with their small size (<100 nm) and low surface charge, can pass through 
the fenestrated vascular endothelium of the liver.  Endocytosis of the intact LNPs, 
followed by fusion with the endosomal membrane and release of the siRNA into the 
cytoplasm, results in the siRNA engaging the endogenous RNAi machinery described 
above to cause targeted degradation of the mRNA, and a consequent reduction in target 
protein levels. 35,36 
1.1.4 
ALN-TTR02 
Alnylam Pharmaceuticals is developing ALN-TTR02 Solution for Injection (hereafter 
referred to as ALN-TTR02), a synthetic investigational RNAi therapeutic comprising an 
siRNA (ALN-18328) targeting the TTR mRNA. 
Unformulated synthetic siRNAs administered by IV injection are rapidly eliminated and, 
thus, do not achieve significant tissue distribution.37  Since 95% of TTR is produced in 
the liver, it was necessary to develop a formulation that could deliver ALN-18328 to the 
liver.  One approach that has been used successfully employs IV delivery of siRNA in 
liposomal formulations.  Recent preclinical studies have demonstrated targeted organ 
distribution, leading to significantly improved efficacy with lipid particle formulated 
siRNAs directed against liver-expressed genes.38,39  Following IV administration, the 
lipid particles enter the circulation and extravasate into the interstitial fluid.  The lipid 
particles accumulate preferentially in the liver due to their ability to pass through the 
fenestrated capillaries in that organ.  Subsequent uptake of the lipid particles is believed 
to result from endocytosis of the intact particles, followed by fusion with the endosomal 
membrane,40 leading to release of the siRNA into the cytoplasm.  The siRNA is then 
available to interact with the endogenous cellular RNAi machinery to bring about 
targeted degradation of the mRNA and subsequent reductions in the target protein levels.   
ALN-TTR02 consists of ALN-18328, an siRNA designed to suppress production of both 
mutant and WT TTR, formulated in an LNP termed AF-011.  The LNP enables delivery 
of the siRNA primarily to the liver upon systemic administration, resulting in the down-
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regulation of hepatic TTR expression, and in turn, reducing serum mutant and WT TTR 
levels.  The proposed indication for ALN-TTR02 is for the treatment of ATTR.  
ALN-TTR02 is intended for administration as an IV infusion over 1 hour.   
ALN-TTR02, a second generation siRNA LNP formulation termed AF-011, employs the 
same siRNA (ALN-18328) as ALN-TTR01, which utilizes the first generation LNP 
(termed stable nucleic acid lipid particles [SNALP]).  Both ALN-TTR01 and 
ALN-TTR02 are intended for the treatment of patients with ATTR; the AF-011 
formulation, however, has been optimized to be more potent such that mRNA and protein 
reduction effects are observed at significantly lower doses with AF-011 than with the 
SNALP formulation.  Furthermore, ALN-PCS02 employs the same AF-011 formulation 
as ALN-TTR02, but has a siRNA targeting a different liver derived protein, that of 
PCSK9.  Since the overall nonclinical toxicology findings are attributable primarily to the 
lipid formulation regardless of the encapsulated siRNA, previous non-clinical evaluation 
(including pharmacology, pharmacokinetics [PK], metabolism, and safety/toxicity), and 
clinical evaluations of ALN-PCS02 and ALN-TTR01 can provide important data 
regarding the anticipated safety of ALN-TTR02 (see Section 1.3). 
1.2 
Summary of ALN-TTR02 Non-Clinical Data  
 
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Further information can be found in the ALN-TTR02 Investigator’s Brochure and its 
Expedited Safety Report addendum dated 7 June 2012. 
1.3 
Summary of Clinical Data with siRNA-LNPs 
Clinical trials with multiple different RNAi medicinal products using local or systemic 
administration in indications including age-related macular degeneration, respiratory 
syncytial virus (RSV) infection, oncology, and renal failure have been conducted.28  
Alnylam currently has experience with 4 systemic delivery programs in the clinic 
evaluating the safety and efficacy of different siRNAs in 2 different LNP formulations, 
including 1 program which employs the same AF-011 formulation as ALN-TTR02.  An 
overview of the safety and pharmacological clinical data with these siRNA-LNPs is 
included in the ALN-TTR02 Investigator’s Brochure (IB), Edition 3, dated 
19 October 2012.  
 
 
 
   
Importantly, a Phase 1 study with ALN-TTR02 was recently completed.  Study ALN-
TTR02-001 was a multicenter, randomized, placebo-controlled, single-blind, single-
ascending dose clinical study conducted in the UK to evaluate the safety, tolerability, PK, 
and pharmacodynamic (PD) in healthy volunteers (EudraCT # 2011 005291-42).  ALN-
TTR02 was administered as a single 60-minute IV infusion to healthy volunteers at the 
following doses: 10, 50, 150, 300, and 500 µg/kg (4 patients per dose level; 3 receiving 
ALN-TTR02 and 1 receiving placebo).  Patients were premedicated with dexamethasone, 
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H1 and H2 blockers, and paracetamol prior to dosing to minimize the risk of infusion 
reaction.  The data show that ALN-TTR02 was safe and well-tolerated and exhibited 
robust effects on serum TTR levels at doses ≥0.15 mg/kg.  Lowering of TTR levels was 
reversible following administration of a single dose, and there were no AEs associated 
with lowering TTR by >90%.  Further details on this study can be found in the ALN-
TTR02 IB, Edition 3. 
1.4 
Study Hypothesis and Rationale 
ALN-TTR02 is a novel drug to treat ATTR and consists of a single LNP-formulated 
siRNA (ALN-18328) targeting both WT and all known mutant forms of TTR.  Since 
TTR amyloid deposits consist of both mutant and WT TTR, it is desirable to be able to 
lower the production of both WT and mutant TTR with a single drug in order to treat the 
different variants of ATTR.  While liver transplantation has shown both the advantages as 
well as the limitations of eliminating mutant TTR in FAP, it also underscores the 
potential advantage of a drug that can lower both mutant and WT TTR for treating both 
the cardiac and neuropathic complications of ATTR.   
The ALN-TTR02 nonclinical pharmacology data described in Section 1.2 demonstrate 
that administration of ALN-TTR02 results in significant suppression of mutant and WT 
TTR mRNA as well as protein, and that this suppression has the potential to prevent the 
deposition of TTR in key tissues.  It is anticipated that lowering of mutant and WT TTR 
protein in humans will result in a decrease in the deposition of amyloid fibrils, thereby 
potentially slowing down or reversing the course of the disease. 
The primary objective of this study is to evaluate the safety and tolerability of a multiple 
doses of ALN-TTR02 administered to patients with ATTR.  Secondary objectives include 
the characterization of plasma and urine PK for ALN-TTR02 as well as to assess 
preliminary evidence of the PD effect of ALN-TTR02 on serum total TTR. 
1.5 
Dose Selection and Rationale 
Two consecutive ALN-TTR02 doses, separated by a 4-week period (or a 3-week period 
in select optional cohorts), will be administered to patients.  Study drug will be 
administered as a 60-minute IV infusion with the following proposed doses for each of 
the original cohorts:  10, 50, 150, and 300 μg/kg ALN-TTR02.  For those patients 
enrolled in an optional cohort evaluating the alternative premedication regimen and 
infusion rate, the study drug will be administered IV over approximately 70 minutes. 
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Based on the preclinical and clinical experience with siRNA-LNPs to date, it appears that 
the translation of data from animals to humans occurs based on a mg/kg basis.  However, 
taking a more conservative approach, exposures based on allometric scaling as well as 
body surface area have been estimated, and safety margins were calculated (see 
Investigator’s Brochure).  Based on allometric scaling, a 2-fold and 44-fold safety margin 
was determined for the starting dose in humans (10 μg/kg)
 
 a similar margin was obtained based on body surface area.  Based 
on body weight, the margin for the proposed human starting dose is 10-fold and 100-fold 
.  The top dose proposed in the study (300 μg/kg) is 
.  Preliminary safety data 
are available from ongoing Phase 1 trials with ALN-TTR02 and ALN-PCS02.  In the 
ALN-TTR02-001 Phase 1 trial in healthy volunteers, these same dose levels were found 
to be safe and well-tolerated.  Furthermore, ALN-PCS02, which uses the same second 
generation LNP formulation as ALN-TTR02, was safe and well-tolerated at doses up to 
400 µg/kg in healthy volunteers with elevated cholesterol.  See the ALN-TTR02 
Investigators Brochure and its Expedited Safety Report addendum dated 7 June 2012 for 
updated information on the ALN-TTR02 and ALN-PCS02 Phase 1 trials. 
Additionally, a conservative dosing approach is being taken.  In each cohort, patients will 
be dosed in a sequential fashion with a minimum of 48 hours elapsing between patients.  
Collective cohort safety and tolerability data on the 3 patients from the prior cohort 
through at least 96 hours post-dose will be reviewed by the Safety Review Committee 
(SRC) prior to approving dosing for the next dose level.  In addition, cumulative safety 
and tolerability data observed in at least 2 patients through at least 96 hours post-second 
dose of the previous cohort will be reviewed by the SRC prior to administration of the 
second dose of study drug.   
Based on the interim evaluation of safety data, it may also be decided by the SRC that an 
optional cohort may be utilized which will include 3 additional patients.  Dosing in these 
cohorts may occur at a previously tested dose that was found to be safe and where 
stopping rules were not met or at an intermediate dose level.  Patients in the optional 
cohort would be dosed and reviewed for safety and tolerability following the same 
procedures as used for other cohorts.  The optional cohort(s) would be included to further 
confirm the safety and/or PD effect of previously evaluated dose levels, which may 
include evaluation of the original dosing regimen (once every 4 weeks), an alternative 
dosing regimen (once every 3 weeks), and/or an alternative premedication regimen and 
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infusion rate.  The dosing regimen for the first optional cohort will be once every 
4 weeks, and the dosing regimen for the remaining 4 optional cohorts will be once every 
3 or 4 weeks.  It is anticipated that the first 2 optional cohorts will use the original 
premedication regimen, and the remaining 3 optional cohorts may be used to explore the 
alternative premedication regimen and infusion rate.  The SRC will review all available 
safety data and make recommendations on dosing and premedication regimens prior to 
dosing of any of the optional cohorts.  If this occurs, the Independent Ethics Committees 
(IECs) will be informed of the implementation of optional cohorts.  Up to 5 optional 
cohorts of 3 patients each are permitted in this study. 
The optional cohorts will follow the same treatment schema as cohorts 1 to 4, as outlined 
in Section 5.6. 
1.6 
Risk-Benefit Assessment 
No benefit is expected from the transient lowering of TTR during this study.  Please see 
Investigator’s Brochure for expanded risk/benefit assessment. 
1.6.1 
Infusion-Related Reactions 
Infusion-related reactions can occur with systemic administration of certain biological 
agents such as liposomes or monoclonal antibodies.  These may include acute reactions 
or delayed febrile reactions.  Premedicating patients with corticosteroids and/or 
antihistamines, or slowing of the infusion rate, are approaches that have been taken to 
reduce the incidence and/or severity of IRRs.41,42  Consistent with this, a premedication 
regimen (dexamethasone or equivalent, paracetamol or equivalent, histamine H1/H2 
receptor antagonist [H1/H2 blocker]) similar to that proposed for this study was used in 
the prior ALN-PCS02 and ALN-TTR01 clinical studies that employed siRNAs in LNP 
formulations (Section 1.3). 
In order to reduce the potential for an IRR with ALN-TTR02, all patients in this study 
will be premedicated prior to dosing with ALN-TTR02.  The premedication regimen will 
include dexamethasone (or equivalent), paracetamol (or equivalent), and H1 and H2 
blockers (as described in Section 5.5).  The infusion rate of 1 hour or longer will also 
help to reduce the potential for acute IRRs.  The suggested clinical course for managing 
IRRs is provided in Section 5.11 and in Appendix 1 and Appendix 2.   
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1.6.2 
Hepatotoxicity 
Alnylam’s previous clinical experience with LNPs, either second generation AF-011 or 
first generation SNALP, in Phase 1 studies suggests that the risk for hepatotoxicity is 
low.  No clinically significant changes in LFTs have been seen to date in the ongoing 
ALN-VSP02, ALN-TTR01, or ALN-PCS02 Phase 1 trials.  In the ALN-TTR02 study, 
the risk of liver toxicity is lowered by requiring patients to have adequate liver function, 
which will then be followed closely through serial measurements after dosing. 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• 
To evaluate the safety and tolerability of multiple doses of ALN-TTR02. 
2.2 
Secondary Objectives 
• 
To characterize the plasma and urine PK of ALN-TTR02. 
• 
To assess preliminary evidence of the PD effect of ALN-TTR02 on serum total 
TTR. 
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3 
STUDY PLAN 
3.1 
Overall Design 
Protocol ALN-TTR02-002 is a multi-national, multi-center, Phase 2, open-label, multi-
dose, dose escalation study designed to determine the safety, tolerability, PK, and PD of 
2 consecutive doses (separated by approximately 4 weeks) of ALN-TTR02 in patients 
with ATTR. 
Patients of any mutant TTR genotype with a biopsy-proven diagnosis of ATTR who 
exhibit documented signs/symptoms of the disease (e.g., sensory, motor, or autonomic 
neuropathy) that are at least mild to moderate in severity will be eligible for the study, 
provided they have a body mass index (BMI) of 17-33 kg/m2, an adequate performance 
status (Karnofsky performance status of 60% or greater; see Appendix 3), adequate 
hepatic and renal function, no active infection or inflammatory disorder, stable cardiac 
status, and have not had a liver transplant.   
Two doses, separated by 4 weeks, of ALN-TTR02 (10, 50, 150, and 300 μg/kg) will be 
investigated in 4 sequential cohorts comprised of 3 patients each.  No patients will be a 
member of more than 1 treatment group.  An alternative dosing regimen of 2 doses of 
ALN-TTR02 (at a dose previously determined by the SRC to be safe and tolerable) 
separated by 3 weeks may be evaluated in the optional cohort(s).  
Within each of the cohorts, the first patient will receive their first dose and if the dose is 
well tolerated (per Section 5.7.3, Dose-limiting Toxicity), Patients 2 and 3 will receive 
their first dose at that same dose level no sooner than 48 hours apart, with Patient 2 
receiving a dose of study drug no sooner than 48 hours after the dosing of Patient 1.  
Similar to the first dose, the second dose will be administered to patients 4 weeks after 
the first dose in a sequential manner with at least 48 hours separating dosing of each 
patient.  If after the first dose, ALT and AST are > 2.5 x ULN, that patient would not 
receive their second dose.    
Dose escalation to the next cohort will proceed after the collective safety and tolerability 
data through at least 96 hours post-first dose from the 3 patients in the previous cohort 
has been reviewed by the SRC.  If the administered dose is found to be safe and well 
tolerated, dosing for the next cohort will begin no sooner than 96 hours after Patient 3 has 
safely received dose 1 from the previous cohort.  Patients in the cohort would be dosed 
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and reviewed for safety and tolerability following the same procedures as used for other 
cohorts (as stated above).   
For patients on all dose levels other than the starting dose level of 10 µg/kg, prior to 
receiving the second dose the SRC will review the cumulative safety and tolerability data 
of at least 2 patients from the previous dose level(s) with at least 96 hours of follow-up 
after receiving a second dose of study drug. 
For any DLT, accrual to that dose level will stop, all dosing will be discontinued, and 
dose escalation will end, pending further evaluation of all available safety data by the 
SRC (see Section 5.7.4).  The SRC may be convened earlier at the discretion of Alnylam 
if important safety issues arise requiring the attention of the committee (e.g., new safety 
information attained in other ongoing studies with ALN-TTR02). 
The duration of patient participation in this study is approximately 36 weeks.  Patients 
will be screened from -45 to -3 days prior to dose administration.  Eligible patients will 
undergo further pre-treatment assessments (performed on Day 0).  Patients receiving the 
original premedication regimen will receive oral premedication with dexamethasone (or 
equivalent), paracetamol (or equivalent), and H1 and H2 blockers the night before and 30 
to 60 minutes prior to each dose of ALN-TTR02 to reduce the potential of an IRR (see 
Section 5.5).  Those patients in an optional cohort evaluating the alternative 
premedication regimen, as agreed upon by the SRC, will receive IV dexamethasone (or 
equivalent), oral paracetamol (or equivalent), and IV H1 and H2 blockers at least 60 
minutes prior to ALN-TTR02 dosing; no premedication will be administered the evening 
prior to dosing.  On Days 0 and 28, patients will receive a single dose of ALN-TTR02 
administered as a 60-minute IV infusion (for cohorts with the original premedication 
regimen and infusion rate), or as an approximate 70-minute IV infusion, for those 
patients in an optional cohort evaluating the alternative premedication regimen and 
infusion rate.  The infusion time may be extended up to 3 hours in the event of a mild or 
moderate infusion reaction (study drug administration will not be resumed for any patient 
following a severe infusion reaction).  Details on the study drug administration are 
provided in Section 5.6.  Patients will be hospitalized at the study site for at least 
24 hours after the end of the study drug infusion. Patients may be discharged upon 
Investigator review of the 24 hour ECG, LFTs, and a subset of serum chemistries 
(sodium, potassium, creatinine, albumin, calcium, glucose, and phosphate), if results are 
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deemed not clinically significant.  Patients will return to the site for out-patient visits for 
safety, PK, and PD monitoring up to 208 days post-dose (see Section 6 for details).   
The SRC will evaluate safety in the study and determine if it remains acceptable to dose 
escalate or administer the second dose to the next dose level per their safety review 
charter.  To ensure timely safety information exchange across the participating study 
centers, the SRC will be comprised of all Principal Investigators (PIs) participating in the 
study or their designee, the Alnylam Medical Monitor, and the Contract Research 
Organization (CRO) Medical Monitor.  The SRC will communicate frequently to ensure 
that patients are dosed according to the time intervals specified in Section 5.6, even as 
patients are being accrued across multiple centers. 
3.2 
Safety Assessments 
Safety monitoring will include assessment of AEs, 12-lead ECGs, cardiac monitoring 
(telemetry), arterial oxygen saturation (SaO2) using pulse oximetry, vital signs (blood 
pressure, pulse rate, oral body temperature, and respiratory rate), clinical laboratory 
safety tests (hematology, serum chemistry, LFTs, thyroid function parameters, serology, 
coagulation parameters, urinalysis, cytokines, CRP, and complement factors), and 
physical examinations.  Patients will be closely monitored for both acute and delayed 
IRRs (see Section 5.11 for clinical guidance).  All IRRs will be recorded as AEs. 
3.3 
Pharmacodynamic Assessments 
The PD of ALN-TTR02 in patients with ATTR will be evaluated by serial measurement 
of serum concentrations of serum total TTR levels. 
3.4 
Pharmacokinetic Assessments 
The PK evaluation will include plasma-concentration time profiles for siRNA 
ALN-18328 and the novel lipid components DLin-MC3-DMA and PEG2000-C-DMG.  
ALN-18328 concentration will be determined at specified time points post-dose.  An 
assessment of plasma concentrations of free and encapsulated siRNA will be determined 
at specified time points.  PEG2000-C-DMG and DLin-MC3-DMA will be determined at 
specified time points up to 180 days post-dose.  Renal clearance (CLR) will be 
determined for ALN-18328 and DLin-MC3-DMA and/or its metabolites excreted in the 
urine. 
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3.5 
Other Assessments 
Serum levels of mutant vs wild-type TTR protein, TTR mRNA, and vitamin A and RBP 
will be assessed in patients with ATTR. 
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4 
PATIENT POPULATION 
4.1 
Eligibility of Patients 
Based on the planned dose escalation scheme (see Section 5.7.1), up to 27 patients are 
expected to be enrolled.  All centers have been selected on the basis of their extensive 
experience with treatment of patients with ATTR, and have the equipment necessary to 
treat patients in case of an emergency. 
4.2 
Inclusion Criteria 
Each patient must meet all of the following criteria within the Screening period 
(Day -45 to Day -3) to be enrolled in the study: 
5. Male or female aged 18 years or older. 
6. Patient has biopsy-proven diagnosis of TTR amyloidosis with documented 
signs/symptoms of the disease (e.g., sensory, motor, or autonomic neuropathy) 
that are at least mild to moderate in severity. 
7. Body mass index of 17–33 kg/m2. 
8. Patient has a Karnofsky performance status of 60% or greater (see Appendix 3). 
9. Patient has an absolute neutrophil count (ANC) ≥1500 cells/mm³, platelet 
count ≥100,000 cells/mm³, and hemoglobin ≥10 g/dL. 
10. Patient has adequate liver function, demonstrated by an aspartate transaminase 
(AST) and alanine transaminase (ALT) ≤2.5 × the upper limit of normal (ULN), 
total bilirubin within normal limits, albumin >3 g/dL, and international 
normalized ratio (INR) ≤1.2. 
11. Patient has adequate renal function: serum creatinine ≤1.5 × ULN. 
12. Patient is seronegative for hepatitis B virus (HBV) and hepatitis C virus (HCV). 
13. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breast feeding, and must be using two highly effective methods of contraception 
prior to screening, throughout study participation, and for 1 month after ending 
study participation.  Highly effective methods of birth control are defined as: 
hormonal - oral, implantable, injectable, or transdermal contraceptives in 
conjunction with spermicide, condom, or diaphragm; mechanical - spermicide in 
conjunction with a barrier such as a condom or diaphragm; intrauterine device in 
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conjunction with spermicide or condom; or surgical sterilization of partner in 
conjunction with spermicide, condom, or diaphragm. 
14. Males agree to use appropriate contraception throughout study participation and 
for 1 month after ending study participation. 
15. Patient is willing and able to comply with protocol-required visit schedule and 
visit requirements and provide written informed consent. 
4.3 
Exclusion Criteria 
Patients meeting any of the following criteria within the Screening period (Day -45 to 
Day -3) will be excluded from the study: 
1. Patient is pregnant or nursing. 
2. Patient has had a liver transplant. 
3. Has a known surgery planned during any point of the study period. 
4. Patient has known human immunodeficiency virus (HIV) positive status. 
5. Has a known or suspected systemic bacterial, viral, parasitic, or fungal infection. 
6. Patient received an investigational agent, other than tafamidis or diflunisal, within 
30 days prior to first dose study drug administration.  
7. Patient has a New York Heart Association heart failure classification >2 (see 
Appendix 5). 
8. Patient has unstable angina. 
9. Patient has uncontrolled clinically significant cardiac arrhythmia. 
10. Patient is considered unfit for the study by the Principal Investigator. 
11. Patient had a prior severe reaction to a liposomal product. 
12. Patient has known hypersensitivity to oligonucleotides. 
13. Patient is an employee or family member of Alnylam, the CRO, or the clinical 
study site personnel. 
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4.4 
Assignment to Dose Cohort/Patient Number 
4.4.1 
Assignment to Dose Cohort 
After confirmation of eligibility during screening, patients satisfying the entry criteria 
will be assigned to the cohort currently enrolling.  Each cohort will comprise 3 patients.  
No patients will be a member of more than 1 treatment group. 
A unique patient identification number will be assigned sequentially after the patient has 
completed all of the screening procedures and is determined to be eligible for the study.  
If applicable, replacement patients will receive the same treatment allocation as those 
whom they replace. 
4.4.2 
Blinding Procedures 
Not applicable. 
4.5 
Early Patient Withdrawal 
Patients are free to withdraw from the study at any time and for any reason, without 
penalty to their continuing medical care.  A patient will be considered to have completed 
the study if the patient receives both doses of study medication and completes protocol-
specified procedures up through Day 56.   
4.5.1 
Reasons for Withdrawal 
The Investigator may withdraw a patient from the study if the patient: 
• 
Is in violation of the protocol. 
• 
Experiences a serious or intolerable AE (including infusion reactions). 
• 
Experiences a DLT (see Section 5.7.3). 
• 
Develops conditions listed in the exclusion criteria during the course of the study. 
• 
Becomes pregnant. 
• 
Requires a prohibited medication (see Section 5.10). 
• 
Requests to be withdrawn from the study. 
The Investigator will also withdraw the patient from the study upon the request of 
Alnylam or the SRC, or if Alnylam terminates the study.  Upon occurrence of a serious or 
intolerable AE, the Investigator will confer with Alnylam before discontinuing the 
patient, and the SRC will be notified.  A patient may withdraw consent to participate in 
the study at any time. 
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4.5.2 
Handling of Withdrawals 
Patients are free to withdraw from the study upon request.  Patient participation in the 
clinical study may be terminated at any time at the discretion of the Investigator or 
Alnylam. 
In the event a patient is withdrawn from the study, the CRO Medical Monitor must be 
informed immediately.  If there is a medical reason for withdrawal, the patient will 
remain under the supervision of the Investigator for protocol-specified safety follow up 
procedures.  The SRC may be notified. 
Patients who voluntarily withdraw are termed dropouts.  Dropouts may be replaced 
following discussion with the Investigator and Alnylam (see Section 4.5.3).   
Patients who are withdrawn due to AEs during infusion of the ALN-TTR02 will not be 
replaced. 
If a patient is withdrawn/withdraws the discharge procedures should be performed and an 
early termination (ET) visit scheduled as follows: 
• 
If a patient is withdrawn/withdraws prior to Day 56 then the Day 56 assessments 
should be completed; 
• 
If a patient is withdrawn/withdraws after Day 56 and prior to Day 208 then the 
Day 208 assessments should be completed. 
If a patient is withdrawn due to an AE, appropriate medical care should be provided and 
the AE should be followed through 56 days post last dose.  Follow-up procedures should 
be conducted as scheduled. 
Patients who fail to return for final evaluations will be contacted by the site in an attempt 
to have them comply with the protocol.  The site will follow up by telephone at least 
twice and send a registered letter to any patient who fails to return for the final 
evaluation. 
When a patient withdraws from the study, the primary reason for discontinuation must be 
recorded in the appropriate section of the case report form (CRF) and all efforts will be 
made to complete and report the observations as thoroughly as possible.   
4.5.3 
Patient Replacement 
Any patient who misses a dose, does not receive 80% of each ALN-TTR02 dose, or who 
discontinues from the study for a non-safety related issue, as determined by the SRC, 
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prior to completing the 56-day study period may be replaced at the advice of the SRC and 
the discretion of Alnylam. 
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5 
STUDY MEDICATION 
5.1 
Presentation of Study Drug 
ALN-TTR02 Solution for Injection is an RNAi therapeutic consisting of drug substance 
ALN-18328 (siRNA targeting TTR mRNA) formulated in LNPs.  The ALN-TTR02 drug 
product is a sterile formulation of ALN-18328 with lipid excipients (DLin-MC3-DMA, 
DSPC, cholesterol and PEG2000-C-DMG) in isotonic phosphate buffered saline.  
ALN-TTR02 Solution for Injection contains 2 mg/mL of drug substance ALN-18328. 
The ALN-TTR02 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. 
5.2 
Preparation of Study Drug 
Each investigational site will be responsible for assembly and labelling according to 
separate IMP handling instructions and allocating treatments to the patients. 
The pharmacist will prepare the study drug under aseptic conditions.  The amount (in µg) 
of ALN-TTR02 to be administered will be determined based on the patient’s weight (kg) 
and the dose cohort they are assigned to.  For the first dose, the weight obtained pre-dose 
on Day 0 will be used to calculate the dose of study drug.  The patient’s weight measured 
pre-dose on Day 28 will be used to calculate the second dose of study drug.  Subjects 
who weigh 105 kg or more will receive ALN-TTR02 dosing based on an assumption of a 
body weight of 104 kg. 
Approximately 200 mL of sterile normal saline (0.9% NaCl) will be added to a sterile 
infusion bag, and the calculated volume of ALN-TTR02 will be withdrawn from the vials 
and injected into the infusion bag. 
Additional study drug preparation details are provided in the ALN-TTR02 Pharmacy 
Manual. 
5.3 
Storage of Study Drug 
All study drug must be stored in a secure location and may be dispensed only by the 
Investigator or by a staff member specifically authorized by the Investigator, or by a 
pharmacist, as appropriate.  All study medication will be stored upright and refrigerated 
at approximately 5 ± 3oC, protected from light in the storage area of the investigational 
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site pharmacy, in a secure, temperature controlled, locked environment with restricted 
access.  Any deviation from the recommended storage conditions should be reported to 
Alnylam and use of the study drug halted until authorization for its continued use has 
been given by Alnylam or designee. 
No special procedures for the safe handling of ALN-TTR02 are required.  Alnylam will 
be permitted upon request to audit the supplies, storage, dispensing procedures, and 
records. 
No trial product(s) may be administered to any person not enrolled in the trial. 
Additional preparation details are provided in the ALN-TTR02 Pharmacy Manual. 
5.4 
Labeling and Packaging of Study Drug 
All packaging and labelling as well as the production of study medication 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. 
Study drug labels for use at study centers 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. 
5.5 
Premedication Plan 
All patients will be premedicated prior to dosing with ALN-TTR02 to reduce the 
potential for an infusion reaction.   
Patients receiving the original premedication regimen will be administered the following: 
• 
Oral dexamethasone (8 mg) or equivalent administered the evening before dosing 
and 20 mg 30 to 60 minutes prior to start of infusion of ALN-TTR02; 
• 
Oral paracetamol (500 mg) or equivalent the evening before dosing and 30 to 
60 minutes prior to the start of infusion of ALN-TTR02; 
• 
Oral H2 blocker (e.g., ranitidine 150 mg, famotidine 20 mg, or equivalent other 
H2 blocker dose) the evening before dosing and 30 to 60 minutes prior to start of 
infusion of ALN-TTR02; 
• 
Oral H1 blocker, 10 mg cetirizine (hydroxyzine 25 mg, fexofenadine, or 
equivalent may be substituted if patient does not tolerate cetirizine) the evening 
before dosing and 30 to 60 minutes prior to start of infusion of ALN-TTR02. 
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Staff at each investigative site should make every effort to contact the patient by 
telephone the day prior to being administered the study drug (Days -1 and 27) to remind 
the patient of the premedication regimen. 
An alternative premedication regimen and infusion rate can be used in select optional 
cohorts, as agreed upon by the SRC.  The dosing regimen for the first optional cohort will 
be once every 4 weeks, and the dosing regimen for the remaining 4 optional cohorts will 
be once every 3 or 4 weeks.  It is anticipated that, the first 2 optional cohorts will use the 
original premedication regimen and the remaining 3 optional cohorts may be used to 
explore the alternative premedication regimen and infusion rate.  Patients in these cohorts 
will not receive any premedications the evening prior to ALN-TTR02 dosing.  Prior to 
each dose of ALN-TTR02, these patients will receive the following premedications: 
• 
Intravenous (IV) dexamethasone (10 mg) or equivalent, administered at least 60 
minutes prior to the start of infusion of ALN-TTR02; 
• 
Oral paracetamol (500 mg) or equivalent at least 60 minutes prior to the start of 
infusion of ALN-TTR02; 
• 
Intravenous H2 blocker (e.g., ranitidine 50 mg, famotidine 20 mg, or equivalent, 
other H2 blocker dose) at least 60 minutes prior to start of infusion of ALN-
TTR02; and 
• 
Intravenous H1 blocker: diphenhydramine 50 mg IV (or equivalent other IV H1 
blocker available at the study site) at least 60 minutes prior to start of infusion of 
ALN-TTR02.  Hydroxyzine or fexofenadine 25 mg PO or cetirizine 10 mg PO 
may be substituted for any patient who does not tolerate IV diphenhydramine or 
other IV H1 blockers. 
Further details can be found in the Study Reference Manual.   
5.6 
Dose, Route, and Schedule of Study Drug Administration 
Consented patients meeting the eligibility criteria will be enrolled into sequential cohorts 
of increasing doses of ALN-TTR02.  Each cohort will consist of 3 patients. 
Study drug will be administered under the supervision of the Investigator or designee.  
Study drug doses will be administered as a 60-minute IV infusion (flow rate of 
approximately 3.3 mL/min) 4 weeks apart.  The dosing of ALN-TTR02 in the optional 
cohorts will be once every 4 weeks for the first optional cohort and once every 3 or 
4 weeks for the remaining 4 optional cohorts, at a dose previously determined by the SRC 
to be safe and tolerable.  Study drug will be administered via a controlled infusion device 
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with an extension set containing a 1.2 micron filter supplied by Alnylam or designee.  
Infusion products containing polyvinyl chloride, di(2-ethylhexyl)phthalate (PVC, DEHP) 
must NOT be used.  For patients enrolled in an optional cohort evaluating the alternative 
premedication regimen, the flow rate will be approximately 1.1 mL/min during the first 
15 minutes (1/3rd the original flow rate) with the remainder of the infusion taking place 
over 55 minutes (at a flow rate of approximately 3.3 mL/min) for a total infusion time of 
approximately 70 minutes. 
The patient’s infusion site will be checked pre-dose, during infusion, and after infusion 
for any safety concerns (e.g., infusion-associated reactions).  The infusion time may be 
extended up to 3 hours in the event of a mild or moderate infusion reaction (study drug 
administration will not be resumed for any patient following a severe infusion reaction).  
Patients will remain hospitalized at the study site for at least 24 hours following 
completion of dosing on Day 0 and Day 28 to be observed for safety assessments and PK 
sampling. 
The planned study drug doses are 10, 50, 150, and 300 µg/kg. 
Subjects who weigh 105 kg or more will receive ALN-TTR02 dosing based on an 
assumption of a body weight of 104 kg. 
Prior to administration of the second dose of ALN-TTR02, the inclusion and exclusion 
criteria must be reassessed to ensure that the patient still qualifies for participation in the 
study. 
 
 
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The planned study drug doses and patient cohorts are identified in Table 5-1.  Dose 
escalation procedures are described in Section 5.7.1. 
Table 5-1: 
Planned Dose Cohorts and Enrollment 
Patient Cohort 
ALN-TTR02 Dose 
(µg/kg) 
Initial Enrollment 
Total Enrollmenta 
1 
10 
3 
Up to 27 patients 
2 
50 
3 
3 
150 
3 
4 
300 
3 
a 
Up to 5 optional cohorts may be included to confirm the safety, tolerability, and/or PD effect of previously 
evaluated dose levels, which may include evaluation of the original dosing regimen (once every 4 weeks), an 
alternative dosing regimen (once every 3 weeks), and/or an alternative premedication regimen and infusion rate at 
a specific dose of ALN-TTR02.  Dosing in these optional cohorts may occur at a previously tested dose that was 
found to be safe and where stopping rules were not met or at an intermediate dose level.  Each optional cohort will 
be comprised of 3 patients. 
5.7 
Criteria for Dose Escalation, Dose Modification or Discontinuation of 
Study Drug 
5.7.1 
Dose Escalation Procedures 
The initial dose of ALN-TTR02 is 10 µg/kg.  Dose escalation to 50, 150, and 300 µg/kg 
is planned.   
Within each of the cohorts, the first patient will receive their first dose and if the dose is 
well tolerated, per Section 5.7.3 (Dose-limiting Toxicity), Patients 2 and 3 will receive 
their first dose at that same dose level no sooner than 48 hours apart, with Patient 2 
receiving a dose of study drug no sooner than 48 hours after the dosing of Patient 1.  
Similar to the first dose, the second dose will be administered to patients 4 weeks after 
the first dose in a sequential manner with at least 48 hours separating dosing of each 
patient.  If after the first dose, ALT and AST are > 2.5 x ULN, that patient would not 
receive their second dose.  Dose escalation to the next cohort will proceed after the 
collective safety and tolerability data through at least 96 hours post-first dose from the 3 
patients in the previous cohort has been reviewed by the SRC.  If the administered dose is 
found to be safe and well tolerated, dosing for the next cohort will begin no sooner than 
96 hours after Patient 3 has safely received dose 1 from the previous cohort.  Patients in 
the cohort would be dosed and reviewed for safety and tolerability following the same 
procedures as used for other cohorts (as stated above).   
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For patients on all dose levels other than the starting dose level of 10 µg/kg, prior to 
receiving the second dose the SRC will review the cumulative safety and tolerability data 
of at least 2 patients from the previous dose level(s) with at least 96 hours of follow-up 
after receiving a second dose of study drug. 
The dosing of patients within each of the first 4 cohorts is depicted in  
 
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. 
 
 
 
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Figure 5-1: 
Scheme for Patient Enrollment and SRC Review Within and 
Between Each Patient Cohort 
 
 
 
a 
Some optional cohorts may have the second dose of ALN-TTR02 administered 3 weeks after the first dose.  
b 
Dosing of next cohort will follow the same schema as outlined in A with the next higher dose level. 
Enroll and administer 
dose to 1st patient
If dose is well tolerated, 
enroll and administer 
dose to the 2nd patient
If dose is well tolerated, 
enroll and administer 
dose to the 3rd patient
≥ 48 hours
≥ 48 hours
SRC review of data 
through at least 
96 hours post-dose for 
all 3 patients
If dose is safe and well 
tolerated, initiate 
dosing of the next 
cohort
A.  First Dose
SRC review of data 
through at least 
96 hours post-dose for 
at least 2 patients
If dose is safe and well 
tolerated, administer 
second dose for the 
next cohortb
Administer dose to 1st
patient
If dose is well tolerated, 
enroll and administer 
dose to the 2nd patient
If dose is well tolerated, 
enroll and administer 
dose to the 3rd patient
≥ 48 hours
B.  Second Dose (4 weeks after first dose)a
≥ 48 hours
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Dose-limiting toxicities are described further in Section 5.7.3, and study stopping rules 
are described in Section 5.7.4.  
5.7.2 
Optional Cohorts 
Based on the interim evaluation of safety data, it may also be decided by the SRC that an 
optional cohort may be utilized which will include 3 additional patients.  Dosing in these 
optional cohorts may occur at a previously tested dose that was found to be safe and 
where stopping rules were not met or at an intermediate dose level.  Patients in the 
optional cohort would be dosed and reviewed for safety and tolerability following the 
same procedures as used for other cohorts.  The optional cohort would be included to 
further confirm the safety and/or PD effect of previously evaluated dose levels, which 
may include evaluation of the original dosing regimen (once every 4 weeks), an 
alternative dosing regimen (once every 3 weeks), and/or to evaluate an alternative 
premedication regimen and infusion rate.  The dosing regimen for the first optional 
cohort will be once every 4 weeks, and the dosing regimen for the remaining 4 optional 
cohorts will be once every 3 or 4 weeks.  It is anticipated that the first 2 optional cohorts 
will use the original premedication regimen, and the remaining 3 optional cohorts may be 
used to explore the alternative premedication regimen and infusion rate.  The SRC will 
review all available safety data and make recommendations on dosing and premedication 
regimens prior to dosing of any of the optional cohorts.  If this occurs, the IECs will be 
informed of the implementation of optional cohorts.  Up to 5 optional cohorts of 
3 patients each are permitted in this study. 
5.7.3 
Dose-limiting Toxicity 
A DLT is defined as: 
• 
Any life-threatening toxicity; 
• 
ALT and AST levels ≥5 × ULN or total bilirubin >2.0 mg/dL; 
• 
An infusion reaction that requires hospitalization, despite premedication; 
• 
Any other toxicity which in the opinion of the SRC would have precluded further 
dosing. 
5.7.4 
Stopping Criteria 
For any DLT, accrual to that dose level will stop, all dosing will be discontinued, and 
dose escalation will end, pending further evaluation of all available safety data by the 
SRC.  
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5.8 
Measurement of Patient Compliance 
Patient compliance with study drug administration is dependent on the proper preparation 
and administration of IV infusions by study center personnel.  Because the study drug 
will be administered by study staff as an IV infusion, treatment compliance will be 
verified by observation in the clinic by study staff.  Treatment will be considered 
completed if 80% or more of each of the doses (based on total volume of the IV solution) 
has been administered to the patient. 
5.9 
Study Drug Accountability 
The Investigator will maintain accurate records of receipt and the condition of all study 
drugs including dates of receipt.  In addition, accurate records will be kept of when and 
how much study drug 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 Alnylam 
Monitor or designee.  Remaining study drug (all used, partially used and unused vials) 
will be returned to Alnylam or its specified designee/depot or destroyed at the site 
according to applicable regulations. 
Study drug must not be used for any purpose other than the present study.  Study drug 
which has been dispensed to a patient and returned unused must not be redispensed to a 
different patient. 
Further instructions about study drug accountability are detailed in the Pharmacy Manual. 
5.10 
Concomitant Medication / Treatment 
Use of the following medications/treatments is prohibited during study participation: 
• 
Any investigational agent other than ALN-TTR02, tafamidis, or diflunisal; 
• 
Corticosteroids, other than those administered as premedications prior to the dose 
of ALN-TTR02, those used to treat an infusion reaction, or topical or inhaled 
corticosteroids. 
Medications and treatments other than those specified above, including palliative and 
supportive care for disease-related symptoms, are permitted during the study. 
Use of all concomitant medications during screening, pre-dose and post-dose up to 
Day 56/ET will be recorded on the patient’s CRF.  This will include all prescription 
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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. 
Any concomitant medication that is required for the patient’s welfare may be given by 
the Investigator.  However, it is the responsibility of the Investigator to ensure that details 
regarding the medication are recorded on the CRF, and coded using an internationally 
recognized and accepted coding dictionary. 
5.11 
Suggested Guidelines for Management of Infusion Reactions 
In the event of an acute infusion reaction, the infusion of study drug will be stopped and 
the patient closely monitored until resolution of the reaction.  A blood sample should be 
obtained for analysis of tryptase, complement factors (including C3a), and cytokines at 
the time of the event, or as soon as possible after onset, 1 hour, and 24 hours after the 
start of the reaction.  In addition, if the infusion is stopped and the site is considering 
restarting, a PK blood sample will be taken when the infusion is stopped and this will be 
treated as the EOI sample if the infusion is restarted. 
Drugs that may be used to facilitate resolution and permit resumption of study drug 
administration include, but are not limited to: paracetamol (or equivalent), additional 
H1/H2 blockers (e.g., ranitidine), non-steroidal anti-inflammatory [NSAID], adrenaline, 
supplemental oxygen, IV fluids, and corticosteroids.  For moderate infusion reactions 
(see Appendix 1), resumption of study drug administration at a slower infusion rate (but 
not to exceed 3 hours) may be considered at the Investigator’s discretion.  Study drug 
administration will not be resumed for any patient following a severe infusion reaction.  
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. 
Infusion reactions may have a delayed onset following the completion of the infusion.  
The medical management of a delayed reaction (e.g., use of corticosteroids, etc.) would 
follow similar guidelines as provided above for acute infusion reactions (see Appendix 
2). 
After dosing, patients will be discharged from the hospital no sooner than 24 hours post-
dose.  Prior to discharge, the 24-hour ECG and local serum chemistries and LFTs must be 
reviewed by the Investigator as described in Section 3.1.  Patients will be discharged with 
directions on self-administration of medications as needed to ameliorate potential delayed 
reactions to study drug infusion, such as fever, chills, and myalgia.  Medications may 
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include, but are not limited to: antipyretics, antihistamines, and oral corticosteroids.  All 
concomitant medications, including self-administered medications, are to be listed on the 
CRF. 
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6 
STUDY VISITS 
The duration of a patient’s participation in this study is approximately 36 weeks.  This 
duration may be extended should optional cohorts with dosing intervals greater than 
4 weeks be included. 
An open-label extension study at the recommended Phase 3 dose and regimen (as derived 
from Study ALN-TTR02-002) is planned, which will enable the patients who enrolled in 
Study ALN-TTR02-002 to receive additional, long-term dosing and safety follow-up.  
For some of the patients, this may preclude the completion of all of the follow-up period 
assessments of Study ALN-TTR02-002 if they are deemed eligible to participate in the 
extension study prior to completion of the full follow up through Day 208.  Such patients 
will be followed up for a minimum of 28 days after their last dose in the current ALN-
TTR02-002 study prior to being enrolled in the extension study.  The extension study will 
be implemented only after dose escalation is completed in Study ALN-TTR02-002, with 
post second dose follow-up through Day 208 in at least 1 cohort at the highest dose. 
Screening evaluations are to be performed within 45 days before receiving the first dose 
of study drug, as indicated in Table 1-1 (Appendix 4 provides the schedule of 
assessments for the optional cohort(s) administered ALN-TTR02 once every 3 weeks). 
Patients determined to be eligible based on screening assessments will receive treatment 
(IV infusion of study drug) on Days 0 (Baseline) and 28 (or date of second dose 
administration in optional cohorts with dosing intervals greater than 4 weeks); for 
patients in optional cohorts evaluating the alternative dosing regimen (once every 
3 weeks), ALN-TTR02 will be administered on Days 0 (Baseline) and 21.  Patients will 
remain hospitalized at the study site for at least 24 hours following completion of dosing 
to be observed for safety assessments and PK sampling.  Patients will return to the study 
site on Days 2, 7, 10, 14, and 21 for follow-up assessments.  In addition, follow-up visits 
after the second dose of study drug (Day 28) will occur on Days 30, 35, 38, 42, 49, and 
56 (end-of-study); patients in optional cohorts evaluating the alternative dosing regimen 
(once every 3 weeks) will have follow-up visits on Days 21, 22, 23, 28, 31, 35, 42, 49, 
and 56.  Patients will also return to the site for a follow-up visit on Days 112 and 208. 
If necessary, visiting nurses will be allowed to conduct visits after Day 2 (but not 
Day 208) that do not require physical examinations.  All patients who discontinue the 
study before Day 56 will return to the study site for their Early Termination visit for 
Day 56 assessments.  All patients who discontinue the study after Day 56 and prior to 
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Day 208 will return to the study site for their Early Termination visit for Day 208 
assessments. 
6.1 
Screening Visit (Day -45 to -3) 
Screening evaluations will be conducted 3 to 45 days prior to administration of the first 
dose of study drug (Day 0).  Table 1-1 provides an overview of the schedule of events 
required for screening. 
Prior to screening activities, the patient will sign and date an informed consent form 
(ICF) and receive a copy of the signed ICF.  No study procedures should be performed 
prior to informed consent being obtained.  The Investigator or another person authorized 
by the Investigator will also sign and date the informed consent prior to giving a copy to 
the patient.  The ICF will be filed in the patient’s medical record. 
The following activities should be performed during the Screening visit: 
• 
Obtain demographic information. 
• 
Obtain medical detailed history information. 
• 
Assess study eligibility using the inclusion and exclusion criteria (e.g., calculate 
BMI). 
• 
Obtain concomitant medications information. 
• 
Perform a physical examination. 
• 
Obtain measurements of weight and height. 
• 
Measure vital signs. 
• 
Perform an echocardiogram if a normal echocardiogram has not been obtained 
within the past 90 days. 
• 
Perform a 12-lead ECG. 
• 
Collect blood samples for clinical laboratory tests, including: 
o Hematology. 
o Serum chemistries. 
o Liver function tests. 
o Coagulation studies. 
o Anti-PEG antibodies (IgG and IgM; immunoglobulin G and immunoglobulin 
M, respectively). 
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o Hepatitis B/C status (serologies include hepatitis B surface antibody [HbsAb], 
hepatitis B surface antigen [HbsAg], and anti–hepatitis C virus antibody [anti-
HCV Ab]). 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
o TTR mRNA. 
o Thyroid function tests. 
o Serum pregnancy test (women of child-bearing potential only). 
• 
Collect urine sample for urinalysis. 
6.2 
Pre-Dosing (Day -1 or Day 27); Day -1 or Day 20 for optional cohorts dosed 
once every 3 weeks 
For those patients receiving the original premedication regimen, on the day prior to 
administration of study drug (Days -1 and 27), study site personnel will contact the 
patient by phone to discuss the pretreatment medication they are to take that evening. 
On the evening before each dosing, patients are to self-administer the following 
medications PO: 8 mg dexamethasone or equivalent, 500 mg paracetamol or equivalent, 
an H1 blocker (10 mg cetirizine hydroxyzine [25 mg, fexofenadine, or equivalent may be 
substituted if patient does not tolerate cetirizine]), and an oral H2 blocker (e.g., ranitidine 
150 mg, famotidine 20 mg, or equivalent other H2 blocker). 
Patients in an optional cohort evaluating the alternative premedication regimen and 
infusion rate will not receive any premedication the evening prior to ALN-TTR02 dosing.   
6.3 
Treatment Visits 
6.3.1 
Day 0 or Day 28 (+2 days); Day 0 or Day 21 for optional cohorts dosed once 
every 3 weeks 
6.3.1.1 Pre-dose 
Patients who are determined to be eligible for the study, based on screening evaluations, 
will be enrolled on Day 0 and assigned to the appropriate dose cohort (see Section 4.4.1). 
Patients will undergo the following procedures before study drug administration on Day 0 
or Day 28 (Day 0 or Day 21 for optional cohorts dosed once every 3 weeks): 
• 
Reassess study eligibility using the inclusion and exclusion criteria. 
• 
Obtain updated medical history information. 
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• 
Conduct a focused physical examination (includes head/ears/eyes/nose/throat 
[HEENT], cardiovascular, respiratory, abdominal and hepatic assessments), 
including weight.  If the screening physical examination was performed within 
72 hours of Day 0, then it does not need to be repeated; however, the patient’s 
weight will need to be obtained.  For the first dose of study drug, this weight 
assessment (Day 0) will be used by the Pharmacy in the preparation of the 
patient’s first dose.   
o Calculate BMI. 
o Measure height. 
• 
Perform a urine pregnancy test (women of child-bearing potential only), the 
results of which must be known prior to the administration of study drug. 
• 
Obtain measurements of: 
o Vital signs 
o Twelve-lead ECG. 
o Pulse oximetry. 
• 
Collect blood samples for clinical laboratory tests (if the screening studies were 
performed within 72 hours of Day 0, then these laboratory tests need not be 
repeated), including: 
o Hematology.* 
o Serum chemistries.* 
o Liver function tests.* 
o Coagulation studies.* 
o Anti-PEG antibodies (IgG and IgM). 
o Thyroid function tests.* 
o Lipid panel (Day 0 only). 
o Complement Bb (within 10 minutes predose). 
o Cytokines (within 10 minutes predose). 
o CRP (within 10 minutes predose). 
Note: those parameters marked with an asterisk do not have to be reassessed on 
Days 0 or 28 (Days 0 or 21 for optional cohorts dosed once every 3 weeks) if 
measures are obtained within 72 hours prior to dosing and meets eligibility 
criteria. 
• 
Collect urine sample for urinalysis.*   
• 
Collect blood sample for PK pre-dose (within 1 hour of planned dosing start). 
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• 
Collect urine sample for PK pre-dose (within 1 hour of planned dosing start). 
• 
Obtain concomitant medications information. 
• 
Collect blood samples for TTR, Vitamin A, and RBP immediately (10 minutes) 
prior to and after administration of oral premedications. 
• 
Collect blood sample for TTR mRNA. 
• 
For patients receiving the original premedication regimen, premedicate the patient 
30 to 60 minutes prior to the start of study drug infusion with the following oral 
medications (or equivalent[s]):  20 mg dexamethasone, 500 mg paracetamol, 
10 mg cetirizine, and an H2 blocker (e.g. 150 mg ranitidine, 20 mg famotidine).  
Patients in select cohorts evaluating the alternative premedication regimen and 
infusion rate will receive the following medications (or equivalent[s]) at least 
60 minutes prior to the start of ALN-TTR02 infusion: IV dexamethasone 10 mg, 
PO paracetamol 500 mg, IV H2 blocker (e.g. ranitidine 50 mg, famotidine 20 mg, 
or equivalent other H2 blocker dose), and IV H1 blocker (e.g. diphenhydramine 
50 mg or equivalent other IV H1 blocker available at the study site; or 
hydroxyzine or fexofenadine 25 mg PO or cetirizine 10 mg PO for any patient 
who does not tolerate IV diphenhydramine or other IV H1 blockers). 
• 
Aliquots of serum samples for testing of exploratory biomarkers should be 
collected prior to infusion, but after premedications have been administered. 
• 
Assessment of the infusion site. 
• 
Initiate cardiac monitoring (telemetry) 30 minute pre-dose. 
6.3.1.2 Administration of Study Drug 
After completion of all pre-dose evaluations and procedures, administer study drug as a 
60-minute IV infusion (or an approximate 70-minute IV infusion for patients in an 
optional cohort evaluating the alternative premedication regimen and infusion rate) via a 
controlled infusion device.  Continue to assess the infusion site for signs of any localized 
reaction through 30 minutes post-infusion. 
The infusion time may be extended up to 3 hours in the event of a mild or moderate 
infusion reaction (study drug administration will not be resumed for any patient following 
a severe infusion reaction).  Suggested guidelines for treatment of infusion reactions are 
provided in Section 5.11.  In addition, if the infusion is stopped and the site is considering 
restarting, a PK blood sample will be taken when the infusion was stopped.  All 
remaining PK samples will be collected according to the schedule of assessments when 
the dose is completed. 
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Prior to administration of second dose of study drug, patients must be reassessed to 
confirm they continue to meet eligibility criteria. 
6.3.1.3 Post-dose 
Patients will undergo the following procedures after study drug administration on Day 0 
and Day 28 (+2 days); or Day 0 and Day 21 for optional cohorts dosed once every 
3 weeks.  Patients will remain hospitalized at the study site for at least 24 hours following 
completion of dosing, to be observed for safety assessments and PK sampling.  Unless 
otherwise specified, for non-PK assessments performed 30 minutes post-infusion, a 
window of ±5 minutes is allowed, a window of ±15 minutes is allowed for assessments 
performed between 1 and 3 hours, and a window of ±30 minutes for 6 through 18 hours 
post-infusion. 
• 
Obtain serial measurement of vital signs at the end of infusion (EOI) and at 
30 minutes and 1, 2, 3, 6, 12, and 18 hours post-infusion. 
• 
Perform serial 12-lead ECGs in triplicate at EOI and at 30 minutes, and 2 and 
4 (±15 minutes) hours post-infusion.   
• 
Continue cardiac monitoring (telemetry) through 24 (+1) hour post-dose. 
• 
Perform serial pulse oximetry at EOI and at 30 minutes and 1, 2, 3, 6, 12, and 
18 hours post-infusion. 
• 
Collect blood samples for clinical laboratory tests, including: 
o Complement Bb at 30 minutes and 2 (±15) hours post-infusion. 
o CRP at 2 and 6 (±15 minutes) hours post-infusion. 
o Cytokines at 2 and 6 (±15 minutes) hours post-infusion. 
o Pharmacokinetic analyses; EOI, 5, 10, and 30 minutes; and 1, 2, 4, and 
6 hours post-infusion.  The following windows are allowed for PK sampling: 
±1 minute for the 5- and 10-minute draws; ±2 minutes for the 30-minute 
draw; ±5 minutes for the 1-, 2-, 4-, and 6-hour draws. 
• 
Collect urine for PK from 0-6 hours post-infusion.   
• 
If an infusion reaction occurs, collect a blood sample for tryptase, complement 
factors (including C3a), and cytokine testing at the time of the event, or as soon as 
possible after onset and 1 hour after the start of the reaction. 
• 
Document any AEs, beginning with the initiation of the infusion. 
• 
Obtain concomitant medications information. 
Patients will remain in the hospital for at least 24 hours.   
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6.3.2 
Day 1 or Day 29; Day 1 or Day 22 for optional cohorts dosed once every 
3 weeks 
Patients will undergo the following procedures on the day following dosing with study 
drug (Days 1 or 29); or Days 1 or 22 for optional cohorts dosed once every 3 weeks: 
• 
Perform focused physical examination. 
• 
Measure serial vital signs 24 (+30 minutes) hours post-infusion. 
• 
Perform serial pulse oximetry at 24 (+30 minutes) hours post-infusion. 
• 
Perform serial 12-lead ECGs in triplicate at 24 (+30 minutes) hours post-infusion. 
• 
Conclude cardiac monitoring (telemetry) at 24 (+1) hours post-infusion. 
• 
Collect blood samples for clinical laboratory tests, including: 
o Hematology. 
o Serum chemistries. 
o Liver function tests. 
o Coagulation studies. 
• 
Collect blood samples for the following assessments: 
o Complement Bb, 24-hour (±120 minutes) post-infusion. 
o CRP, 24-hour (±120 minutes) post-infusion. 
o Cytokines, 24-hour (±120 minutes) post-infusion. 
o 24-hour (±120 minutes) PK sample. 
o Serum TTR protein, TTR mRNA, vitamin A, and RBP.  Additionally, aliquots 
of serum samples will be taken and frozen, to permit testing of additional 
proteins related to ATTR. 
o For patients who experience an infusion reaction, collect a blood sample for 
tryptase, complement factors (including C3a), and cytokine testing 24 hours 
after the start of the reaction. 
• 
Collect urine sample for urinalysis. 
• 
Collect urine sample for 24-hour PK analysis. 
• 
Document any AEs. 
• 
Obtain concomitant medications information. 
Patients may be discharged upon completion of review by the Investigator of ECG, 
sodium, potassium, creatinine, albumin, calcium, glucose, phosphate , and LFTs results 
obtained at 24-hours post-infusion, if results are deemed not clinically significant. Any 
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clinically significant findings must be discussed with the medical monitor to determine 
whether patient can be discharged and to formulate plans for patient follow-up. 
6.3.3 
Day 2 or Day 30; Day 2 or Day 23 for optional cohorts dosed once every 
3 weeks 
Patients will undergo the following procedures on Days 2 and 30; or Days 2 and 23 for 
optional cohorts dosed once every 3 weeks: 
• 
Perform focused physical examination. 
• 
Measure vital signs. 
• 
Collect blood samples for the following tests: 
o Liver function tests. 
o Serum TTR protein, TTR mRNA, vitamin A, and RBP.  Additionally, aliquots 
of serum samples will be taken and frozen, to permit testing of additional 
proteins related to ATTR. 
o 48-hour (±120 minutes) PK sample. 
• 
Collect urine sample for PK analysis. 
• 
Document any AEs. 
• 
Obtain concomitant medications information. 
6.3.4 
Day 7 or Day 35 ±1 day; or Day 7 or Day 28 for optional cohorts dosed 
once every 3 weeks) 
Patients will undergo the following procedures on the Day 7 and 35 study visits (or Day 7 
and 28 for optional cohorts dosed every 3 weeks): 
• 
Collect blood samples for the following tests: 
o Liver function tests. 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
o Anti-PEG antibodies (IgG and IgM). 
o Pharmacokinetic assessments. 
• 
Collect urine sample for PK assessments. 
• 
Document any AEs. 
• 
Obtain concomitant medications information. 
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6.3.5 
Day 10 or Day 38 ±2 days; or Day 10 or Day 31 for optional cohorts dosed 
once every 3 weeks 
Patients will undergo the following procedures the Day 10 and 38 study visits (or 
Days 10 and 28 for optional cohorts dosed every 3 weeks): 
• 
Collect blood samples for the following assessments: 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
• 
Document any AEs. 
• 
Obtain concomitant medications information. 
6.3.6 
Day 14 or Day 42 ±3 days; or Day 14 and Day 35 for optional cohorts dosed 
once every 3 weeks 
Patients will undergo the following procedures on the Day 14 and 42 study visits (or 
Days 14 and 35 for optional cohorts dosed once every 3 weeks): 
• 
Perform focused physical examination. 
• 
Measure vital signs. 
• 
Collect blood samples for the following tests: 
o Hematology. 
o Serum chemistries. 
o Liver function tests. 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
o Thyroid function tests. 
o Pharmacokinetic assessments. 
• 
Collect urine sample for urinalysis. 
• 
Collect urine sample for PK assessments. 
• 
Document any AEs. 
• 
Obtain concomitant medications information. 
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6.3.7 
Day 21 or Day 49 ±3 days; or Day 21 and Day 42 for optional cohorts dosed 
once every 3 weeks 
Patients will undergo the following procedures on the Day 21 and 49 study visits (or 
Days 21 and 42 for optional cohorts dosed once every 3 weeks): 
• 
Collect blood samples for the following assessments: 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
o Pharmacokinetic assessments. 
• 
Collect urine sample for PK assessments. 
• 
Document any AEs. 
• 
Obtain concomitant medications information. 
6.3.8 
Day 56 (±3 days; End of Study) 
Patients will undergo the following procedures on the Day 56 study visit: 
• 
Perform physical examination. 
• 
Measure vital signs. 
• 
Perform 12-lead ECG. 
• 
Perform serum pregnancy test (women of child-bearing potential only). 
• 
Collect blood samples for the following tests: 
o Hematology. 
o Serum chemistries. 
o Liver function tests. 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
Note: A patient will be followed every 2 weeks after Day 56 if the TTR level 
continues to recover but is not found to have returned to within at least 80% of 
the baseline value (see Section 6.5).   
o Thyroid function tests. 
o Anti-PEG antibodies (IgG and IgM). 
o Day 56 PK sample. 
• 
Collect urine sample for urinalysis. 
• 
Collect urine sample for PK analysis. 
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• 
Document any AEs. 
• 
Obtain concomitant medications information. 
6.3.9 
Day 112 (±10 days)  
Patients will undergo the following procedures on the Day 112 study visit: 
• 
Collect blood samples for the following tests: 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
o Day 112 PK sample. 
• 
Collect urine for PK analysis. 
6.3.10 
Day 208 (±2 weeks)  
Patients will undergo the following procedures on the Day 208 study visit: 
• 
Collect blood samples for the following tests: 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
o Anti-PEG antibodies (IgG and IgM). 
o Day 208 PK sample. 
• 
Collect urine for PK analysis. 
6.4 
Early Termination 
Patients coming off study before Day 56 will return to the study site to complete their 
Early Termination visit which will include Day 56 assessments.  Patients coming off 
study after Day 56 and before Day 208 will return to the study site to complete their 
Early Termination visit which will include Day 208 assessments. 
6.5 
Unscheduled Visits 
Unscheduled visits may occur if deemed clinically significant by the Investigator. 
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A patient will be followed every 2 weeks (±3 days) after Day 56 if their TTR level 
continues to recover, but is not found to have returned to within at least 80% of the 
baseline value.  The patient will have blood samples collected for the following clinical 
laboratory tests at these visits: 
o Serum TTR protein, vitamin A, and RBP.  Additionally, aliquots of serum 
samples will be taken and frozen, to permit testing of additional proteins 
related to ATTR. 
These patients will be followed and discussed at each SRC meeting until their TTR level 
returns to within at least 80% of the baseline value. 
6.6 
Participation in an Open-label Extension Study 
An open-label extension study at the recommended Phase 3 dose and regimen (as derived 
from Study ALN-TTR02-002) is planned, which will enable the patients who enrolled in 
Study ALN-TTR02-002 to receive additional, long-term dosing and safety follow-up.  
For some of the patients, this may preclude the completion of all of the follow-up period 
assessments of Study ALN-TTR02-002 if they are deemed eligible to participate in the 
extension study prior to completion of the full follow up through Day 208.  Such patients 
will be followed up for a minimum of 28 days after their last dose in the current ALN-
TTR02-002 study prior to being enrolled in the extension study.  The extension study will 
be implemented only after dose escalation is completed in Study ALN-TTR02-002, with 
post second dose follow-up through Day 208 in at least 1 cohort at the highest dose 
deemed safe. 
 
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7 
STUDY ASSESSMENTS 
7.1 
Demographic Data and Medical History 
Patient demographic data will be obtained during screening, and a complete medical 
history will be obtained during screening and updated on Days 0 and 28 (or Days 0 and 
21 for optional cohorts dosed once every 3 weeks) as needed.  The medical history is to 
include background information confirming a diagnosis of ATTR through biopsy and 
ongoing documented signs/symptoms of the disease (e.g., sensory, motor, or autonomic 
neuropathy) that are at least mild to moderate in severity. 
7.2 
Safety Assessments 
All safety assessment measures will be recorded in the patient’s CRF. 
7.2.1 
Physical Examination 
Physical examinations will be performed by a physician and will include the examination 
of the following: general appearance, head, eyes, ears, nose, throat, chest/respiratory, 
heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, 
dermatological/skin, thyroid/neck, lymph nodes, and neurological/psychiatric.  
Body weight will be measured at Screening for assessment of eligibility, and on the 
Day 0 and 28 (or Days 0 and 21 for optional cohorts dosed once every 3 weeks) study 
visits.  The weight measured pre-dose on Days 0 and 28 will be used to calculate the first 
and second dose of ALN-TTR02, respectively. 
Height will be measured at Screening. 
7.2.2 
Vital Signs 
Vital signs are to be measured at Screening and the Day 2, 14, 30, 42, and 56 (or Days 2, 
14, 23, 35, and 56 for optional cohorts dosed once every 3 weeks; or time of early 
termination, if applicable) study visits and include systolic/diastolic blood pressure, pulse 
rate, respiration rate, and oral body temperature.  Vital signs 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.  Oral 
temperature will be recorded in Celsius.  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. 
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On Days 0 and 28 (or Days 0 and 21 for optional cohorts dosed once every 3 weeks), 
serial vital signs are to be measured within 30 minutes pre-dose, at EOI; and at 
30 (±5) minutes;1, 2, and 3 (±15 minutes) hours; 6, 12, and 18 hours (±30 minutes) post-
infusion.  On Days 1 and 29 (or Days 1 and 22 for optional cohorts dosed once every 
3 weeks), serial vital signs are to be measured at 24 hours (+30 minutes) post-infusion. 
For the safety of the patient, additional vital signs may be added at the discretion of the 
Investigator. 
7.2.3 
Echocardiogram 
An echocardiogram is to be conducted during Screening, to assess any cardiac 
abnormalities as part of the screening criteria.  If a normal echocardiogram has been 
obtained within the past 90 days, there is no need to perform an echocardiogram at 
Screening. 
7.2.4 
Electrocardiogram 
Computerised 12-lead ECG recordings will be obtained.  Each lead shall be recorded for 
at least 3 beats at a speed of 25 mm/s.  Triplicate recordings will be made at the time 
points indicated in Table 1-1. 
Serial ECGs will be collected in triplicate 30 minutes prior to dosing (Days 0 and 28 [or 
Days 0 and 21 for optional cohorts dosed once every 3 weeks]), EOI, and 30 (±5) 
minutes, 2 and 4 (±15 minutes) hours, and on Days 1 and 29 (or Days 1 and 22 for 
optional cohorts dosed once every 3 weeks) at 24 (+30 minutes) hours post-infusion. 
The following electrophysiologic parameters will be assessed: rhythm, ventricular rate, 
PR interval, QRS duration, and QT interval.  Either Bazett’s and/or Fridericia’s formula 
will be used to calculate the heart rate corrected QT interval (QTc). 
The Investigator or designee is responsible for reviewing the ECG to assess whether the 
ECG is within normal limits and to determine the clinical significance of the results.  
Prior to discharge from the hospital on Days 1 and 29 (or Days 1 and 22 for optional 
cohorts dosed once every 3 weeks), the ECG must be reviewed by the Investigator and 
the results deemed not clinically significant.  Any clinically significant findings must be 
discussed with the medical monitor to determine whether patient can be discharged and 
to formulate plans for patient follow-up. 
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For any clinically significant abnormal results, the Investigator must contact the Medical 
Monitor to discuss continued participation of the patient in the study (e.g., ischemic ECG 
changes, wave/interval changes, or arrhythmia).  
7.2.5 
Pulse Oximetry 
Arterial oxygen saturation will be assessed by serial pulse oximetry on Days 0 and 28 (or 
Days 0 and 21 for optional cohorts dosed once every 3 weeks) within 30 (±5) minutes 
pre-dose; at EOI; at 30 (±5) minutes; at 1, 2, 3 hours (±15 minutes); and at 6, 12, and 
18 hours (±15 minutes) post-infusion on Days 0 and 28 (or Days 0 and 21 for optional 
cohorts dosed once every 3 weeks); and at 24 hours (+30 minutes) post-infusion on 
Days 1 and 29 (or Days 1 and 22 for optional cohorts dosed once every 3 weeks). 
7.2.6 
Cardiac Monitoring 
Continuous cardiac monitoring will be performed via telemetry starting no later than 30 
minutes prior to dosing and continuing through 24 hours (+1 hour) post-dose. 
7.2.7 
Clinical Laboratory Tests 
Laboratory tests of hematology, serum chemistries, liver function, coagulation studies, 
CRP, urinalysis, pregnancy (serum and urine), hepatitis B and C serologies, lipids, and 
thyroid function will be performed by each study center’s local laboratory. 
The following laboratory tests will be performed at the laboratories listed below: 
• 
Cytokines, complement factor Bb, anti-PEG antibody formatio
 
 
 
• 
Tryptase
 
 
Additional laboratory tests may be performed centrally, depending upon the capabilities 
of the local laboratory. 
Prior to study drug administration, samples for clinical laboratory tests are to be collected 
and results of serum chemistries, hematology, LFTs, and coagulation parameters (where 
applicable) reviewed and approved by the Investigator or qualified designee 
(e.g., physician’s assistant, nurse practitioner). 
In the event of an unexplained clinically relevant abnormal laboratory test occurring after 
study drug administration, the test should be repeated and followed up at the discretion of 
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the Investigator until it has returned to the normal range or stabilized, and/or a diagnosis 
is made to adequately explain the abnormality. 
The following clinical laboratory parameters are to be determined:  
Hematology 
• Hematocrit 
• Neutrophils, absolute and % 
• Hemoglobin 
• Lymphocytes, absolute and % 
• Red blood cell (RBC) count 
• Monocytes, absolute and % 
• White blood cell (WBC) count 
• Eosinophils, absolute and % 
• Mean corpuscular volume 
• Basophils, absolute and % 
• Mean corpuscular hemoglobin 
• Platelet count 
• Mean corpuscular hemoglobin concentration 
 
Serum Chemistriesa 
 
• 
Sodium 
• 
Glucose 
• 
Potassium 
• 
Phosphate 
• 
Blood urea nitrogen (BUN) 
• 
Lactate dehydrogenase (LDH) 
• 
Creatinine 
• 
Troponin I 
• 
C-reactive protein (CRP) 
• 
Creatinine phosphokinase (CPK) 
• 
Albumin 
• 
Myocardial band enzymes of CPK 
(CPK-MB) 
• 
Calcium 
Liver Function Tests 
• 
Aspartate transaminase (AST) 
• 
Alkaline phosphatase 
• 
Alanine transaminase (ALT) 
• 
Bilirubin (total and direct) 
Thyroid Function Tests 
• 
Thyroid stimulating hormone (TSH) 
• 
Triiodothyronine (T3) 
• 
Thyroxine (T4) 
 
Coagulation Studies 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 
• 
Activated partial thromboplastin time 
(aPTT) 
 
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Serology 
 
• 
Anti-PEG antibody formation (IgG and IgM) 
• 
Hepatitis C (anti-HCV Ab) 
• 
Hepatitis B (HBsAg and HBsAb) 
 
Urinalysis 
 
• 
Visual inspection for color and appearance 
• 
Leukocytes 
• 
pH 
• 
Bilirubin 
• 
Specific gravity 
• 
Nitrite 
• 
Ketones 
• 
Urobilinogen 
• 
Protein 
• 
Microscopic inspection of sediment 
• 
Glucose 
 
Complement Factors 
• 
Bb 
• 
C3ab 
Cytokines 
• 
Interferon-alpha (IFN-α) 
• 
Interleukin-6 (IL-6) 
• 
Interferon-gamma (IFN-γ) 
• 
Interleukin-12 (IL-12) 
• 
Tumor necrosis factor-alpha (TNF-α) 
• 
Interferon-inducible protein-10 (IP-10) 
• 
Interleukin-1β (IL-1β) 
• 
Granulocyte-colony stimulating factor 
(G-CSF) 
• 
IL-1 receptor antagonist (IL-1 RA) 
Other 
• 
β-human chorionic gonadotropin (women of child-bearing potential only) 
• 
Tryptaseb 
a 
A non-fasting lipid panel (including total cholesterol, high density lipoprotein [HDL], low density lipoprotein 
[LDL], very low density lipoprotein [VLDL], and triglycerides) will be performed pre-dose on Day 0 only. 
b 
To be performed only in the event of an infusion reaction. 
Additional and repeat testing may be performed at the discretion of the Investigator. 
7.2.7.1 Hematology, Serum Chemistries, and Urinalysis 
Blood samples for hematology and serum chemistries and urine for urinalysis are to be 
collected at Screening, pre-dose on Day 0 (unless the screening evaluations were 
performed within the previous 72 hours) and Day 28 (or Day 21 for optional cohorts 
dosed once every 3 weeks), and on the Day 1, 14, 29, 42, and 56 study visits (or Days 1, 
14, 22, 35, and 56 for optional cohorts dosed once every 3 weeks), or at the time of early 
termination, if applicable. 
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Prior to discharge from the hospital on Days 1 and 29 (or Days 1 and 22 for optional 
cohorts dosed once every 3 weeks), local serum laboratories (specifically, sodium, 
potassium, creatinine, albumin, calcium, glucose, and phosphate) must be reviewed by 
the Investigator and the results deemed not clinically significant.  Any clinically 
significant findings must be discussed with the medical monitor to determine whether 
patient can be discharged and to formulate plans for patient follow-up. 
Blood for CRP is to be collected pre-dose (within 10 minutes) on Days 0 and 28 (or 
Days 0 and 21 for optional cohorts dosed once every 3 weeks), and at 2 and 6 hours 
(±15 minutes), and 24 hours (± 120 minutes) post-infusion. 
7.2.7.2 Liver Function Tests 
Blood for LFTs is to be collected at Screening, pre-dose on Day 0 (unless the screening 
evaluations were performed within the previous 72 hours) and Day 28, and at the Day 1, 
2, 7, 14, 29, 30, 35, 42, and 56 study visits (or Days 1, 2, 7, 14, 22, 23, 28, 35, and 56 for 
optional cohorts dosed once every 3 weeks), or at the time of early termination, if 
applicable.  These samples are to be processed at the site’s local laboratory. 
Prior to discharge from the hospital on Days 1 and 29 (or Days 1 and 22 for optional 
cohorts dosed once every 3 weeks), local LFTs must be reviewed by the Investigator and 
the results deemed not clinically significant.  Any clinically significant findings must be 
discussed with the medical monitor to determine whether patient can be discharged and 
to formulate plans for patient follow-up. 
7.2.7.3 Lipid Panel 
Blood for determination of the lipid panel is to be collected pre-dose on Day 0. 
7.2.7.4 Coagulation Studies 
Blood for coagulation studies is to be collected at Screening, pre-dose on Days 0 (unless 
the screening evaluations were performed within the previous 72 hours) and 28 (or 
Day 21 for optional cohorts dosed once every 3 weeks), at the Days 1 and 29 (or 
Days 1 and 22 for optional cohorts dosed once every 3 weeks) study visits. 
7.2.7.5 Thyroid Function Tests 
Blood for thyroid function tests is to be collected at Screening, pre-dose on Days 0 
(unless the screening evaluations were performed within the previous 72 hours) and 28 
(or Days 0 and 21 for optional cohorts dosed once every 3 weeks), and at Day 14, 42, and 
56 (or Days 14, 35, and 56 for optional cohorts dosed once every 3 weeks) study visits, or 
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at the time of early termination, if applicable.  These samples are to be processed at the 
site’s local laboratory. 
7.2.7.6 Complement 
Blood for complement factor Bb, is to be collected pre-dose (within 10 minutes) on 
Days 0 and 28 (or Days 0 and 21 for optional cohorts dosed once every 3 weeks), and 30 
(± 5) minutes and 2 (± 15 minutes) and 24 hours (± 120 minutes) post-infusion.  If the 
patient experiences an infusion reaction, a blood sample for analysis of complement 
factors (including complement C3a) should be obtained within 1 hour of the start of the 
reaction. 
7.2.7.7 Cytokines 
Blood for cytokine assessment is to be collected pre-dose (within 10 minutes) on Days 0 
and 28 (or Days 0 and 21 for optional cohorts dosed once every 3 weeks), at 2 (±15 
minutes), and 6 hours (±15 minutes), and 24 hours (±120 minutes) post-infusion.  If the 
patient experiences an infusion reaction, a blood sample for analysis of cytokines should 
be obtained within 1 hour of the start of the reaction. 
7.2.7.8 Pregnancy Test 
A serum pregnancy test will be performed for women of child-bearing potential at 
Screening, at the Day 56 study visit, and any time pregnancy is suspected.  A urine 
pregnancy test will be performed pre-dose on Day 0 for women of child-bearing 
potential, the results of which must be known prior to administration of study drug.  
Patients who are pregnant are not eligible for study participation.  Patients determined to 
be pregnant while on study will be followed until pregnancy outcome is known (see 
Section 8.12). 
7.2.7.9 Hepatitis B/C Status 
Blood for HBV (Hepatitis B surface antibody [HbsAb], Hepatitis B surface antigen 
[HbsAg]), and HCV (anti-HCV) are to be collected at Screening.  Patients with positive 
HBV or HCV serologies are not eligible for study participation. 
7.3 
Pharmacodynamic Assessments 
7.3.1 
Transthyretin Protein 
Blood for serum TTR protein levels (WT and mutant) is to be collected at Screening, 
immediately prior (within 10 minutes) to the administration of the premedications, 
immediately pre-dose (within 10 minutes) on Days 0 (Baseline) and 28, and on Days 1, 2, 
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7, 10, 14, 21, 29, 30, 35, 38, 42, 49, 56 (end-of-study), 112, and 208 or at the time of 
early termination.  For optional cohorts dosed once every 3 weeks, blood for serum TTR 
protein levels will be collected at Screening, immediately prior (within 10 minutes) to the 
administration of the premedications, immediately pre-dose (within 10 minutes) on 
Days 0 (Baseline) and 21, and on Days 1, 2, 7, 10, 14, 22, 23, 28, 31, 35, 42, 49, 56 (end-
of-study), 112, and 208 or at the time of early termination.  A patient will be followed 
every 2 weeks after Day 56 if the TTR level continues to recover but is not found to have 
returned to within at least 80% of the baseline value.  If this occurs, the patient will be 
followed and discussed at each SRC meeting until the TTR level returns to within at least 
80% of the baseline value.  Additionally, aliquots of serum samples drawn for 
measurement of TTR levels will be taken and frozen, to permit testing of total, WT and 
mutant TTR and other types of testing related to ATTR. 
Details of how samples will be collected, processed, and stored will be in the Study 
Laboratory Manual.  The Central Laboratory for TTR analysis is: 
 
 
 
 
7.3.2 
Transthyretin mRNA 
Blood for serum TTR mRNA is to be collected at Screening, immediately prior (within 
10 minutes) to the administration of the premedications on Days 0 (Baseline) and 28, and 
on Days 1, 2, 29, and 30.  For optional cohorts dosed once every 3 weeks, blood for 
serum TTR mRNA will be collected at Screening and on Days 0 (Baseline) and 21, and 
on Days 1, 2, 22, and 23. 
The Testing Laboratory for TTR mRNA analysis is: 
 
 
 
 
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7.3.2.1 Vitamin A and Retinol Binding Protein 
Blood for measurements of vitamin A and RBP is to be collected at Screening, 
immediately prior (within 10 minutes) to the administration of the premedications, 
immediately pre-dose (within 10 minutes) on Days 0 and 28, and on Days 1, 2, 7, 10, 14, 
21, 29, 30, 35, 38, 42, 49, 56 (end-of-study), 112, and 208 or at the time of early 
termination.  For optional cohorts dosed once every 3 weeks, blood for measurements of 
vitamin A and RBP will be collected at Screening, immediately prior (within 10 minutes) 
to the administration of the premedications, immediately pre-dose (within 10 minutes) on 
Days 0 (Baseline) and 21, and on Days 1, 2, 7, 10, 14, 22, 23, 28, 31, 35, 42, 49, 56 (end-
of-study), 112, and 208 or at the time of early termination.  
Serum samples will be evaluated by HPLC to determine vitamin A levels and by 
nephelometry to determine RBP levels. 
The laboratory for serum vitamin A and RBP analysis is: 
 
 
 
 
7.4 
Pharmacokinetic Evaluations 
7.4.1 
Plasma Pharmacokinetics 
The PK parameter estimates and dose proportionality profiles of ALN-TTR02 will be 
determined for ALN-TTR02 siRNA (ALN-18328) and liposome lipid components, 
DLin-MC3-DMA and PEG2000-C-DMG.  The plasma concentration-time profiles for 
ALN-18328, DLin-MC3-DMA, and PEG2000-C-DMG will be determined and used in the 
PK analysis for all dose cohorts.  In addition, free and encapsulated concentrations of 
siRNA will be determined in plasma at specified time points (see Table 1-1) for cohort 3 
and onward, including any optional cohorts.  The drug concentrations in the lower 
cohorts are expected to be undetectable for this analysis. 
Blood sample collection times are included in the schedule of events (see Table 1-1).  
Plasma PK samples (siRNA and lipids) will be collected pre-dose (within 1 hour of 
planned dosing start), at EOI, and then 5, 10, and 30 minutes, and at 1, 2, 4, 6, 24, and 
48 hours post infusion.  Samples will also be collected on Days 7, 14, 21, 35, 42, 49, 56, 
112, and 208 post infusion as well as at the ET visit (if applicable); for optional cohorts 
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dosed once every 3 weeks, samples will be collected on Days 7, 14, 21, 28, 35, 42, 56, 
112, and 208 post infusion as well as at the ET visit (if applicable). 
For the PK blood draws, the sampling windows are ±1 minute for the 5- and 10- minute 
draws; ±2 minutes for the 30-minute draws; ±5 minutes for the 1-, 2-, 4-, and 6-hour 
draws; and ±120 minutes for the 24- and 48-hour draws. 
The EOI will usually occur at 60 minutes after the start of infusion, except in patients 
where the infusion has been prolonged.  If the infusion is stopped, a PK blood sample 
will be taken when the infusion is stopped, and this sample will be treated as the EOI 
sample if the infusion is restarted.  All remaining PK samples will be collected according 
to the schedule of assessments when the dose is completed (i.e., all post-infusion times 
are relative to the EOI, regardless of the duration of infusion). 
In the event that a patient receives only 1 dose of study drug, plasma PK samples should 
be collected pre-dose (within 1 hour of planned dosing start), EOI, and then 5, 10, and 
30 minutes; and 1, 2, 4, 6, 24 and 48 hours post infusion; and at Day 208. 
Details of sample collection and processing for PK analyses will be included in a 
laboratory manual. 
Pharmacokinetic analyses will consist of a non-compartmental and/or compartmental 
evaluation of ALN-TTR02 siRNA (ALN-18328), and of ALN-TTR02 lipids 
DLin-MC3-DMA and PEG2000-C-DMG plasma concentration-time profiles to determine 
PK parameter estimates using a validated software program, 
.  
Pharmacokinetic parameter estimates to be calculated for all patients receiving 
ALN-TTR02 will include, but may not be limited to: 
• 
Observed Cmax. 
• 
Time of observed maximum concentration (tmax). 
• 
Partial area under the plasma concentration-time curve (AUCp). 
• 
Area under the plasma concentration-time curve to the last measurable 
concentration (AUC0-t). 
• 
Area under the plasma concentration-time curve from zero to the last measurable 
time point (AUC0-last). 
• 
Area under the plasma concentration-time curve extrapolated to infinity 
(AUC0-∞). 
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• 
Terminal elimination half-life (t1/2β and t1/2α). 
• 
Elimination rate constant (λz). 
• 
Systemic clearance (CL). 
• 
Volume of distribution at steady state (Vss). 
• 
Volume of distribution based on the terminal phase (Vz). 
Other parameters may be calculated if deemed necessary. 
Plasma samples will be evaluated by 
 
using a validated ATTO-Probe-HPLC assay to determine ALN-18328 concentration.  
The concentrations of DLin-MC3-DMA and PEG2000-C-DMG in plasma samples will be 
evaluated by a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay at 
   
The Central Laboratory for plasma PK analysis is: 
  
  
  
 
 
7.4.2 
Urine Pharmacokinetics 
The PK profiles of ALN-18328 and DLin-MC3-DMA in urine will be evaluated to 
determine the CLR of ALN-18328 and DLin-MC3-DMA and/or its metabolites after 
dosing with ALN-TTR02.  Urine sample collection times are included in the schedule of 
assessments (see Table 1-1 or Table 12-1 for optional cohorts dosed once every 3 weeks).  
Urine will be collected into suitable containers and kept refrigerated.  Pre-dose samples 
will be collected within 1 hour of the planned dosing start.  For the 0 to 6 hour collection, 
the patient should void at time 0 hours and discard the specimen.  Details of sample 
collection and processing for PK analyses will be included in the laboratory manual. 
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The Central Laboratory for urine PK analysis is: 
:  
  
 
 
7.4.3 
Banking of Serum for Future Studies 
To explore the expression of hepatocyte derived proteins to further characterize the 
biological effects of siRNA, serum and plasma samples will be collected at selected time 
points (see Table 1-1). 
Biological samples for biomarker research can be retained on behalf of Alnylam for a 
maximum of 15 years following the last patient’s last visit in the study. 
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8 
REPORTING ADVERSE EVENTS 
8.1 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
8.2 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death; 
• 
Is life-threatening (an event which places the patient at immediate risk of death 
from the event as it occurred.  It does not include an event that had it occurred in a 
more severe form might have caused death); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Is a congenital anomaly or birth defect; 
• 
An important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above 
(e.g., such events include allergic bronchospasm, blood dyscrasias or convulsions, 
or the development of drug dependency or abuse). 
8.3 
Eliciting Adverse Event Information 
The patient should be asked about medically relevant changes in his/her health since the 
last visit.  The patient should also be asked if he/she has been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication routines (both 
prescription and OTC). 
In addition to patient observations, AEs will be documented from any laboratory 
findings, physical examination findings, ECG changes or other documents. 
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8.4 
Adverse Event Reporting 
The Investigator is responsible for reporting all AEs that are observed or reported after 
the first dose of study drug regardless of their relationship to study drug through to 
Day 56. 
Any medical condition that is present when a patient is screened 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 for 28 days from the start of infusion 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 for 28 days following the last dose of study drug 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 at follow up. 
8.5 
Adverse Event Reporting Period 
As stated in Section 8.4, AEs will be assessed for 28 days following the last dose of study 
drug (Day 56 for patients receiving both doses of ALN-TTR02) or until recovery to the 
normal state has been achieved, whichever occurs first; all AEs that occur after the start 
of study drug administration on Day 0 (Baseline) must be reported in detail on the 
appropriate CRF page and followed to satisfactory resolution, or a period of 28 days after 
the last dose of study drug administration, whichever is shorter.   
Serious AEs will be followed for 28 days following the last dose of study drug (Day 56 
for patients receiving both doses of ALN-TTR02), or until satisfactory resolution, or until 
the SAE is considered by the Investigator to be chronic or the patient is stable, whichever 
occurs first. 
8.6 
Assessment of Causality 
Causal relationship assessment to drug treatments is required for purposes of reporting 
AEs.  To promote consistency, the following guidelines should be taken into 
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considerations 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. 
8.7 
Assessment of Severity 
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 
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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). 
8.8 
Action Taken for Adverse Event 
Action taken in regards to study medication will be defined as: 
• 
None; 
• 
Infusion interrupted and restarted at a later time; 
• 
Infusion stopped and was not restarted at a later time. 
8.9 
Outcome of Adverse Event 
Outcome will be defined as: 
• 
Resolved (with or without sequelae); 
• 
Ongoing; 
• 
Lost to follow up. 
8.10 
Coding of Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code AEs. 
8.11 
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 8.2) must 
be reported immediately to Alnylam, always within 24 hours from the time that site 
personnel first learn of the event.  Every SAE must be documented by the Investigator on 
the Serious Adverse Event Report in addition to the documentation on the AE form in the 
CRF.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
• 
Patient’s study number. 
• 
Description and date of onset of the event. 
• 
Criterion for serious. 
• 
Preliminary assignment of causality to study drug. 
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The report should be faxed to
, as follows: 
 
 
 
 
 
 
If follow up is required, new information should be provided to Alnylam as it becomes 
available using the Serious Adverse Event Reporting form.  Copies of discharge 
summaries, consultant reports, autopsy reports, and any other relevant documents may 
also be requested. 
Appropriate remedial measures should be taken by the Investigator using his/her best 
medical judgment to treat the SAE.  These measures and the patient’s response to these 
measures should be recorded.  All SAEs, regardless of relationship to study drug, will be 
followed by the Investigator until satisfactory resolution or the Investigator deems the 
SAE to be chronic or stable.  Clinical, laboratory, and diagnostic measures should be 
employed by the Investigator as needed to adequately determine the etiology of the event.   
The Investigator will be responsible for reporting all SAEs to the local IEC when 
required by national regulations. 
Alnylam 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 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 has first knowledge of 
them. 
The Investigator may be informed by Alnylam of SAEs from other Investigators or 
clinical studies which may have relevance to this clinical trial.  These SAEs should also 
be reported promptly to the IEC or Clinical Events Committee (CEC) which approved the 
study.  All SAE reports should be transmitted to the IEC/CEC with a cover letter or 
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transmittal form, and a copy of that transmittal should be maintained in the Investigator’s 
files and forwarded to Alnylam. 
8.12 
Pregnancy Reporting 
A female patient with a positive pregnancy test at Screening or Day 0 is ineligible for this 
trial.  If a female patient is determined to be pregnant within 2 months after receiving 
study drug, the Investigator should report the pregnancy to Alnylam within 24 hours of 
being notified of the pregnancy.  Details of the pregnancy will be recorded on the 
pregnancy reporting form.  The patient should receive any necessary counseling 
regarding the risks of continuing the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until the outcome of the pregnancy is known.   
Pregnancy occurring in the partner of a patient participating in the study should also be 
reported to the Investigator and Alnylam.  The partner should be counseled and followed 
as described above. 
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9 
STATISTICAL METHODS 
9.1 
Sample Size 
Based on the planned dose escalation scheme (see Section 5.7.1), up to 27 patients are 
expected to be enrolled.  Three patients are to be enrolled at each of 5 planned dose 
levels.  An additional 3 cohorts of 3 patients may be enrolled onto 1 or more of these 
specified dose levels to further evaluate safety and tolerability or PD effects. 
9.2 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature.  Adverse event summaries will 
include tabulations of all treatment-emergent AEs, treatment-related AEs, SAEs, 
discontinuations due to AEs, and AEs of various grading severity.  By-patient listings 
will be provided for deaths, SAEs, and AEs leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data, vital signs data, and 
ECG interval data, presented as both actual values and changes from baseline relative to 
each on-study evaluation.  Laboratory shift tables from baseline to worst values will be 
presented. 
Tabulations will be presented by dose level.  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. 
9.2.1 
Populations to be Analyzed 
The following patient populations (i.e., analysis sets) may be evaluated and used for 
presentation of the data: 
• 
Intent-to-Treat (ITT) Analysis Set:  All patients who were enrolled and received 
study treatment.  The ITT analysis set will be the primary set for the analysis of 
safety data. 
• 
Per-Protocol (PP) Analysis Set:  All patients in the ITT Analysis Set who had no 
major protocol violations.  
• 
Pharmacokinetic (PK) Analysis Set:  All patients in the ITT Analysis Set who 
have adequate data to determine a full PK profile. 
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9.2.2 
Baseline Evaluations 
Demographic and baseline disease characteristic data will be summarized in order to 
descriptively assess the comparability of dose groups.  Data to be tabulated will include 
sex, age, and race, as well as disease-specific information. 
9.2.3 
Safety Analyses 
A summary of study drug exposure, including the duration of the infusion and dose, and 
the proportion of patients with modifications in the duration of infusion will be produced. 
Adverse events will be summarized by 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.  By-patient listings will be provided for deaths, SAEs, 
DLTs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data, including cytokines, as 
well as 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. 
Descriptive statistics will be provided for ECG interval data and presented as both actual 
values and changes from baseline relative to each on-study evaluation and to last 
evaluation on study. 
9.2.4 
Pharmacodynamics 
Serial measurements of serum TTR over a 208-day period post-dose will allow for 
determination of the nadir following dosing as well as the timing of the nadir post-dose 
and the duration of TTR suppression.  A standard ELISA assay will be used to measure 
serum total TTR in patients.  Also, TTR testing will be performed as a LC/MS assay, to 
measure mutant and WT TTR.   
Pre- and post-dose measurements of serum TTR mRNA will assist in determining 
whether any observed effects of ALN-TTR02 on TTR protein are being mediated by 
RNAi.  Transthyretin mRNA in the serum will be detected using a qRT – PCR based 
assay. 
9.2.5 
Pharmacokinetics 
Pharmacokinetic analyses will consist of a non-compartmental and/or compartmental 
evaluation of siRNA ALN-18328 of ALN-TTR02 and DLin-MC3-DMA and PEG2000-C-
DMG plasma concentration-time profile to determine PK parameter estimates using a 
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validated software program, 
  Pharmacokinetic parameter estimates to be 
calculated for all patients receiving ALN-TTR02 will include, but may not be limited to: 
Cmax; tmax; t½β; t1/2α, AUCp, AUC0-t, AUC0-last and AUC0-∞; λz; CL, Vss and Vz.  The dose 
proportionality of ALN-TTR02 following a single, 15-minute infusion will also be 
determined. 
Plasma and urine samples will be evaluated by 
 using a validated 
hybridization enzyme-linked immunosorbent assay for each of the two siRNAs (both 
encapsulated and unencapsulated).  Analysis of the concentration-time data will also be 
performed by 
.  The methods will be validated as per 
 
 Standard Operating Procedures.  The PK profile of each patient will be 
characterized by non-compartmental analysis of each siRNA plasma concentration using 
validated computer software
 
.  Parameters will include, but may not be limited to: Cmax, tmax, AUC, CL, Vss, and 
Vz.  The AUC will be calculated using the linear trapezoidal method (linear 
interpolation).  Other parameters may be calculated, if deemed necessary.  If possible, the 
terminal elimination phase of the PK profile will be identified and its slope calculated 
using log-linear regression.  The coefficient of determination of the line fitted to the 
terminal elimination phase will be calculated.  Pharmacokinetic parameters describing the 
systemic exposure of the test article in the test system will be estimated from observed 
plasma concentration values for each patient.  The amount of siRNA excreted in the urine 
over the 2 separate and combined collection intervals will be determined and CLR 
calculated for each patient, if possible. 
9.2.6 
Summary of Pharmacodynamic and Pharmacokinetic Analyses 
Pharmacokinetic and PD data will be assessed descriptively whenever possible and by 
exploratory statistical comparisons.  Pharmacokinetic/PD analyses will include 
evaluation with respect to siRNA ALN-18328 of ALN-TTR02 plasma concentrations, 
exposure, or the relationship of any PK/PD parameter estimate to TTR concentration 
after ALN-TTR02 following a single, 15-minute infusion.  Attempts will be made to 
perform PK/PD analysis to determine PK/PD parameters (e.g., ED50, EC50[50% effective 
dose, 50% effective concentration, respectively]). 
9.2.7 
Interim Analysis 
There is no formal interim analysis planned for this study. 
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10 
STUDY MANAGEMENT 
The Investigator is accountable for the conduct of the trial.  If any responsibilities are 
delegated, the Investigator should maintain a list of appropriately qualified staff to whom 
he/she has delegated specified significant trial related duties. 
10.1 
Data Handling and Quality Assurance 
10.1.1 
Case Report Forms 
The Investigator and designees agree to maintain accurate CRFs and source 
documentation as part of these case histories.  Source documents are the originals of any 
documents used by the Investigator or hospital/institution that allow verification of the 
existence of the patient and substantiate the integrity of the data collected during the trial. 
Alnylam will supply either paper or electronic CRFs for each patient.  Case report forms 
must be completed only by persons designated by the Investigator.  Corrections must be 
made so as not to obliterate original data and must be identified and dated by the person 
who made the correction.  All data entered into the CRF must also be available in the 
source documents.  The Investigator will allow designated Alnylam representatives and 
regulatory bodies to have direct access to the source documents to verify the data 
reported in the CRFs. 
Each completed CRF must be reviewed and signed by the Investigator or designee in a 
timely manner.  The completed CRF will be collected by Alnylam monitor as soon as 
practical after completion.  A copy of the CRF will remain in the Investigator’s files. 
10.1.2 
Monitoring 
The clinical monitor, as a representative of Alnylam, has an obligation to follow the study 
closely.  In doing so, the monitor will visit the Investigator and site periodically as well as 
maintain frequent telephone and letter contact.  The monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation and discussion of the conduct of the study with the Investigator and staff. 
All aspects of the study will be carefully monitored by Alnylam or its designee for 
compliance with applicable government regulations in respect to Good Clinical Practice 
(GCP) and current standard operating procedures. 
10.1.3 
Inspections 
The Investigator will permit trial-related monitoring, audits and review by the IEC and/or 
Regulatory Authorities, providing direct access to source data/documents.  The study 
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may be subject to audit by Alnylam or its representatives or by regulatory authorities.  If 
such an audit occurs, the Investigator must agree to allow access to the required patient 
records.  In the event of an audit, the Investigator agrees to allow Alnylam, 
representatives from Alnylam, or regulatory agencies access to all study records. 
10.2 
Regulatory Guidelines 
This study will be performed in accordance with the clinical trial agreement, the protocol, 
all applicable government laws, regulations, and guidances where the study is being 
conducted including the World Health Organization (WHO) Declaration of Helsinki 
(Appendix 6), the International Conference on Harmonization (ICH) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use, the Health Insurance 
Portability and Accountability Act of 1996 (“HIPAA”), and all other applicable medical 
privacy laws and regulations. 
10.2.1 
Independent Ethics Committee 
National regulations and ICH require that approval be obtained from an IEC prior to 
participation of patients in research studies.  Prior to the study onset, the protocol, any 
protocol amendments, ICFs, advertisements to be used for patient recruitment, and any 
other written information regarding this study to be provided to a patient or patient’s legal 
guardian must be approved by the IEC. 
All IEC approvals must be dated and signed by the IEC Chairman or designee and must 
identify the IEC by name and address, the clinical protocol by title and/or protocol 
number, and the date approval or favorable opinion was granted for the clinical research. 
No drug will be released to the site to dose a patient until written IEC authorization has 
been received by Alnylam. 
The Investigator is responsible for obtaining continuing review of the clinical research at 
least annually or more often if specified by the IEC.  The Investigator must supply 
Alnylam with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
10.2.2 
Regulatory Authorities 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations. 
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10.2.3 
Modification of the Protocol 
Major changes in this research activity, except those to remove an apparent immediate 
hazard to the patient, must be reviewed and approved by Alnylam and the IEC which 
approved the study.  Amendments to the protocol must be submitted in writing to the 
Investigator’s IEC and the Competent Authority for approval prior to patients being 
enrolled into the amended protocol. 
10.2.4 
Informed Consent Form 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 
and ICH will be obtained from each patient prior to undergoing any protocol-specific 
tests or procedures which are not part of routine care.   
Alnylam will provide an ICF template to the Investigator for use in developing a site-
specific ICF.  Prior to submission of the site-specific ICF to the IEC, the site-specific ICF 
must be reviewed and approved by Alnylam or designee.  Any changes requested by the 
IEC must also be approved by Alnylam.  The final IEC approved ICF must be provided 
to Alnylam.  Revisions to the ICF required during the study must be approved by 
Alnylam, and a copy of the revised ICF provided to Alnylam. 
Before recruitment and enrollment, each prospective patient (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 
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. 
10.2.5 
Study Reporting Requirements 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be 
made available to Alnylam or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to 
Alnylam within 24 hours of knowledge of the event. 
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Any communications from regulatory agencies in regard to inspections, other studies 
which impact this protocol or the qualifications of study personnel should be promptly 
reported to Alnylam. 
10.2.6 
Financial Disclosure Reporting Obligations 
Each Investigator (including principal and/or any subinvestigators) 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. 
10.3 
Study Committees 
An SRC will be formed that will evaluate safety and tolerability data and determine if it 
remains acceptable to continue dosing (administration of second dose of study drug 
within cohorts) or to dose escalate (between cohorts).  The SRC will also be convened in 
the event of any potential DLT to determine whether stopping rules for accrual to a 
particular dose level have been met (see Section 5.7.4 for study stopping rules).  The SRC 
is also responsible for making recommendations regarding replacement of subjects that 
have withdrawn before Day 56 without experiencing a DLT.  In addition, the SRC may 
be convened at the discretion of Alnylam if important safety issues arise requiring the 
attention of the committee (e.g., new safety information attained in other ongoing studies 
with ALN-TTR02). 
To ensure timely safety information exchange across the participating study centres, the 
SRC will be comprised of all Principal Investigators participating in the study, or their 
designee, Alnylam Medical Monitor, and the CRO Medical Monitor.  The SRC will 
evaluate the available safety data post infusion including but not limited to: AEs, vital 
signs, pulse oximetry, 12-lead ECGs, and available laboratory parameters.  The SRC will 
communicate frequently to ensure that patients are dosed according to the time intervals 
specified in Section 5.6, even as patients are being accrued across multiple centers. 
The options based on SRC discussion (if stopping criteria have not been met) are to: 
• 
Escalate the dose as planned; 
• 
Escalate/decrease the dose to an intermediate level; 
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• 
Repeat the dose level only in the event of a safety signal (not considered severe) 
that indicates that any further dose escalation may affect the safety of the study 
patients (or to re-evaluate the PK data or to further characterize PD markers); 
• 
Terminate the study. 
The membership of the SRC and reporting structure are defined in the SRC Charter. 
10.4 
Ancillary Research 
Research ancillary to this main protocol may not be performed by individual study sites 
without prior discussion with Alnylam. 
10.5 
Study Record Retention 
Essential documents should be retained for the period of time required by applicable local 
law.  The essential documents include the signed and dated final protocol, signed and 
dated amendments(s), if applicable, signed and dated Curriculum Vitae (CVs) of the 
Investigators, copies of the completed CRFs, signed ICFs, IEC approval and all related 
correspondence, financial agreements, regulatory approval, drug accountability, study 
correspondence, and patient identification codes.  Records will not be destroyed without 
informing Alnylam in writing and giving Alnylam the opportunity to store the records for 
a longer period of time at Alnylam’s expense. 
The International Conference on Harmonization requires that patient identification codes 
be retained for at least 15 years after the completion or discontinuation of the study. 
10.6 
Discontinuation of the Study by Alnylam 
Alnylam reserves the right to discontinue the study for clinical or administrative reasons 
at any time.  If the site does not recruit at a reasonable rate, the study may be 
discontinued.  Should the study be terminated and/or the site closed for whatever reason, 
all documentation and study medication pertaining to the study must be returned to 
Alnylam or its representative, and the Investigators, IEC and Regulatory Authorities will 
be promptly informed of the termination and the reason for the decision.  The 
Investigator should promptly inform the patients and assure appropriate therapy and 
follow-up. 
10.7 
Study Documentation 
Prior to beginning the study, the Investigator will be asked to comply with ICH E6 and 
21 CFR by providing at least the following essential documents: 
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• 
An original signed Investigator agreement page of the protocol and any 
amendments; 
• 
An IEC and Alnylam approved ICF; 
• 
Independent Ethics Committee approval of the protocol, and any amendments; 
• 
Curriculum Vitae for the Investigator signed and dated by the Investigator 
indicating that it is current; 
• 
Financial Disclosure information (if applicable). 
• 
Other documents which the Investigator should provide before study start or 
shortly thereafter include: 
o Curriculum Vitaes for all Sub-Investigators; these should be signed and dated 
by the Sub-investigators indicating that they are current; 
o Financial disclosure information for all Sub-investigators (if applicable); 
o Advertisements for patient recruitment and any other written information to be 
given to patients or legal guardians and IEC approval of any advertisements 
and any other written information; 
o Independent Ethics Committee composition:  If the Investigator or any of the 
Sub-investigators is a member of the IEC, assurance that he/she refrained 
from voting should be provided; 
o Laboratory accreditation and reference ranges for any laboratory values for 
local laboratories. 
10.8 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained.  On the 
CRFs or other documents submitted to Alnylam, 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, the names (except for initials) will be 
obliterated and the assigned patient number added to the document.  Documents not for 
submission to Alnylam (e.g. signed ICFs) should be maintained by the Investigator in 
strict confidence. 
Following the principles of the Good Clinical Research Practices and the Portuguese 
Protection of Personal Data Directive 95/46/EC, only a patient’s number and initials will 
be used to identify the patient on their study records.  Laboratory samples will 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, thereby allowing no unwarranted access to the 
information.  When reporting results for interim safety assessment and at the end of the 
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study, the code will be shared per standard operating procedures with the responsible 
member of the Biostatistical and Data Management Departments of the CRO.  The 
numbering code will also be held for samples in storage until marketing approval of the 
ALN-TTR02 in the countries where this study was conducted, or until clinical 
development of ALN-TTR02 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.  Alnylam must 
approve any transfer of information not directly involved in the study. 
10.9 
Publications/Reports 
Following completion of the study, the data may be considered for publication in a 
scientific journal or for reporting at a scientific meeting.  A copy of the manuscript must 
be provided to Alnylam at least 30 days prior to its submission. 
No submission of a manuscript may be made until the results from all of the study centers 
have been received and analyzed by Alnylam, or the study has been terminated at all 
centers.  A separate, individual publication of the results of the study will be delayed until 
initial publication of the results of the multi-center 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 of the manuscript to Alnylam 30 days prior to 
submission. 
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11 
REFERENCES 
 
1  
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2  
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Palha JA, Hays MT, Morreale de Escobar G, et al. Transthyretin is not essential 
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Physiol. 1997;272:E485-493. 
4  
Episkopou V, Maeda S, Nishiguchi S, et al. Disruption of the transthyretin gene 
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Natl Acad Sci USA. 1993;90:2375-2379. 
5  
Van Bennekum AM, Wei S, Gamble MV, et al. Biochemical basis for depressed 
serum retinol levels in transthyretin-deficient mice. J Biol Chem. 2001;276:1107-
1113. 
6  
Biesalski HK, Frank J, Beck SC, et al. Biochemical bur not clinical vitamin A 
deficiency results from mutations in the gene for retinol binding protein. Am J 
Clin Nutr. 1999;69:931-936. 
7  
Decensi A, Fontana V, Fioretto M, et al. Long-term effects of fenretinide on 
retinal function. Eur J Cancer. 1997;33:80-84. 
8  
Torrisi R, Parodi S, Fontana V, et al. Factors affecting plasma retinol decline 
during long-term administration of the synthetic retinoid fenretinide in breast 
cancer patients. Cancer Epidemiol Biomarkers Prev. 1994;3:507-10. 
9  
Hou X, Aguilar MI, Small DH. Transthyretin and familial amyloidotic 
polymeutopathy. Recent progress in understanding the molecular mechanism of 
neurodegeneration. FEBS Journal. 2007;274:1637-1650. 
10  
Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE. Tabulation of 
human transthyretin (TTR) variants. Amyloid. 2003;10:160-184. 
11  
Suhr OB, Herlenius G, Friman S, Ericzon BG. Liver transplantation for hereditary 
transthyretin amyloidosis. Liver Transpl. 2000;6:263-276. 
12  
Yazaki M, Tokuda T, Nakamura A, et al. Cardiac amyloid in patients with 
familial amyloid polyneuropathy consists of abundant wild-type transthyretin. 
Biochem Biophys Res Commun. 2000;274:702-706. 
13  
Carvalho, M., Alves, M., Luis, M.L., 1992, Octreotide--a new treatment for 
diarrhoea in familial amyloidotic polyneuropathy. J Neurol Neurosurg Psychiatry 
55, 860-861. 
14  
Soares, M.L., Coelho, T., Sousa, A., Batalov, S., Conceicao, I., Sales-Luis, M.L., 
Ritchie, M.D., Williams, S.M., Nievergelt, C.M., Schork, N.J., Saraiva, M.J., 
Buxbaum, J.N., 2005, Susceptibility and modifier genes in Portuguese 
transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease. 
Hum Mol Genet 14, 543-553. 
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15  
Eriksson, P., Olofsson, B.O., 1984, Pacemaker treatment in familial amyloidosis 
with polyneuropathy. Pacing Clin Electrophysiol 7, 702-706. 
16  
Delahaye, N., Dinanian, S., Slama, M.S., Mzabi, H., Samuel, D., Adams, D., 
Merlet, P., Le Guludec, D., 1999, Cardiac sympathetic denervation in familial 
amyloid polyneuropathy assessed by iodine-123 metaiodobenzylguanidine 
scintigraphy and heart rate variability. Eur J Nucl Med 26, 416-424. 
17  
Buxbaum, JN. Transthyretin and the transthyretin amyloidoses.  In: Protein 
Reviews: Protein Misfolding, Aggregation, and Conformaational Diseases.  
Edited by Uversky VNAF. Springer US, New York. 2007. Pp. 259-283. 
18  
Jacobson, D.R., Pastore, R.D., Yaghoubian, R., Kane, I., Gallo, G., Buck, F.S., 
Buxbaum, J.N., 1997, Variant-sequence transthyretin (isoleucine 122) in late-
onset cardiac amyloidosis in black Americans. N Engl J Med 336, 466-473. 
19  
Araki, S., 1984, [Amyloidosis and amyloid protein]. Tanpakushitsu Kakusan 
Koso 29, 1770-1782. 
20  
Benson, M.D., 1989, Familial amyloidotic polyneuropathy. Trends Neurosci 12, 
88-92. 
21  
Okamoto S, Wixner J, Obayashi K, et al. Liver transplantation for familial 
amyloidotic polyneuropathy: impact on Swedish patients' survival. Liver Transpl. 
2009;15:1229-1235. 
22  
Adams, D., Samuel, D., Goulon-Goeau, C., Nakazato, M., Costa, P.M., Feray, C., 
Plante, V., Ducot, B., Ichai, P., Lacroix, C., Metral, S., Bismuth, H., Said, G., 
2000, The course and prognostic factors of familial amyloid polyneuropathy after 
liver transplantation. Brain 123 ( Pt 7), 1495-1504. 
23  
Sharma, P., Rakela, J., 2005a, Management of pre-liver transplantation patient--
part 2. Liver Transpl 11, 249-260. 
24  
Sharma, P., Rakela, J., 2005b, Management of pre-liver transplantation patients--
part 1. Liver Transpl 11, 124-133. 
25  
Suhr, O.B., Friman, S., Ericzon, B.G., 2005, Early liver transplantation improves 
familial amyloidotic polyneuropathy patients' survival. Amyloid 12, 233-238. 
26  
Yazaki M, Mitsuhashi S, Tokuda T, et al. Progressive wild-type transthyretin 
deposition after liver transplantation preferentially occurs onto myocardium in 
FAP patients. Am J Transplant. 2007;7:235-242. 
27  
European Medicines Agency. Vyndaqel: EPAR-Product Information. 2011. 
Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines
/002294/human med 001498.jsp&mid=WC0b01ac058001d124. Last accessed 
on 8 December 2011. 
28  
Vaishnaw AK, Gollob J, Gamba-Vitalo C, et al. A status report on RNAi 
therapeutics. Silence. 2010;1(1):14. 
29  
Elbashir SM, Lendeckel W, Tuschi T. RNA interference is mediated by 21- and 
22-nucleotide RNAs. Genes Dev. 2001;15:188-200. 
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30  
Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous 
gene by systemic administration of modified siRNAs. Nature. 2004;432:173-178. 
31  
Geisbert TW, Hensley LE, Kagan E, et al. Postexposure protection of guinea pigs 
against a lethal ebola virus challenge is conferred by RNA interference. J Infect 
Dis. 2006;193:1650-1657. 
32  
Judge AD, Bola G, Lee AC, MacLachlan I. Design of noninflammatory synthetic 
siRNA mediating potent gene silencing in vivo. Mol Ther. 2006;13:494-505. 
33  
Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-
HBV activity of chemically modified siRNAs. Nat Biotechnol. 2005;23:1002-
1007. 
34  
Zimmermann TS, Lee AC, Akinc A, et al. RNAi-mediated gene silencing in non-
human primates. Nature. 2006;441(7089):111-4.  
35  
Maurer N, Mori A, Palmer L, et al. Lipid-based systems for the intracellular 
delivery of genetic drugs. Mol Membr Biol. 1999;16:129-140. 
36  
Akinc A, Querbes W, De S, Qin J, et al. Targeted delivery of RNAi therapeutics 
with endogenous and exogenous ligand-based mechanisms. Mol Ther. 
2010;18(7):1357-1364. 
37  
Soutschek, J., Akinc, A., Bramlage, B., Charisse, K., Constien, R., Donoghue, M., 
Elbashir, S., Geick, A., Hadwiger, P., Harborth, J., John, M., Kesavan, V., Lavine, 
G., Pandey, R.K., Racie, T., Rajeev, K.G., Rohl, I., Toudjarska, I., Wang, G., 
Wuschko, S., Bumcrot, D., Koteliansky, V., Limmer, S., Manoharan, M., 
Vornlocher, H.P., 2004, Therapeutic silencing of an endogenous gene by systemic 
administration of modified siRNAs. Nature 432, 173-178. 
38  
Bumcrot, D., Manoharan, M., Koteliansky, V., Sah, D.W., 2006, RNAi 
therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2, 
711-719. 
39  
Koller, E., Propp, S., Zhang, H., Zhao, C., Xiao, X., Chang, M., Hirsch, S.A., 
Shepard, P.J., Koo, S., Murphy, C., Glazer, R.I., Dean, N.M., 2006, Use of a 
chemically modified antisense oligonucleotide library to identify and validate Eg5 
(kinesin-like 1) as a target for antineoplastic drug development. Cancer Res 66, 
2059-2066. 
40  
Maurer, N., Mori, A., Palmer, L., Monck, M.A., Mok, K.W., Mui, B., Akhong, 
Q.F., Cullis, P.R., 1999, Lipid-based systems for the intracellular delivery of 
genetic drugs. Mol Membr Biol 16, 129-140. 
41  
Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Current 
Opinion in Allergy & Clin. Immunol. 2005;5(4):309-316. 
42  
Solensky R. Drug hypersensitivity. Med Clin North Am. 2006;90:233-260. 
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12 
APPENDICES 
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Appendix 1: 
Guidelines for Acute Infusion-Related Reactions 
Mild or Moderate Reaction 
In the event of mild or moderate symptom(s) and/or sign(s) discontinue infusion and treat 
as below: 
• Medication as clinically indicated (e.g., paracetamol, additional H1/H2 blocker, non-
steroidal anti-inflammatory [NSAID], small volumes of physiological saline, and/or 
≤5 L/min oxygen or the reaction is classified as severe); 
• Re-challenge with slower infusion rate (no greater than 3 hour duration) after 
resolution of the reaction; 
• If reaction recurs with re-challenge this patient, this will be a DLT and the patient 
will receive no further study drug. 
Severe Reaction 
In the event of severe sign(s) and symptom(s) discontinue infusion and treat as below:  
• Medication as clinically indicated (e.g., fluids [>1 L saline], oxygen [>5 L/min], 
adrenaline, glucocorticoids, H1/H2 blocker);  
• If a severe acute reaction occurs in any patient, this is a DLT and no more patients 
will be dosed; 
Life-Threatening Reaction 
• If a life-threatening reaction occurs in any patient, this is considered a DLT and no 
further patients will be dosed. 
 
 
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Appendix 2: 
Guidelines for Delayed Infusion-Related Reactions 
Mild or Moderate Reaction 
In the event of mild or moderate symptom(s) and/or sign(s) discontinue infusion and treat 
as below: 
• Sign(s) and/or symptom(s) must be self-limiting or respond to treatment (e.g., 
paracetamol, narcotics, loperamide, NSAIDs, small volumes of physiological saline, 
and/or ≤5 L/min oxygen or the reaction is classified as severe. 
Severe Reaction 
Severe symptom(s) and/or sign(s): 
• Requiring more intensive intervention than for moderate reaction with fluids (>1 L 
saline), oxygen (> 5L/min), and/or glucocorticoids; 
• If severe reaction occurs in any patient, this is a DLT and no more patients will be 
dosed; 
Life-Threatening Reaction 
• If a life-threatening reaction occurs in any patient, this is considered a DLT and no 
further patients will be dosed. 
 
 
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Appendix 3: 
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 4: 
Schedule of Assessments for Optional Cohorts Administered ALN-
TTR02 Once Every Three Weeks 
Up to 4 optional cohorts may be administered ALN-TTR02 once every 3 weeks.  The 
schedule of assessments for these cohorts is provided in Table 12-1. 
 
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Table 12-1: 
Schedule of Assessment for Optional Cohorts Administered ALN-TTR02 Once Every Three Weeks 
Procedures 
Screening
Pre-Dosing 
Dosing Cycles 
Follow-Up 
D -45 to  
D -3 
D -1 
D 0 
D 0 
D 1 
D 2 
D 7 
(±1 D) 
D 10 
(±2 D) 
D 14 
(±3 D) 
 
 
D 56a 
(±3 D) 
D 112 
(±10 D)
D 208a
(±2 W)
D 20 
D 21 
(+2 D) 
D 21 
(+2 D) 
D 22 
D 23 
D 28 
(±1 D) 
D 31 
(±2 D) 
D 35 
(±3 D) 
D 42 
(±3 D) 
D 49 
(±3 D) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination, excluding weight 
X 
 
Xc 
 
Xc 
Xc 
 
 
Xc 
 
 
X 
 
 
Weight 
X 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index (BMI) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signse 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital Signs (Serial)f 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Echocardiogramg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG (Serial)h 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Inpatient at Study Site 
 
 
X 
X 
Xi 
 
 
 
 
 
 
 
 
 
Cardiac Monitoring (Telemetry)j 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pulse Oximetry (Serial)f 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (females only) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine Pregnancy Test (females only)k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C Statusl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry, Hematology, 
Urinalysis 
X 
 
Xm 
 
X 
 
 
 
X 
 
 
X 
 
 
Liver Function Testsn 
X 
 
Xm 
 
X 
X 
X 
 
X 
 
 
X 
 
 
Coagulation Studieso 
X 
 
Xm 
 
X 
 
 
 
 
 
 
 
 
 
Lipid Panelp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
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Procedures 
Screening
Pre-Dosing 
Dosing Cycles 
Follow-Up 
D -45 to  
D -3 
D -1 
D 0 
D 0 
D 1 
D 2 
D 7 
(±1 D) 
D 10 
(±2 D) 
D 14 
(±3 D) 
 
 
D 56a 
(±3 D) 
D 112 
(±10 D)
D 208a
(±2 W)
D 20 
D 21 
(+2 D) 
D 21 
(+2 D) 
D 22 
D 23 
D 28 
(±1 D) 
D 31 
(±2 D) 
D 35 
(±3 D) 
D 42 
(±3 D) 
D 49 
(±3 D) 
TTR protein, Vitamin A, and RBP in 
serum 
X 
 
Xq 
 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
TTR mRNA in serum 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Thyroid Function Testss 
X 
 
Xm 
 
 
 
 
 
X 
 
 
X 
 
 
Complement Bbt 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
If infusion reaction:  
Tryptase and C3au 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Premedicationv 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Premedication reminderw 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
 
 
Xx 
 
 
 
 
 
 
 
 
 
 
Anti-PEG Antibody Testing (IgG, IgM) 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Cytokines and CRPy 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Plasma PK Samplingz 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Urine PK Samplingaa 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Exploratory Biomarkers 
X 
 
Xbb 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Medications 
X 
 
 
 
Continuous Monitoring 
 
 
Review/Record AEs 
 
 
 
 
 
 
Study Completion 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Footnotes on following pages. 
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a 
Early termination procedures: if a patient withdraws prior to Day 56, then the Days 56 and 208 visits should be performed.  If a patient is withdrawn/withdraws after Day 56 
and prior to Day 208, then the Day 208 visit should be performed. 
b 
Interval medical history. 
c 
Focused physical examination (includes head/ears/eyes/nose/throat [HEENT], cardiovascular, respiratory, abdominal, and hepatic assessments).  If the screening physical 
examination was performed within 72 hours of Day 0, then the pre-dose (Day 0) physical examination does not need to be repeated; however, the patient’s weight will be 
obtained. 
d 
Weight measured on Day 0 and Day 21 will be used for calculating first and second dose, respectively. 
e 
Vital signs to include: blood pressure, pulse rate, oral body temperature, and respiratory rate.  Parameters are to be measured in the supine position using an automated 
instrument after the patient has rested comfortably for 10 minutes. 
f 
Serial measures (vital signs and pulse oximetry) are to be measured within 30 minutes pre-dose; at the end of infusion (EOI); and 30 (±5) minutes; 1, 2, and 3 (±15 minutes) 
hours; 6, 12, and 18 (±30 minutes) hours; and 24 (+30 minutes) hours post-infusion. 
g 
Not needed if a normal echocardiogram has been obtained within the past 90 days. 
h 
Serial electrocardiograms (ECGs) will be collected in 3 replicates within 30 minutes pre-dose, EOI, and 30 (±5) minutes, 2 and 4 (±15 minutes) hours, and 24 (+30 minutes) 
hours post-infusion. 
i 
Patients will be hospitalized at the study site for at least 24 hours after the end of infusion of study drug.  Patients may be discharged upon completion of review by the 
Investigator of ECG, sodium, potassium, creatinine, albumin, calcium, glucose, phosphate, and LFTs results obtained at 24-hours post-infusion, if results are deemed not 
clinically significant. Any clinically significant findings must be discussed with the medical monitor to determine whether patient can be discharged and to formulate plans for 
patient follow-up. 
j 
Continuous cardiac monitoring will be performed via telemetry starting no later than 30 minutes prior to dosing and continuing through 24 hours (+1 hour) post-dose. 
k 
Day 0 pre-dose only, not performed on Day 21. 
l 
Serologies include hepatitis B surface antibody (HbsAb), hepatitis B surface antigen (HbsAg), and anti–hepatitis C virus antibody (anti-HCV Ab). 
m 
If the parameter was assessed and meets eligibility requirements within 72 hours of Days 0 and 21, then it does not need to be repeated pre-dose (Days 0 and 21, respectively). 
n 
Liver function tests include aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and bilirubin (total and direct). 
o 
Coagulation studies include prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR). 
p 
Lipid panel (non-fasting) includes total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), and triglycerides 
will be collected on Day 0 only. 
q 
Pre-dose samples for TTR protein, vitamin A, and RBP measurements will be drawn immediately (within 10 minutes) prior to the premedications and immediately prior to 
dosing. 
r 
A patient will be followed approximately every 2 weeks after Day 56 if their TTR level continues to recover but is not found to have returned to within at least 80% of the 
baseline value.  If this occurs, the patient will be followed and discussed at each SRC meeting until the TTR level returns to within at least 80% of the baseline value. 
s 
Thyroid function tests include thyroid stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3). 
t 
A blood sample will be collected for the assessment of complement Bb immediately (within 10 minutes) pre-dose, and 30 (±5) minutes, and 2 and 24 hours (±120 minutes) 
post infusion.  If the patient experiences an infusion reaction, a blood sample for analysis of complement factors should be obtained within 1 hour of the start of the reaction. 
u 
A blood sample for the assessment of tryptase and C3a is to be collected only in the event of an acute infusion reaction: at time of event or as soon as possible after onset, 
1 hour, and 24 hours after the event. 
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v 
Premedications include dexamethasone (8 mg, or equivalent), paracetamol (500 mg, or equivalent), H2 blocker (e.g. 150 mg ranitidine or 20 mg famotidine, or equivalent 
other H2 blocker dose), and H1 blocker (10 mg cetirizine, 25 mg hydroxyzine, fexofenadine or equivalent may be substituted) will be self-administered per os (PO) the 
evening before study drug administration.  Thirty to 60 minutes prior to the start of study drug infusion, dexamethasone (20 mg PO, or equivalent), paracetamol (500 mg PO, 
or equivalent), an H2 blocker (PO), and an H1 blocker (PO) will be administered by study site personnel.  Patients enrolled in an optional cohort evaluating the use of an 
alternative premedication regimen, as agreed upon by the SRC, will receive the following medications at least 60 minutes prior to the start of infusion of ALN-TTR02:  
dexamethasone (10 mg IV, or equivalent), paracetamol (PO 500 mg; or equivalent), IV H2 blocker (e.g. ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 blocker 
dose), and IV H1 blocker (e.g., diphenhydramine 50 mg or equivalent; hydroxyzine or fexofenadine 25 mg PO or cetirizine 10 mg PO may be substituted for any patient who 
does not tolerate IV diphenhydramine or other IV H1 blockers).  These patients will not receive any premedications the evening prior to ALN-TTR02 dosing. 
w 
Site personnel are to call patients the day before dosing to remind them to take premedications that evening (the day before dosing).  This reminder will not be needed for 
patients enrolled in optional cohorts evaluating the alternative premedication regimen. 
x 
The infusion site will be assessed for any localized reaction pre-dose, during infusion, and for 30 minutes after the infusion. 
y 
A blood sample for the assessment of cytokines and C-reactive protein (CRP) will be collected immediately (within 10 minutes) pre-dose, and 2 (±15 minutes), 6 
(±15 minutes), and 24 hours (±120 minutes) post infusion.  If the patient experiences an infusion reaction, a blood sample for analysis of cytokines should be obtained within 
1 hour of the start of the reaction. 
z 
For each dose, plasma PK samples (siRNA and lipids) will be collected pre-dose (within 1 hour of planned dosing start), EOI, and then 5, 10, and 30 minutes, and 1, 2, 4, 6, 
24 and 48 hours post infusion.  Samples will also be collected on Days 7, 14, 28, 35, 42, 49, 56, 112, and 208.  Plasma PK on Day 0 at EOI and then 2 hours post-infusion will 
be analyzed for both free and encapsulated siRNA for cohort 3 and onward, including any optional cohorts.  For each post dose PK blood draw, the following sampling 
windows are allowed: ±1 minute for the 5- and 10-minute draws; ±2 minutes for the 30-minute draws; ±5 minutes for the 1-, 2-, 4-, and 6-hour draws; and ±120 minutes for 
the 24- and 48-hour draws. 
aa 
For each dose, urine PK samples will be collected pre-dose (within 1 hour of planned dosing start), and from 0-6 hours post-infusion (pooled). Samples will also be collected 
on Days 7, 14, 28, 35, 42, 49, 56, 112, and 208.   
bb Pre-dose samples should be collected prior to infusion, but after premedications have been administered. 
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Appendix 5: 
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 6: 
World Medical Association Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Patients 
Recommendations guiding physicians in biomedical research involving human patients 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the: 
29th WMA General Assembly, Tokyo, Japan (October 1975)  
35th WMA General Assembly, Venice, Italy (October 1983) 
41st WMA General Assembly, Hong Kong (September 1989) 
48th WMA General Assembly, Somerset West, Republic of South Africa (October 1996) 
52nd WMA General Assembly, Edinburgh, Scotland (October 2000) 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on Paragraph 29) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30) 
59th WMA General Assembly, Seoul, October 2008 
INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving human 
patients, including research on identifiable human material and data. The 
Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant 
paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA 
encourages other participants in medical research involving human patients to 
adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, 
including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The 
health of my patient will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act in the patient's best interest 
when providing medical care." 
5. Medical progress is based on research that ultimately must include studies 
involving human patients. Populations that are underrepresented in medical 
research should be provided appropriate access to participation in research. 
6. In medical research involving human patients, the well-being of the individual 
research patient must take precedence over all other interests. 
7. The primary purpose of medical research involving human patients is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
8. In medical practice and in medical research, most interventions involve risks and 
burdens. 
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9. Medical research is patient to ethical standards that promote respect for all human 
patients and protect their health and rights. Some research populations are 
particularly vulnerable and need special protection. These include those who 
cannot give or refuse consent for themselves and those who may be vulnerable to 
coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards 
for research involving human patients in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for 
research patients set forth in this Declaration. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality 
of personal information of research patients. 
12. Medical research involving human patients must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, 
other relevant sources of information, and adequate laboratory and, as 
appropriate, animal experimentation. The welfare of animals used for research 
must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that 
may harm the environment. 
14. The design and performance of each research study involving human patients 
must be clearly described in a research protocol. The protocol should contain a 
statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, other potential 
conflicts of interest, incentives for patients and provisions for treating and/or 
compensating patients who are harmed as a consequence of participation in the 
research study. The protocol should describe arrangements for post-study access 
by study patients to interventions identified as beneficial in the study or access to 
other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance 
and approval to a research ethics committee before the study begins. This 
committee must be independent of the researcher, the sponsor and any other 
undue influence. It must take into consideration the laws and regulations of the 
country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research patients set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information 
about any serious adverse events. No change to the protocol may be made without 
consideration and approval by the committee. 
16. Medical research involving human patients must be conducted only by individuals 
with the appropriate scientific training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately 
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qualified physician or other health care professional. The responsibility for the 
protection of research patients must always rest with the physician or other health 
care professional and never the research patients, even though they have given 
consent. 
17. Medical research involving a disadvantaged or vulnerable population or 
community is only justified if the research is responsive to the health needs and 
priorities of this population or community and if there is a reasonable likelihood 
that this population or community stands to benefit from the results of the 
research. 
18. Every medical research study involving human patients must be preceded by 
careful assessment of predictable risks and burdens to the individuals and 
communities involved in the research in comparison with foreseeable benefits to 
them and to other individuals or communities affected by the condition under 
investigation. 
19. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first patient. 
20. Physicians may not participate in a research study involving human patients 
unless they are confident that the risks involved have been adequately assessed 
and can be satisfactorily managed. Physicians must immediately stop a study 
when the risks are found to outweigh the potential benefits or when there is 
conclusive proof of positive and beneficial results. 
21. Medical research involving human patients may only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
research patients. 
22. Participation by competent individuals as patients in medical research must be 
voluntary. Although it may be appropriate to consult family members or 
community leaders, no competent individual may be enrolled in a research study 
unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research patients and the 
confidentiality of their personal information and to minimize the impact of the 
study on their physical, mental and social integrity. 
24. In medical research involving competent human patients, each potential patient 
must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may 
entail, and any other relevant aspects of the study. The potential patient must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential patients as well as to the 
methods used to deliver the information. After ensuring that the potential patient 
has understood the information, the physician or another appropriately qualified 
individual must then seek the potential patient's freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-
written consent must be formally documented and witnessed. 
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25. For medical research using identifiable human material or data, physicians must 
normally seek consent for the collection, analysis, storage and/or reuse. There 
may be situations where consent would be impossible or impractical to obtain for 
such research or would pose a threat to the validity of the research. In such 
situations the research may be done only after consideration and approval of a 
research ethics committee. 
26. When seeking informed consent for participation in a research study the physician 
should be particularly cautious if the potential patient is in a dependent 
relationship with the physician or may consent under duress. In such situations the 
informed consent should be sought by an appropriately qualified individual who 
is completely independent of this relationship. 
27. For a potential research patient who is incompetent, the physician must seek 
informed consent from the legally authorized representative. These individuals 
must not be included in a research study that has no likelihood of benefit for them 
unless it is intended to promote the health of the population represented by the 
potential patient, the research cannot instead be performed with competent 
persons, and the research entails only minimal risk and minimal burden. 
28. When a potential research patient who is deemed incompetent is able to give 
assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorized representative. The 
potential patient's dissent should be respected. 
29. Research involving patients who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary 
characteristic of the research population. In such circumstances the physician 
should seek informed consent from the legally authorized representative. If no 
such representative is available and if the research cannot be delayed, the study 
may proceed without informed consent provided that the specific reasons for 
involving patients with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved 
by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the patient or a legally authorized 
representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the 
publication of the results of research. Authors have a duty to make publicly 
available the results of their research on human patients and are accountable for 
the completeness and accuracy of their reports. They should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive 
results should be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest should be declared in the 
publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
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ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent 
that the research is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as 
research patients. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following 
circumstances: 
• 
The use of placebo, or no treatment, is acceptable in studies where no current 
proven intervention exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be patient to any risk of 
serious or irreversible harm. Extreme care must be taken to avoid abuse of this 
option. 
33. At the conclusion of the study, patients entered into the study are entitled to be 
informed about the outcome of the study and to share any benefits that result from 
it, for example, access to interventions identified as beneficial in the study or to 
other appropriate care or benefits. 
34. The physician must fully inform the patient which aspects of the care are related 
to the research. The refusal of a patient to participate in a study or the patient's 
decision to withdraw from the study must never interfere with the patient-
physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorized representative, may use an unproven 
intervention if in the physician's judgment it offers hope of saving life, re-
establishing health or alleviating suffering.  Where possible, this intervention 
should be made the object of research, designed to evaluate its safety and 
efficacy.  In all cases, new information should be recorded and, where 
appropriate, made publicly available. 
 
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Protocol ALN-TTR02-002 
Amendment 2.1 Change Summary 
A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Infusions of 
ALN-TTR02 in Patients with TTR Amyloidosis 
Changes included in Amendment 2.1, from Amendment 1.1 of Protocol ALN-TTR02-
002 (dated 24 September 2012; original protocol dated 03 February 2012, Amendment 1 
dated 19 June 2012), are itemized below and detailed in the pages that follow.   
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
   
 
 
 
 
 
 
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Table 1: Premedication and Infusion Rate Changes Proposed in Amendment #2.1 
Medication 
Current Protocol 
Proposed Amendment #2.1 
Dexamethasone  
(or equivalent) 
The evening before study drug 
administration, 8 mg PO; self-
administered.   
Thirty to 60 minutes prior to the start of 
study drug infusion, 20 mg PO; 
administered by study site personnel. 
No dexamethasone the evening prior to 
ALN-TTR02 dosing. 
 
To be administered by study site 
personnel at least 60 minutes prior to 
the start of study drug infusion, 10 mg 
IV. 
Paracetamol (or 
equivalent) 
The evening before study drug 
administration, 500 mg PO; self-
administered.   
Thirty to 60 minutes prior to the start of 
study drug infusion, 500 mg PO; 
administered by study site personnel. 
No paracetamol the evening prior to 
ALN-TTR02 dosing. 
 
To be administered by study site 
personnel at least 60 minutes prior to 
the start of study drug infusion, 500 mg 
PO. 
H1 blocker 
Oral cetirizine 10 mg (hydroxyzine 
25 mg, fexofenadine, or equivalent may 
be substituted if patient does not 
tolerate cetirizine).  To be administered: 
 
The evening before study drug 
administration; self-administered.   
Thirty to 60 minutes prior to the start of 
study drug infusion; administered by 
study site personnel. 
Diphenhydramine 50 mg IV (or 
equivalent other IV H1 blocker 
available at the study site).  
Hydroxyzine or fexofenadine 25 mg 
PO or cetirizine 10 mg PO may be 
substituted for any patient who does not 
tolerate IV H1 blockers.   
To be administered by study site 
personnel at least 60 minutes prior to 
the start of study drug infusion. 
(No H1 blocker the evening prior to 
ALN-TTR02 dosing.) 
H2 blocker 
Oral ranitidine 150 mg or famotidine 20 
mg or equivalent other H2 blocker 
dose.  To be administered:  
The evening before study drug 
administration; self-administered.   
Thirty to 60 minutes prior to the start of 
study drug infusion; administered by 
study site personnel. 
Intravenous ranitidine 50 mg, 
famotidine 20 mg or another equivalent 
IV H2 blocker dose.   
To be administered at least 60 minutes 
prior to the start of study drug infusion. 
(No H2 blocker the evening prior to 
ALN-TTR02 dosing.) 
Infusion rate  
Over 60 minutes (~3.3 mL/min) 
Approximately 1.1 mL/min over the 
first 15 minutes, with the remainder of 
the infusion administered at 
3.3 mL/min (total infusion time: 
~70 min). 
 
 
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Other changes from Amendment 1.1 to Amendment 2.1 include: 
• Increased the number of optional cohorts from 3 to 5 to allow for the evaluation 
of once every 3 weeks dosing interval as well as an alternative premedication 
regimen and slower infusion rate.   
• Added an additional schedule of assessments for optional cohorts administered 
ALN-TTR02 once every 3 weeks (refer to Appendix 4). 
• The dosing regimen in the first optional cohort will be once every 4 weeks; in the 
remaining 4 optional cohorts the dosing regimen will be once every 3 or 4 weeks.  
The decision on dosing every 3 or 4 weeks will be made by the SRC based on 
safety.  
• The alternative premedication regimen and infusion rate (detailed in Table 1) will 
be evaluated in up to 3 optional cohorts once the safety of the original 
premedication regimen and infusion rate is further established in the first 
2 optional cohorts.   
• Section 1.3 (Summary of Clinical Data with siRNA-LNPs) of the protocol has 
been simplified and primarily cross-references the IB, Edition 3, which contains 
the updated clinical information. 
• Removed the Principal Investigators’ contact information from the protocol itself.  
This information is included in the Study Procedures Manual. 
• Made minor editorial changes (e.g., corrections of typographical, grammatical, 
and spelling errors as well as formatting changes and changes for consistency); 
these changes are not listed individually. 
 
 
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Text deleted is indicated by strikeout while text added is indicated by bold font. 
Section 
Prior Text 
Changed To 
Contact Information 
Principal Investigator 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
Principal Investigator 
 
 
 
 
  
 
Principal Investigator 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
Principal Investigator 
 
 
 
  
 
 
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Section 
Prior Text 
Changed To 
 
 
 
Principal Investigator 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 
Principal Investigator 
Marcia Waddington Cruz, MD, PhD 
 
 
 
 
Synopsis: Design 
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
 
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Section 
Prior Text 
Changed To 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001). 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001). 
Synopsis: Study Sites 
This study is planned to be conducted at up to 8 study 
centers in Europe and South America. 
This study is planned to be conducted at up to 8 10 
study centers in Europe and South Americaworldwide. 
Synopsis: Dosage, Route of 
Administration and 
Duration of Treatment of 
Investigational Drug 
The optional cohort would be included to further 
confirm the safety and/or pharmacodynamic (PD) 
effect.  If this occurs, the Independent Ethics 
Committees (IECs) will be informed of the expansion.  
Up to 3 optional cohorts are permitted in this study. 
All patients will receive the following premedications 
prior to each dose of ALN-TTR02: 
• 
Oral (PO) dexamethasone (8 mg) or equivalent 
administered the evening before dosing and 20 
mg 30 to 60 minutes prior to start of infusion of 
ALN-TTR02; 
• 
Oral paracetamol (500 mg) or equivalent the 
evening before dosing and 30 to 60 minutes prior 
to the start of infusion of ALN-TTR02; 
• 
Oral H2 blocker (i.e., ranitidine 150 mg or 
famotidine 20 mg or equivalent other H2 blocker 
dose) the evening before dosing and 30 to 60 
minutes prior to start of infusion of ALN-TTR02; 
• 
Oral H1 blocker, 10 mg cetirizine or equivalent 
(hydroxyzine 25 mg or fexofenadine may be 
substituted if patient does not tolerate cetirizine) 
the evening before dosing and 30 to 60  minutes 
The oOptional cohort(s) would be included to further 
confirm the safety and/or pharmacodynamic (PD) 
effect of previously evaluated dose levels, which may 
include evaluation of the original dosing regimen 
(once every 4 weeks), an alternative dosing regimen 
(once every 3 weeks), and/or an alternative 
premedication regimen and infusion rate.  The 
dosing regimen for the first optional cohort will be 
once every 4 weeks, and the dosing regimen for the 
remaining 4 optional cohorts will be once every 3 or 
4 weeks.  It is anticipated that the first 2 optional 
cohorts will use the original premedication regimen, 
and the remaining 3 optional cohorts may be used to 
explore the alternative premedication regimen and 
infusion rate.   
The SRC will review all available safety data and 
make recommendations on dosing and 
premedication regimens prior to dosing of any of 
the optional cohorts.  
If this occurs, tThe Independent Ethics Committees 
(IECs) will be informed of the 
expansionimplementation of optional cohorts.  Up to 
3 5 optional cohorts are permitted in this study. 
All patients will receive the followingPatients 
 
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Section 
Prior Text 
Changed To 
prior to start of infusion of ALN-TTR02; 
Doses of ALN-TTR02 will be administered IV over 
60 minutes by a controlled infusion device.   
receiving the original premedication regimen will be 
administered the followings prior to each dose of 
ALN-TTR02: 
• Oral (PO) dexamethasone (8 mg) or equivalent 
administered the evening before dosing and 
20 mg 30 to 60 minutes prior to start of 
infusion of ALN-TTR02; 
• Oral paracetamol (500 mg) or equivalent the 
evening before dosing and 30 to 60 minutes 
prior to the start of infusion of ALN-TTR02; 
• Oral H2 blocker (i.ee.g., ranitidine 150 mg or 
famotidine 20 mg or equivalent other H2 
blocker dose) the evening before dosing and 
30 to 60 minutes prior to start of infusion of 
ALN-TTR02; and  
• Oral H1 blocker, 10 mg cetirizine or equivalent 
(hydroxyzine 25 mg or fexofenadine may be 
substituted if patient does not tolerate 
cetirizine) the evening before dosing and 
30 to 60  minutes prior to start of infusion of 
ALN-TTR02. 
The alternative premedication regimen that can be 
used in select optional cohorts, as agreed upon by 
the SRC, will be administered prior to each dose of 
ALN-TTR02 and includes the following: 
• Intravenous (IV) dexamethasone (10 mg) or 
equivalent, administered at least 
 
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Section 
Prior Text 
Changed To 
60 minutes prior to the start of infusion of 
ALN-TTR02; 
• Oral paracetamol (500 mg) or equivalent at 
least 60 minutes prior to the start of 
infusion of ALN-TTR02; 
• Intravenous H2 blocker (e.g., ranitidine 
50 mg, famotidine 20 mg, or equivalent 
other H2 blocker dose) at least 60 minutes 
prior to start of infusion of ALN-TTR02; 
and 
• Intravenous H1 blocker: diphenhydramine 
50 mg (or equivalent other IV H1 blocker 
available at the study site) at least 60 
 minutes prior to start of infusion of ALN-
TTR02.  Hydroxyzine or fexofenadine 25 
mg PO or cetirizine 10 mg PO may be 
substituted for any patient who does not 
tolerate IV diphenhydramine or other IV 
H1 blocker. 
For patients receiving the original premedication 
regimen and infusion rate, doses of ALN-TTR02 will 
be administered IV over 60 minutes by a controlled 
infusion device at a flow rate of approximately 3.3 
mL/min.   
For patients enrolled in the optional cohorts 
evaluating the alternative premedication regimen 
and infusion rate, the flow rate of ALN-TTR02 will 
 
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be approximately 1.1 mL/min during the first 
15 minutes (1/3rd the original flow rate) with the 
remainder of the infusion administered at a flow 
rate of 3.3 mL/min for a total infusion time of 
approximately 70 minutes 
Time on Study 
Added language to allow an open-label extension 
study. 
An open-label extension study at the recommended 
Phase 3 dose and regimen (as derived from Study 
ALN-TTR02-002) is planned, which will enable the 
patients who enrolled in Study ALN-TTR02-002 to 
receive additional, long-term dosing and safety 
follow-up.  For some of the patients, this may 
preclude the completion of all of the follow-up 
period assessments of Study ALN-TTR02-002 if 
they are deemed eligible to participate in the 
extension study prior to completion of the full follow 
up through Day 208.  Such patients will be followed 
up for a minimum of 28 days after their last dose in 
the current ALN-TTR02-002 study prior to being 
enrolled in the extension study.  The extension study 
will be implemented only after dose escalation is 
completed in Study ALN-TTR02-002, with post 
second dose follow-up through Day 208 in at least 1 
cohort at the highest dose. 
Synopsis: Sample Size 
Based on the entry criteria and the proposed dose 
escalation scheme, up to 21 patients are expected to be 
enrolled.  Three patients are to be enrolled at each dose 
level and up to 3 optional cohorts of 3 patients each 
will be permitted. 
Based on the entry criteria and the proposed dose 
escalation scheme, up to 21 27 patients are expected to 
be enrolled.  Three patients are to be enrolled at each 
dose level and up to 3 5 optional cohorts of 3 patients 
each will be permitted. 
Synopsis: Dose-Limiting 
3.  An infusion reaction that requires hospitalization, 
3.  An infusion reaction that requires hospitalization, 
 
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Toxicities and Stopping 
Criteria 
despite proper premedication. 
despite proper premedication. 
Table 1.1 
Schedule of Assessments  
Schedule of Assessments for Cohorts Administered 
ALN-TTR02 Once Every Four Weeks 
 
 
Added note 
Note:  The schedule of assessments for optional 
cohorts administered ALN-TTR02 once every 
3 weeks is provided in Appendix 4. 
 
 
v.  Premedications include dexamethasone (8 mg, or 
equivalent), paracetamol (500 mg, or equivalent), H2 
blocker (i.e. 150 mg ranitidine or 20 mg famotidine), 
and H1 blocker (10 mg cetirizine, 25 mg hydroxyzine, 
fexofenadine or equivalent may be substituted) will be 
self-administered per os (PO) the evening before study 
drug administration.  Thirty to 60 minutes prior to the 
start of study drug infusion, dexamethasone (20 mg 
PO, or equivalent), paracetamol (500 mg PO, or 
equivalent), an H2 blocker (PO), and an H1 blocker 
(PO) will be administered by study site personnel. 
v.  Premedications include dexamethasone (8 mg, or 
equivalent), paracetamol (500 mg, or equivalent), H2 
blocker (i.ee.g. 150 mg ranitidine, or 20 mg famotidine, 
or equivalent other H2 blocker dose), and H1 blocker 
(10 mg cetirizine, 25 mg hydroxyzine, fexofenadine or 
equivalent may be substituted) will be self-
administered per os (PO) the evening before study drug 
administration.  Thirty to 60 minutes prior to the start 
of study drug infusion, dexamethasone (20 mg PO, or 
equivalent), paracetamol (500 mg PO, or equivalent), 
an H2 blocker (PO), and an H1 blocker (PO) will be 
administered by study site personnel.  Patients 
enrolled in an optional cohort evaluating the use of 
an alternative premedication regimen, as agreed 
upon by the SRC, will receive the following 
medications at least 60 minutes prior to the start of 
infusion of ALN-TTR02:  dexamethasone (10 mg 
IV, or equivalent), paracetamol (PO 500 mg; or 
equivalent), IV H2 blocker (e.g. ranitidine 50 mg, 
famotidine 20 mg, or equivalent other H2 blocker 
 
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dose), and IV H1 blocker (e.g., diphenhydramine 50 
mg or equivalent; hydroxyzine or fexofenadine 25 
mg PO or cetirizine 10 mg PO may be substituted 
for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blockers).  These 
patients will not receive any premedications the 
evening prior to ALN-TTR02 dosing. 
 
 
w.  Site personnel are to call patients the day before 
dosing to remind them to take premedications that 
evening (the day before dosing). 
w.  Site personnel are to call patients the day before 
dosing to remind them to take premedications that 
evening (the day before dosing).  This reminder will 
not be needed for patients enrolled in optional 
cohorts evaluating the alternative premedication 
regimen. 
1.3: Summary of Clinical 
Data with siRNA-LNPs 
A Phase 1 multi-centre, randomized, placebo-
controlled, single-blind, single-ascending dose clinical 
study to evaluate the safety, tolerability, PK, and 
pharmacodynamic (PD) of ALN-TTR02 in healthy 
volunteers was approved by MHRA (EUDRACT 
# 2011-005291-42) and has completed dosing.  ALN-
TTR02 was administered as a single 60-minute IV 
infusion to healthy volunteers at the following doses: 
10, 50, 150, 300, and 500 µg/kg (4 patients per dose 
level; 3 receiving ALN-TTR02 and 1 receiving 
placebo).  The dose level of ALN-TTR02 administered 
to any cohort in study ALN-TTR02-002 may not be 
higher than that deemed safe and tolerable in the Phase 
1 single-dose study of ALN-TTR02 (Study ALN-
TTR02-001).  Patients will be pre-medicated with 
A Phase 1 multi-centre, randomized, placebo-
controlled, single-blind, single-ascending dose clinical 
study to evaluate the safety, tolerability, PK, and 
pharmacodynamic (PD) of ALN-TTR02 in healthy 
volunteers was approved by MHRA (EUDRACT 
# 2011-005291-42) and has completed dosing.  ALN-
TTR02 was administered as a single 60-minute IV 
infusion to healthy volunteers at the following doses: 
10, 50, 150, 300, and 500 µg/kg (4 patients per dose 
level; 3 receiving ALN-TTR02 and 1 receiving 
placebo).  The dose level of ALN-TTR02 administered 
to any cohort in study ALN-TTR02-002 may not be 
higher than that deemed safe and tolerable in the Phase 
1 single-dose study of ALN-TTR02 (Study ALN-
TTR02-001).  Patients will be pre-medicated with 
 
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dexamethasone, H1 and H2 blockers, and paracetamol 
prior to dosing to minimize the risk of infusion 
reaction.  Preliminary data show that ALN-TTR02 was 
safe and well-tolerated and exhibited robust effects on 
serum TTR levels at the top doses. To date, no stopping 
rules have been met and there have been no early 
discontinuations due to adverse events. Further 
information on the ALN-TTR02-001 Phase 1 study can 
be found in the ALN-TTR02 Investigators Brochure 
and its Expedited Safety Report addendum dated 7 
June 2012. 
 
dexamethasone, H1 and H2 blockers, and paracetamol 
prior to dosing to minimize the risk of infusion 
reaction.  Preliminary data show that ALN-TTR02 was 
safe and well-tolerated and exhibited robust effects on 
serum TTR levels at the top doses. To date, no stopping 
rules have been met and there have been no early 
discontinuations due to adverse events. Further 
information on the ALN-TTR02-001 Phase 1 study can 
be found in the ALN-TTR02 Investigators Brochure 
and its Expedited Safety Report addendum dated 7 
June 2012. 
 
Clinical trials with multiple different RNAi medicinal 
products using local or systemic administration in 
indications including age-related macular degeneration, 
respiratory syncytial virus (RSV) infection, oncology, 
and renal failure have been conducted.28  Alnylam 
currently has 3 ongoing systemic delivery programs in 
the clinic evaluating the safety and efficacy of different 
siRNAs in 2 different LNP formulations.  Specifically, 
the active Phase 1 clinical trials most relevant to ALN-
TTR02 include ALN-PCS02, which uses the same LNP 
formulation, and ALN-TTR01, which uses the same 
siRNA as ALN-TTR02 but in a different LNP 
formulation.  The clinical safety data from the ALN-
PCS02 study in particular provides some reassurance 
regarding the safety of this formulation (common with 
ALN-TTR02) after a single dose.   
Further, cClinical trials with multiple different RNAi 
medicinal products using local or systemic 
administration in indications including age-related 
macular degeneration, respiratory syncytial virus 
(RSV) infection, oncology, and renal failure have been 
conducted.28  Alnylam currently has experience with 
34 ongoing systemic delivery programs in the clinic 
evaluating the safety and efficacy of different siRNAs 
in 2 different LNP formulations, including 1 program 
which employs the same AF-011 formulation as 
ALN-TTR02.  Specifically, the active Phase 1 clinical 
trials most relevant to ALN-TTR02 include 
ALN-PCS02, which uses the same LNP formulation, 
and ALN-TTR01, which uses the same siRNA as 
ALN-TTR02 but in a different LNP formulation.  The 
clinical safety data from the ALN-PCS02 study in 
particular provides some reassurance regarding the 
 
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safety of this formulation (common with ALN-TTR02) 
after a single dose.  An overview of the safety and 
pharmacological clinical data with these siRNA-
LNPs is included in the ALN-TTR02 Investigator’s 
Brochure (IB), Edition 3, dated 19 October 2012.  
 
  
Furthermore, the Phase 1 data with all 4 of the 
siRNA-LNPs have shown that
 
 
.  
 
 
ALN-PCS02-001 is a Phase 1 multi-centre, 
randomized, placebo-controlled, single-blind, single-
ascending dose clinical study to evaluate the safety, 
tolerability, PK, and PD of ALN-PCS02.  The study is 
ongoing in the United Kingdom (EudraCT #2011-
000581-36).  ALN-PCS02 was administered as a single 
60-minute IV infusion to healthy volunteers with 
elevated low density lipoprotein-C (LDL-C; >3 
mmol/L) at the following doses: 15, 45, 90, 150, and 
250 µg/kg (4 patients per dose level; 3 receiving ALN-
PCS02 and 1 receiving placebo).  Patients were pre-
medicated with dexamethasone, H1 and H2 blockers, 
and paracetamol prior to dosing to minimize the risk of 
infusion reaction.  As of December 2011, 24 patients 
(23 males and 1 female) have been enrolled in the 
ALN-PCS02-001 study and 18 patients (17 males and 1 
female) have received ALN-PCS02 in 6 cohorts at 
Importantly, a Phase 1 study with ALN-TTR02 was 
recently completed.  Study ALN-TTR02-001 was a 
multicenter, randomized, placebo-controlled, single-
blind, single-ascending dose clinical study 
conducted in the UK to evaluate the safety, 
tolerability, PK, and pharmacodynamic (PD) in 
healthy volunteers (EudraCT # 2011 005291-42).  
ALN-TTR02 was administered as a single 60-
minute IV infusion to healthy volunteers at the 
following doses: 10, 50, 150, 300, and 500 µg/kg (4 
patients per dose level; 3 receiving ALN-TTR02 and 
1 receiving placebo).  Patients were premedicated 
with dexamethasone, H1 and H2 blockers, and 
paracetamol prior to dosing to minimize the risk of 
infusion reaction.  The data show that ALN-TTR02 
was safe and well-tolerated and exhibited robust 
effects on serum TTR levels at doses ≥0.15 mg/kg.  
 
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doses ranging from 15 to 250 µg/kg (including 2 
cohorts dosed at the 250 µg/kg dose).   
No dose-limiting toxicities (DLTs) have been reported 
to date, and no patient has prematurely withdrawn from 
the study due to an adverse event (AE).  There was one 
serious adverse event (SAE; bilateral pulmonary 
emboli in a patient with chronic deep vein thrombosis) 
considered unrelated to study drug that occurred in 1 
patient dosed at 45 µg/kg.  There have been no 
laboratory AEs related to study drug; specifically, there 
have been no clinically significant changes in liver 
function tests (LFTs), electrolytes, hematology 
parameters, or renal function post-dose.   
Mild self-limiting erythematous skin rashes not 
requiring treatment were seen in 6 patients dosed with 
ALN-PCS02 (1 each at 15 and 45 µg/kg, and in 4 
patients at 0.25 mg/kg).  Transient elevations in the 
complement pathway Bb (1.25- to 4.6-fold) have 
occurred in 14 patients 30 minutes post-infusion and 
have been observed across all dose levels and were not 
associated with signs or symptoms.  There have been 
no cytokine or CRP elevations in any of the patients.  
Stopping rules for dose escalation have not been met, 
and the study is ongoing.  
Preliminary PD data with ALN-PCS02 showed an 
approximately 60% reduction in PCSK9 serum protein 
at the 150 and 250 µg/kg doses compared with baseline 
Lowering of TTR levels was reversible following 
administration of a single dose, and there were no 
AEs associated with lowering TTR by >90%.  
Further details on this study can be found in the 
ALN-TTR02 IB, Edition 3. 
ALN-PCS02-001 is a Phase 1 multi-centre, 
randomized, placebo-controlled, single-blind, single-
ascending dose clinical study to evaluate the safety, 
tolerability, PK, and PD of ALN-PCS02.  The study is 
ongoing in the United Kingdom (EudraCT #2011-
000581-36).  ALN-PCS02 was administered as a single 
60-minute IV infusion to healthy volunteers with 
elevated low density lipoprotein-C (LDL-C; >3 
mmol/L) at the following doses: 15, 45, 90, 150, and 
250 µg/kg (4 patients per dose level; 3 receiving ALN-
PCS02 and 1 receiving placebo).  Patients were pre-
medicated with dexamethasone, H1 and H2 blockers, 
and paracetamol prior to dosing to minimize the risk of 
infusion reaction.  As of December 2011, 24 patients 
(23 males and 1 female) have been enrolled in the 
ALN-PCS02-001 study and 18 patients (17 males and 1 
female) have received ALN-PCS02 in 6 cohorts at 
doses ranging from 15 to 250 µg/kg (including 2 
cohorts dosed at the 250 µg/kg dose).   
No dose-limiting toxicities (DLTs) have been reported 
to date, and no patient has prematurely withdrawn from 
the study due to an adverse event (AE).  There was one 
serious adverse event (SAE; bilateral pulmonary 
 
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levels, with a return toward baseline after ~ 28 days. 
The ALN-TTR01 Phase 1 clinical trial (ALN-TTR01-
001) is a multi-centre, randomized, placebo-controlled, 
single-blind, single-ascending dose study to evaluate 
the safety, tolerability, PK and PD of ALN-TTR01.  
The study is ongoing in France, Portugal, Sweden, and 
the United Kingdom (EudraCT # 2009-017383-16).  
The data from this study are relevant to provide the 
effect of TTR lowering using the same siRNA as ALN-
TTR02 albeit in a different formulation.  ALN-TTR01 
was administered as a single 15-minute IV infusion to 
ATTR Stage 1 patients at the following doses: 10, 30, 
100, 200, 400, 700, and 1000 µg/kg (4 patients per dose 
level; 3 receiving ALN-TTR01 and 1 receiving 
placebo).  Patients were pre-medicated with a similar 
regimen used for ALN-PCS02.  A total of 32 patients 
were enrolled in this study (including 8 at 1000 µg/kg 
and 4 each at 10-700 µg/kg), of whom 24 (14 males 
and 10 females) received ALN-TTR01. 
There were no laboratory AEs and no significant 
changes in LFTs, electrolytes, hematology parameters, 
or renal function post-dose.  No clinically significant 
changes in testosterone were observed in males.  No 
drug-related SAEs or DLTs occurred, and no patient 
withdrew prematurely from the study due to an AE.  
There were 5 acute infusion-related reactions (IRRs): 1 
each at 400 and 700 µg/kg and 3 at 1000 µg/kg, for an 
overall rate of 21%, all of which were mild to moderate 
emboli in a patient with chronic deep vein thrombosis) 
considered unrelated to study drug that occurred in 1 
patient dosed at 45 µg/kg.  There have been no 
laboratory AEs related to study drug; specifically, there 
have been no clinically significant changes in liver 
function tests (LFTs), electrolytes, hematology 
parameters, or renal function post-dose.   
Mild self-limiting erythematous skin rashes not 
requiring treatment were seen in 6 patients dosed with 
ALN-PCS02 (1 each at 15 and 45 µg/kg, and in 4 
patients at 0.25 mg/kg).  Transient elevations in the 
complement pathway Bb (1.25- to 4.6-fold) have 
occurred in 14 patients 30 minutes post-infusion and 
have been observed across all dose levels and were not 
associated with signs or symptoms.  There have been 
no cytokine or CRP elevations in any of the patients.  
Stopping rules for dose escalation have not been met, 
and the study is ongoing.  
Preliminary PD data with ALN-PCS02 showed an 
approximately 60% reduction in PCSK9 serum protein 
at the 150 and 250 µg/kg doses compared with baseline 
levels, with a return toward baseline after ~ 28 days. 
The ALN-TTR01 Phase 1 clinical trial (ALN-TTR01-
001) is a multi-centre, randomized, placebo-controlled, 
single-blind, single-ascending dose study to evaluate 
the safety, tolerability, PK and PD of ALN-TTR01.  
The study is ongoing in France, Portugal, Sweden, and 
the United Kingdom (EudraCT # 2009-017383-16).  
 
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in severity, and where necessary, responded to 
temporary halting of the infusion followed by 
resumption of the infusion at a slower rate.  Regardless 
of whether a patient experienced an IRR, all study drug 
infusions were successfully administered to 
completion.  Transient elevations of Bb were observed 
across all dose levels, with higher induction seen in 
patients with acute IRRs.  There have been no changes 
in C3, C4, or CH50.  Modest elevations in both IL-6 (2 
to 7-fold over baseline) and CRP (4 to 9-fold over 
baseline) were observed in 3 patients treated at 1000 
µg/kg and were not associated with fever or chills.  
Preliminary plasma PK results indicate a generally 
dose-proportional increase in the area under the plasma 
concentration-time curve (AUC) and the observed 
maximum concentration (Cmax) and the long term 
exposure in humans is higher than predicted by the 
preclinical animal studies.   
The PD effects of ALN-TTR01 were assessed through 
serial measurements of serum TTR protein.i  There 
were no significant changes in TTR relative to placebo 
at doses below 1000 µg/kg.  At 1000 µg/kg (n=5), a 
mean decline in TTR protein of 41% relative to 
baseline and placebo was observed by Day 7 post-dose 
(geometric mean; p=0.02), with recovery to 80% of 
pre-treatment level for the group by Day 28.  In 1 
patient, the serum TTR declined by 81%; this was 
accompanied by a similar decrease in RBP and 
vitamin A, as predicted by preclinical data with ALN-
The data from this study are relevant to provide the 
effect of TTR lowering using the same siRNA as ALN-
TTR02 albeit in a different formulation.  ALN-TTR01 
was administered as a single 15-minute IV infusion to 
ATTR Stage 1 patients at the following doses: 10, 30, 
100, 200, 400, 700, and 1000 µg/kg (4 patients per dose 
level; 3 receiving ALN-TTR01 and 1 receiving 
placebo).  Patients were pre-medicated with a similar 
regimen used for ALN-PCS02.  A total of 32 patients 
were enrolled in this study (including 8 at 1000 µg/kg 
and 4 each at 10-700 µg/kg), of whom 24 (14 males 
and 10 females) received ALN-TTR01. 
There were no laboratory AEs and no significant 
changes in LFTs, electrolytes, hematology parameters, 
or renal function post-dose.  No clinically significant 
changes in testosterone were observed in males.  No 
drug-related SAEs or DLTs occurred, and no patient 
withdrew prematurely from the study due to an AE.  
There were 5 acute infusion-related reactions (IRRs): 1 
each at 400 and 700 µg/kg and 3 at 1000 µg/kg, for an 
overall rate of 21%, all of which were mild to moderate 
in severity, and where necessary, responded to 
temporary halting of the infusion followed by 
resumption of the infusion at a slower rate.  Regardless 
of whether a patient experienced an IRR, all study drug 
infusions were successfully administered to 
completion.  Transient elevations of Bb were observed 
across all dose levels, with higher induction seen in 
patients with acute IRRs.  There have been no changes 
 
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Changed To 
TTR01 in NHPs and the known role of TTR in binding 
to and stabilizing circulating RBP.  By Day 70, TTR 
and vitamin A had recovered to approximate pre-
treatment levels without any reported signs or 
symptoms and did not require the need for 
supplementation.  There were no significant changes in 
thyroid hormone levels or thyroid stimulating hormone 
(TSH) in this patient, and no adverse effects associated 
with TTR lowering.  A similar pattern of 
TTR/RBP/vitamin A decrease and recovery without 
any impact on safety was observed in all patients on the 
study treated at 1.0 mg/kg who showed a response to 
ALN-TTR01.  As with the PD data with ALN-PCS02, 
these data show the translatability of the PD effect from 
the monkey to human on a mg/kg dose basis, and show 
predictable reversibility. 
The safety of giving multiple doses of an siRNA-LNP 
has been established with ALN-VSP02, which uses the 
same first generation LNP formulation as ALN-TTR01 
(see Investigator’s Brochure).  In a Phase 1 study 
performed in advanced cancer patients with liver 
involvement, chronic bi-weekly dosing with doses as 
high as 1.0 mg/kg was safe and well-tolerated using the 
same premedication regimen as ALN-TTR01, with no 
significant dose-dependent effect on liver function.  
Three patients with tumor shrinkage or prolonged 
disease stabilization who have received biweekly doses 
at 0.7-1.0 mg/kg for as long as 12-18 months are 
in C3, C4, or CH50.  Modest elevations in both IL-6 (2 
to 7-fold over baseline) and CRP (4 to 9-fold over 
baseline) were observed in 3 patients treated at 1000 
µg/kg and were not associated with fever or chills.  
Preliminary plasma PK results indicate a generally 
dose-proportional increase in the area under the plasma 
concentration-time curve (AUC) and the observed 
maximum concentration (Cmax) and the long term 
exposure in humans is higher than predicted by the 
preclinical animal studies.   
The PD effects of ALN-TTR01 were assessed through 
serial measurements of serum TTR protein.ii  There 
were no significant changes in TTR relative to placebo 
at doses below 1000 µg/kg.  At 1000 µg/kg (n=5), a 
mean decline in TTR protein of 41% relative to 
baseline and placebo was observed by Day 7 post-dose 
(geometric mean; p=0.02), with recovery to 80% of 
pre-treatment level for the group by Day 28.  In 1 
patient, the serum TTR declined by 81%; this was 
accompanied by a similar decrease in RBP and 
vitamin A, as predicted by preclinical data with ALN-
TTR01 in NHPs and the known role of TTR in binding 
to and stabilizing circulating RBP.  By Day 70, TTR 
and vitamin A had recovered to approximate pre-
treatment levels without any reported signs or 
symptoms and did not require the need for 
supplementation.  There were no significant changes in 
thyroid hormone levels or thyroid stimulating hormone 
(TSH) in this patient, and no adverse effects associated 
 
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continuing their treatment on an extension study. 
Thus, the nonclinical data with ALN-TTR02 and the 
preliminary clinical data with ALN-PCS02, ALN-
TTR01, and ALN-VSP02 support the proposed early 
phase clinical trials evaluating ascending doses (single 
or multiple) of ALN-TTR02 (studies ALN-TTR02-001 
and ALN-TTR02-002). 
Further information, including preliminary safety and 
efficacy updates from the recently completed Phase 1 
trials of ALN-TTR02 in healthy volunteers and ALN-
PCS02 in healthy volunteers with elevated cholesterol, 
can be found in the Investigator’s Brochure and its 
Expedited Safety Report addendum dated 7 June 2012.  
Alnylam will immediately notify the Principal 
Investigators if any relevant new safety or toxicology 
information becomes available during the study. 
with TTR lowering.  A similar pattern of 
TTR/RBP/vitamin A decrease and recovery without 
any impact on safety was observed in all patients on the 
study treated at 1.0 mg/kg who showed a response to 
ALN-TTR01.  As with the PD data with ALN-PCS02, 
these 
 
, and show 
predictable reversibility. 
The safety of giving multiple doses of an siRNA-LNP 
has been established with ALN-VSP02, which uses the 
same first generation LNP formulation as ALN-TTR01 
(see Investigator’s Brochure).  In a Phase 1 study 
performed in advanced cancer patients with liver 
involvement, chronic bi-weekly dosing with doses as 
high as 1.0 mg/kg was safe and well-tolerated using the 
same premedication regimen as ALN-TTR01, with no 
significant dose-dependent effect on liver function.  
Three patients with tumor shrinkage or prolonged 
disease stabilization who have received biweekly doses 
at 0.7-1.0 mg/kg for as long as 12-18 months are 
continuing their treatment on an extension study. 
Thus, the nonclinical data with ALN-TTR02 and the 
preliminary clinical data with ALN-PCS02, ALN-
TTR01, and ALN-VSP02 support the proposed early 
phase clinical trials evaluating ascending doses (single 
or multiple) of ALN-TTR02 (studies ALN-TTR02-001 
and ALN-TTR02-002). 
Further information, including preliminary safety and 
 
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efficacy updates from the recently completed Phase 1 
trials of ALN-TTR02 in healthy volunteers and ALN-
PCS02 in healthy volunteers with elevated cholesterol, 
can be found in the Investigator’s Brochure and its 
Expedited Safety Report addendum dated 7 June 2012.  
Alnylam will immediately notify the Principal 
Investigators if any relevant new safety or toxicology 
information becomes available during the study. 
1.5:  Dose Selection and 
Rationale 
Two consecutive ALN-TTR02 doses, separated by a 4-
week period, will be administered to patients.  Study 
drug will be administered as a 60-minute IV infusion 
with the following proposed doses for each cohort:  10, 
50, 150, and 300 μg/kg ALN-TTR02.   
Two consecutive ALN-TTR02 doses, separated by a 
4-week period (or a 3-week period in select optional 
cohorts), will be administered to patients.  Study drug 
will be administered as a 60-minute IV infusion with 
the following proposed doses for each of the original 
cohorts:  10, 50, 150, and 300 μg/kg ALN-TTR02.  For 
those patients enrolled in an optional cohort 
evaluating the alternative premedication regimen 
and infusion rate, the study drug will be 
administered IV over approximately 70 minutes. 
 
 
In addition, cumulative safety and tolerability data 
observed in at least 2 patients through at least 96 hours 
post-second dose of the previous cohort will be 
reviewed by the SRC prior to administration of the 
second dose of study drug.  The dose level of ALN-
TTR02 administered to any cohort in study ALN-
TTR02-002 may not be higher than that deemed safe 
and tolerable in the Phase 1 single-dose study of ALN-
TTR02 (Study ALN-TTR02-001). 
In addition, cumulative safety and tolerability data 
observed in at least 2 patients through at least 96 hours 
post-second dose of the previous cohort will be 
reviewed by the SRC prior to administration of the 
second dose of study drug.  The dose level of ALN-
TTR02 administered to any cohort in study ALN-
TTR02-002 may not be higher than that deemed safe 
and tolerable in the Phase 1 single-dose study of ALN-
TTR02 (Study ALN-TTR02-001). 
 
 
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The optional cohort would be included to further 
confirm the safety and/or PD effect.  If this occurs, the 
Independent Ethics Committees (IECs) will be 
informed of the expansion.  Up to 3 optional cohorts of 
3 patients each are permitted in this study. 
The optional cohort(s) would be included to further 
confirm the safety and/or PD effect of previously 
evaluated dose levels, which may include evaluation 
of the original dosing regimen (once every 4 weeks), 
an alternative dosing regimen (once every 3 weeks), 
and/or an alternative premedication regimen and 
infusion rate.  The dosing regimen for the first 
optional cohort will be once every 4 weeks, and the 
dosing regimen for the remaining 4 optional cohorts 
will be once every 3 or 4 weeks.  It is anticipated 
that the first 2 optional cohorts will use the original 
premedication regimen, and the remaining 
3 optional cohorts may be used to explore the 
alternative premedication regimen and infusion 
rate.  The SRC will review all available safety data 
and make recommendations on dosing and 
premedication regimens prior to dosing of any of 
the optional cohorts.   If this occurs, the Independent 
Ethics Committees (IECs) will be informed of the 
expansionimplementation of optional cohorts.  Up to 
3 5 optional cohorts of 3 patients each are permitted in 
this study. 
1.6.1:  Infusion-Related 
Reactions 
The premedication regimen will include orally (PO) 
administered dexamethasone (or equivalent), 
paracetamol (or equivalent), and H1 and H2 blockers 
(as described in Section 5.5).  The rate of infusion 
(over the course of 1 hour) will also help to reduce the 
potential for acute IRRs.   
The premedication regimen will include orally (PO) 
administered dexamethasone (or equivalent), 
paracetamol (or equivalent), and H1 and H2 blockers 
(as described in Section 5.5).  The infusion rate of 
1 hour or longerinfusion (over the course of 1 hour) 
will also help to reduce the potential for acute IRRs.   
3.1:  Overall Design 
No patients will be a member of more than 1 treatment 
No patients will be a member of more than 1 treatment 
 
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group.   
group.  An alternative dosing regimen of 2 doses of 
ALN-TTR02 (at a dose previously determined by 
the SRC to be safe and tolerable) separated by 
3 weeks may be evaluated in the optional cohort(s).   
 
 
For patients on all dose levels other than the starting 
dose level of 10 µg/kg, prior to receiving the second 
dose the SRC will review the cumulative safety and 
tolerability data of at least 2 patients from the previous 
dose level(s) with at least 96 hours of follow-up after 
receiving a second dose of study drug.  The dose level 
of ALN-TTR02 administered to any cohort in study 
ALN-TTR02-002 may not be higher than that deemed 
safe and tolerable in the Phase 1 single-dose study of 
ALN-TTR02 (Study ALN-TTR02-001). 
For patients on all dose levels other than the starting 
dose level of 10 µg/kg, prior to receiving the second 
dose the SRC will review the cumulative safety and 
tolerability data of at least 2 patients from the previous 
dose level(s) with at least 96 hours of follow-up after 
receiving a second dose of study drug.  The dose level 
of ALN-TTR02 administered to any cohort in study 
ALN-TTR02-002 may not be higher than that deemed 
safe and tolerable in the Phase 1 single-dose study of 
ALN-TTR02 (Study ALN-TTR02-001). 
 
 
Eligible patients will undergo further pre-treatment 
assessments (performed on Day 0).  All patients will 
receive oral premedication with dexamethasone (or 
equivalent), paracetamol (or equivalent), and H1 and 
H2 blockers the night before and 30 to 60 minutes prior 
to each dose of ALN-TTR02 to reduce the potential of 
an IRR (see Section 5.5).  On Days 0 and 28, patients 
will receive a single dose of ALN-TTR02 administered 
as a 60-minute IV infusion   
Eligible patients will undergo further pre-treatment 
assessments (performed on Day 0).  All Patients 
receiving the original premedication regimenpatients 
will receive oral premedication with dexamethasone (or 
equivalent), paracetamol (or equivalent), and H1 and 
H2 blockers the night before and 30 to 60 minutes prior 
to each dose of ALN-TTR02 to reduce the potential of 
an IRR (see Section 5.5).  Those patients in an 
optional cohort evaluating the alternative 
premedication regimen, as agreed upon by the SRC, 
will receive IV dexamethasone (or equivalent), oral 
paracetamol (or equivalent), and IV H1 and H2 
blockers at least 60 minutes prior to ALN-TTR02 
 
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dosing; no premedication will be administered the 
evening prior to dosing.  On Days 0 and 28, patients 
will receive a single dose of ALN-TTR02 administered 
as a 60-minute IV infusion (for cohorts with the 
original premedication regimen and infusion rate), 
or as an approximate 70-minute IV infusion, for 
those patients in an optional cohort evaluating the 
alternative premedication regimen and infusion 
rate.   
4.1:  Eligibility of Patients 
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 21 patients are expected to be 
enrolled.   
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 21 27 patients are expected to be 
enrolled.   
5.5:  Premedication Plan 
Premedication will be administered as follows: 
Patients receiving the original premedication 
regimen will be administered the following 
Premedication will be administered as follows: 
 
 
Added language for an alternative premedication 
regimen and infusion rate. 
 
An alternative premedication regimen and infusion 
rate can be used in select optional cohorts, as agreed 
upon by the SRC.  The dosing regimen for the first 
optional cohort will be once every 4 weeks, and the 
dosing regimen for the remaining 4 optional cohorts 
will be once every 3 or 4 weeks.  It is anticipated 
that the first 2 optional cohorts will use the original 
premedication regimen, and the remaining 
3 optional cohorts may be used to explore the 
alternative premedication regimen and infusion 
rate.  Patients in these cohorts will not receive any 
premedications the evening prior to ALN-TTR02 
dosing.  Prior to each dose of ALN-TTR02, these 
 
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patients will receive the following premedications: 
• 
Intravenous (IV) dexamethasone (10 mg) or 
equivalent, administered at least 60 minutes 
prior to the start of infusion of ALN-TTR02; 
• 
Oral paracetamol (500 mg) or equivalent at 
least 60 minutes prior to the start of infusion of 
ALN-TTR02; 
• 
Intravenous H2 blocker (e.g., ranitidine 50 mg, 
famotidine 20 mg, or equivalent, other H2 
blocker dose) at least 60 minutes prior to start 
of infusion of ALN-TTR02; and 
• 
Intravenous H1 blocker: diphenhydramine 
50 mg (or equivalent other IV H1 blocker 
available at the study site) at least 60 minutes 
prior to start of infusion of ALN-TTR02.  
Hydroxyzine or fexofenadine 25 mg PO or 
cetirizine 10 mg PO may be substituted for any 
patient who does not tolerate IV 
diphenhydramine or other IV H1 blockers. 
5.6:  Dose, Route, and 
Schedule of Study Drug 
Administration 
Study drug doses will be administered as a 60-minute 
IV infusion 4 weeks apart.  Study drug will be 
administered via a controlled infusion device with an 
extension set containing a 1.2 micron filter supplied by 
Alnylam or designee.  Infusion products containing 
polyvinyl chloride, di(2-ethylhexyl)phthalate (PVC, 
DEHP) must NOT be used.   
Study drug doses will be administered as a 60-minute 
IV infusion (flow rate of approximately 3.3 mL/min) 
4 weeks apart.  The dosing of ALN-TTR02 in the 
optional cohorts will be once every 4 weeks for the 
first optional cohort and once every 3 or 4 weeks for 
the remaining 4 optional cohorts, at a dose 
previously determined by the SRC to be safe and 
tolerable.  Study drug will be administered via a 
 
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controlled infusion device with an extension set 
containing a 1.2 micron filter supplied by Alnylam or 
designee.  Infusion products containing polyvinyl 
chloride, di(2-ethylhexyl)phthalate (PVC, DEHP) must 
NOT be used.  For patients enrolled in an optional 
cohort evaluating the alternative premedication 
regimen, the flow rate will be approximately 1.1 
mL/min during the first 15 minutes (1/3rd the 
original flow rate) with the remainder of the 
infusion taking place over 55 minutes (at a flow rate 
of approximately 3.3 mL/min) for a total infusion 
time of approximately 70 minutes. 
 
 
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001).  
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001).  
Table 5-1 
Total number of patients to be enrolled = 21 
Changed the total number of patients to be enrolled 
from 21 patients to 27 patients 
 
 
a 
Up to 3 optional cohorts may be included to 
confirm the safety, tolerability, and/or PD effect at 
a specific dose.   
a 
Up to 35 optional cohorts may be included to 
confirm the safety, tolerability, and/or PD effect of 
previously evaluated dose levels, which may 
include evaluation of the original dosing 
regimen (once every 4 weeks), an alternative 
dosing regimen (once every 3 weeks), and/or an 
alternative premedication regimen and infusion 
 
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rate at a specific dose of ALN-TTR02.   
5.7.1:  Dose Escalation 
Procedures 
The initial dose of ALN-TTR02 is 10 µg/kg.  Dose 
escalation to 50, 150, and 300 µg/kg is planned.  The 
dose level of ALN-TTR02 administered to any cohort 
in study ALN-TTR02-002 may not be higher than that 
deemed safe and tolerable in the Phase 1 single-dose 
study of ALN-TTR02 (Study ALN-TTR02-001). 
The initial dose of ALN-TTR02 is 10 µg/kg.  Dose 
escalation to 50, 150, and 300 µg/kg is planned.  The 
dose level of ALN-TTR02 administered to any cohort 
in study ALN-TTR02-002 may not be higher than that 
deemed safe and tolerable in the Phase 1 single-dose 
study of ALN-TTR02 (Study ALN-TTR02-001). 
Figure 5-1 
Footnote a added 
a 
Some optional cohorts may have the second dose 
of ALN-TTR02 administered 3 weeks after the 
first dose. 
5.7.2:  Optional Cohorts 
The optional cohort would be included to further 
confirm the safety and/or PD effect.  If this occurs, the 
IECs will be informed of the expansion.  Up to 
3 optional cohorts of 3 patients each are permitted in 
this study. 
The optional cohort would be included to further 
confirm the safety and/or PD effect of previously 
evaluated dose levels, which may include evaluation 
of the original dosing regimen (once every 4 weeks), 
an alternative dosing regimen (once every 3 weeks), 
and/or to evaluate an alternative premedication 
regimen and infusion rate.  The dosing regimen for 
the first optional cohort will be once every 4 weeks, 
and the dosing regimen for the remaining 4 optional 
cohorts will be once every 3 or 4 weeks.  It is 
anticipated that the first 2 optional cohorts will use 
the original premedication regimen, and the 
remaining 3 optional cohorts may be used to explore 
the alternative premedication regimen and infusion 
rate.  The SRC will review all available safety data 
and make recommendations on dosing and 
premedication regimens prior to dosing of any of 
the optional cohorts.   If this occurs, the IECs will be 
 
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informed of the expansionimplementation of optional 
cohorts.  Up to 3 5 optional cohorts of 3 patients each 
are permitted in this study. 
5.7.3:  Dose-limiting 
Toxicity 
A DLT is defined as: 
• 
Any life-threatening toxicity; 
• 
ALT and AST levels ≥5 × ULN or total bilirubin 
>2.0 mg/dL; 
• 
An infusion reaction that requires hospitalization, 
despite proper premedication; 
• 
Any other toxicity which in the opinion of the SRC 
would have precluded further dosing. 
A DLT is defined as: 
• 
Any life-threatening toxicity; 
• 
ALT and AST levels ≥5 × ULN or total bilirubin 
>2.0 mg/dL; 
• 
An infusion reaction that requires hospitalization, 
despite proper premedication; 
• 
Any other toxicity which in the opinion of the SRC 
would have precluded further dosing. 
6:  Study Visits 
Added language regarding an open-label extension 
study 
An open-label extension study at the recommended 
Phase 3 dose and regimen (as derived from Study 
ALN-TTR02-002) is planned, which will enable the 
patients who enrolled in Study ALN-TTR02-002 to 
receive additional, long-term dosing and safety 
follow-up.  For some of the patients, this may 
preclude the completion of all of the follow-up 
period assessments of Study ALN-TTR02-002 if 
they are deemed eligible to participate in the 
extension study prior to completion of the full follow 
up through Day 208.  Such patients will be followed 
up for a minimum of 28 days after their last dose in 
the current ALN-TTR02-002 study prior to being 
enrolled in the extension study.  The extension study 
 
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will be implemented only after dose escalation is 
completed in Study ALN-TTR02-002, with post 
second dose follow-up through Day 208 in at least 1 
cohort at the highest dose. 
 
 
Screening evaluations are to be performed within 
45 days before receiving the first dose of study drug, as 
indicated in Table 1-1.  Patients determined to be 
eligible based on screening assessments will receive 
treatment (IV infusion of study drug) on Days 0 
(Baseline) and 28 (or date of second dose 
administration in optional cohorts with dosing intervals 
greater than 4 weeks).  Patients will remain 
hospitalized at the study site for at least 24 hours 
following completion of dosing to be observed for 
safety assessments and PK sampling.  Patients will 
return to the study site on Days 2, 7, 10, 14, and 21 for 
follow-up assessments.  In addition, follow-up visits 
after the second dose of study drug (Day 28) will occur 
on Days 30, 35, 38, 42, 49, and 56 (end-of-study).  
Patients will also return to the site for a follow-up visit 
on Days 112 and 208. 
Screening evaluations are to be performed within 
45 days before receiving the first dose of study drug, as 
indicated in Table 1-1 (Appendix 4 provides the 
schedule of assessments for the optional cohort(s) 
administered ALN-TTR02 once every 3 weeks).  
Patients determined to be eligible based on screening 
assessments will receive treatment (IV infusion of 
study drug) on Days 0 (Baseline) and 28 (or date of 
second dose administration in optional cohorts with 
dosing intervals greater than 4 weeks); for patients in 
optional cohorts evaluating the alternative dosing 
regimen (once every 3 weeks), ALN-TTR02 will be 
administered on Days 0 (Baseline) and 21.  Patients 
will remain hospitalized at the study site for at least 24 
hours following completion of dosing to be observed 
for safety assessments and PK sampling.  Patients will 
return to the study site on Days 2, 7, 10, 14, and 21 for 
follow-up assessments.  In addition, follow-up visits 
after the second dose of study drug (Day 28) will occur 
on Days 30, 35, 38, 42, 49, and 56 (end-of-study); 
patients in optional cohorts evaluating the 
alternative dosing regimen (once every 3 weeks) will 
have follow-up visits on Days 21, 22, 23, 28, 31, 35, 
 
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42, 49, and 56.  Patients will also return to the site for a 
follow-up visit on Days 112 and 208. 
6.2:  Pre-Dosing (Day -1 or 
Day 27) 
(Title) Pre-Dosing (Day -1 or Day 27) 
(Title) Pre-Dosing (Day -1 or Day 27; Day -1 or 
Day 20 for optional cohorts dosed once every 
3 weeks) 
 
 
On the day prior to administration of study drug 
(Days -1 and 27), study site personnel will contact the 
patient by phone to discuss the pretreatment medication 
they are to take that evening. 
For those patients receiving the original 
premedication regimen, on the day prior to 
administration of study drug (Days -1 and 27), study 
site personnel will contact the patient by phone to 
discuss the pretreatment medication they are to take 
that evening. 
 
 
On the evening before each dosing, patients are to self-
administer the following medications PO: 8 mg 
dexamethasone or equivalent, 500 mg paracetamol or 
equivalent, an H1 blocker (10 mg cetirizine 
hydroxyzine [25 mg, fexofenadine, or equivalent may 
be substituted if patient does not tolerate cetirizine]), 
and an oral H2 blocker (i.e., ranitidine 150 mg or 
famotidine 20 mg or equivalent). 
On the evening before each dosing, patients are to self-
administer the following medications PO: 8 mg 
dexamethasone or equivalent, 500 mg paracetamol or 
equivalent, an H1 blocker (10 mg cetirizine 
hydroxyzine [25 mg, fexofenadine, or equivalent may 
be substituted if patient does not tolerate cetirizine]), 
and an oral H2 blocker (i.ee.g., ranitidine 150 mg, or 
famotidine 20 mg, or equivalent other H2 blocker). 
Patients in an optional cohort evaluating the 
alternative premedication regimen and infusion rate 
will not receive any premedication the evening prior 
to ALN-TTR02 dosing. 
6.3.1:  Day 0 or Day 28 (+2 
days) 
(Title) Day 0 or Day 28 (+2 days) 
(Title) Day 0 or Day 28 (+2 days); Day 0 or Day 21 
for optional cohorts dosed once every 3 weeks 
6.3.1.1:  Pre-dose 
Patients will undergo the following procedures before 
Patients will undergo the following procedures before 
 
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study drug administration on Day 0 or Day 28: 
study drug administration on Day 0 or Day 28 (Day 0 
or Day 21 for optional cohorts dosed once every 
3 weeks): 
 
 
Note: those parameters marked with an asterisk do not 
have to be reassessed on Days 0 or 28 if measures are 
obtained within 72 hours prior to dosing and meets 
eligibility criteria. 
Note: those parameters marked with an asterisk do not 
have to be reassessed on Days 0 or 28 (Days 0 or 21 
for optional cohorts dosed once every 3 weeks) if 
measures are obtained within 72 hours prior to dosing 
and meets eligibility criteria. 
 
 
• 
Premedicate patient 30 to 60 minutes prior to the 
start of study drug infusion with the following oral 
medications (or equivalent[s]):  
20 mg dexamethasone, 500 mg paracetamol, 10 mg 
cetirizine, and an H2 blocker (e.g. 150 mg 
ranitidine, 20 mg famotidine). 
• 
For patients receiving the original 
premedication regimen, Ppremedicate the patient 
30 to 60 minutes prior to the start of study drug 
infusion with the following oral medications (or 
equivalent[s]):  20 mg dexamethasone, 500 mg 
paracetamol, 10 mg cetirizine, and an H2 blocker 
(e.g. 150 mg ranitidine, 20 mg famotidine).  
Patients in select optional cohorts evaluating the 
alternative premedication regimen and infusion 
rate will receive the following medications (or 
equivalent[s]) at least 60 minutes prior to the 
start of ALN-TTR02 infusion: 
IV dexamethasone 10 mg, PO paracetamol 500 
mg, IV H2 blocker (e.g. ranitidine 50 mg, 
famotidine 20 mg, or equivalent other H2 
blocker dose), and IV H1 blocker (e.g. 
diphenhydramine 50 mg or equivalent other IV 
 
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H1 blocker available at the study site; or 
hydroxyzine or fexofenadine 25 mg PO or 
cetirizine 10 mg PO for any patient who does 
not tolerate IV diphenhydramine or other IV 
H1 blockers). 
6.3.1.2:  Administration of 
Study Drug 
After completion of all pre-dose evaluations and 
procedures, administer study drug as a 60-minute IV 
infusion via a controlled infusion device.   
After completion of all pre-dose evaluations and 
procedures, administer study drug as a 60-minute IV 
infusion (or an approximate 70-minute IV infusion 
for patients in an optional cohort evaluating the 
alternative premedication regimen and infusion 
rate) via a controlled infusion device.   
6.3.1.3:  Post-dose 
Patients will undergo the following procedures after 
study drug administration on Day 0 and Day 28 
(+2 days).   
Patients will undergo the following procedures after 
study drug administration on Day 0 and Day 28 
(+2 days); or Day 0 and Day 21 for optional cohorts 
dosed once every 3 weeks.   
6.3.2:  Day 1 or Day 29 
(Title) Day 1 or Day 29 
Patients will undergo the following procedures on the 
day following dosing with study drug (Days 1 or 29): 
(Title) Day 1 or Day 29; Day 1 or Day 22 for optional 
cohorts dosed once every 3 weeks 
Patients will undergo the following procedures on the 
day following dosing with study drug (Days 1 or 29; or 
Days 1 or 22 for optional cohorts dosed once every 3 
weeks): 
6.3.3:  Day 2 or Day 30 
(Title) Day 2 or Day 30 
Patients will undergo the following procedures on 
Days 2 and 30: 
(Title) Day 2 or Day 30; Day 2 or Day 23 for optional 
cohorts dosed once every 3 weeks 
Patients will undergo the following procedures on 
Days 2 and 30; or Days 2 or 23 for optional cohorts 
dosed once every 3 weeks: 
6.3.4:  Day 7 or Day 35 
(±1 day) 
(Title) Day 7 or Day 35 ±1 day 
 
Patients will undergo the following procedures on the 
(Title) Day 7 or Day 35 ±1 day; or Day 7 or Day 28 
for optional cohorts dosed once every 3 weeks 
Patients will undergo the following procedures on the 
 
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Day 7 and 35 study visits: 
Day 7 and 35 study visits (or Day 7 and 28 for 
optional cohorts dosed once every 3 weeks): 
6.3.5:  Day 10 or Day 38 
(±2 day) 
(Title) Day 10 or Day 38 (±2 day) 
 
Patients will undergo the following procedures on the 
Day 10 and 38 study visits: 
(Title) Day 10 or Day 38 ±2 day; or Day 10 or Day 31 
for optional cohorts dosed once every 3 weeks 
Patients will undergo the following procedures on the 
Day 10 and 38 study visits (or Day 10 and 28 for 
optional cohorts dosed once every 3 weeks): 
6.3.6:  Day 14 or Day 42 
(±3 days) 
(Title) Day 14 or Day 42 (±3 days) 
 
 
Patients will undergo the following procedures on the 
Day 14 and 42 study visits: 
(Title) Day 14 or Day 42 ±3 days; or Day 14 or 
Day 35 for optional cohorts dosed once every 
3 weeks 
Patients will undergo the following procedures on the 
Day 14 and 42 study visits (or Day 14 and 35 for 
optional cohorts dosed once every 3 weeks): 
6.3.7:  Day 21 or Day 49 
(±3 days) 
(Title) Day 21 or Day 49 (±3 days) 
 
 
Patients will undergo the following procedures on the 
Day 21 and 49 study visits: 
(Title) Day 21 or Day 49 ±3 days; or Day 21 or 
Day 42 for optional cohorts dosed once every 
3 weeks 
Patients will undergo the following procedures on the 
Day 21 and 49 study visits (or Day 21 and 42 for 
optional cohorts dosed once every 3 weeks): 
6.6:  Participation in an 
Open-label Extension Study 
Added new section 
An open-label extension study at the recommended 
Phase 3 dose and regimen (as derived from Study 
ALN-TTR02-002) is planned, which will enable the 
patients who enrolled in Study ALN-TTR02-002 to 
receive additional, long-term dosing and safety 
follow-up.  For some of the patients, this may 
preclude the completion of all of the follow-up 
period assessments of Study ALN-TTR02-002 if 
they are deemed eligible to participate in the 
extension study prior to completion of the full follow 
 
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up through Day 208.  Such patients will be followed 
up for a minimum of 28 days after their last dose in 
the current ALN-TTR02-002 study prior to being 
enrolled in the extension study.  The extension study 
will be implemented only after dose escalation is 
completed in Study ALN-TTR02-002, with post 
second dose follow-up through Day 208 in at least 
1 cohort at the highest dose deemed safe. 
7.1:  Demographic Data and 
Medical History 
Patient demographic data will be obtained during 
screening, and a complete medical history will be 
obtained during screening and updated on Days 0 and 
28 as needed.   
Patient demographic data will be obtained during 
screening, and a complete medical history will be 
obtained during screening and updated on Days 0 and 
28 (or Days 0 and 21 for optional cohorts dosed once 
every 3 weeks) as needed.   
7.2.1:  Physical Examination Body weight will be measured at Screening for 
assessment of eligibility, and on the Day 0 and 28 study 
visits.   
Body weight will be measured at Screening for 
assessment of eligibility, and on the Day 0 and 28 (or 
Day 0 and 21 for optional cohorts dosed once every 
3 weeks) study visits.   
7.2.2:  Vital Signs 
Vital signs are to be measured at Screening and the 
Day 2, 14, 30, 42, and 56 (or time of early termination, 
if applicable) study visits and include systolic/diastolic 
blood pressure, pulse rate, respiration rate, and oral 
body temperature.   
Vital signs are to be measured at Screening and the 
Day 2, 14, 30, 42, and 56 (or Days 2, 14, 23, 35, and 
56 for optional cohorts dosed once every 3 weeks; or 
time of early termination, if applicable) study visits and 
include systolic/diastolic blood pressure, pulse rate, 
respiration rate, and oral body temperature.   
 
 
On Days 0 and 28, serial vital signs are to be measured 
within 30 minutes pre-dose, at EOI; and at 
30 (±5) minutes;1, 2, and 3 (±15 minutes) hours; 6, 12, 
and 18 hours (±30 minutes) post-infusion.  On Days 1 
and 29, serial vital signs are to be measured at 24 hours 
On Days 0 and 28 (or Day 21 for optional cohorts 
dosed once every 3 weeks), serial vital signs are to be 
measured within 30 minutes pre-dose, at EOI; and at 
30 (±5) minutes;1, 2, and 3 (±15 minutes) hours; 6, 12, 
and 18 hours (±30 minutes) post-infusion.  On Days 1 
 
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(+30 minutes) post-infusion. 
and 29 (or Day 22 for optional cohorts dosed once 
every 3 weeks), serial vital signs are to be measured at 
24 hours (+30 minutes) post-infusion. 
7.2.4:  Electrocardiogram 
Serial ECGs will be collected in triplicate 30 minutes 
prior to dosing (Days 0 and 28), EOI, and 30 (±5) 
minutes, 2 and 4 (±15 minutes) hours, and on Days 1 
and 29 at 24 (+30 minutes) hours post-infusion. 
Serial ECGs will be collected in triplicate 30 minutes 
prior to dosing (Days 0 and 28 [or Days 0 and 21 for 
optional cohorts dosed once every 3 weeks]), EOI, 
and 30 (±5) minutes, 2 and 4 (±15 minutes) hours, and 
on Days 1 and 29 (or Days 1 and 22 for optional 
cohorts dosed once every 3 weeks) at 
24 (+30 minutes) hours post-infusion. 
 
 
Prior to discharge from the hospital on Days 1 and 29, 
the ECG must be reviewed by the Investigator and the 
results deemed not clinically significant.  
Prior to discharge from the hospital on Days 1 and 29 
(or Days 1 and 22 for optional cohorts dosed once 
every 3 weeks), the ECG must be reviewed by the 
Investigator and the results deemed not clinically 
significant.   
7.2.5:  Pulse Oximetry 
Arterial oxygen saturation will be assessed by serial 
pulse oximetry on Days 0 and 28 within 30 (±5) 
minutes pre-dose; at EOI; at 30 (±5) minutes; at 1, 2, 3 
hours (±15 minutes); and at 6, 12, and 18 hours 
(±15 minutes) post-infusion on Days 0 and 28; and at 
24 hours (+30 minutes) post-infusion on Days 1 and 
29. 
Arterial oxygen saturation will be assessed by serial 
pulse oximetry on Days 0 and 28 (or Days 0 and 21 
for optional cohorts dosed once every 3 weeks) 
within 30 (±5) minutes pre-dose; at EOI; at 
30 (±5) minutes; at 1, 2, 3 hours (±15 minutes); and at 
6, 12, and 18 hours (±15 minutes) post-infusion on 
Days 0 and 28 (or Days 0 and 21 for optional cohorts 
dosed once every 3 weeks); and at 24 hours (+30 
minutes) post-infusion on Days 1 and 29 (or Days 1 
and 22 for optional cohorts dosed once every 3 
weeks). 
7.2.7.1:  Hematology, Serum 
Chemistries, and Urinalysis 
Blood samples for hematology and serum chemistries 
and urine for urinalysis are to be collected at Screening, 
Blood samples for hematology and serum chemistries 
and urine for urinalysis are to be collected at Screening, 
 
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pre-dose on Day 0 (unless the screening evaluations 
were performed within the previous 72 hours) and Day 
28, and on the Day 1, 14, 29, 42, and 56 study visits, or 
at the time of early termination, if applicable. 
pre-dose on Day 0 (unless the screening evaluations 
were performed within the previous 72 hours) and Day 
28 (or Day 21 for optional cohorts dosed once every 
3 weeks), and on the Day 1, 14, 29, 42, and 56 study 
visits (or Days 1, 14, 22, 35, and 56 for optional 
cohorts dosed once every 3 weeks), or at the time of 
early termination, if applicable. 
 
Prior to discharge from the hospital on Days 1 and 29, 
local serum laboratories (specifically, sodium, 
potassium, creatinine, albumin, calcium, glucose, and 
phosphate) must be reviewed by the Investigator and 
the results deemed not clinically significant.   
Prior to discharge from the hospital on Days 1 and 29 
(or Days 1 and 22 for optional cohorts dosed once 
every 3 weeks), local serum laboratories (specifically, 
sodium, potassium, creatinine, albumin, calcium, 
glucose, and phosphate) must be reviewed by the 
Investigator and the results deemed not clinically 
significant.   
 
 
Blood for CRP is to be collected pre-dose (within 10 
minutes) on Days 0 and 28, and at 2 and 6 hours (± 15 
minutes), and 24 hours (± 120 minutes) post-infusion. 
Blood for CRP is to be collected pre-dose (within 10 
minutes) on Days 0 and 28 (or Days 0 and 21 for 
optional cohorts dosed once every 3 weeks), and at 2 
and 6 hours (± 15 minutes), and 24 hours (± 120 
minutes) post-infusion. 
7.2.7.2:  Liver Function 
Tests 
Blood for LFTs is to be collected at Screening, pre-
dose on Day 0 (unless the screening evaluations were 
performed within the previous 72 hours) and Day 28, 
and at the Day 1, 2, 7, 14, 29, 30, 35, 42, and 56 study 
visits, or at the time of early termination, if applicable.   
Blood for LFTs is to be collected at Screening, pre-
dose on Day 0 (unless the screening evaluations were 
performed within the previous 72 hours) and Day 28, 
and at the Day 1, 2, 7, 14, 29, 30, 35, 42, and 56 study 
visits (or Days 1, 2, 7, 14, 22, 23, 28, 35, and 56 for 
optional cohorts dosed once every 3 weeks), or at the 
time of early termination, if applicable.   
 
 
Prior to discharge from the hospital on Days 1 and 29, 
Prior to discharge from the hospital on Days 1 and 29 
 
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local LFTs must be reviewed by the Investigator and 
the results deemed not clinically significant.   
(or Days 1 and 22 for optional cohorts dosed once 
every 3 weeks), local LFTs must be reviewed by the 
Investigator and the results deemed not clinically 
significant. 
7.2.7.4:  Coagulation Studies Blood for coagulation studies is to be collected at 
Screening, pre-dose on Days 0 (unless the screening 
evaluations were performed within the previous 72 
hours) and 28, at the Day 1 and 29 study visits. 
Blood for coagulation studies is to be collected at 
Screening, pre-dose on Days 0 (unless the screening 
evaluations were performed within the previous 72 
hours) and 28 (or Day 21 for optional cohorts dosed 
once every 3 weeks), at the Day 1 and 29 (or Day 1 
and 22 for optional cohorts dosed once every 3 
weeks) study visits. 
7.2.7.5:  Thyroid Function 
Tests 
Blood for thyroid function tests is to be collected at 
Screening, pre-dose on Days 0 (unless the screening 
evaluations were performed within the previous 72 
hours) and 28, and at Day 14, 42, and 56 study visits, 
or at the time of early termination, if applicable.   
Blood for thyroid function tests is to be collected at 
Screening, pre-dose on Days 0 (unless the screening 
evaluations were performed within the previous 72 
hours) and 28 (or Days 0 and 21 for optional cohorts 
dosed once every 3 weeks), and at Day 14, 42, and 56 
study visits (or Days 14, 35, and 56 for optional 
cohorts dosed once every 3 weeks), or at the time of 
early termination, if applicable.   
7.2.7.6:  Complement 
Blood for complement factor Bb, is to be collected pre-
dose (within 10 minutes) on Days 0 and 28, and 30 
(± 5) minutes and 2 (± 15 minutes) and 24 hours (± 120 
minutes) post-infusion.   
Blood for complement factor Bb, is to be collected pre-
dose (within 10 minutes) on Days 0 and 28 (or Days 0 
and 21 for optional cohorts dosed once every 
3 weeks), and 30 (± 5) minutes and 2 (± 15 minutes) 
and 24 hours (± 120 minutes) post-infusion.   
 
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7.2.7.7:  Cytokines 
Blood for cytokine assessment is to be collected on 
Days 0 and 28 pre-dose (within 10 minutes), at 2 (±15 
minutes), and 6 hours (±15 minutes), and 24 hours 
(±120 minutes) post-infusion.   
Blood for cytokine assessment is to be collected pre-
dose (within 10 minutes) on Days 0 and 28 (or Days 0 
and 21 for optional cohorts dosed once every 3 
weeks) pre-dose (within 10 minutes), at 2 (±15 
minutes), and 6 hours (±15 minutes), and 24 hours 
(±120 minutes) post-infusion.   
7.3.1:  Transthyretin 
Protein 
Blood for serum TTR protein levels (WT and mutant) 
is to be collected at Screening, immediately prior 
(within 10 minutes) to the administration of the 
premedications, immediately pre-dose (within 10 
minutes) on Days 0 (Baseline) and 28, and on Days 1, 
2, 7, 10, 14, 21, 29, 30, 35, 38, 42, 49, 56 (end-of-
study), 112, and 208 or at the time of early termination.   
Blood for serum TTR protein levels (WT and mutant) 
is to be collected at Screening, immediately prior 
(within 10 minutes) to the administration of the 
premedications, immediately pre-dose (within 10 
minutes) on Days 0 (Baseline) and 28, and on Days 1, 
2, 7, 10, 14, 21, 29, 30, 35, 38, 42, 49, 56 (end-of-
study), 112, and 208 or at the time of early termination.  
For optional cohorts dosed once every 3 weeks, 
blood for serum TTR protein levels will be collected 
at Screening, immediately prior (within 10 minutes) 
to the administration of the premedications, 
immediately pre-dose (within 10 minutes) on Days 0 
(Baseline) and 21, and on Days 1, 2, 7, 10, 14, 22, 23, 
28, 31, 35, 42, 49, 56 (end-of-study), 112, and 208 or 
at the time of early termination.   
7.3.2:  Transthyretin mRNA 
Blood for serum TTR mRNA is to be collected at 
Screening, immediately prior (within 10 minutes) to the 
administration of the premedications on Days 0 
(Baseline) and 28, and on Days 1, 2, 29, and 30. 
Blood for serum TTR mRNA is to be collected at 
Screening, immediately prior (within 10 minutes) to the 
administration of the premedications on Days 0 
(Baseline) and 28, and on Days 1, 2, 29, and 30.  For 
optional cohorts dosed once every 3 weeks, blood for 
serum TTR mRNA will be collected at Screening 
and on Days 0 (Baseline) and 21, and on Days 1, 2, 
22, and 23. 
 
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7.3.2.1:  Vitamin A and 
Retinol Binding Protein 
Blood for measurements of vitamin A and RBP is to be 
collected at Screening, immediately prior (within 10 
minutes) to the administration of the premedications, 
immediately pre-dose (within 10 minutes) on Days 0 
and 28, and on Days 1, 2, 7, 10, 14, 21, 29, 30, 35, 38, 
42, 49, 56 (end-of-study), 112, and 208 or at the time of 
early termination.   
Blood for measurements of vitamin A and RBP is to be 
collected at Screening, immediately prior (within 10 
minutes) to the administration of the premedications, 
immediately pre-dose (within 10 minutes) on Days 0 
and 28, and on Days 1, 2, 7, 10, 14, 21, 29, 30, 35, 38, 
42, 49, 56 (end-of-study), 112, and 208 or at the time of 
early termination.  For optional cohorts dosed once 
every 3 weeks, blood for measurements of vitamin A 
and RBP will be collected at Screening, immediately 
prior (within 10 minutes) to the administration of 
the premedications, immediately pre-dose (within 
10 minutes) on Days 0 (Baseline) and 21, and on 
Days 1, 2, 7, 10, 14, 22, 23, 28, 31, 35, 42, 49, 56 (end-
of-study), 112, and 208 or at the time of early 
termination.   
7.4.1:  Plasma 
Pharmacokinetics 
Samples will also be collected on Days 7, 14, 21, 35, 
42, 49, 56, 112, and 208 post infusion as well as at the 
ET visit (if applicable).   
Samples will also be collected on Days 7, 14, 21, 35, 
42, 49, 56, 112, and 208 post infusion as well as at the 
ET visit (if applicable); for optional cohorts dosed 
once every 3 weeks, samples will be collected on 
Days 7, 14, 21, 28, 35, 42, 56, 112, and 208 post 
infusion as well as at the ET visit (if applicable). 
7.4.2:  Urine 
Pharmacokinetics 
Urine sample collection times are included in the 
schedule of assessments (see Table 1-1).   
Urine sample collection times are included in the 
schedule of assessments (see Table 1-1 or Table 12-1 
for optional cohorts dosed once every 3 weeks).   
9.1:  Sample Size 
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 21 patients are expected to be 
enrolled.   
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 21 27 patients are expected to be 
enrolled.   
Appendices 
Added Appendix 4 
Appendix 4: 
Schedule of Assessments for 
Optional Cohorts Administered ALN-TTR02 Once 
 
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Every Three Weeks 
Added Table 12-1 
 
 
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Protocol ALN-TTR02-002 
Amendment 2 Change Summary 
A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Infusions of 
ALN-TTR02 in Patients with TTR Amyloidosis 
Changes included in Amendment 2, from Amendment 1 of Protocol ALN-TTR02-002 
(dated 19 June 2012; original protocol dated 04 January 2012), are itemized below and 
detailed in the pages that follow.   
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
   
 
 
 
 
 
 
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.   
 
 
 
 
 
 
 
 
 
  
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Table 1: Premedication and Infusion Rate Changes Proposed in Amendment #2 
Medication 
Current Protocol 
Proposed Amendment #2 
Dexamethasone  
(or equivalent) 
The evening before study drug 
administration, 8 mg PO; self-
administered.   
Thirty to 60 minutes prior to the start of 
study drug infusion, 20 mg PO; 
administered by study site personnel. 
No dexamethasone the evening prior to 
ALN-TTR02 dosing. 
 
To be administered by study site 
personnel at least 60 minutes prior to 
the start of study drug infusion, 10 mg 
IV. 
Paracetamol (or 
equivalent) 
The evening before study drug 
administration, 500 mg PO; self-
administered.   
Thirty to 60 minutes prior to the start of 
study drug infusion, 500 mg PO; 
administered by study site personnel. 
No paracetamol the evening prior to 
ALN-TTR02 dosing. 
 
To be administered by study site 
personnel at least 60 minutes prior to 
the start of study drug infusion, 500 mg 
PO. 
H1 blocker 
Oral cetirizine 10 mg (hydroxyzine 
25 mg, fexofenadine, or equivalent may 
be substituted if patient does not 
tolerate cetirizine).  To be administered: 
 
The evening before study drug 
administration; self-administered.   
Thirty to 60 minutes prior to the start of 
study drug infusion; administered by 
study site personnel. 
Diphenhydramine 50 mg IV (or 
equivalent other IV H1 blocker 
available at the study site).  
Hydroxyzine or fexofenadine 25 mg 
PO or cetirizine 10 mg PO may be 
substituted for any patient who does not 
tolerate IV H1 blockers.   
To be administered by study site 
personnel at least 60 minutes prior to 
the start of study drug infusion. 
(No H1 blocker the evening prior to 
ALN-TTR02 dosing.) 
H2 blocker 
Oral ranitidine 150 mg or famotidine 20 
mg or equivalent other H2 blocker 
dose.  To be administered:  
The evening before study drug 
administration; self-administered.   
Thirty to 60 minutes prior to the start of 
study drug infusion; administered by 
study site personnel. 
Intravenous ranitidine 50 mg, 
famotidine 20 mg or another equivalent 
IV H2 blocker dose.   
To be administered at least 60 minutes 
prior to the start of study drug infusion. 
(No H2 blocker the evening prior to 
ALN-TTR02 dosing.) 
Infusion rate  
Over 60 minutes (~3.3 mL/min) 
Approximately 1.1 mL/min over the 
first 15 minutes, with the remainder of 
the infusion administered at 
3.3 mL/min (total infusion time: 
~70 min). 
 
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Other changes from Amendment 1 to Amendment 2 include: 
 Increased the number of optional cohorts from 3 to 5 to allow for the evaluation 
of once every 3 weeks dosing interval as well as an alternative premedication 
regimen and slower infusion rate.   
 Added an additional schedule of assessments for optional cohorts administered 
ALN-TTR02 once every 3 weeks (refer to Appendix 4). 
 The dosing regimen in the first optional cohort will be once every 4 weeks; in the 
remaining 4 optional cohorts the dosing regimen will be once every 3 or 4 weeks.  
The decision on dosing every 3 or 4 weeks will be made by the SRC based on 
safety.  
 The alternative premedication regimen and infusion rate (detailed in Table 1) will 
be evaluated in up to 3 optional cohorts once the safety of the original 
premedication regimen and infusion rate is further established in the first 
2 optional cohorts.   
 Section 1.3 (Summary of Clinical Data with siRNA-LNPs) of the protocol has 
been simplified and primarily cross-references the IB, Edition 3, which contains 
the updated clinical information. 
 Removed the Principal Investigators’ contact information from the protocol itself.  
This information is included in the Study Procedures Manual. 
 Made minor editorial changes (e.g., corrections of typographical, grammatical, 
and spelling errors as well as formatting changes and changes for consistency); 
these changes are not listed individually. 
 
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Text deleted is indicated by strikeout while text added is indicated by bold font. 
Section 
Prior Text 
Changed To 
Contact Information 
Principal Investigator 
 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
  
 
Principal Investigator 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
  
 
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Section 
Prior Text 
Changed To 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
Synopsis: Design 
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
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Section 
Prior Text 
Changed To 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001). 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001). 
Synopsis: Study Sites 
This study is planned to be conducted at up to 8 study 
centers in Europe and South America. 
This study is planned to be conducted at up to 8 10 
study centers in Europe and South Americaworldwide. 
Synopsis: Dosage, Route of 
Administration and 
Duration of Treatment of 
Investigational Drug 
The optional cohort would be included to further 
confirm the safety and/or pharmacodynamic (PD) 
effect.  If this occurs, the Independent Ethics 
Committees (IECs) will be informed of the expansion.  
Up to 3 optional cohorts are permitted in this study. 
All patients will receive the following premedications 
prior to each dose of ALN-TTR02: 
 
Oral (PO) dexamethasone (8 mg) or equivalent 
administered the evening before dosing and 20 
mg 30 to 60 minutes prior to start of infusion of 
ALN-TTR02; 
 
Oral paracetamol (500 mg) or equivalent the 
evening before dosing and 30 to 60 minutes prior 
to the start of infusion of ALN-TTR02; 
 
Oral H2 blocker (i.e., ranitidine 150 mg or 
famotidine 20 mg or equivalent other H2 blocker 
dose) the evening before dosing and 30 to 60 
minutes prior to start of infusion of ALN-TTR02; 
 
Oral H1 blocker, 10 mg cetirizine or equivalent 
(hydroxyzine 25 mg or fexofenadine may be 
substituted if patient does not tolerate cetirizine) 
the evening before dosing and 30 to 60  minutes 
The oOptional cohort(s) would be included to further 
confirm the safety and/or pharmacodynamic (PD) 
effect of previously evaluated dose levels, which may 
include evaluation of the original dosing regimen 
(once every 4 weeks), an alternative dosing regimen 
(once every 3 weeks), and/or an alternative 
premedication regimen and infusion rate.  The 
dosing regimen for the first optional cohort will be 
once every 4 weeks, and the dosing regimen for the 
remaining 4 optional cohorts will be once every 3 or 
4 weeks.  It is anticipated that the first 2 optional 
cohorts will use the original premedication regimen, 
and the remaining 3 optional cohorts may be used to 
explore the alternative premedication regimen and 
infusion rate.   
The SRC will review all available safety data and 
make recommendations on dosing and 
premedication regimens prior to dosing of any of 
the optional cohorts.  
If this occurs, tThe Independent Ethics Committees 
(IECs) will be informed of the 
expansionimplementation of optional cohorts.  Up to 
3 5 optional cohorts are permitted in this study. 
All patients will receive the followingPatients 
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Section 
Prior Text 
Changed To 
prior to start of infusion of ALN-TTR02; 
Doses of ALN-TTR02 will be administered IV over 
60 minutes by a controlled infusion device.   
receiving the original premedication regimen will be 
administered the followings prior to each dose of 
ALN-TTR02: 
 Oral (PO) dexamethasone (8 mg) or equivalent 
administered the evening before dosing and 
20 mg 30 to 60 minutes prior to start of 
infusion of ALN-TTR02; 
 Oral paracetamol (500 mg) or equivalent the 
evening before dosing and 30 to 60 minutes 
prior to the start of infusion of ALN-TTR02; 
 Oral H2 blocker (i.ee.g., ranitidine 150 mg or 
famotidine 20 mg or equivalent other H2 
blocker dose) the evening before dosing and 
30 to 60 minutes prior to start of infusion of 
ALN-TTR02; and  
 Oral H1 blocker, 10 mg cetirizine or equivalent 
(hydroxyzine 25 mg or fexofenadine may be 
substituted if patient does not tolerate 
cetirizine) the evening before dosing and 
30 to 60  minutes prior to start of infusion of 
ALN-TTR02. 
The alternative premedication regimen that can be 
used in select optional cohorts, as agreed upon by 
the SRC, will be administered prior to each dose of 
ALN-TTR02 and includes the following: 
 Intravenous (IV) dexamethasone (10 mg) or 
equivalent, administered at least 
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Prior Text 
Changed To 
60 minutes prior to the start of infusion of 
ALN-TTR02; 
 Oral paracetamol (500 mg) or equivalent at 
least 60 minutes prior to the start of 
infusion of ALN-TTR02; 
 Intravenous H2 blocker (e.g., ranitidine 
50 mg, famotidine 20 mg, or equivalent 
other H2 blocker dose) at least 60 minutes 
prior to start of infusion of ALN-TTR02; 
and 
 Intravenous H1 blocker: diphenhydramine 
50 mg (or equivalent other IV H1 blocker 
available at the study site) at least 60 
 minutes prior to start of infusion of ALN-
TTR02.  Hydroxyzine or fexofenadine 25 
mg PO or cetirizine 10 mg PO may be 
substituted for any patient who does not 
tolerate IV diphenhydramine or other IV 
H1 blocker. 
For patients receiving the original premedication 
regimen and infusion rate, doses of ALN-TTR02 will 
be administered IV over 60 minutes by a controlled 
infusion device at a flow rate of approximately 3.3 
mL/min.   
For patients enrolled in the optional cohorts 
evaluating the alternative premedication regimen 
and infusion rate, the flow rate of ALN-TTR02 will 
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Section 
Prior Text 
Changed To 
be approximately 1.1 mL/min during the first 
15 minutes (1/3rd the original flow rate) with the 
remainder of the infusion administered at a flow 
rate of 3.3 mL/min for a total infusion time of 
approximately 70 minutes 
Time on Study 
Added language to allow an open-label extension 
study. 
An open-label extension study at the recommended 
Phase 3 dose and regimen (as derived from Study 
ALN-TTR02-002) is planned, which will enable the 
patients who enrolled in Study ALN-TTR02-002 to 
receive additional, long-term dosing and safety 
follow-up.  For some of the patients, this may 
preclude the completion of all of the follow-up 
period assessments of Study ALN-TTR02-002 if 
they are deemed eligible to participate in the 
extension study prior to completion of the full follow 
up through Day 208.  Such patients will be followed 
up for a minimum of 28 days after their last dose in 
the current ALN-TTR02-002 study prior to being 
enrolled in the extension study.  The extension study 
will be implemented only after dose escalation is 
completed in Study ALN-TTR02-002, with post 
second dose follow-up through Day 208 in at least 1 
cohort at the highest dose. 
Synopsis: Sample Size 
Based on the entry criteria and the proposed dose 
escalation scheme, up to 21 patients are expected to be 
enrolled.  Three patients are to be enrolled at each dose 
level and up to 3 optional cohorts of 3 patients each 
will be permitted. 
Based on the entry criteria and the proposed dose 
escalation scheme, up to 21 27 patients are expected to 
be enrolled.  Three patients are to be enrolled at each 
dose level and up to 3 5 optional cohorts of 3 patients 
each will be permitted. 
Synopsis: Dose-Limiting 
3.  An infusion reaction that requires hospitalization, 
3.  An infusion reaction that requires hospitalization, 
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Section 
Prior Text 
Changed To 
Toxicities and Stopping 
Criteria 
despite proper premedication. 
despite proper premedication. 
Table 1.1 
Schedule of Assessments  
Schedule of Assessments for Cohorts Administered 
ALN-TTR02 Once Every Four Weeks 
 
 
Added note 
Note:  The schedule of assessments for optional 
cohorts administered ALN-TTR02 once every 
3 weeks is provided in Appendix 4. 
 
 
v.  Premedications include dexamethasone (8 mg, or 
equivalent), paracetamol (500 mg, or equivalent), H2 
blocker (i.e. 150 mg ranitidine or 20 mg famotidine), 
and H1 blocker (10 mg cetirizine, 25 mg hydroxyzine, 
fexofenadine or equivalent may be substituted) will be 
self-administered per os (PO) the evening before study 
drug administration.  Thirty to 60 minutes prior to the 
start of study drug infusion, dexamethasone (20 mg 
PO, or equivalent), paracetamol (500 mg PO, or 
equivalent), an H2 blocker (PO), and an H1 blocker 
(PO) will be administered by study site personnel. 
v.  Premedications include dexamethasone (8 mg, or 
equivalent), paracetamol (500 mg, or equivalent), H2 
blocker (i.ee.g. 150 mg ranitidine, or 20 mg famotidine, 
or equivalent other H2 blocker dose), and H1 blocker 
(10 mg cetirizine, 25 mg hydroxyzine, fexofenadine or 
equivalent may be substituted) will be self-
administered per os (PO) the evening before study drug 
administration.  Thirty to 60 minutes prior to the start 
of study drug infusion, dexamethasone (20 mg PO, or 
equivalent), paracetamol (500 mg PO, or equivalent), 
an H2 blocker (PO), and an H1 blocker (PO) will be 
administered by study site personnel.  Patients 
enrolled in an optional cohort evaluating the use of 
an alternative premedication regimen, as agreed 
upon by the SRC, will receive the following 
medications at least 60 minutes prior to the start of 
infusion of ALN-TTR02:  dexamethasone (10 mg 
IV, or equivalent), paracetamol (PO 500 mg; or 
equivalent), IV H2 blocker (e.g. ranitidine 50 mg, 
famotidine 20 mg, or equivalent other H2 blocker 
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dose), and IV H1 blocker (e.g., diphenhydramine 50 
mg or equivalent; hydroxyzine or fexofenadine 25 
mg PO or cetirizine 10 mg PO may be substituted 
for any patient who does not tolerate IV 
diphenhydramine or other IV H1 blockers).  These 
patients will not receive any premedications the 
evening prior to ALN-TTR02 dosing. 
 
 
w.  Site personnel are to call patients the day before 
dosing to remind them to take premedications that 
evening (the day before dosing). 
w.  Site personnel are to call patients the day before 
dosing to remind them to take premedications that 
evening (the day before dosing).  This reminder will 
not be needed for patients enrolled in optional 
cohorts evaluating the alternative premedication 
regimen. 
1.3: Summary of Clinical 
Data with siRNA-LNPs 
A Phase 1 multi-centre, randomized, placebo-
controlled, single-blind, single-ascending dose clinical 
study to evaluate the safety, tolerability, PK, and 
pharmacodynamic (PD) of ALN-TTR02 in healthy 
volunteers was approved by MHRA (EUDRACT 
# 2011-005291-42) and has completed dosing.  ALN-
TTR02 was administered as a single 60-minute IV 
infusion to healthy volunteers at the following doses: 
10, 50, 150, 300, and 500 g/kg (4 patients per dose 
level; 3 receiving ALN-TTR02 and 1 receiving 
placebo).  The dose level of ALN-TTR02 administered 
to any cohort in study ALN-TTR02-002 may not be 
higher than that deemed safe and tolerable in the Phase 
1 single-dose study of ALN-TTR02 (Study ALN-
TTR02-001).  Patients will be pre-medicated with 
A Phase 1 multi-centre, randomized, placebo-
controlled, single-blind, single-ascending dose clinical 
study to evaluate the safety, tolerability, PK, and 
pharmacodynamic (PD) of ALN-TTR02 in healthy 
volunteers was approved by MHRA (EUDRACT 
# 2011-005291-42) and has completed dosing.  ALN-
TTR02 was administered as a single 60-minute IV 
infusion to healthy volunteers at the following doses: 
10, 50, 150, 300, and 500 g/kg (4 patients per dose 
level; 3 receiving ALN-TTR02 and 1 receiving 
placebo).  The dose level of ALN-TTR02 administered 
to any cohort in study ALN-TTR02-002 may not be 
higher than that deemed safe and tolerable in the Phase 
1 single-dose study of ALN-TTR02 (Study ALN-
TTR02-001).  Patients will be pre-medicated with 
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dexamethasone, H1 and H2 blockers, and paracetamol 
prior to dosing to minimize the risk of infusion 
reaction.  Preliminary data show that ALN-TTR02 was 
safe and well-tolerated and exhibited robust effects on 
serum TTR levels at the top doses. To date, no stopping 
rules have been met and there have been no early 
discontinuations due to adverse events. Further 
information on the ALN-TTR02-001 Phase 1 study can 
be found in the ALN-TTR02 Investigators Brochure 
and its Expedited Safety Report addendum dated 7 
June 2012. 
 
dexamethasone, H1 and H2 blockers, and paracetamol 
prior to dosing to minimize the risk of infusion 
reaction.  Preliminary data show that ALN-TTR02 was 
safe and well-tolerated and exhibited robust effects on 
serum TTR levels at the top doses. To date, no stopping 
rules have been met and there have been no early 
discontinuations due to adverse events. Further 
information on the ALN-TTR02-001 Phase 1 study can 
be found in the ALN-TTR02 Investigators Brochure 
and its Expedited Safety Report addendum dated 7 
June 2012. 
 
Clinical trials with multiple different RNAi medicinal 
products using local or systemic administration in 
indications including age-related macular degeneration, 
respiratory syncytial virus (RSV) infection, oncology, 
and renal failure have been conducted.28  Alnylam 
currently has 3 ongoing systemic delivery programs in 
the clinic evaluating the safety and efficacy of different 
siRNAs in 2 different LNP formulations.  Specifically, 
the active Phase 1 clinical trials most relevant to ALN-
TTR02 include ALN-PCS02, which uses the same LNP 
formulation, and ALN-TTR01, which uses the same 
siRNA as ALN-TTR02 but in a different LNP 
formulation.  The clinical safety data from the ALN-
PCS02 study in particular provides some reassurance 
regarding the safety of this formulation (common with 
ALN-TTR02) after a single dose.   
Further, cClinical trials with multiple different RNAi 
medicinal products using local or systemic 
administration in indications including age-related 
macular degeneration, respiratory syncytial virus 
(RSV) infection, oncology, and renal failure have been 
conducted.28  Alnylam currently has experience with 
34 ongoing systemic delivery programs in the clinic 
evaluating the safety and efficacy of different siRNAs 
in 2 different LNP formulations, including 1 program 
which employs the same AF-011 formulation as 
ALN-TTR02.  Specifically, the active Phase 1 clinical 
trials most relevant to ALN-TTR02 include 
ALN-PCS02, which uses the same LNP formulation, 
and ALN-TTR01, which uses the same siRNA as 
ALN-TTR02 but in a different LNP formulation.  The 
clinical safety data from the ALN-PCS02 study in 
particular provides some reassurance regarding the 
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safety of this formulation (common with ALN-TTR02) 
after a single dose.  An overview of the safety and 
pharmacological clinical data with these siRNA-
LNPs is included in the ALN-TTR02 Investigator’s 
Brochure (IB), Edition 3, dated 19 October 2012.  
 
s.  
Furthermore, the Phase 1 data with all 4 of the 
siRNA-LNPs have shown that the 
 
 
 
 
 
ALN-PCS02-001 is a Phase 1 multi-centre, 
randomized, placebo-controlled, single-blind, single-
ascending dose clinical study to evaluate the safety, 
tolerability, PK, and PD of ALN-PCS02.  The study is 
ongoing in the United Kingdom (EudraCT #2011-
000581-36).  ALN-PCS02 was administered as a single 
60-minute IV infusion to healthy volunteers with 
elevated low density lipoprotein-C (LDL-C; >3 
mmol/L) at the following doses: 15, 45, 90, 150, and 
250 g/kg (4 patients per dose level; 3 receiving ALN-
PCS02 and 1 receiving placebo).  Patients were pre-
medicated with dexamethasone, H1 and H2 blockers, 
and paracetamol prior to dosing to minimize the risk of 
infusion reaction.  As of December 2011, 24 patients 
(23 males and 1 female) have been enrolled in the 
ALN-PCS02-001 study and 18 patients (17 males and 1 
female) have received ALN-PCS02 in 6 cohorts at 
Importantly, a Phase 1 study with ALN-TTR02 was 
recently completed.  Study ALN-TTR02-001 was a 
multicenter, randomized, placebo-controlled, single-
blind, single-ascending dose clinical study 
conducted in the UK to evaluate the safety, 
tolerability, PK, and pharmacodynamic (PD) in 
healthy volunteers (EudraCT # 2011 005291-42).  
ALN-TTR02 was administered as a single 60-
minute IV infusion to healthy volunteers at the 
following doses: 10, 50, 150, 300, and 500 g/kg (4 
patients per dose level; 3 receiving ALN-TTR02 and 
1 receiving placebo).  Patients were premedicated 
with dexamethasone, H1 and H2 blockers, and 
paracetamol prior to dosing to minimize the risk of 
infusion reaction.  The data show that ALN-TTR02 
was safe and well-tolerated and exhibited robust 
effects on serum TTR levels at doses ≥0.15 mg/kg.  
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doses ranging from 15 to 250 g/kg (including 2 
cohorts dosed at the 250 g/kg dose).   
No dose-limiting toxicities (DLTs) have been reported 
to date, and no patient has prematurely withdrawn from 
the study due to an adverse event (AE).  There was one 
serious adverse event (SAE; bilateral pulmonary 
emboli in a patient with chronic deep vein thrombosis) 
considered unrelated to study drug that occurred in 1 
patient dosed at 45 g/kg.  There have been no 
laboratory AEs related to study drug; specifically, there 
have been no clinically significant changes in liver 
function tests (LFTs), electrolytes, hematology 
parameters, or renal function post-dose.   
Mild self-limiting erythematous skin rashes not 
requiring treatment were seen in 6 patients dosed with 
ALN-PCS02 (1 each at 15 and 45 g/kg, and in 4 
patients at 0.25 mg/kg).  Transient elevations in the 
complement pathway Bb (1.25- to 4.6-fold) have 
occurred in 14 patients 30 minutes post-infusion and 
have been observed across all dose levels and were not 
associated with signs or symptoms.  There have been 
no cytokine or CRP elevations in any of the patients.  
Stopping rules for dose escalation have not been met, 
and the study is ongoing.  
Preliminary PD data with ALN-PCS02 showed an 
approximately 60% reduction in PCSK9 serum protein 
at the 150 and 250 g/kg doses compared with baseline 
Lowering of TTR levels was reversible following 
administration of a single dose, and there were no 
AEs associated with lowering TTR by >90%.  
Further details on this study can be found in the 
ALN-TTR02 IB, Edition 3. 
ALN-PCS02-001 is a Phase 1 multi-centre, 
randomized, placebo-controlled, single-blind, single-
ascending dose clinical study to evaluate the safety, 
tolerability, PK, and PD of ALN-PCS02.  The study is 
ongoing in the United Kingdom (EudraCT #2011-
000581-36).  ALN-PCS02 was administered as a single 
60-minute IV infusion to healthy volunteers with 
elevated low density lipoprotein-C (LDL-C; >3 
mmol/L) at the following doses: 15, 45, 90, 150, and 
250 g/kg (4 patients per dose level; 3 receiving ALN-
PCS02 and 1 receiving placebo).  Patients were pre-
medicated with dexamethasone, H1 and H2 blockers, 
and paracetamol prior to dosing to minimize the risk of 
infusion reaction.  As of December 2011, 24 patients 
(23 males and 1 female) have been enrolled in the 
ALN-PCS02-001 study and 18 patients (17 males and 1 
female) have received ALN-PCS02 in 6 cohorts at 
doses ranging from 15 to 250 g/kg (including 2 
cohorts dosed at the 250 g/kg dose).   
No dose-limiting toxicities (DLTs) have been reported 
to date, and no patient has prematurely withdrawn from 
the study due to an adverse event (AE).  There was one 
serious adverse event (SAE; bilateral pulmonary 
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levels, with a return toward baseline after ~ 28 days. 
The ALN-TTR01 Phase 1 clinical trial (ALN-TTR01-
001) is a multi-centre, randomized, placebo-controlled, 
single-blind, single-ascending dose study to evaluate 
the safety, tolerability, PK and PD of ALN-TTR01.  
The study is ongoing in France, Portugal, Sweden, and 
the United Kingdom (EudraCT # 2009-017383-16).  
The data from this study are relevant to provide the 
effect of TTR lowering using the same siRNA as ALN-
TTR02 albeit in a different formulation.  ALN-TTR01 
was administered as a single 15-minute IV infusion to 
ATTR Stage 1 patients at the following doses: 10, 30, 
100, 200, 400, 700, and 1000 g/kg (4 patients per dose 
level; 3 receiving ALN-TTR01 and 1 receiving 
placebo).  Patients were pre-medicated with a similar 
regimen used for ALN-PCS02.  A total of 32 patients 
were enrolled in this study (including 8 at 1000 g/kg 
and 4 each at 10-700 g/kg), of whom 24 (14 males 
and 10 females) received ALN-TTR01. 
There were no laboratory AEs and no significant 
changes in LFTs, electrolytes, hematology parameters, 
or renal function post-dose.  No clinically significant 
changes in testosterone were observed in males.  No 
drug-related SAEs or DLTs occurred, and no patient 
withdrew prematurely from the study due to an AE.  
There were 5 acute infusion-related reactions (IRRs): 1 
each at 400 and 700 g/kg and 3 at 1000 g/kg, for an 
overall rate of 21%, all of which were mild to moderate 
emboli in a patient with chronic deep vein thrombosis) 
considered unrelated to study drug that occurred in 1 
patient dosed at 45 g/kg.  There have been no 
laboratory AEs related to study drug; specifically, there 
have been no clinically significant changes in liver 
function tests (LFTs), electrolytes, hematology 
parameters, or renal function post-dose.   
Mild self-limiting erythematous skin rashes not 
requiring treatment were seen in 6 patients dosed with 
ALN-PCS02 (1 each at 15 and 45 g/kg, and in 4 
patients at 0.25 mg/kg).  Transient elevations in the 
complement pathway Bb (1.25- to 4.6-fold) have 
occurred in 14 patients 30 minutes post-infusion and 
have been observed across all dose levels and were not 
associated with signs or symptoms.  There have been 
no cytokine or CRP elevations in any of the patients.  
Stopping rules for dose escalation have not been met, 
and the study is ongoing.  
Preliminary PD data with ALN-PCS02 showed an 
approximately 60% reduction in PCSK9 serum protein 
at the 150 and 250 g/kg doses compared with baseline 
levels, with a return toward baseline after ~ 28 days. 
The ALN-TTR01 Phase 1 clinical trial (ALN-TTR01-
001) is a multi-centre, randomized, placebo-controlled, 
single-blind, single-ascending dose study to evaluate 
the safety, tolerability, PK and PD of ALN-TTR01.  
The study is ongoing in France, Portugal, Sweden, and 
the United Kingdom (EudraCT # 2009-017383-16).  
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in severity, and where necessary, responded to 
temporary halting of the infusion followed by 
resumption of the infusion at a slower rate.  Regardless 
of whether a patient experienced an IRR, all study drug 
infusions were successfully administered to 
completion.  Transient elevations of Bb were observed 
across all dose levels, with higher induction seen in 
patients with acute IRRs.  There have been no changes 
in C3, C4, or CH50.  Modest elevations in both IL-6 (2 
to 7-fold over baseline) and CRP (4 to 9-fold over 
baseline) were observed in 3 patients treated at 1000 
g/kg and were not associated with fever or chills.  
Preliminary plasma PK results indicate a generally 
dose-proportional increase in the area under the plasma 
concentration-time curve (AUC) and the observed 
maximum concentration (Cmax) and the long term 
exposure in humans is higher than predicted by the 
preclinical animal studies.   
The PD effects of ALN-TTR01 were assessed through 
serial measurements of serum TTR protein.i  There 
were no significant changes in TTR relative to placebo 
at doses below 1000 g/kg.  At 1000 g/kg (n=5), a 
mean decline in TTR protein of 41% relative to 
baseline and placebo was observed by Day 7 post-dose 
(geometric mean; p=0.02), with recovery to 80% of 
pre-treatment level for the group by Day 28.  In 1 
patient, the serum TTR declined by 81%; this was 
accompanied by a similar decrease in RBP and 
vitamin A, as predicted by preclinical data with ALN-
The data from this study are relevant to provide the 
effect of TTR lowering using the same siRNA as ALN-
TTR02 albeit in a different formulation.  ALN-TTR01 
was administered as a single 15-minute IV infusion to 
ATTR Stage 1 patients at the following doses: 10, 30, 
100, 200, 400, 700, and 1000 g/kg (4 patients per dose 
level; 3 receiving ALN-TTR01 and 1 receiving 
placebo).  Patients were pre-medicated with a similar 
regimen used for ALN-PCS02.  A total of 32 patients 
were enrolled in this study (including 8 at 1000 g/kg 
and 4 each at 10-700 g/kg), of whom 24 (14 males 
and 10 females) received ALN-TTR01. 
There were no laboratory AEs and no significant 
changes in LFTs, electrolytes, hematology parameters, 
or renal function post-dose.  No clinically significant 
changes in testosterone were observed in males.  No 
drug-related SAEs or DLTs occurred, and no patient 
withdrew prematurely from the study due to an AE.  
There were 5 acute infusion-related reactions (IRRs): 1 
each at 400 and 700 g/kg and 3 at 1000 g/kg, for an 
overall rate of 21%, all of which were mild to moderate 
in severity, and where necessary, responded to 
temporary halting of the infusion followed by 
resumption of the infusion at a slower rate.  Regardless 
of whether a patient experienced an IRR, all study drug 
infusions were successfully administered to 
completion.  Transient elevations of Bb were observed 
across all dose levels, with higher induction seen in 
patients with acute IRRs.  There have been no changes 
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TTR01 in NHPs and the known role of TTR in binding 
to and stabilizing circulating RBP.  By Day 70, TTR 
and vitamin A had recovered to approximate pre-
treatment levels without any reported signs or 
symptoms and did not require the need for 
supplementation.  There were no significant changes in 
thyroid hormone levels or thyroid stimulating hormone 
(TSH) in this patient, and no adverse effects associated 
with TTR lowering.  A similar pattern of 
TTR/RBP/vitamin A decrease and recovery without 
any impact on safety was observed in all patients on the 
study treated at 1.0 mg/kg who showed a response to 
ALN-TTR01.  As with the PD data with ALN-PCS02, 
these data show 
 
 and show 
predictable reversibility. 
The safety of giving multiple doses of an siRNA-LNP 
has been established with ALN-VSP02, which uses the 
same first generation LNP formulation as ALN-TTR01 
(see Investigator’s Brochure).  In a Phase 1 study 
performed in advanced cancer patients with liver 
involvement, chronic bi-weekly dosing with doses as 
high as 1.0 mg/kg was safe and well-tolerated using the 
same premedication regimen as ALN-TTR01, with no 
significant dose-dependent effect on liver function.  
Three patients with tumor shrinkage or prolonged 
disease stabilization who have received biweekly doses 
at 0.7-1.0 mg/kg for as long as 12-18 months are 
in C3, C4, or CH50.  Modest elevations in both IL-6 (2 
to 7-fold over baseline) and CRP (4 to 9-fold over 
baseline) were observed in 3 patients treated at 1000 
g/kg and were not associated with fever or chills.  
Preliminary plasma PK results indicate a generally 
dose-proportional increase in the area under the plasma 
concentration-time curve (AUC) and the observed 
maximum concentration (Cmax) and the long term 
exposure in humans is higher than predicted by the 
preclinical animal studies.   
The PD effects of ALN-TTR01 were assessed through 
serial measurements of serum TTR protein.ii  There 
were no significant changes in TTR relative to placebo 
at doses below 1000 g/kg.  At 1000 g/kg (n=5), a 
mean decline in TTR protein of 41% relative to 
baseline and placebo was observed by Day 7 post-dose 
(geometric mean; p=0.02), with recovery to 80% of 
pre-treatment level for the group by Day 28.  In 1 
patient, the serum TTR declined by 81%; this was 
accompanied by a similar decrease in RBP and 
vitamin A, as predicted by preclinical data with ALN-
TTR01 in NHPs and the known role of TTR in binding 
to and stabilizing circulating RBP.  By Day 70, TTR 
and vitamin A had recovered to approximate pre-
treatment levels without any reported signs or 
symptoms and did not require the need for 
supplementation.  There were no significant changes in 
thyroid hormone levels or thyroid stimulating hormone 
(TSH) in this patient, and no adverse effects associated 
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continuing their treatment on an extension study. 
Thus, the nonclinical data with ALN-TTR02 and the 
preliminary clinical data with ALN-PCS02, ALN-
TTR01, and ALN-VSP02 support the proposed early 
phase clinical trials evaluating ascending doses (single 
or multiple) of ALN-TTR02 (studies ALN-TTR02-001 
and ALN-TTR02-002). 
Further information, including preliminary safety and 
efficacy updates from the recently completed Phase 1 
trials of ALN-TTR02 in healthy volunteers and ALN-
PCS02 in healthy volunteers with elevated cholesterol, 
can be found in the Investigator’s Brochure and its 
Expedited Safety Report addendum dated 7 June 2012.  
Alnylam will immediately notify the Principal 
Investigators if any relevant new safety or toxicology 
information becomes available during the study. 
with TTR lowering.  A similar pattern of 
TTR/RBP/vitamin A decrease and recovery without 
any impact on safety was observed in all patients on the 
study treated at 1.0 mg/kg who showed a response to 
ALN-TTR01.  As with the PD data with ALN-PCS02, 
these data show 
 
 and show 
predictable reversibility. 
The safety of giving multiple doses of an siRNA-LNP 
has been established with ALN-VSP02, which uses the 
same first generation LNP formulation as ALN-TTR01 
(see Investigator’s Brochure).  In a Phase 1 study 
performed in advanced cancer patients with liver 
involvement, chronic bi-weekly dosing with doses as 
high as 1.0 mg/kg was safe and well-tolerated using the 
same premedication regimen as ALN-TTR01, with no 
significant dose-dependent effect on liver function.  
Three patients with tumor shrinkage or prolonged 
disease stabilization who have received biweekly doses 
at 0.7-1.0 mg/kg for as long as 12-18 months are 
continuing their treatment on an extension study. 
Thus, the nonclinical data with ALN-TTR02 and the 
preliminary clinical data with ALN-PCS02, ALN-
TTR01, and ALN-VSP02 support the proposed early 
phase clinical trials evaluating ascending doses (single 
or multiple) of ALN-TTR02 (studies ALN-TTR02-001 
and ALN-TTR02-002). 
Further information, including preliminary safety and 
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efficacy updates from the recently completed Phase 1 
trials of ALN-TTR02 in healthy volunteers and ALN-
PCS02 in healthy volunteers with elevated cholesterol, 
can be found in the Investigator’s Brochure and its 
Expedited Safety Report addendum dated 7 June 2012.  
Alnylam will immediately notify the Principal 
Investigators if any relevant new safety or toxicology 
information becomes available during the study. 
1.5:  Dose Selection and 
Rationale 
Two consecutive ALN-TTR02 doses, separated by a 4-
week period, will be administered to patients.  Study 
drug will be administered as a 60-minute IV infusion 
with the following proposed doses for each cohort:  10, 
50, 150, and 300 μg/kg ALN-TTR02.   
Two consecutive ALN-TTR02 doses, separated by a 
4-week period (or a 3-week period in select optional 
cohorts), will be administered to patients.  Study drug 
will be administered as a 60-minute IV infusion with 
the following proposed doses for each of the original 
cohorts:  10, 50, 150, and 300 μg/kg ALN-TTR02.  For 
those patients enrolled in an optional cohort 
evaluating the alternative premedication regimen 
and infusion rate, the study drug will be 
administered IV over approximately 70 minutes. 
 
 
In addition, cumulative safety and tolerability data 
observed in at least 2 patients through at least 96 hours 
post-second dose of the previous cohort will be 
reviewed by the SRC prior to administration of the 
second dose of study drug.  The dose level of ALN-
TTR02 administered to any cohort in study ALN-
TTR02-002 may not be higher than that deemed safe 
and tolerable in the Phase 1 single-dose study of ALN-
TTR02 (Study ALN-TTR02-001). 
In addition, cumulative safety and tolerability data 
observed in at least 2 patients through at least 96 hours 
post-second dose of the previous cohort will be 
reviewed by the SRC prior to administration of the 
second dose of study drug.  The dose level of ALN-
TTR02 administered to any cohort in study ALN-
TTR02-002 may not be higher than that deemed safe 
and tolerable in the Phase 1 single-dose study of ALN-
TTR02 (Study ALN-TTR02-001). 
 
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The optional cohort would be included to further 
confirm the safety and/or PD effect.  If this occurs, the 
Independent Ethics Committees (IECs) will be 
informed of the expansion.  Up to 3 optional cohorts of 
3 patients each are permitted in this study. 
The optional cohort(s) would be included to further 
confirm the safety and/or PD effect of previously 
evaluated dose levels, which may include evaluation 
of the original dosing regimen (once every 4 weeks), 
an alternative dosing regimen (once every 3 weeks), 
and/or an alternative premedication regimen and 
infusion rate.  The dosing regimen for the first 
optional cohort will be once every 4 weeks, and the 
dosing regimen for the remaining 4 optional cohorts 
will be once every 3 or 4 weeks.  It is anticipated 
that the first 2 optional cohorts will use the original 
premedication regimen, and the remaining 
3 optional cohorts may be used to explore the 
alternative premedication regimen and infusion 
rate.  The SRC will review all available safety data 
and make recommendations on dosing and 
premedication regimens prior to dosing of any of 
the optional cohorts.   If this occurs, the Independent 
Ethics Committees (IECs) will be informed of the 
expansionimplementation of optional cohorts.  Up to 
3 5 optional cohorts of 3 patients each are permitted in 
this study. 
1.6.1:  Infusion-Related 
Reactions 
The premedication regimen will include orally (PO) 
administered dexamethasone (or equivalent), 
paracetamol (or equivalent), and H1 and H2 blockers 
(as described in Section 5.5).  The rate of infusion 
(over the course of 1 hour) will also help to reduce the 
potential for acute IRRs.   
The premedication regimen will include orally (PO) 
administered dexamethasone (or equivalent), 
paracetamol (or equivalent), and H1 and H2 blockers 
(as described in Section 5.5).  The infusion rate of 
1 hour or longerinfusion (over the course of 1 hour) 
will also help to reduce the potential for acute IRRs.   
3.1:  Overall Design 
No patients will be a member of more than 1 treatment 
No patients will be a member of more than 1 treatment 
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group.   
group.  An alternative dosing regimen of 2 doses of 
ALN-TTR02 (at a dose previously determined by 
the SRC to be safe and tolerable) separated by 
3 weeks may be evaluated in the optional cohort(s).   
 
 
For patients on all dose levels other than the starting 
dose level of 10 g/kg, prior to receiving the second 
dose the SRC will review the cumulative safety and 
tolerability data of at least 2 patients from the previous 
dose level(s) with at least 96 hours of follow-up after 
receiving a second dose of study drug.  The dose level 
of ALN-TTR02 administered to any cohort in study 
ALN-TTR02-002 may not be higher than that deemed 
safe and tolerable in the Phase 1 single-dose study of 
ALN-TTR02 (Study ALN-TTR02-001). 
For patients on all dose levels other than the starting 
dose level of 10 g/kg, prior to receiving the second 
dose the SRC will review the cumulative safety and 
tolerability data of at least 2 patients from the previous 
dose level(s) with at least 96 hours of follow-up after 
receiving a second dose of study drug.  The dose level 
of ALN-TTR02 administered to any cohort in study 
ALN-TTR02-002 may not be higher than that deemed 
safe and tolerable in the Phase 1 single-dose study of 
ALN-TTR02 (Study ALN-TTR02-001). 
 
 
Eligible patients will undergo further pre-treatment 
assessments (performed on Day 0).  All patients will 
receive oral premedication with dexamethasone (or 
equivalent), paracetamol (or equivalent), and H1 and 
H2 blockers the night before and 30 to 60 minutes prior 
to each dose of ALN-TTR02 to reduce the potential of 
an IRR (see Section 5.5).  On Days 0 and 28, patients 
will receive a single dose of ALN-TTR02 administered 
as a 60-minute IV infusion   
Eligible patients will undergo further pre-treatment 
assessments (performed on Day 0).  All Patients 
receiving the original premedication regimenpatients 
will receive oral premedication with dexamethasone (or 
equivalent), paracetamol (or equivalent), and H1 and 
H2 blockers the night before and 30 to 60 minutes prior 
to each dose of ALN-TTR02 to reduce the potential of 
an IRR (see Section 5.5).  Those patients in an 
optional cohort evaluating the alternative 
premedication regimen, as agreed upon by the SRC, 
will receive IV dexamethasone (or equivalent), oral 
paracetamol (or equivalent), and IV H1 and H2 
blockers at least 60 minutes prior to ALN-TTR02 
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dosing; no premedication will be administered the 
evening prior to dosing.  On Days 0 and 28, patients 
will receive a single dose of ALN-TTR02 administered 
as a 60-minute IV infusion (for cohorts with the 
original premedication regimen and infusion rate), 
or as an approximate 70-minute IV infusion, for 
those patients in an optional cohort evaluating the 
alternative premedication regimen and infusion 
rate.   
4.1:  Eligibility of Patients 
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 21 patients are expected to be 
enrolled.   
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 21 27 patients are expected to be 
enrolled.   
5.5:  Premedication Plan 
Premedication will be administered as follows: 
Patients receiving the original premedication 
regimen will be administered the following 
Premedication will be administered as follows: 
 
 
Added language for an alternative premedication 
regimen and infusion rate. 
 
An alternative premedication regimen and infusion 
rate can be used in select optional cohorts, as agreed 
upon by the SRC.  The dosing regimen for the first 
optional cohort will be once every 4 weeks, and the 
dosing regimen for the remaining 4 optional cohorts 
will be once every 3 or 4 weeks.  It is anticipated 
that the first 2 optional cohorts will use the original 
premedication regimen, and the remaining 
3 optional cohorts may be used to explore the 
alternative premedication regimen and infusion 
rate.  Patients in these cohorts will not receive any 
premedications the evening prior to ALN-TTR02 
dosing.  Prior to each dose of ALN-TTR02, these 
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patients will receive the following premedications: 
 
Intravenous (IV) dexamethasone (10 mg) or 
equivalent, administered at least 60 minutes 
prior to the start of infusion of ALN-TTR02; 
 
Oral paracetamol (500 mg) or equivalent at 
least 60 minutes prior to the start of infusion of 
ALN-TTR02; 
 
Intravenous H2 blocker (e.g., ranitidine 50 mg, 
famotidine 20 mg, or equivalent, other H2 
blocker dose) at least 60 minutes prior to start 
of infusion of ALN-TTR02; and 
 
Intravenous H1 blocker: diphenhydramine 
50 mg (or equivalent other IV H1 blocker 
available at the study site) at least 60 minutes 
prior to start of infusion of ALN-TTR02.  
Hydroxyzine or fexofenadine 25 mg PO or 
cetirizine 10 mg PO may be substituted for any 
patient who does not tolerate IV 
diphenhydramine or other IV H1 blockers. 
5.6:  Dose, Route, and 
Schedule of Study Drug 
Administration 
Study drug doses will be administered as a 60-minute 
IV infusion 4 weeks apart.  Study drug will be 
administered via a controlled infusion device with an 
extension set containing a 1.2 micron filter supplied by 
Alnylam or designee.  Infusion products containing 
polyvinyl chloride, di(2-ethylhexyl)phthalate (PVC, 
DEHP) must NOT be used.   
Study drug doses will be administered as a 60-minute 
IV infusion (flow rate of approximately 3.3 mL/min) 
4 weeks apart.  The dosing of ALN-TTR02 in the 
optional cohorts will be once every 4 weeks for the 
first optional cohort and once every 3 or 4 weeks for 
the remaining 4 optional cohorts, at a dose 
previously determined by the SRC to be safe and 
tolerable.  Study drug will be administered via a 
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controlled infusion device with an extension set 
containing a 1.2 micron filter supplied by Alnylam or 
designee.  Infusion products containing polyvinyl 
chloride, di(2-ethylhexyl)phthalate (PVC, DEHP) must 
NOT be used.  For patients enrolled in an optional 
cohort evaluating the alternative premedication 
regimen, the flow rate will be approximately 1.1 
mL/min during the first 15 minutes (1/3rd the 
original flow rate) with the remainder of the 
infusion taking place over 55 minutes (at a flow rate 
of approximately 3.3 mL/min) for a total infusion 
time of approximately 70 minutes. 
 
 
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001).  
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001).  
Table 5-1 
Total number of patients to be enrolled = 21 
Changed the total number of patients to be enrolled 
from 21 patients to 27 patients 
 
 
a 
Up to 3 optional cohorts may be included to 
confirm the safety, tolerability, and/or PD effect at 
a specific dose.   
a 
Up to 35 optional cohorts may be included to 
confirm the safety, tolerability, and/or PD effect of 
previously evaluated dose levels, which may 
include evaluation of the original dosing 
regimen (once every 4 weeks), an alternative 
dosing regimen (once every 3 weeks), and/or an 
alternative premedication regimen and infusion 
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rate at a specific dose of ALN-TTR02.   
5.7.1:  Dose Escalation 
Procedures 
The initial dose of ALN-TTR02 is 10 g/kg.  Dose 
escalation to 50, 150, and 300 g/kg is planned.  The 
dose level of ALN-TTR02 administered to any cohort 
in study ALN-TTR02-002 may not be higher than that 
deemed safe and tolerable in the Phase 1 single-dose 
study of ALN-TTR02 (Study ALN-TTR02-001). 
The initial dose of ALN-TTR02 is 10 g/kg.  Dose 
escalation to 50, 150, and 300 g/kg is planned.  The 
dose level of ALN-TTR02 administered to any cohort 
in study ALN-TTR02-002 may not be higher than that 
deemed safe and tolerable in the Phase 1 single-dose 
study of ALN-TTR02 (Study ALN-TTR02-001). 
Figure 5-1 
Footnote a added 
a 
Some optional cohorts may have the second dose 
of ALN-TTR02 administered 3 weeks after the 
first dose. 
5.7.2:  Optional Cohorts 
The optional cohort would be included to further 
confirm the safety and/or PD effect.  If this occurs, the 
IECs will be informed of the expansion.  Up to 
3 optional cohorts of 3 patients each are permitted in 
this study. 
The optional cohort would be included to further 
confirm the safety and/or PD effect of previously 
evaluated dose levels, which may include evaluation 
of the original dosing regimen (once every 4 weeks), 
an alternative dosing regimen (once every 3 weeks), 
and/or to evaluate an alternative premedication 
regimen and infusion rate.  The dosing regimen for 
the first optional cohort will be once every 4 weeks, 
and the dosing regimen for the remaining 4 optional 
cohorts will be once every 3 or 4 weeks.  It is 
anticipated that the first 2 optional cohorts will use 
the original premedication regimen, and the 
remaining 3 optional cohorts may be used to explore 
the alternative premedication regimen and infusion 
rate.  The SRC will review all available safety data 
and make recommendations on dosing and 
premedication regimens prior to dosing of any of 
the optional cohorts.   If this occurs, the IECs will be 
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informed of the expansionimplementation of optional 
cohorts.  Up to 3 5 optional cohorts of 3 patients each 
are permitted in this study. 
5.7.3:  Dose-limiting 
Toxicity 
A DLT is defined as: 
 
Any life-threatening toxicity; 
 
ALT and AST levels ≥5 × ULN or total bilirubin 
>2.0 mg/dL; 
 
An infusion reaction that requires hospitalization, 
despite proper premedication; 
 
Any other toxicity which in the opinion of the SRC 
would have precluded further dosing. 
A DLT is defined as: 
 
Any life-threatening toxicity; 
 
ALT and AST levels ≥5 × ULN or total bilirubin 
>2.0 mg/dL; 
 
An infusion reaction that requires hospitalization, 
despite proper premedication; 
 
Any other toxicity which in the opinion of the SRC 
would have precluded further dosing. 
6:  Study Visits 
Added language regarding an open-label extension 
study 
An open-label extension study at the recommended 
Phase 3 dose and regimen (as derived from Study 
ALN-TTR02-002) is planned, which will enable the 
patients who enrolled in Study ALN-TTR02-002 to 
receive additional, long-term dosing and safety 
follow-up.  For some of the patients, this may 
preclude the completion of all of the follow-up 
period assessments of Study ALN-TTR02-002 if 
they are deemed eligible to participate in the 
extension study prior to completion of the full follow 
up through Day 208.  Such patients will be followed 
up for a minimum of 28 days after their last dose in 
the current ALN-TTR02-002 study prior to being 
enrolled in the extension study.  The extension study 
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will be implemented only after dose escalation is 
completed in Study ALN-TTR02-002, with post 
second dose follow-up through Day 208 in at least 1 
cohort at the highest dose. 
 
 
Screening evaluations are to be performed within 
45 days before receiving the first dose of study drug, as 
indicated in Table 1-1.  Patients determined to be 
eligible based on screening assessments will receive 
treatment (IV infusion of study drug) on Days 0 
(Baseline) and 28 (or date of second dose 
administration in optional cohorts with dosing intervals 
greater than 4 weeks).  Patients will remain 
hospitalized at the study site for at least 24 hours 
following completion of dosing to be observed for 
safety assessments and PK sampling.  Patients will 
return to the study site on Days 2, 7, 10, 14, and 21 for 
follow-up assessments.  In addition, follow-up visits 
after the second dose of study drug (Day 28) will occur 
on Days 30, 35, 38, 42, 49, and 56 (end-of-study).  
Patients will also return to the site for a follow-up visit 
on Days 112 and 208. 
Screening evaluations are to be performed within 
45 days before receiving the first dose of study drug, as 
indicated in Table 1-1 (Appendix 4 provides the 
schedule of assessments for the optional cohort(s) 
administered ALN-TTR02 once every 3 weeks).  
Patients determined to be eligible based on screening 
assessments will receive treatment (IV infusion of 
study drug) on Days 0 (Baseline) and 28 (or date of 
second dose administration in optional cohorts with 
dosing intervals greater than 4 weeks); for patients in 
optional cohorts evaluating the alternative dosing 
regimen (once every 3 weeks), ALN-TTR02 will be 
administered on Days 0 (Baseline) and 21.  Patients 
will remain hospitalized at the study site for at least 24 
hours following completion of dosing to be observed 
for safety assessments and PK sampling.  Patients will 
return to the study site on Days 2, 7, 10, 14, and 21 for 
follow-up assessments.  In addition, follow-up visits 
after the second dose of study drug (Day 28) will occur 
on Days 30, 35, 38, 42, 49, and 56 (end-of-study); 
patients in optional cohorts evaluating the 
alternative dosing regimen (once every 3 weeks) will 
have follow-up visits on Days 21, 22, 23, 28, 31, 35, 
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42, 49, and 56.  Patients will also return to the site for a 
follow-up visit on Days 112 and 208. 
6.2:  Pre-Dosing (Day -1 or 
Day 27) 
(Title) Pre-Dosing (Day -1 or Day 27) 
(Title) Pre-Dosing (Day -1 or Day 27; Day -1 or 
Day 20 for optional cohorts dosed once every 
3 weeks) 
 
 
On the day prior to administration of study drug 
(Days -1 and 27), study site personnel will contact the 
patient by phone to discuss the pretreatment medication 
they are to take that evening. 
For those patients receiving the original 
premedication regimen, on the day prior to 
administration of study drug (Days -1 and 27), study 
site personnel will contact the patient by phone to 
discuss the pretreatment medication they are to take 
that evening. 
 
 
On the evening before each dosing, patients are to self-
administer the following medications PO: 8 mg 
dexamethasone or equivalent, 500 mg paracetamol or 
equivalent, an H1 blocker (10 mg cetirizine 
hydroxyzine [25 mg, fexofenadine, or equivalent may 
be substituted if patient does not tolerate cetirizine]), 
and an oral H2 blocker (i.e., ranitidine 150 mg or 
famotidine 20 mg or equivalent). 
On the evening before each dosing, patients are to self-
administer the following medications PO: 8 mg 
dexamethasone or equivalent, 500 mg paracetamol or 
equivalent, an H1 blocker (10 mg cetirizine 
hydroxyzine [25 mg, fexofenadine, or equivalent may 
be substituted if patient does not tolerate cetirizine]), 
and an oral H2 blocker (i.ee.g., ranitidine 150 mg, or 
famotidine 20 mg, or equivalent other H2 blocker). 
Patients in an optional cohort evaluating the 
alternative premedication regimen and infusion rate 
will not receive any premedication the evening prior 
to ALN-TTR02 dosing. 
6.3.1:  Day 0 or Day 28 (+2 
days) 
(Title) Day 0 or Day 28 (+2 days) 
(Title) Day 0 or Day 28 (+2 days); Day 0 or Day 21 
for optional cohorts dosed once every 3 weeks 
6.3.1.1:  Pre-dose 
Patients will undergo the following procedures before 
Patients will undergo the following procedures before 
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study drug administration on Day 0 or Day 28: 
study drug administration on Day 0 or Day 28 (Day 0 
or Day 21 for optional cohorts dosed once every 
3 weeks): 
 
 
Note: those parameters marked with an asterisk do not 
have to be reassessed on Days 0 or 28 if measures are 
obtained within 72 hours prior to dosing and meets 
eligibility criteria. 
Note: those parameters marked with an asterisk do not 
have to be reassessed on Days 0 or 28 (Days 0 or 21 
for optional cohorts dosed once every 3 weeks) if 
measures are obtained within 72 hours prior to dosing 
and meets eligibility criteria. 
 
 
 
Premedicate patient 30 to 60 minutes prior to the 
start of study drug infusion with the following oral 
medications (or equivalent[s]):  
20 mg dexamethasone, 500 mg paracetamol, 10 mg 
cetirizine, and an H2 blocker (e.g. 150 mg 
ranitidine, 20 mg famotidine). 
 
For patients receiving the original 
premedication regimen, Ppremedicate the patient 
30 to 60 minutes prior to the start of study drug 
infusion with the following oral medications (or 
equivalent[s]):  20 mg dexamethasone, 500 mg 
paracetamol, 10 mg cetirizine, and an H2 blocker 
(e.g. 150 mg ranitidine, 20 mg famotidine).  
Patients in select optional cohorts evaluating the 
alternative premedication regimen and infusion 
rate will receive the following medications (or 
equivalent[s]) at least 60 minutes prior to the 
start of ALN-TTR02 infusion: 
IV dexamethasone 10 mg, PO paracetamol 500 
mg, IV H2 blocker (e.g. ranitidine 50 mg, 
famotidine 20 mg, or equivalent other H2 
blocker dose), and IV H1 blocker (e.g. 
diphenhydramine 50 mg or equivalent other IV 
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H1 blocker available at the study site; or 
hydroxyzine or fexofenadine 25 mg PO or 
cetirizine 10 mg PO for any patient who does 
not tolerate IV diphenhydramine or other IV 
H1 blockers). 
6.3.1.2:  Administration of 
Study Drug 
After completion of all pre-dose evaluations and 
procedures, administer study drug as a 60-minute IV 
infusion via a controlled infusion device.   
After completion of all pre-dose evaluations and 
procedures, administer study drug as a 60-minute IV 
infusion (or an approximate 70-minute IV infusion 
for patients in an optional cohort evaluating the 
alternative premedication regimen and infusion 
rate) via a controlled infusion device.   
6.3.1.3:  Post-dose 
Patients will undergo the following procedures after 
study drug administration on Day 0 and Day 28 
(+2 days).   
Patients will undergo the following procedures after 
study drug administration on Day 0 and Day 28 
(+2 days); or Day 0 and Day 21 for optional cohorts 
dosed once every 3 weeks.   
6.3.2:  Day 1 or Day 29 
(Title) Day 1 or Day 29 
Patients will undergo the following procedures on the 
day following dosing with study drug (Days 1 or 29): 
(Title) Day 1 or Day 29; Day 1 or Day 22 for optional 
cohorts dosed once every 3 weeks 
Patients will undergo the following procedures on the 
day following dosing with study drug (Days 1 or 29; or 
Days 1 or 22 for optional cohorts dosed once every 3 
weeks): 
6.3.3:  Day 2 or Day 30 
(Title) Day 2 or Day 30 
Patients will undergo the following procedures on 
Days 2 and 30: 
(Title) Day 2 or Day 30; Day 2 or Day 23 for optional 
cohorts dosed once every 3 weeks 
Patients will undergo the following procedures on 
Days 2 and 30; or Days 2 or 23 for optional cohorts 
dosed once every 3 weeks: 
6.3.4:  Day 7 or Day 35 
(±1 day) 
(Title) Day 7 or Day 35 ±1 day 
 
Patients will undergo the following procedures on the 
(Title) Day 7 or Day 35 ±1 day; or Day 7 or Day 28 
for optional cohorts dosed once every 3 weeks 
Patients will undergo the following procedures on the 
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Day 7 and 35 study visits: 
Day 7 and 35 study visits (or Day 7 and 28 for 
optional cohorts dosed once every 3 weeks): 
6.3.5:  Day 10 or Day 38 
(±2 day) 
(Title) Day 10 or Day 38 (±2 day) 
 
Patients will undergo the following procedures on the 
Day 10 and 38 study visits: 
(Title) Day 10 or Day 38 ±2 day; or Day 10 or Day 31 
for optional cohorts dosed once every 3 weeks 
Patients will undergo the following procedures on the 
Day 10 and 38 study visits (or Day 10 and 28 for 
optional cohorts dosed once every 3 weeks): 
6.3.6:  Day 14 or Day 42 
(±3 days) 
(Title) Day 14 or Day 42 (±3 days) 
 
 
Patients will undergo the following procedures on the 
Day 14 and 42 study visits: 
(Title) Day 14 or Day 42 ±3 days; or Day 14 or 
Day 35 for optional cohorts dosed once every 
3 weeks 
Patients will undergo the following procedures on the 
Day 14 and 42 study visits (or Day 14 and 35 for 
optional cohorts dosed once every 3 weeks): 
6.3.7:  Day 21 or Day 49 
(±3 days) 
(Title) Day 21 or Day 49 (±3 days) 
 
 
Patients will undergo the following procedures on the 
Day 21 and 49 study visits: 
(Title) Day 21 or Day 49 ±3 days; or Day 21 or 
Day 42 for optional cohorts dosed once every 
3 weeks 
Patients will undergo the following procedures on the 
Day 21 and 49 study visits (or Day 21 and 42 for 
optional cohorts dosed once every 3 weeks): 
6.6:  Participation in an 
Open-label Extension Study 
Added new section 
An open-label extension study at the recommended 
Phase 3 dose and regimen (as derived from Study 
ALN-TTR02-002) is planned, which will enable the 
patients who enrolled in Study ALN-TTR02-002 to 
receive additional, long-term dosing and safety 
follow-up.  For some of the patients, this may 
preclude the completion of all of the follow-up 
period assessments of Study ALN-TTR02-002 if 
they are deemed eligible to participate in the 
extension study prior to completion of the full follow 
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up through Day 208.  Such patients will be followed 
up for a minimum of 28 days after their last dose in 
the current ALN-TTR02-002 study prior to being 
enrolled in the extension study.  The extension study 
will be implemented only after dose escalation is 
completed in Study ALN-TTR02-002, with post 
second dose follow-up through Day 208 in at least 
1 cohort at the highest dose deemed safe. 
7.1:  Demographic Data and 
Medical History 
Patient demographic data will be obtained during 
screening, and a complete medical history will be 
obtained during screening and updated on Days 0 and 
28 as needed.   
Patient demographic data will be obtained during 
screening, and a complete medical history will be 
obtained during screening and updated on Days 0 and 
28 (or Days 0 and 21 for optional cohorts dosed once 
every 3 weeks) as needed.   
7.2.1:  Physical Examination Body weight will be measured at Screening for 
assessment of eligibility, and on the Day 0 and 28 study 
visits.   
Body weight will be measured at Screening for 
assessment of eligibility, and on the Day 0 and 28 (or 
Day 0 and 21 for optional cohorts dosed once every 
3 weeks) study visits.   
7.2.2:  Vital Signs 
Vital signs are to be measured at Screening and the 
Day 2, 14, 30, 42, and 56 (or time of early termination, 
if applicable) study visits and include systolic/diastolic 
blood pressure, pulse rate, respiration rate, and oral 
body temperature.   
Vital signs are to be measured at Screening and the 
Day 2, 14, 30, 42, and 56 (or Days 2, 14, 23, 35, and 
56 for optional cohorts dosed once every 3 weeks; or 
time of early termination, if applicable) study visits and 
include systolic/diastolic blood pressure, pulse rate, 
respiration rate, and oral body temperature.   
 
 
On Days 0 and 28, serial vital signs are to be measured 
within 30 minutes pre-dose, at EOI; and at 
30 (5) minutes;1, 2, and 3 (±15 minutes) hours; 6, 12, 
and 18 hours (30 minutes) post-infusion.  On Days 1 
and 29, serial vital signs are to be measured at 24 hours 
On Days 0 and 28 (or Day 21 for optional cohorts 
dosed once every 3 weeks), serial vital signs are to be 
measured within 30 minutes pre-dose, at EOI; and at 
30 (5) minutes;1, 2, and 3 (±15 minutes) hours; 6, 12, 
and 18 hours (30 minutes) post-infusion.  On Days 1 
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(+30 minutes) post-infusion. 
and 29 (or Day 22 for optional cohorts dosed once 
every 3 weeks), serial vital signs are to be measured at 
24 hours (+30 minutes) post-infusion. 
7.2.4:  Electrocardiogram 
Serial ECGs will be collected in triplicate 30 minutes 
prior to dosing (Days 0 and 28), EOI, and 30 (±5) 
minutes, 2 and 4 (±15 minutes) hours, and on Days 1 
and 29 at 24 (+30 minutes) hours post-infusion. 
Serial ECGs will be collected in triplicate 30 minutes 
prior to dosing (Days 0 and 28 [or Days 0 and 21 for 
optional cohorts dosed once every 3 weeks]), EOI, 
and 30 (±5) minutes, 2 and 4 (±15 minutes) hours, and 
on Days 1 and 29 (or Days 1 and 22 for optional 
cohorts dosed once every 3 weeks) at 
24 (+30 minutes) hours post-infusion. 
 
 
Prior to discharge from the hospital on Days 1 and 29, 
the ECG must be reviewed by the Investigator and the 
results deemed not clinically significant.  
Prior to discharge from the hospital on Days 1 and 29 
(or Days 1 and 22 for optional cohorts dosed once 
every 3 weeks), the ECG must be reviewed by the 
Investigator and the results deemed not clinically 
significant.   
7.2.5:  Pulse Oximetry 
Arterial oxygen saturation will be assessed by serial 
pulse oximetry on Days 0 and 28 within 30 (±5) 
minutes pre-dose; at EOI; at 30 (5) minutes; at 1, 2, 3 
hours (±15 minutes); and at 6, 12, and 18 hours 
(15 minutes) post-infusion on Days 0 and 28; and at 
24 hours (+30 minutes) post-infusion on Days 1 and 
29. 
Arterial oxygen saturation will be assessed by serial 
pulse oximetry on Days 0 and 28 (or Days 0 and 21 
for optional cohorts dosed once every 3 weeks) 
within 30 (±5) minutes pre-dose; at EOI; at 
30 (5) minutes; at 1, 2, 3 hours (±15 minutes); and at 
6, 12, and 18 hours (15 minutes) post-infusion on 
Days 0 and 28 (or Days 0 and 21 for optional cohorts 
dosed once every 3 weeks); and at 24 hours (+30 
minutes) post-infusion on Days 1 and 29 (or Days 1 
and 22 for optional cohorts dosed once every 3 
weeks). 
7.2.7.1:  Hematology, Serum 
Chemistries, and Urinalysis 
Blood samples for hematology and serum chemistries 
and urine for urinalysis are to be collected at Screening, 
Blood samples for hematology and serum chemistries 
and urine for urinalysis are to be collected at Screening, 
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pre-dose on Day 0 (unless the screening evaluations 
were performed within the previous 72 hours) and Day 
28, and on the Day 1, 14, 29, 42, and 56 study visits, or 
at the time of early termination, if applicable. 
pre-dose on Day 0 (unless the screening evaluations 
were performed within the previous 72 hours) and Day 
28 (or Day 21 for optional cohorts dosed once every 
3 weeks), and on the Day 1, 14, 29, 42, and 56 study 
visits (or Days 1, 14, 22, 35, and 56 for optional 
cohorts dosed once every 3 weeks), or at the time of 
early termination, if applicable. 
 
Prior to discharge from the hospital on Days 1 and 29, 
local serum laboratories (specifically, sodium, 
potassium, creatinine, albumin, calcium, glucose, and 
phosphate) must be reviewed by the Investigator and 
the results deemed not clinically significant.   
Prior to discharge from the hospital on Days 1 and 29 
(or Days 1 and 22 for optional cohorts dosed once 
every 3 weeks), local serum laboratories (specifically, 
sodium, potassium, creatinine, albumin, calcium, 
glucose, and phosphate) must be reviewed by the 
Investigator and the results deemed not clinically 
significant.   
 
 
Blood for CRP is to be collected pre-dose (within 10 
minutes) on Days 0 and 28, and at 2 and 6 hours ( 15 
minutes), and 24 hours ( 120 minutes) post-infusion. 
Blood for CRP is to be collected pre-dose (within 10 
minutes) on Days 0 and 28 (or Days 0 and 21 for 
optional cohorts dosed once every 3 weeks), and at 2 
and 6 hours ( 15 minutes), and 24 hours ( 120 
minutes) post-infusion. 
7.2.7.2:  Liver Function 
Tests 
Blood for LFTs is to be collected at Screening, pre-
dose on Day 0 (unless the screening evaluations were 
performed within the previous 72 hours) and Day 28, 
and at the Day 1, 2, 7, 14, 29, 30, 35, 42, and 56 study 
visits, or at the time of early termination, if applicable.   
Blood for LFTs is to be collected at Screening, pre-
dose on Day 0 (unless the screening evaluations were 
performed within the previous 72 hours) and Day 28, 
and at the Day 1, 2, 7, 14, 29, 30, 35, 42, and 56 study 
visits (or Days 1, 2, 7, 14, 22, 23, 28, 35, and 56 for 
optional cohorts dosed once every 3 weeks), or at the 
time of early termination, if applicable.   
 
 
Prior to discharge from the hospital on Days 1 and 29, 
Prior to discharge from the hospital on Days 1 and 29 
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Changed To 
local LFTs must be reviewed by the Investigator and 
the results deemed not clinically significant.   
(or Days 1 and 22 for optional cohorts dosed once 
every 3 weeks), local LFTs must be reviewed by the 
Investigator and the results deemed not clinically 
significant. 
7.2.7.4:  Coagulation Studies Blood for coagulation studies is to be collected at 
Screening, pre-dose on Days 0 (unless the screening 
evaluations were performed within the previous 72 
hours) and 28, at the Day 1 and 29 study visits. 
Blood for coagulation studies is to be collected at 
Screening, pre-dose on Days 0 (unless the screening 
evaluations were performed within the previous 72 
hours) and 28 (or Day 21 for optional cohorts dosed 
once every 3 weeks), at the Day 1 and 29 (or Day 1 
and 22 for optional cohorts dosed once every 3 
weeks) study visits. 
7.2.7.5:  Thyroid Function 
Tests 
Blood for thyroid function tests is to be collected at 
Screening, pre-dose on Days 0 (unless the screening 
evaluations were performed within the previous 72 
hours) and 28, and at Day 14, 42, and 56 study visits, 
or at the time of early termination, if applicable.   
Blood for thyroid function tests is to be collected at 
Screening, pre-dose on Days 0 (unless the screening 
evaluations were performed within the previous 72 
hours) and 28 (or Days 0 and 21 for optional cohorts 
dosed once every 3 weeks), and at Day 14, 42, and 56 
study visits (or Days 14, 35, and 56 for optional 
cohorts dosed once every 3 weeks), or at the time of 
early termination, if applicable.   
7.2.7.6:  Complement 
Blood for complement factor Bb, is to be collected pre-
dose (within 10 minutes) on Days 0 and 28, and 30 
( 5) minutes and 2 ( 15 minutes) and 24 hours ( 120 
minutes) post-infusion.   
Blood for complement factor Bb, is to be collected pre-
dose (within 10 minutes) on Days 0 and 28 (or Days 0 
and 21 for optional cohorts dosed once every 
3 weeks), and 30 ( 5) minutes and 2 ( 15 minutes) 
and 24 hours ( 120 minutes) post-infusion.   
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7.2.7.7:  Cytokines 
Blood for cytokine assessment is to be collected on 
Days 0 and 28 pre-dose (within 10 minutes), at 2 (15 
minutes), and 6 hours (15 minutes), and 24 hours 
(120 minutes) post-infusion.   
Blood for cytokine assessment is to be collected pre-
dose (within 10 minutes) on Days 0 and 28 (or Days 0 
and 21 for optional cohorts dosed once every 3 
weeks) pre-dose (within 10 minutes), at 2 (15 
minutes), and 6 hours (15 minutes), and 24 hours 
(120 minutes) post-infusion.   
7.3.1:  Transthyretin 
Protein 
Blood for serum TTR protein levels (WT and mutant) 
is to be collected at Screening, immediately prior 
(within 10 minutes) to the administration of the 
premedications, immediately pre-dose (within 10 
minutes) on Days 0 (Baseline) and 28, and on Days 1, 
2, 7, 10, 14, 21, 29, 30, 35, 38, 42, 49, 56 (end-of-
study), 112, and 208 or at the time of early termination.   
Blood for serum TTR protein levels (WT and mutant) 
is to be collected at Screening, immediately prior 
(within 10 minutes) to the administration of the 
premedications, immediately pre-dose (within 10 
minutes) on Days 0 (Baseline) and 28, and on Days 1, 
2, 7, 10, 14, 21, 29, 30, 35, 38, 42, 49, 56 (end-of-
study), 112, and 208 or at the time of early termination.  
For optional cohorts dosed once every 3 weeks, 
blood for serum TTR protein levels will be collected 
at Screening, immediately prior (within 10 minutes) 
to the administration of the premedications, 
immediately pre-dose (within 10 minutes) on Days 0 
(Baseline) and 21, and on Days 1, 2, 7, 10, 14, 22, 23, 
28, 31, 35, 42, 49, 56 (end-of-study), 112, and 208 or 
at the time of early termination.   
7.3.2:  Transthyretin mRNA 
Blood for serum TTR mRNA is to be collected at 
Screening, immediately prior (within 10 minutes) to the 
administration of the premedications on Days 0 
(Baseline) and 28, and on Days 1, 2, 29, and 30. 
Blood for serum TTR mRNA is to be collected at 
Screening, immediately prior (within 10 minutes) to the 
administration of the premedications on Days 0 
(Baseline) and 28, and on Days 1, 2, 29, and 30.  For 
optional cohorts dosed once every 3 weeks, blood for 
serum TTR mRNA will be collected at Screening 
and on Days 0 (Baseline) and 21, and on Days 1, 2, 
22, and 23. 
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7.3.2.1:  Vitamin A and 
Retinol Binding Protein 
Blood for measurements of vitamin A and RBP is to be 
collected at Screening, immediately prior (within 10 
minutes) to the administration of the premedications, 
immediately pre-dose (within 10 minutes) on Days 0 
and 28, and on Days 1, 2, 7, 10, 14, 21, 29, 30, 35, 38, 
42, 49, 56 (end-of-study), 112, and 208 or at the time of 
early termination.   
Blood for measurements of vitamin A and RBP is to be 
collected at Screening, immediately prior (within 10 
minutes) to the administration of the premedications, 
immediately pre-dose (within 10 minutes) on Days 0 
and 28, and on Days 1, 2, 7, 10, 14, 21, 29, 30, 35, 38, 
42, 49, 56 (end-of-study), 112, and 208 or at the time of 
early termination.  For optional cohorts dosed once 
every 3 weeks, blood for measurements of vitamin A 
and RBP will be collected at Screening, immediately 
prior (within 10 minutes) to the administration of 
the premedications, immediately pre-dose (within 
10 minutes) on Days 0 (Baseline) and 21, and on 
Days 1, 2, 7, 10, 14, 22, 23, 28, 31, 35, 42, 49, 56 (end-
of-study), 112, and 208 or at the time of early 
termination.   
7.4.1:  Plasma 
Pharmacokinetics 
Samples will also be collected on Days 7, 14, 21, 35, 
42, 49, 56, 112, and 208 post infusion as well as at the 
ET visit (if applicable).   
Samples will also be collected on Days 7, 14, 21, 35, 
42, 49, 56, 112, and 208 post infusion as well as at the 
ET visit (if applicable); for optional cohorts dosed 
once every 3 weeks, samples will be collected on 
Days 7, 14, 21, 28, 35, 42, 56, 112, and 208 post 
infusion as well as at the ET visit (if applicable). 
7.4.2:  Urine 
Pharmacokinetics 
Urine sample collection times are included in the 
schedule of assessments (see Table 1-1).   
Urine sample collection times are included in the 
schedule of assessments (see Table 1-1 or Table 12-1 
for optional cohorts dosed once every 3 weeks).   
9.1:  Sample Size 
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 21 patients are expected to be 
enrolled.   
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 21 27 patients are expected to be 
enrolled.   
Appendices 
Added Appendix 4 
Appendix 4: 
Schedule of Assessments for 
Optional Cohorts Administered ALN-TTR02 Once 
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Section 
Prior Text 
Changed To 
Every Three Weeks 
Added Table 12-1 
 
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Protocol ALN-TTR02-002 
Amendment 1.1 Change Summary 
A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Infusions of ALN-
TTR02 in Patients with TTR Amyloidosis 
Changes included in Amendment 1.1 to Protocol ALN-TTR02-002, dated 24 September 
2012, are itemized below and detailed on the following page. 
• Pages 39 and 50 of the Protocol were updated to add requested language from the 
French CEC (insert name of EC) regarding AST and ALT levels and receipt of 
second dose.  Statements were added to the pertinent sections of the protocol so that if 
after receipt of the first dose of study drug the patient’s ALT and AST levels are 
reported to be greater than 2.5 times the upper limit of normal, the patient will not 
receive the second dose of study drug.   
• Made minor editorial changes (e.g., corrections of typographical, grammatical, and 
spelling errors as well as formatting changes and changes for consistency); these 
changes are not listed individually. 
 
 
 
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Text deleted is indicated by strikeout while text added is indicated by bold font. 
Section 
Prior Text 
Changed To 
3.1 Overall Design 
Within each of the cohorts, the first patient will 
receive their first dose and if the dose is well 
tolerated (per Section 5.7.15.7.3, Dose-limiting 
Toxicity), Patients 2 and 3 will receive their first 
dose at that same dose level no sooner than 48 hours 
apart, with Patient 2 receiving a dose of study drug 
no sooner than 48 hours after the dosing of Patient 
1.  Similar to the first dose, the second dose will be 
administered to patients 4 weeks after the first dose 
in a sequential manner with at least 48 hours 
separating dosing of each patient. 
  
Within each of the cohorts, the first patient will 
receive their first dose and if the dose is well tolerated 
(per Section 5.7.15.7.3, Dose-limiting Toxicity), 
Patients 2 and 3 will receive their first dose at that 
same dose level no sooner than 48 hours apart, with 
Patient 2 receiving a dose of study drug no sooner 
than 48 hours after the dosing of Patient 1.  Similar to 
the first dose, the second dose will be administered to 
patients 4 weeks after the first dose in a sequential 
manner with at least 48 hours separating dosing of 
each patient.  If after the first dose, ALT and AST 
are > 2.5 x ULN, that patient will not receive their 
second dose.    
 
 
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Section 
Prior Text 
Changed To 
5.7.1 
Dose-
escalation 
Procedures  
Within each of the cohorts, the first patient will 
receive their first dose and if the dose is well 
tolerated, per Section 5.7.15.7.3 (Dose-limiting 
Toxicity), Patients 2 and 3 will receive their first 
dose at that same dose level no sooner than 48 hours 
apart, with Patient 2 receiving a dose of study drug 
no sooner than 48 hours after the dosing of Patient 
1.  Similar to the first dose, the second dose will be 
administered to patients 4 weeks after the first dose 
in a sequential manner with at least 48 hours 
separating dosing of each patient. 
Within each of the cohorts, the first patient will 
receive their first dose and if the dose is well 
tolerated, per Section 5.7.15.7.3 (Dose-limiting 
Toxicity), Patients 2 and 3 will receive their first dose 
at that same dose level no sooner than 48 hours apart, 
with Patient 2 receiving a dose of study drug no 
sooner than 48 hours after the dosing of Patient 1.  
Similar to the first dose, the second dose will be 
administered to patients 4 weeks after the first dose in 
a sequential manner with at least 48 hours separating 
dosing of each patient.  If after the first dose, ALT 
and AST are > 2.5 x ULN, that patient will not 
receive their second dose.   
 
 
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Protocol ALN-TTR02-002 
Amendment 1 Change Summary 
A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Infusions of ALN-
TTR02 in Patients with TTR Amyloidosis 
Changes included in Amendment 1 to Protocol ALN-TTR02-002, dated 19 June 2012, 
are itemized below and detailed in the pages that follow. 
 Added pertinent information from the ongoing chronic GLP toxicology study in non-
human primates (Study 504265); also, reference is made to the Expedited Safety 
Report addendum dated 7 June 2012 to the IB, which contains the details of the 
nonclinical finding from this study. 
 Made additional references, where relevant, to the Expedited Safety Report 
addendum dated 7 June 2012, which in addition to providing pertinent data from the 
ongoing chronic GLP toxicology study in non-human primates, also includes 
preliminary safety and efficacy updates from the Phase 1 trials of ALN-TTR02 in 
healthy volunteers (ALN-TTR02-001) and ALN-PCS02 in healthy volunteers with 
elevated cholesterol (ALN-PCS02-001).  
 In light of the favorable single-dose safety data that have emerged from the recently 
completed Phase 1 trials of ALN-TTR02 and ALN-PCS02 at doses greater than or 
equal to the top dose on this study (detailed in Expedited Safety Report addendum 
dated 7 June 2012 to the IB), we have removed the requirement that the SRC review 
safety data on all patients within a dose level following first dose prior to any patient 
at that dose level receiving their second dose. 
 Removed the 500 g/kg dose cohort (highest dose) since the ALN-TTR02-001 study 
has completed enrollment and demonstrated adequate pharmacology at the 0.3 mg/kg 
dose. 
 Having removed the top dose, thus reducing the total number of patients in the study 
from 24 to 21.  Instead, the number of optional cohorts has been increased from 3 to 4 
to allow for further evaluation of safety and/or pharmacodynamic effect. 
 Extended the post-dose on-site observation period from 6 hours to 24 hours post-
infusion
 
  
 Added the following additional safety evaluations to further ensure patient safety: 
 Continuous cardiac monitoring (telemetry) to be performed during dosing and for 
24 hours post-dose (from Days 0 to 1 and again from Days 28 to 29). 
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 Serial vital signs and pulse oximetry assessments at 12 and 18 hours (±30 
minutes), and 24 (+30 minutes) hours post-infusion. 
 Serial electrocardiogram at 24 (+30 minutes) hours post-infusion. 
 
Added specific instructions, consistent with that contained in the ALN-TTR02-01 
protocol, for dosing of patients who weigh 105 kg or less. 
 Language regarding Early Termination visits was made consistent with the Informed 
Consent Form. 
 Made minor editorial changes (e.g., corrections of typographical, grammatical, and 
spelling errors as well as formatting changes and changes for consistency); these 
changes are not listed individually. 
 
 
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Text deleted is indicated by strikeout while text added is indicated by bold font. 
Section 
Prior Text 
Changed To 
Contact Information 
 
 
 
 
 
 
Synopsis: 
Design 
Dosing within a cohort: The first patient will receive their 
first dose and if the dose is well tolerated, Patients 2 and 3 
will receive their first dose at that same dose level no 
sooner than 48 hours apart, with Patient 2 receiving a dose 
of study drug no sooner than 48 hours after the dosing of 
Patient 1.  Cumulative safety and tolerability data on all 
patients will be reviewed by the SRC after the last patient 
has at least 96 hours of follow-up and prior to the 
administration of each patient within the cohort’s second 
dose.  If deemed safe and tolerated by the SRC, patients 
will receive their 2nd dose of study drug approximately 
4 weeks after receiving their first dose.  Similar to the first 
dose, the second dose will be administered to patients in a 
sequential manner with at least 48 hours separating dosing 
of each patient. 
Dosing within a cohort: The first patient will receive their 
first dose and if the dose is well tolerated, per Section 
5.7.3 (Dose-limiting Toxicity), Patients 2 and 3 will 
receive their first dose at that same dose level no sooner 
than 48 hours apart, with Patient 2 receiving a dose of 
study drug no sooner than 48 hours after the dosing of 
Patient 1.  Cumulative safety and tolerability data on all 
patients will be reviewed by the SRC after the last patient 
has at least 96 hours of follow-up and prior to the 
administration of each patient within the cohort’s second 
dose.  If deemed safe and tolerated by the SRC, patients 
will receive their 2nd dose of study drug approximately 
4 weeks after receiving their first dose.  Similar to the first 
dose, the second dose will be administered to patients 
4 weeks after the first dose in a sequential manner with at 
least 48 hours separating dosing of each patient. 
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Dosing of the next cohort: Collective cohort safety and 
tolerability data on Patients 1 to 3 through at least 96 hours 
post-first dose will be reviewed by the SRC; if the 
administered dose is found to be safe and well tolerated, 
dosing for the next protocol-specified dose level will begin 
no sooner than 96 hours after Patient 3 had safely received 
dose 1 from the previous cohort.  Patients in the cohort 
would be dosed and reviewed for safety and tolerability 
following the same procedures as used for other cohorts (as 
stated above).  Prior to receiving the second dose, the SRC 
will review the cumulative safety and tolerability data of at 
least 2 patients from the previous cohort with at least 
96 hours of follow-up after receiving a second dose of 
study drug. 
Dosing of the next cohort: Collective cohort safety and 
tolerability data on Patients 1 to 3 through at least 96 hours 
post-first dose will be reviewed by the SRC; if the 
administered dose is found to be safe and well tolerated, 
dosing for the next protocol-specified dose levelcohort 
will begin no sooner than 96 hours after Patient 3 had 
safely received dose 1 from the previous cohort.  Patients 
in the cohort would be dosed and reviewed for safety and 
tolerability following the same procedures as used for 
other cohorts (as stated above).   
For patients on all dose levels other than the starting 
dose level of 10 µg/kg, prior to receiving the second dose, 
the SRC will review the cumulative safety and tolerability 
data of at least 2 patients from the previous cohort dose 
level(s) with at least 96 hours of follow-up after receiving 
a second dose of study drug. 
Synopsis 
Dosage, Route of 
Administration and 
Duration of 
Treatment of 
Investigational Drug 
Five cohorts are planned to be enrolled to evaluate 
2 consecutive doses, 4 weeks apart of the following dose 
levels: 10, 50, 150, 300, and 500 µg/kg ALN-TTR02.  
Based on the interim evaluation of safety data, it may also 
be decided by the SRC that an optional cohort may be 
utilized which will include 3 additional patients.  These 
optional cohorts may occur at a previously tested dose that 
was found to be safe and where stopping rules were not 
met or at an intermediate dose level. 
Five Four cohorts are planned to be enrolled to evaluate 
2 consecutive doses, 4 weeks apart of the following dose 
levels: 10, 50, 150, and 300, and 500 µg/kg ALN-TTR02.  
Based on the interim evaluation of safety data, it may also 
be decided by the SRC that an optional cohort may be 
utilized which will include 3 additional patients.  Dosing 
in these optional cohorts may occur at a previously tested 
dose that was found to be safe and where stopping rules 
were not met or at an intermediate dose level. 
Up to 3 optional cohorts are permitted in this study. 
Up to 43 optional cohorts are permitted in this study. 
Patients will be observed at the clinic for up to 6 hours 
Patients will remain hospitalized at the study site for at 
 
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Section 
Prior Text 
Changed To 
following completion of dosing on Days 0 and 28, for 
safety assessments and pharmacokinetic (PK) sampling. 
least 24 hours be observed at the clinic for up to 6 hours 
following completion of dosing on Days 0 and 28, for 
safety assessments and pharmacokinetic (PK) sampling. 
Synopsis 
Sample Size 
Based on the entry criteria and the proposed dose 
escalation scheme, up to 24 patients are expected to be 
enrolled. 
Based on the entry criteria and the proposed dose 
escalation scheme, up to 24 21 patients are expected to be 
enrolled. 
Synopsis 
Safety Assessments 
Safety evaluations will include assessment of adverse 
events (AEs), electrocardiograms (ECGs), arterial oxygen 
saturation (SaO2) using pulse oximetry, vital signs (blood 
pressure, pulse rate, oral body temperature, and respiration 
rate), clinical laboratory safety tests (hematology, serum 
chemistry, liver function tests, thyroid function parameters, 
serology, coagulation parameters, urinalysis, cytokines, C-
reactive protein, complement factors), and physical 
examinations. 
Safety evaluations will include assessment of adverse 
events (AEs), electrocardiograms (ECGs), cardiac 
monitoring (telemetry), arterial oxygen saturation (SaO2) 
using pulse oximetry, vital signs (blood pressure, pulse 
rate, oral body temperature, and respiration rate), clinical 
laboratory safety tests (hematology, serum chemistry, liver 
function tests, thyroid function parameters, serology, 
coagulation parameters, urinalysis, cytokines, C-reactive 
protein, complement factors), and physical examinations. 
Table 1-1: 
Schedule of 
Assessments 
Changes to timing of assessments: 
Vital signs 
Vital signs (serial) 
ECG (serial) 
Pulse oximetry (serial) 
Assessments added: 
Inpatient at study site 
Cardiac monitoring (telemetry) 
Changes to timing of assessments: 
Vital signs: removed D1/D29 time point 
Vital signs (serial): added D1/D29 time point 
ECG (serial): added D1/D29 time point 
Pulse oximetry: added D1/D29 time point 
Assessments added: 
Inpatient at study site: scheduled for the D0/D28 (predose); 
D0/D28 (postdose) and D1/D29 time points  
Cardiac monitoring (telemetry): scheduled for the D0/D28 
(predose); D0/D28 (postdose) and D1/D29 time points 
Footnote f: Serial measures (vital signs and pulse 
Footnote f: Serial measures (vital signs and pulse 
oximetry) are to be measured within 30 minutes pre-dose; 
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Section 
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Changed To 
oximetry) are to be measured within 30 minutes pre-dose; 
at the end of infusion (EOI); and 30 (±5) minutes; and 1, 2, 
3, and 6 (±15 minutes) hours post-infusion. 
at the end of infusion (EOI); and 30 (±5) minutes; 1, 2, 
and 3 (±15 minutes) hours; 6, 12, and 18 (±30 minutes) 
hours; and 24 (+30 minutes) hours post-infusion. 
Footnote h: Serial electrocardiograms (ECGs) will be 
collected in 3 replicates within 30 minutes pre-dose, EOI, 
and 30 (±5) minutes, and 2 and 4 (±15 minutes) hours 
post-infusion 
Footnote h: Serial electrocardiograms (ECGs) will be 
collected in 3 replicates within 30 minutes pre-dose, EOI, 
and 30 (±5) minutes, and 2 and 4 (±15 minutes) hours, and 
24 (+30 minutes) hours post-infusion 
 
Added footnote i. 
Patients will be hospitalized at the study site for at least 
24 hours after the end of infusion of study drug. 
Patients may be discharged upon completion of review 
by the Investigator of ECG, sodium, potassium, 
creatinine, albumin, calcium, glucose, phosphate, and 
LFTs results obtained at 24-hours post-infusion, if 
results are deemed not clinically significant. Any 
clinically significant findings must be discussed with the 
medical monitor to determine whether patient can be 
discharged and to formulate plans for patient follow-
up. 
Added footnote j. 
Continuous cardiac monitoring will be performed via 
telemetry starting no later than 30 minutes prior to 
dosing and continuing through 24 hours (+1 hour) post-
dose. 
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Section 
Prior Text 
Changed To 
Section 1.2: 
Summary of ALN-
TTR02 Non-clinical 
Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Further information can be found in the ALN-TTR02 
Investigator’s Brochure. 
Further information can be found in the ALN-TTR02 
Investigator’s Brochure and its Expedited Safety Report 
addendum dated 7 June 2012. 
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Section 1.3: 
Summary of Clinical 
Data with siRNA-
LNPs 
Although no clinical data are yet available with ALN-
TTR02, a Phase 1 multi-centre, randomized, placebo-
controlled, single-blind, single-ascending dose clinical 
study to evaluate the safety, tolerability, PK, and 
pharmacodynamic (PD) of ALN-TTR02 in healthy 
volunteers is currently approved by MHRA (EUDRACT # 
2011-005291-42) and will begin dosing shortly.  ALN-
TTR02 will be administered as a single 60-minute IV 
infusion to healthy volunteers at the same doses proposed 
for this study: 10, 50, 150, 300, and 500 g/kg (4 patients 
per dose level; 3 receiving ALN-TTR02 and 1 receiving 
placebo).  The dose level of ALN-TTR02 administered to 
any cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 single-
dose study of ALN-TTR02 (Study ALN-TTR02-001).  
Patients will be pre-medicated with dexamethasone, H1 
and H2 blockers, and paracetamol prior to dosing to 
minimize the risk of infusion reaction.   
Although no clinical data are yet available with ALN-
TTR02, A Phase 1 multi-centre, randomized, placebo-
controlled, single-blind, single-ascending dose clinical 
study to evaluate the safety, tolerability, PK, and 
pharmacodynamic (PD) of ALN-TTR02 in healthy 
volunteers is currently was approved by MHRA 
(EUDRACT # 2011-005291-42) and will begin dosing 
shortly has completed dosing.  ALN-TTR02 will be was 
administered as a single 60-minute IV infusion to healthy 
volunteers at the same following doses proposed for this 
study: 10, 50, 150, 300, and 500 g/kg (4 patients per dose 
level; 3 receiving ALN-TTR02 and 1 receiving placebo).  
The dose level of ALN-TTR02 administered to any cohort 
in study ALN-TTR02-002 may not be higher than that 
deemed safe and tolerable in the Phase 1 single-dose study 
of ALN-TTR02 (Study ALN-TTR02-001).  Patients will 
be pre-medicated with dexamethasone, H1 and H2 
blockers, and paracetamol prior to dosing to minimize the 
risk of infusion reaction.  Preliminary data show that 
ALN-TTR02 was safe and well-tolerated and exhibited 
robust effects on serum TTR levels at the top doses. To 
date, no stopping rules have been met and there have 
been no early discontinuations due to adverse events. 
Further information on the ALN-TTR02-001 Phase 1 
study can be found in the ALN-TTR02 Investigators 
Brochure and its Expedited Safety Report addendum 
dated 7 June 2012. 
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Further information can be found in the Investigator’s 
Brochure. 
Further information, including preliminary safety and 
efficacy updates from the recently completed Phase 1 
trials of ALN-TTR02 in healthy volunteers and ALN-
PCS02 in healthy volunteers with elevated cholesterol, 
can be found in the Investigator’s Brochure and its 
Expedited Safety Report addendum dated 7 June 2012. 
Section 1.5: 
Dose Selection and 
Rationale 
Study drug will be administered as a 60-minute IV infusion 
with the following proposed doses for each cohort:  10, 50, 
150, 300, and 500 μg/kg ALN-TTR02. 
Study drug will be administered as a 60-minute IV infusion 
with the following proposed doses for each cohort:  10, 50, 
150, and 300, and 500 μg/kg ALN-TTR02. 
Added information from the ongoing chronic GLP 
toxicology study in non-human primates (Study 504265). 
The top dose proposed in the study (500 μg/kg)
 
 
The top dose proposed in the study (500 300 μg/kg) is
 
 
.  Preliminary safety data are available from 
ongoing Phase 1 trials with ALN-TTR02 and ALN-
PCS02.  In the ALN-TTR02-001 Phase 1 trial in 
healthy volunteers, these same dose levels were found to 
be safe and well-tolerated. Furthermore, ALN-PCS02, 
which uses the same second generation LNP 
formulation as ALN-TTR02, was safe and well-
tolerated at doses up to 400 g/kg in healthy volunteers 
with elevated cholesterol. See the ALN-TTR02 
Investigators Brochure and its Expedited Safety Report 
addendum dated 7 June 2012 for updated information 
on the ALN-TTR02 and ALN-PCS02 Phase 1 trials. 
Additionally, a conservative dosing approach is being 
taken.  In each cohort, patients will be dosed in a 
sequential fashion with a minimum of 48 hours elapsing 
between patients.  Collective cohort safety and tolerability 
data on the 3 patients from the prior cohort through at least 
Additionally, a conservative dosing approach is being 
taken.  In each cohort, patients will be dosed in a 
sequential fashion with a minimum of 48 hours elapsing 
between patients.  Collective cohort safety and tolerability 
data on the 3 patients from the prior cohort through at least 
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96 hours post-dose will be reviewed by the Safety Review 
Committee (SRC) prior to approving dosing for the next 
protocol-specified dose level.  In addition, cumulative 
safety and tolerability data observed through at least 96 
hours post-second dose of the previous cohort will be 
reviewed by the SRC prior to administration of the second 
dose of study drug. 
96 hours post-dose will be reviewed by the Safety Review 
Committee (SRC) prior to approving dosing for the next 
protocol-specified dose level.  In addition, cumulative 
safety and tolerability data observed in at least 2 patients 
through at least 96 hours post-second dose of the previous 
cohort will be reviewed by the SRC prior to administration 
of the second dose of study drug. 
The top dose proposed in the study (500 μg/kg) is 
 
.  
The top dose proposed in the study (500 300 μg/kg) is
 
 
   
Up to 3 optional cohorts may be enrolled, each comprised 
of 3 patients, to further evaluate a dose level or dosing 
intervals greater than 4 weeks.  The optional cohorts will 
follow the same treatment schema as cohorts 1 to 5, as 
outlined in Section 5.6. 
Based on the interim evaluation of safety data, it may 
also be decided by the SRC that an optional cohort may 
be utilized which will include 3 additional patients.  
Dosing in these optional cohorts may occur at a 
previously tested dose that was found to be safe and 
where stopping rules were not met or at an 
intermediate dose level.  Patients in the optional cohort 
would be dosed and reviewed for safety and tolerability 
following the same procedures as used for other 
cohorts.  The optional cohort would be included to 
further confirm the safety and/or PD effect.  If this 
occurs, the Independent Ethics Committees (IECs) will 
be informed of the expansion.  Up to 3 optional cohorts 
of 3 patients each are permitted in this study. 
Up to 3 optional cohorts may be enrolled, each comprised 
of 3 patients, to further evaluate a dose level or dosing 
intervals greater than 4 weeks.  The optional cohorts will 
follow the same treatment schema as cohorts 1 to 54, as 
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outlined in Section 5.6. 
Section 3.1: 
Overall Design 
Two doses, separated by 4 weeks, of ALN-TTR02 (10, 50, 
150, 300, and 500 μg/kg) will be investigated in 5 
sequential cohorts comprised of 3 patients each.  No 
patients will be a member of more than 1 treatment group.  
Three optional cohorts may also be included to further 
explore the safety and PD effect at any dose or the PD 
effect of extending the dosing intervals of ALN-TTR02 
beyond 4 weeks (see Section 5.7.2). 
Two doses, separated by 4 weeks, of ALN-TTR02 (10, 50, 
150, and 300, and 500 μg/kg) will be investigated in 5 4 
sequential cohorts comprised of 3 patients each.  No 
patients will be a member of more than 1 treatment group.  
Three optional cohorts may also be included to further 
explore the safety and PD effect at any dose or the PD 
effect of extending the dosing intervals of ALN-TTR02 
beyond 4 weeks (see Section 5.7.2). 
Within each of the cohorts, patients will be dosed in a 
sequential fashion with a minimum of 48-hours of 
observation between each patient.  Continuation of dosing 
(administration of second dose) of the current cohort and 
dose escalation to the next cohort will proceed after the 
collective safety and tolerability data for Patients 1 to 3 of 
the current cohort through at least 96 hours post-first dose 
are reviewed by the SRC.  The continuation dosing 
(administration of second dose) of subsequent cohorts is 
dependent upon the SRC determining administration of 
second doses of study drug were safe and tolerable in 
previous cohorts. 
Within each of the cohorts, patients will be dosed in a 
sequential fashion with a minimum of 48-hours of 
observation between each patient.  Continuation of dosing 
(administration of second dose) of the current cohort and 
dose escalation to the next cohort will proceed after the 
collective safety and tolerability data for Patients 1 to 3 of 
the current cohort through at least 96 hours post-first dose 
are reviewed by the SRC.  The continuation dosing 
(administration of second dose) of subsequent cohorts is 
dependent upon the SRC determining administration of 
second doses of study drug were safe and tolerable in 
previous cohorts. 
Within each of the cohorts, the first patient will receive 
their first dose and if the dose is well tolerated (per 
Section 5.7.3, Dose-limiting Toxicity), Patients 2 and 3 
will receive their first dose at that same dose level no 
sooner than 48 hours apart, with Patient 2 receiving a 
dose of study drug no sooner than 48 hours after the 
dosing of Patient 1.  Similar to the first dose, the second 
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dose will be administered to patients 4 weeks after in a 
sequential manner with at least 48 hours separating 
dosing of each patient. 
Dose escalation to the next cohort will proceed after the 
collective safety and tolerability data through at least 
96 hours post-first dose from the 3 patients in the 
previous cohort has been reviewed by the SRC.  If the 
administered dose is found to be safe and well 
tolerated, dosing for the next cohort will begin no 
sooner than 96 hours after Patient 3 has safely received 
dose 1 from the previous cohort.  Patients in the cohort 
would be dosed and reviewed for safety and tolerability 
following the same procedures as used for other cohorts 
(as stated above).   
For patients on all dose levels other than the starting 
dose level of 10 g/kg, prior to receiving the second 
dose the SRC will review the cumulative safety and 
tolerability data of at least 2 patients from the previous 
dose level(s) with at least 96 hours of follow-up after 
receiving a second dose of study drug. 
The dose level of ALN-TTR02 administered to any 
cohort in study ALN-TTR02-002 may not be higher 
than that deemed safe and tolerable in the Phase 1 
single-dose study of ALN-TTR02 (Study ALN-TTR02-
001). 
Patients will be observed for 6 hours after ALN-TTR02 
dose administration and will return to the site for out-
Patients will be hospitalized at the study site for at least 
24 hours after the end of the study drug infusion. 
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patient visits for safety, PK, and PD monitoring up to 
208 days post-dose (see Section 6 for details). 
Patients may be discharged upon Investigator review of 
the 24 hour ECG, LFTs, and a subset of serum 
chemistries (sodium, potassium, creatinine, albumin, 
calcium, glucose, and phosphate), if results are deemed 
not clinically significant.   Patients will be observed for 6 
hours after ALN-TTR02 dose administration and will 
return to the site for out-patient visits for safety, PK, and 
PD monitoring up to 208 days post-dose (see Section 6 for 
details). 
The SRC will evaluate safety in the study and determine if 
it remains acceptable to proceed with dosing 
(administration of second dose) or dose escalate per their 
safety review charter. 
The SRC will evaluate safety in the study and determine if 
it remains acceptable to proceed with dosing 
(administration of second dose) or dose escalate or 
administer the second dose to the next dose level per 
their safety review charter. 
Section 3.2: 
Safety Assessments 
Safety monitoring will include assessment of AEs, 12-lead 
ECGs, arterial oxygen saturation (SaO2) using pulse 
oximetry, vital signs (blood pressure, pulse rate, oral body 
temperature, and respiratory rate), clinical laboratory 
safety tests (hematology, serum chemistry, liver function 
tests, thyroid function parameters, serology, coagulation 
parameters, urinalysis, cytokines, CRP, and complement 
factors), and physical examinations. 
Safety monitoring will include assessment of AEs, 12-lead 
ECGs, cardiac monitoring (telemetry), arterial oxygen 
saturation (SaO2) using pulse oximetry, vital signs (blood 
pressure, pulse rate, oral body temperature, and respiratory 
rate), clinical laboratory safety tests (hematology, serum 
chemistry, LFTs, thyroid function parameters, serology, 
coagulation parameters, urinalysis, cytokines, CRP, and 
complement factors), and physical examinations. 
Section 4.1: 
Eligibility of Patients 
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 24 patients are expected to be 
enrolled. 
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 24 21 patients are expected to be 
enrolled. 
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Section 5.2: 
Preparation of Study 
Drug 
Added instructions for calculating study drug dose to be 
consistent with ALN-TTR02-001. 
Subjects who weigh 105 kg or more will receive 
ALN-TTR02 dosing based on an assumption of a body 
weight of 104 kg. 
Section 5.6: 
Dose, Route, and 
Schedule of Study 
Drug Administration 
Study drug doses will be administered as a 60-minute IV 
infusion. 
Study drug doses will be administered as a 60-minute IV 
infusion 4 weeks apart. 
Patients will remain at the study site for 6 hours following 
completion of dosing on Day 0 and Day 28 (or date of 
second dose administration in optional cohorts with dosing 
intervals greater than 4 weeks), to be observed for safety 
assessments and PK sampling. 
Patients will remain hospitalized at the study site for at 
least 6 24 hours following completion of dosing on Day 0 
and Day 28 (or date of second dose administration in 
optional cohorts with dosing intervals greater than 4 
weeks), to be observed for safety assessments and PK 
sampling. 
The planned study drug doses are 10, 50, 150, 300, and 
500 g/kg, with safety monitoring between patients and 
interim review by the SRC after each cohort’s dose 
administration. 
The planned study drug doses are 10, 50, 150, and 300, 
and 500 g/kg, with safety monitoring between patients 
and interim review by the SRC after each cohort’s dose 
administration. 
Added instructions for calculating study drug dose to be 
consistent with ALN-TTR02-001. 
Subjects who weigh 105 kg or more will receive 
ALN-TTR02 dosing based on an assumption of a body 
weight of 104 kg. 
Within each cohort, the first patient will receive their first 
dose and if the dose is well tolerated, Patient 2 will receive 
their first dose of study drug no sooner than 48 hours after 
the dosing of Patient 1.  Similarly, if no safety or 
tolerability issues are observed with the first 2 patients, 
Patient 3 will receive their first dose no sooner than 
48 hours after Patient 2.  After all patients in a cohort have 
at least 96 hours of follow-up, the cumulative safety and 
Within each cohort, the first patient will receive their first 
dose and if the dose is well tolerated, Patient 2 will receive 
their first dose of study drug no sooner than 48 hours after 
the dosing of Patient 1.  Similarly, if no safety or 
tolerability issues are observed with the first 2 patients, 
Patient 3 will receive their first dose no sooner than 48 
hours after Patient 2.  After all patients in a cohort have at 
least 96 hours of follow-up, the cumulative safety and 
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tolerability data on all patients will be reviewed by the 
SRC prior to the administration of each cohort’s second 
dose.  If deemed safe and tolerated by the SRC, Patients 1-
3 will receive their second dose of study drug 
approximately 4 weeks after receiving their first dose.  
Patients will continue to be dosed in a sequential fashion 
with a minimum of a 48-hour observation period prior to 
the dosing of the subsequent patient.   
Prior to escalating to the next cohort, each of the 3 patients 
in the current cohort must have received study drug with at 
least 96 hours of follow-up, for that cohort to be eligible 
for SRC review.  If the administered dose is found to be 
safe and well tolerated, dosing for the next protocol-
specified dose level will begin no sooner than 7 days after 
Patient 3 in the previous cohort had safely received the 
first dose of study drug.  Prior to administration of the 
second dose of study drug, the SRC will review the 
cumulative safety and tolerability data of at least 2 patients 
from the previous cohort with at least 96 hours of follow-
up after receiving the second dose of study drug.  If 
deemed safe and tolerable by the SRC, patients in the 
current cohort will receive their second dose of study drug.   
tolerability data on all patients will be reviewed by the 
SRC prior to the administration of each cohort’s second 
dose.  If deemed safe and tolerated by the SRC, Patients 1-
3 will receive their second dose of study drug 
approximately 4 weeks after receiving their first dose.  
Patients will continue to be dosed in a sequential fashion 
with a minimum of a 48-hour observation period prior to 
the dosing of the subsequent patient.   
Prior to escalating to the next cohort, each of the 3 patients 
in the current cohort must have received study drug with at 
least 96 hours of follow-up, for that cohort to be eligible 
for SRC review.  If the administered dose is found to be 
safe and well tolerated, dosing for the next protocol-
specified dose level will begin no sooner than 7 days after 
Patient 3 in the previous cohort had safely received the 
first dose of study drug.  Prior to administration of the 
second dose of study drug, the SRC will review the 
cumulative safety and tolerability data of at least 2 patients 
from the previous cohort with at least 96 hours of follow-
up after receiving the second dose of study drug.  If 
deemed safe and tolerable by the SRC, patients in the 
current cohort will receive their second dose of study drug.  
Within each of the cohorts, the first patient will receive 
their first dose and if the dose is well tolerated, per 
Section 5.7.3 (Dose-limiting Toxicity), Patients 2 and 3 
will receive their first dose at that same dose level no 
sooner than 48 hours apart, with Patient 2 receiving a 
dose of study drug no sooner than 48 hours after the 
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dosing of Patient 1.  Similar to the first dose, the second 
dose will be administered to patients in a sequential 
manner with at least 48 hours separating dosing of each 
patient. 
Dose escalation to the next cohort will proceed after the 
collective safety and tolerability data through at least 
96 hours post-first dose from the 3 patients in the 
previous cohort has been reviewed by the SRC.  If the 
administered dose is found to be safe and well 
tolerated, dosing for the next cohort will begin no 
sooner than 96 hours after Patient 3 has safely received 
dose 1 from the previous cohort.  Patients in the cohort 
would be dosed and reviewed for safety and tolerability 
following the same procedures as used for other cohorts 
(as stated above).   
For patients on all dose levels other than the starting 
dose level of 10 g/kg, prior to receiving the second 
dose the SRC will review the cumulative safety and 
tolerability data of at least 2 patients from the previous 
dose level(s) with at least 96 hours of follow-up after 
receiving a second dose of study drug.  
Figure 5-1 
Removed previous figure 
Replaced figure with one that accurately depicts the dosing 
as described in this amendment. 
This figure has been moved from Section 5.6 to 
Section 5.7.1. 
Table 5-1 
Last row containing Cohort 5 (500 g/kg dose) 
This last row has been removed. 
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Total enrollment: Up to 24 patients 
Total enrollment: Up to 24 21 patients 
Footnote a:  
Up to 3 optional cohorts may be included to confirm the 
safety, tolerability, and/or PD effect at a specific dose.  
Each optional cohort will be comprised of 3 patients 
Up to 3 optional cohorts may be included to confirm the 
safety, tolerability, and/or PD effect at a specific dose.  
Dosing in these optional cohorts may occur at a 
previously tested dose that was found to be safe and 
where stopping rules were not met or at an 
intermediate dose level.  Each optional cohort will be 
comprised of 3 patients 
Section 5.7.1 
Dose Escalation 
Procedures 
Dose escalation to 50, 150, 300, and 500 g/kg is planned. 
Dose escalation to 50, 150, and 300, and 500 g/kg is 
planned. 
 
Study drug doses will be escalated sequentially after the 
SRC reviews safety data, as detailed in the SRC Charter, 
collected from all 3 patients at the current dose level.  The 
SRC will evaluate safety in the study and determine if it 
remains acceptable to dose escalate per their safety review 
charter after each cohort based on pre-established stopping 
rules.  Collective post-first dose safety and tolerability data 
on the 3 patients in a cohort through at least 96 hours post-
dose will be reviewed by the SRC, and if the administered 
dose is found to be safe and well tolerated, dosing of the 
next protocol-specified dose level will occur.  For any 
DLT, accrual to that dose level will stop, all dosing will be 
discontinued, and dose escalation will end, pending 
evaluation of all available safety data by the SRC.   
 
Study drug doses will be escalated sequentially after the 
SRC reviews safety data, as detailed in the SRC Charter, 
collected from all 3 patients at the current dose level.  The 
SRC will evaluate safety in the study and determine if it 
remains acceptable to dose escalate per their safety review 
charter after each cohort based on pre-established stopping 
rules.  Collective post-first dose safety and tolerability data 
on the 3 patients in a cohort through at least 96 hours post-
dose will be reviewed by the SRC, and if the administered 
dose is found to be safe and well tolerated, dosing of the 
next protocol-specified dose level will occur.  For any 
DLT, accrual to that dose level will stop, all dosing will be 
discontinued, and dose escalation will end, pending 
evaluation of all available safety data by the SRC.   
Within each of the cohorts, the first patient will receive 
their first dose and if the dose is well tolerated, per 
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Section 5.7.3 (Dose-limiting Toxicity), Patients 2 and 3 
will receive their first dose at that same dose level no 
sooner than 48 hours apart, with Patient 2 receiving a 
dose of study drug no sooner than 48 hours after the 
dosing of Patient 1.  Similar to the first dose, the second 
dose will be administered to patients 4 weeks after the 
first dose in a sequential manner with at least 48 hours 
separating dosing of each patient. 
Dose escalation to the next cohort will proceed after the 
collective safety and tolerability data through at least 
96 hours post-first dose from the 3 patients in the 
previous cohort has been reviewed by the SRC.  If the 
administered dose is found to be safe and well 
tolerated, dosing for the next cohort will begin no 
sooner than 96 hours after Patient 3 has safely received 
dose 1 from the previous cohort.  Patients in the cohort 
would be dosed and reviewed for safety and tolerability 
following the same procedures as used for other cohorts 
(as stated above).   
For patients on all dose levels other than the starting 
dose level of 10 g/kg, prior to receiving the second 
dose the SRC will review the cumulative safety and 
tolerability data of at least 2 patients from the previous 
dose level(s) with at least 96 hours of follow-up after 
receiving a second dose of study drug. 
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Section 5.7.2 
Optional Cohorts 
Based on the interim evaluation of safety data, it may also 
be decided by the SRC that an optional cohort may be 
utilized to include 3 additional patients.  These optional 
cohorts will be included to further confirm the safety 
and/or PD effect.  Up to 3 optional cohorts are permitted in 
this study.  The dose of study drug administered to patients 
in these cohorts can be a previously tested dose that was 
found to be safe and where stopping rules were not met or 
at an intermediate dose level.  Patients in any optional 
cohort would be dosed and reviewed for safety and 
tolerability following the same procedures as used for 
other cohorts. 
The Independent Ethics Committee (IEC) will be informed 
of any optional cohorts utilized. 
Based on the interim evaluation of safety data, it may also 
be decided by the SRC that an optional cohort may be 
utilized to include 3 additional patients.  These optional 
cohorts will be included to further confirm the safety 
and/or PD effect.  Up to 3 optional cohorts are permitted in 
this study.  The dose of study drug administered to patients 
in these cohorts can be a previously tested dose that was 
found to be safe and where stopping rules were not met or 
at an intermediate dose level.  Patients in any optional 
cohort would be dosed and reviewed for safety and 
tolerability following the same procedures as used for 
other cohorts. 
The Independent Ethics Committee (IEC) will be informed 
of any optional cohorts utilized. 
Based on the interim evaluation of safety data, it may 
also be decided by the SRC that an optional cohort may 
be utilized which will include 3 additional patients.  
Dosing in these optional cohorts may occur at a 
previously tested dose that was found to be safe and 
where stopping rules were not met or at an 
intermediate dose level.  Patients in the optional cohort 
would be dosed and reviewed for safety and tolerability 
following the same procedures as used for other 
cohorts.  The optional cohort would be included to 
further confirm the safety and/or PD effect.  If this 
occurs, the IECs will be informed of the expansion.  Up 
to 3 optional cohorts of 3 patients each are permitted in 
this study. 
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Section 5.7.3 
Dose-limiting 
Toxicity 
 
Any other toxicity which in the opinion of the SRC 
would have precluded administration of a second dose. 
 
Any other toxicity which in the opinion of the SRC 
would have precluded administration of a second 
dosefurther dosing. 
Section 5.11 
Suggested Guidelines 
for Management of 
Infusion Reactions 
After dosing, patients should be discharged from the clinic 
no sooner than 6 hours post-dose with directions on self-
administration of medications as needed to ameliorate 
potential delayed reactions to study drug infusion, such as 
fever, chills, and myalgia. 
After dosing, patients should will be discharged from the 
clinic hospital no sooner than 6 24 hours post-dose.  Prior 
to discharge, the 24-hour ECG and local serum 
chemistries and LFTs must be reviewed by the 
Investigator as described in Section 3.1.  Patients will 
be discharged with directions on self-administration of 
medications as needed to ameliorate potential delayed 
reactions to study drug infusion, such as fever, chills, and 
myalgia. 
Section 6 
Study Visits 
Patients will remain at the study site for 6 hours following 
completion of dosing to be observed for safety assessments 
and PK sampling.  All study center visits will be conducted 
on an out-patient basis.  After receiving the first dose of 
study drug, patients will have follow-up visits on Days 1, 
2, 7, 10, 14, and 21.  In addition, follow-up visits after the 
second dose of study drug (Day 28) will occur on Days 29, 
30, 35, 38, 42, 49, and 56 (end-of-study). 
Patients will remain hospitalized at the study site for at 
least 6 24 hours following completion of dosing to be 
observed for safety assessments and PK sampling.  All 
study center visits will be conducted on an out-patient 
basis.  After receiving the first dose of study drug, patients 
will have follow-up visitsreturn to the study site on Days 
1, 2, 7, 10, 14, and 21 for follow-up assessments.  In 
addition, follow-up visits after the second dose of study 
drug (Day 28) will occur on Days 29, 30, 35, 38, 42, 49, 
and 56 (end-of-study). 
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19 June 2012 
 
 
 
Final Amendment #1 
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Section 
Prior Text 
Changed To 
All patients who discontinue the study before Day 56 will 
be encouraged to return to the study site for the Days 56 
and 208 study visits.  All patients who discontinue the 
study after Day 56 and prior to Day 208 will be 
encouraged to complete the Day 208 visit. 
All patients who discontinue the study before Day 56 will 
be encouraged to return to the study site for their Early 
Termination visit for Days 56 assessments.and 208 study 
visits.  All patients who discontinue the study after Day 56 
and prior to Day 208 will be encouraged to 
completereturn to the study site for their Early 
Termination visit for the Day 208 visitassessments. 
Section 6.3.1.1 
Pre-dose 
Obtain serial measurements of: 
Obtain serial measurements of: 
Added cardiac monitoring. 
Initiate cardiac monitoring (telemetry) 30 minute pre-
dose. 
Section 6.3.1.3 
Post-dose 
Patients will remain at the study site for 6 hours following 
completion of dosing, to be observed for safety 
assessments and PK sampling.  For non-PK assessments 
performed 30 minutes post-infusion, a window of 
±5 minutes is allowed, a window of ±15 minutes is 
allowed for assessments performed through 6 hours post-
infusion, and a window of ±120 minutes is allowed for 
assessments performed 24 hours post-infusion. 
Patients will remain hospitalized at the study site for at 
least 6 24 hours following completion of dosing, to be 
observed for safety assessments and PK sampling.  For 
non-PK assessments performed 30 minutes post-infusion, a 
window of ±5 minutes is allowed, a window of 
±15 minutes is allowed for assessments performed 
between 1 and 3 hours, and a window of ±30 minutes 
for through 6 through 18 hours post-infusion, and a 
window of ±120 minutes is allowed for assessments 
performed 24 hours post-infusion. 
 
Obtain serial measurement of vital signs at the end of 
infusion (EOI) and at 30 minutes and 1, 2, 3, and 
6 hours post-infusion. 
 
Obtain serial measurement of vital signs at the end of 
infusion (EOI) and at 30 minutes and 1, 2, 3, and 6, 12, 
and 18 hours post-infusion. 
Added cardiac monitoring. 
Continue cardiac monitoring (telemetry) through 24 
(+1) hour post-dose. 
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TTR02-002 Transthyretin-mediated Amyloidosis 
 
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Final Amendment #1 
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Section 
Prior Text 
Changed To 
Perform serial pulse oximetry at EOI and at 30 minutes 
and 1, 2, 3, and 6 hours post-infusion. 
Perform serial pulse oximetry at EOI and at 30 minutes 
and 1, 2, 3, and 6, 12, and 18 hours post-infusion. 
Patients will remain in the hospital for a total of 6 hours 
before they are discharged. 
Patients will remain in the hospital for a total of 6at least 
24 hours.  before they are discharged. 
Section 6.3.2 
Day 1 or Day 29 
Added serial pulse oximetry, ECG, and cardiac monitoring 
time points.  
Clarified when vital signs were to be measured. 
 
Measure vital signs. 
 
Measure vital signs 24 (+30 minutes) hours post-
infusion. 
 
Perform serial pulse oximetry at 24 (+30 minutes) 
hours post-infusion. 
 
Perform serial 12-lead ECGs in triplicate at 24 (+30 
minutes) hours post-infusion. 
 
Conclude cardiac monitoring (telemetry) at 24 (+1) 
hours post-infusion. 
Added discharge instructions. 
Patients will be discharged from the study site after the 
ECG and local serum chemistries and LFTs have been 
reviewed by the Investigator and deemed not clinically 
significant. 
Section 6.4 
Early Termination 
Patients coming off study before Day 56 will be 
encouraged to complete the Days 56 and 208 study visits.  
Patients coming off study after Day 56 and before Day 208 
will be encouraged to complete the Day 208 study visit. 
Patients coming off study before Day 56 will be 
encouragedreturn to the study site to complete their 
Early Termination visit which will include the Days 56 
and 208 study visitsassessments.  Patients coming off 
study after Day 56 and before Day 208 will be 
encouragedreturn to the study site to complete their 
Early Termination visit which will include to complete 
the Day 208 study visitassessments. 
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TTR02-002 Transthyretin-mediated Amyloidosis 
 
19 June 2012 
 
 
 
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Section 
Prior Text 
Changed To 
Section 7.2.2 
Vital Signs 
Vital signs are to be measured at Screening and the Day 1, 
2, 14, 29, 30, 42, and 56 (or time of early termination, if 
applicable) study visits and include systolic/diastolic blood 
pressure, pulse rate, respiration rate, and oral body 
temperature. 
Vital signs are to be measured at Screening and the Day 1, 
2, 14, 29, 30, 42, and 56 (or time of early termination, if 
applicable) study visits and include systolic/diastolic blood 
pressure, pulse rate, respiration rate, and oral body 
temperature. 
On Days 0 and 28, serial vital signs are to be measured 
within 30 minutes pre-dose, at EOI, and at 30 (5) minutes 
and 1, 2, 3, and 6 hours (15 minutes) post-infusion.   
On Days 0 and 28, serial vital signs are to be measured 
within 30 minutes pre-dose, at EOI; and at 
30 (5) minutes; and 1, 2, and 3 (±15 minutes) hours; and 
6, 12, and 18 hours (15 30 minutes) post-infusion.  On 
Days 1 and 29, serial vital signs are to be measured at 
24 hours (+30 minutes) post-infusion. 
Section 7.2.4 
Electrocardiogram 
Serial ECGs will be collected in triplicate 30 minutes prior 
to dosing (Days 0 and 28), EOI, and 30 (±5) minutes, and 2 
and 4 (±15 minutes) hours post-infusion. 
Serial ECGs will be collected in triplicate 30 minutes prior 
to dosing (Days 0 and 28), EOI, and 30 (±5) minutes, and 2 
and 4 (±15 minutes) hours, and on Days 1 and 29 at 
24 (+30 minutes) hours post-infusion. 
Added discharge instructions. 
Prior to discharge from the hospital on Days 1 and 29, 
the ECG must be reviewed by the Investigator and the 
results deemed not clinically significant.  Any clinically 
significant findings must be discussed with the medical 
monitor to determine whether patient can be 
discharged and to formulate plans for patient follow-
up. 
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TTR02-002 Transthyretin-mediated Amyloidosis 
 
19 June 2012 
 
 
 
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Section 
Prior Text 
Changed To 
Section 7.2.5 
Pulse Oximetry 
Arterial oxygen saturation will be assessed by serial pulse 
oximetry on Days 0 and 28 within 30 minutes pre-dose, at 
EOI, and at 30 (5) minutes and 1, 2, 3, and 6 hours 
(15 minutes) post-infusion on Days 0 and 28. 
Arterial oxygen saturation will be assessed by serial pulse 
oximetry on Days 0 and 28 within 30 (±5) minutes pre-
dose; at EOI;, and  at 30 (5) minutes; and at 1, 2, 3 hours 
(±15 minutes); and at 6, 12, and 18 hours 
(15 minutes) post-infusion on Days 0 and 28; and at 24 
hours (+30 minutes) post-infusion on Days 1 and 29. 
Section 7.2.6 
Cardiac Monitoring 
Added cardiac monitoring instructions. 
Continuous cardiac monitoring will be performed via 
telemetry starting no later than 30 minutes prior to 
dosing and continuing through 24 hours (+1 hour) post-
dose. 
Section 7.2.7.1 
Hematology, Serum 
Chemistries, and 
Urinalysis 
Added discharge instructions. 
Prior to discharge from the hospital on Days 1 and 29, 
local serum laboratories (specifically, sodium, 
potassium, creatinine, albumin, calcium, glucose, and 
phosphate) must be reviewed by the Investigator and 
the results deemed not clinically significant.  Any 
clinically significant findings must be discussed with the 
medical monitor to determine whether patient can be 
discharged and to formulate plans for patient follow-
up. 
Section 7.2.7.2 
Liver Function Tests 
Added discharge instructions. 
Prior to discharge from the hospital on Days 1 and 29, 
local LFTs must be reviewed by the Investigator and 
the results deemed not clinically significant.  Any 
clinically significant findings must be discussed with the 
medical monitor to determine whether patient can be 
discharged and to formulate plans for patient follow-
up. 
546


 
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TTR02-002 Transthyretin-mediated Amyloidosis 
 
19 June 2012 
 
 
 
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Section 
Prior Text 
Changed To 
Section 9.1: 
Sample Size 
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 24 patients are expected to be 
enrolled. 
Based on the planned dose escalation scheme (see 
Section 5.7.1), up to 24 21 patients are expected to be 
enrolled. 
 
547

SAP_000.pdf: 
 
 
Official Title:  
A Phase 2, Open‐Label, Multi‐Dose, Dose Escalation Trial to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
Intravenous Infusions of ALN‐TTR02 in Patients with TTR Amyloidosis 
 
NCT Number:    
NCT01617967 
 
Document Date:   
Statistical Analysis Plan, Version 1.0, 23 July 2013 






Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
3 
TABLE OF CONTENTS 
Section 
Page 
1. 
Information from the Study Protocol .......................................................................... 10 
1.1. 
Introduction and Objectives ............................................................................. 10 
1.1.1. 
Introduction ........................................................................................... 10 
1.1.2. 
Study Objectives ................................................................................... 11 
1.2. 
Study Design ....................................................................................................... 12 
1.2.1. 
Synopsis of Study Design ..................................................................... 12 
1.2.2. 
Randomization Methodology ............................................................... 14 
1.2.3. 
Stopping Rules and Unblinding ............................................................ 14 
1.2.4. 
Study Procedures .................................................................................. 14 
1.2.5. 
Pharmacodynamic and Safety Parameters ............................................ 23 
2. 
Subject Population ......................................................................................................... 24 
2.1. 
Population Definitions ....................................................................................... 24 
2.2. 
Protocol Violations ............................................................................................. 24 
3. 
General Statistical Methods .......................................................................................... 25 
3.1. 
Sample Size Justification ................................................................................... 25 
3.2. 
General Methods ................................................................................................ 25 
3.3. 
Computing Environment .................................................................................. 26 
3.4. 
Baseline Definitions ............................................................................................ 26 
3.5. 
Methods of Pooling Data ................................................................................... 26 
3.6. 
Adjustments for Covariates .............................................................................. 26 
3.7. 
Multiple Comparisons/Multiplicity .................................................................. 26 
3.8. 
Subpopulations ................................................................................................... 26 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up ..................................................... 26 
3.10. Missing, Unused, and Spurious Data ............................................................... 27 
3.11. Visit Windows..................................................................................................... 27 
3.12. Interim Analyses ................................................................................................ 27 
4. 
Study Analyses ............................................................................................................... 28 
4.1. 
Subject Disposition............................................................................................. 28 
4.2. 
Demographics and Baseline Characteristics ................................................... 28 
4.3. 
Pharmacodynamic Evaluation .......................................................................... 28 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
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Section 
Page 
4.3.1. 
Total Serum TTR (ELISA) ................................................................... 28 
4.3.2. 
Vitamin A and Retinol Binding Protein ............................................... 30 
4.4. 
Pharmacokinetic Evaluations ........................................................................... 30 
4.5. 
Safety Analyses ................................................................................................... 30 
4.5.1. 
Study Drug Exposure ............................................................................ 30 
4.5.2. 
Adverse Events ..................................................................................... 30 
4.5.3. 
Laboratory Data .................................................................................... 32 
4.5.4. 
Vital Signs and Physical Examination .................................................. 33 
4.5.5. 
Electrocardiogram ................................................................................. 33 
4.5.6. 
Concomitant Medications ..................................................................... 34 
5. 
Changes to Planned Analyses ....................................................................................... 35 
6. 
References ....................................................................................................................... 36 
7. 
Clinical Study Report Appendices ............................................................................... 37 
7.1. 
Statistical Tables to be Generated .................................................................... 37 
7.2. 
Data Listings to be Generated .......................................................................... 40 
7.3. 
Figures to be Generated .................................................................................... 42 
8. 
Table Shells ..................................................................................................................... 44 
9. 
Data Listing Shells ......................................................................................................... 70 
 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
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TABLES INCLUDED IN THE TEXT 
 
Page 
Table 1-1 
Schedule of Assessments for Cohorts Administered ALN-TTR02 Once 
Every 4 Weeks (from Protocol version 2.1 dated 16 January 2013) ............................... 15 
Table 1-2 
Schedule of Assessments for Optional Cohorts Administered ALN-TTR02 
Once Every 3 Weeks (from Protocol version 2.1 dated 16 January 2013) ..................... 19 
 
 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
z 
Elimination rate constant 
AE 
Adverse event 
ALT 
Alanine transaminase 
anti-HCV Ab 
Anti–hepatitis C virus antibody 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
ATC 
Anatomic therapeutic class 
ATTR 
Transthyretin-mediated amyloidosis 
AUC 
Area under the plasma concentration-time curve 
AUC0- 
Area under the plasma concentration-time curve 
extrapolated to infinity 
AUC0-last 
Area under the plasma concentration-time curve from zero 
to the last measurable time point 
AUC0-t 
Area under the plasma concentration-time curve to the last 
measurable concentration 
AUCp 
Partial area under the plasma concentration-time curve 
Bb 
Activation fragment of complement fragment B 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
C3a 
Complement component 3a 
CI 
Confidence interval 
CL 
Systemic clearance 
CLR 
Renal clearance 
Cmax 
Observed maximum plasma concentration  
CPK 
Creatine phosphokinase 
CPK-MB 
Myocardial band of enzymes of creatine phosphokinase 
CRF/eCRF 
Case report form/Electronic case report form 
CRO 
Contract Research Organization 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
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Abbreviation 
Definition 
CRP 
C-reactive protein 
CSR 
Clinical study report 
DLin-MC3-DMA 
1,2-Dilinoleyloxy-N,N-dimethylpropylamine 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
EOI 
End of infusion 
ET 
Early termination 
EU 
European Union 
G-CSF 
Granulocyte-colony stimulating factor 
H1/H2 blocker 
Histamine H1/H2 receptor antagonist 
HbsAb 
Hepatitis B surface antibody 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HEENT 
Head/ears/eyes/nose/throat 
ICH 
International Conference on Harmonization 
IFN-α 
Interferon-alpha 
IFN-γ 
Interferon-gamma 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL-1β 
Interleukin-1 beta 
IL-1RA 
IL-1 receptor antagonist 
IL-6 
Interleukin-6 
IL-12 
Interleukin-12 
INR 
International normalized ratio 
IP-10 
Interferon-inducible protein-10 
IRR 
Infusion-related reaction 
ITT 
Intent-to-treat 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
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CONFIDENTIAL 
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Abbreviation 
Definition 
IV 
Intravenous(ly) 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LFT 
Liver function test 
LNP 
Lipid nanoparticles 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
Messenger ribonucleic acid 
PD 
Pharmacodynamic 
PEG2000-C-DMG 
3-N-[(ω-methoxy poly(ethylene glycol)2000) carbamoyl]-
1,2-dimyristyloxy-propylamine 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PO 
Per os (orally) 
PP 
Per-protocol 
PT 
Prothrombin time 
QTc 
QT interval corrected for heart rate 
RBC 
Red blood cell 
RBP 
Retinol binding protein 
RNAi 
Ribonucleic interference 
SAE 
Serious adverse event 
SaO2 
Arterial oxygen saturation 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SI 
International system of units 
siRNA 
Small interfering ribonucleic acid 
SNALP 
Stable nucleic acid lipid particles 
SOC 
System organ class 
SRC 
Safety Review Committee 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
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Abbreviation 
Definition 
t1/2 
Terminal elimination half-life 
t1/2 
Alpha half-life 
t1/2β 
Beta half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
tmax 
Time of observed maximum plasma concentration 
TNF- 
Tumor necrosis factor-alpha 
TSH 
Thyroid stimulating hormone 
TTR 
Transthyretin 
ULN 
Upper limit of normal 
US/USA 
United States 
VLDL 
Very low density lipoprotein 
Vss 
Volume of distribution at steady state 
Vz 
Volume of distribution based on the terminal phase 
WBC 
White blood cell 
WHO 
World Health Organization 
WT 
Wild type 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
Transthyretin (TTR), also known as prealbumin, is a tetramer protein produced predominantly 
by hepatocytes (>95% of TTR is liver-derived), with a small fraction produced in the choroid 
plexus and retina.[1]  The primary physiological role of TTR is to serve as a carrier of retinol 
(also known as vitamin A); it also plays a minor role as a carrier for thyroxine (T4). 
Mutations in the TTR gene can lead to destabilization of the tetrameric protein and 
disassociation of the TTR subunits into dimers and individual monomers.  These misfolded TTR 
monomers (both mutant and wild type [WT]) can then self-assemble into amyloid fibrils.[2]  
The amyloid fibrils are deposited into the extracellular space of various tissues where they form 
amyloid plaques, with the peripheral nervous system, gastrointestinal tract, and heart being 
among the major sites of deposition. 
There are over 100 reported TTR genetic mutations, and phenotypically these result in a 
spectrum of disease which is collectively referred to as TTR-mediated amyloidosis (ATTR).[3]  
There is a range of clinical manifestations of ATTR; the most common manifestations include 
some form of cardiac and/or neurologic involvement (e.g., cardiomyopathy, autonomic 
neuropathy, and sensory and motor neuropathy) that depends, in part, upon the particular TTR 
mutation and the site of amyloid deposition.  Transthyretin amyloidosis is associated with 
severe morbidity and mortality, with a life expectancy limited to approximately 5 to 15 years 
from symptom onset.[4] 
Because the liver is the primary source of mutant TTR, liver transplantation has been used over 
the past 20 years in an attempt to treat ATTR.  However, the procedure is only effective in 
halting or slowing the progression of disease in patients with an early age of onset[5], especially 
for those with the V30M mutation and short disease duration prior to transplant; consequently, 
almost two-thirds of ATTR patients are not transplant-eligible.  Tafamidis, a TTR tetramer 
stabilizer, was approved (November 2011) in the European Union (EU) for the treatment of 
ATTR in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic 
impairment.[6]  The large majority of ATTR patients do not qualify for either liver 
transplantation or tafamidis.  In these patients, the disease is primarily managed with palliative 
care. 


Alnylam Pharmaceuticals, Inc. 
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Ribonucleic interference (RNAi) is a naturally occurring cellular mechanism for regulating gene 
expression that is mediated by “small interfering ribonucleic acids” (siRNAs).[7]  Typically, 
synthetic siRNAs are 19 to 23 base pair double-stranded oligonucleotides in a staggered duplex 
with a 2-nucleotide overhang at 1 or both of the 3' ends.  Such siRNAs can be designed to target 
an endogenous or virally-expressed gene.  When introduced into cells, the net effect of an 
RNAi-based pharmacological approach is the binding of the siRNA to its complementary 
messenger ribonucleic acid (mRNA) sequence, cleavage of this target mRNA, and suppression 
of the target protein.[8]  The ability to selectively and potently degrade the mRNA encoding the 
TTR protein using a siRNA offers a potent and specific approach for the treatment of ATTR. 
Alnylam Pharmaceuticals is developing ALN-TTR02 Solution for Injection (hereafter referred 
to as ALN-TTR02), a synthetic investigational RNAi therapeutic comprising a siRNA targeting 
the TTR mRNA formulated in a lipid nanoparticle (LNP) termed AF-011.  The LNP enables 
delivery of the siRNA primarily to the liver upon systemic administration, resulting in the 
down-regulation of hepatic TTR expression and, in turn, reducing serum mutant and WT TTR 
levels.  The proposed indication for ALN-TTR02 is for the treatment of ATTR.  ALN-TTR02 is 
intended for administration as an intravenous (IV) infusion over 1 hour. 
ALN-TTR02, a second generation siRNA LNP formulation termed AF-011, employs the same 
siRNA as ALN-TTR01, which utilizes the first generation LNP (termed stable nucleic acid lipid 
particles [SNALP]).  Both ALN-TTR01 and ALN-TTR02 are intended for the treatment of 
patients with ATTR; the AF-011 formulation, however, has been optimized to be more potent 
such that mRNA and protein reduction effects are observed at significantly lower doses with 
AF-011 than with the SNALP formulation. 
1.1.2. 
Study Objectives 
The primary objective of this study is to evaluate the safety and tolerability of multiple doses of 
ALN-TTR02. 
The secondary objectives of this study are: 
 To characterize the plasma and urine pharmacokinetics (PK) of ALN-TTR02. 
 To assess preliminary evidence of the pharmacodynamic (PD) effect of ALN-TTR02 on 
serum total TTR levels. 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s).  Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided.  The statistical 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
12 
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.  Pharmacokinetic (PK) and 
pharmacokinetic/pharmacodynamics (PK/PD) analyses will be described in a separate analytical 
plan, will be performed by Alnylam Pharmaceuticals or its designated Contract Research 
Organization (CRO), and presented in a separate report (to be included in the CSR). 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
Protocol ALN-TTR02-002 is a multi-national, multi-center, Phase 2, open-label, multi-dose, 
dose escalation study designed to determine the safety, tolerability, PK, and PD of 2 consecutive 
doses (separated by approximately 4 weeks) of ALN-TTR02 in patients with ATTR. 
Patients of any mutant TTR genotype with a biopsy-proven diagnosis of ATTR who exhibit 
documented signs/symptoms of the disease (e.g., sensory, motor, or autonomic neuropathy) that 
are at least mild to moderate in severity will be eligible for the study, provided they have a body 
mass index (BMI) of 17-33 kg/m2, an adequate performance status (Karnofsky performance 
status of 60% or greater), adequate hepatic and renal function, no active infection or 
inflammatory disorder, stable cardiac status, and have not had a liver transplant. 
Two doses of ALN-TTR02 will be given 4 weeks apart to 4 sequential cohorts comprised of 3 
patients each.  The 4 cohorts will receive ascending doses of 10, 50, 150, and 300 μg/kg.  No 
patient will be a member of more than 1 treatment group.  An alternative dosing regimen of 2 
doses of ALN-TTR02 (at a dose previously determined by the Safety Review Committee [SRC] 
to be safe and tolerable) separated by 3 weeks may be evaluated in the optional cohort(s). 
Within each of the cohorts, the first patient will receive their first dose and if the dose is well-
tolerated (per protocol Section 5.7.3, Dose-limiting Toxicity), Patients 2 and 3 will receive their 
first dose at that same dose level no sooner than 48 hours apart, with Patient 2 receiving a dose 
of study drug no sooner than 48 hours after the dosing of Patient 1.  Similar to the first dose, the 
second dose will be administered to patients 4 weeks after the first dose in a sequential manner 
with at least 48 hours separating dosing of each patient.  If after the first dose, ALT and AST are 
>2.5 ×ULN, that patient would not receive their second dose. 
Dose escalation to the next cohort will proceed after the collective safety and tolerability data 
through at least 96 hours post-first dose from the 3 patients in the previous cohort has been 


Alnylam Pharmaceuticals, Inc. 
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CONFIDENTIAL 
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reviewed by the SRC.  If the administered dose is found to be safe and well-tolerated, dosing for 
the next cohort will begin no sooner than 96 hours after Patient 3 has safely received dose 1 
from the previous cohort.  Patients in the cohort would be dosed and reviewed for safety and 
tolerability following the same procedures as used for other cohorts (as stated above). 
For patients on all dose levels other than the starting dose level of 10 g/kg, prior to receiving 
the second dose the SRC will review the cumulative safety and tolerability data of at least 
2 patients from the previous dose level(s) with at least 96 hours of follow-up after receiving a 
second dose of study drug. 
For any dose-limiting toxicity (DLT), accrual to that dose level will stop, all dosing will be 
discontinued, and dose escalation will end, pending further evaluation of all available safety 
data by the SRC (see protocol Section 5.7.4).  The SRC may be convened earlier at the 
discretion of Alnylam if important safety issues arise requiring the attention of the committee 
(e.g., new safety information attained in other ongoing studies with ALN-TTR02). 
The duration of patient participation in this study is approximately 36 weeks.  Patients will be 
screened from -45 to -3 days prior to dose administration.  Eligible patients will undergo further 
pre-treatment assessments (performed on Day 0).  Patients receiving the original premedication 
regimen will receive oral premedication with dexamethasone (or equivalent), paracetamol (or 
equivalent), and H1 and H2 blockers the night before and 30 to 60 minutes prior to each dose of 
ALN-TTR02 to reduce the potential of an infusion-related reaction (IRR) (see protocol 
Section 5.5).  Those patients in an optional cohort evaluating an alternative premedication 
regimen, as agreed upon by the SRC, will receive IV dexamethasone (or equivalent), oral 
paracetamol (or equivalent), and IV H1 and H2 blockers at least 60 minutes prior to ALN-
TTR02 dosing; no premedication will be administered the evening prior to dosing.  On Days 0 
and 28, patients on the 4-week dosing regimen will receive a single dose of ALN-TTR02 
administered as a 60-minute IV infusion (for cohorts with the original premedication regimen 
and infusion rate), or as an approximate 70-minute IV infusion for those patients in an optional 
cohort evaluating the alternative premedication regimen and infusion rate.  The infusion time 
may be extended up to 3 hours in the event of a mild or moderate infusion reaction (study drug 
administration will not be resumed for any patient following a severe infusion reaction).  Details 
on the study drug administration are provided in protocol Section 5.6.  Patients will be 
hospitalized at the study site for at least 24 hours after the end of the study drug infusion.  
Patients may be discharged upon Investigator review of the 24-hour electrocardiogram (ECG), 
liver function tests (LFTs), and a subset of serum chemistries (sodium, potassium, creatinine, 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
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CONFIDENTIAL 
14 
albumin, calcium, glucose, and phosphate), if results are deemed not clinically significant.  
Patients will return to the site for outpatient visits for safety, PK, and PD monitoring up to 
208 days post-dose (see protocol Section 6 for details). 
The SRC will evaluate safety in the study and determine if it remains acceptable to dose escalate 
or administer the second dose to the next dose level per their safety review charter.  To ensure 
timely safety information exchange across the participating study centers, the SRC will be 
comprised of all Principal Investigators (PIs) participating in the study or their designee, the 
Alnylam Medical Monitor, and the CRO Medical Monitor.  The SRC will communicate 
frequently to ensure that patients are dosed according to the time intervals specified in protocol 
Section 5.6, even as patients are being accrued across multiple centers. 
An open-label extension study at the recommended Phase 3 dose and regimen (as determined 
from Study ALN-TTR02-002) is planned, which will enable the patients who enrolled in Study 
ALN-TTR02-002 to receive additional, long-term dosing and safety follow-up.  For some of the 
patients, this may preclude the completion of all of the follow-up period assessments of Study 
ALN-TTR02-002 if they are deemed eligible to participate in the extension study prior to 
completion of the full follow up through Day 208.  Such patients will be followed up for a 
minimum of 28 days after their last dose in the current ALN-TTR02-002 study prior to being 
enrolled in the extension study.  The extension study will be implemented only after dose 
escalation is completed in Study ALN-TTR02-002, with post second dose follow-up through 
Day 208 in at least 1 cohort at the highest dose. 
1.2.2. 
Randomization Methodology 
Not applicable. 
1.2.3. 
Stopping Rules and Unblinding 
For any DLT, accrual to that dose level will stop, all dosing will be discontinued, and dose 
escalation will end, pending further evaluation of all available safety data by the SRC. 
Unblinding is not applicable to this open-label study. 
1.2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1-1 (for 
cohorts administered ALN-TTR02 once every 4 weeks) and Table 1-2 (for optional cohort(s) 
dosed once every 3 weeks). 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
15 
Table 1-1 
Schedule of Assessments for Cohorts Administered ALN-TTR02 Once Every 4 Weeks (from Protocol version 
2.1 dated 16 January 2013) 
Procedures 
Screening 
Pre-Dosing 
Dosing Cycles 
Follow-Up 
D -45 to  
D -3 
D -1 
D 0 
D 0 
D 1 
D 2 
D 7 
(±1 D) 
D 10 
(±2 D) 
D 14 
(±3 D) 
D 21 
(±3 D) 
D 56a 
(±3 D) 
D 112 
(±10 D) 
D 208a 
(±2 W) 
D 27 
D 28 
(+2 D) 
D 28 
(+2 D) 
D 29 
D 30 
D 35 
(±1 D) 
D 38 
(±2 D) 
D 42 
(±3 D) 
D 49 
(±3 D) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
Xb 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination, 
excluding weight 
X 
 
Xc 
 
Xc 
Xc 
 
 
Xc 
 
X 
 
 
Weight 
X 
 
Xd 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index (BMI) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signse 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Vital Signs (Serial)f 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Echocardiogramg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG (Serial)h 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Inpatient at Study Site 
 
 
X 
X 
Xi 
 
 
 
 
 
 
 
 
Cardiac Monitoring 
(Telemetry)j 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Pulse Oximetry (Serial)f 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
(females only) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine Pregnancy Test 
(females only)k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C Statusl 
X 
 
 
 
 
 
 
 
 
 
 
 
 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
16 
Procedures 
Screening 
Pre-Dosing 
Dosing Cycles 
Follow-Up 
D -45 to  
D -3 
D -1 
D 0 
D 0 
D 1 
D 2 
D 7 
(±1 D) 
D 10 
(±2 D) 
D 14 
(±3 D) 
D 21 
(±3 D) 
D 56a 
(±3 D) 
D 112 
(±10 D) 
D 208a 
(±2 W) 
D 27 
D 28 
(+2 D) 
D 28 
(+2 D) 
D 29 
D 30 
D 35 
(±1 D) 
D 38 
(±2 D) 
D 42 
(±3 D) 
D 49 
(±3 D) 
Serum Chemistry, 
Hematology, Urinalysis 
X 
 
Xm 
 
X 
 
 
 
X 
 
X 
 
 
Liver Function Testsn 
X 
 
Xm 
 
X 
X 
X 
 
X 
 
X 
 
 
Coagulation Studieso 
X 
 
Xm 
 
X 
 
 
 
 
 
 
 
 
Lipid Panelp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
TTR protein, Vitamin A, 
and RBP in serum 
X 
 
Xq 
 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
TTR mRNA in serum 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Thyroid Function Testss 
X 
 
Xm 
 
 
 
 
 
X 
 
X 
 
 
Complement Bbt 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
If infusion reaction:  
Tryptase and C3au 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Premedicationv 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Premedication reminderw 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Administration 
 
 
 
Xx 
 
 
 
 
 
 
 
 
 
Anti-PEG Antibody 
Testing (IgG, IgM) 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Cytokines and CRPy 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Plasma PK Samplingz 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urine PK Samplingaa 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Exploratory Biomarkers 
X 
 
Xbb 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant 
Medications 
X 
 
 
Continuous Monitoring 
 
 
Review/Record AEs 
 
 
 
 
 
Study Completion 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Footnotes on following pages. 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
17 
Note: The schedule of assessments for optional cohorts administered ALN-TTR02 once every 3 weeks is provided in Table 1-2. 
a 
Early termination procedures: if a patient withdraws prior to Day 56, then the Days 56 and 208 visits should be performed.  If a patient is withdrawn/withdraws after Day 56 
and prior to Day 208, then the Day 208 visit should be performed. 
b 
Interval medical history. 
c 
Focused physical examination (includes head/ears/eyes/nose/throat [HEENT], cardiovascular, respiratory, abdominal, and hepatic assessments).  If the screening physical 
examination was performed within 72 hours of Day 0, then the pre-dose (Day 0) physical examination does not need to be repeated; however, the patient’s weight will be 
obtained. 
d 
Weight measured on Day 0 and Day 28 will be used for calculating first and second dose, respectively. 
e 
Vital signs to include: blood pressure, pulse rate, oral body temperature, and respiratory rate.  Parameters are to be measured in the supine position using an automated 
instrument after the patient has rested comfortably for 10 minutes. 
f 
Serial measures (vital signs and pulse oximetry) are to be measured within 30 minutes pre-dose; at the end of infusion (EOI); and 30 (±5) minutes; 1, 2, and 3 (±15 minutes) 
hours; 6, 12, and 18 (±30 minutes) hours; and 24 (+30 minutes) hours post-infusion. 
g 
Not needed if a normal echocardiogram has been obtained within the past 90 days. 
h 
Serial electrocardiograms (ECGs) will be collected in 3 replicates within 30 minutes pre-dose, EOI, and 30 (±5) minutes, 2 and 4 (±15 minutes) hours, and 24 (+30 minutes) 
hours post-infusion. 
i 
Patients will be hospitalized at the study site for at least 24 hours after the end of infusion of study drug.  Patients may be discharged upon completion of review by the 
Investigator of ECG, sodium, potassium, creatinine, albumin, calcium, glucose, phosphate, and LFTs results obtained at 24-hours post-infusion, if results are deemed not 
clinically significant.  Any clinically significant findings must be discussed with the medical monitor to determine whether patient can be discharged and to formulate plans 
for patient follow-up. 
j 
Continuous cardiac monitoring will be performed via telemetry starting no later than 30 minutes prior to dosing and continuing through 24 hours (+1 hour) post-dose. 
k 
Day 0 pre-dose only, not performed on Day 28. 
l 
Serologies include hepatitis B surface antibody (HbsAb), hepatitis B surface antigen (HbsAg), and anti–hepatitis C virus antibody (anti-HCV Ab). 
m 
If the parameter was assessed and meets eligibility requirements within 72 hours of Days 0 and 28, then it does not need to be repeated pre-dose (Days 0 and 28, respectively). 
n 
Liver function tests include aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and bilirubin (total and direct). 
o 
Coagulation studies include prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR). 
p 
Lipid panel (non-fasting) includes total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), and triglycerides 
will be collected on Day 0 only. 
q 
Pre-dose samples for TTR protein, vitamin A, and RBP measurements will be drawn immediately (within 10 minutes) prior to the premedications and immediately prior to 
dosing. 
r 
A patient will be followed approximately every 2 weeks after Day 56 if their TTR level continues to recover but is not found to have returned to within at least 80% of the 
baseline value.  If this occurs, the patient will be followed and discussed at each SRC meeting until the TTR level returns to within at least 80% of the baseline value. 
s 
Thyroid function tests include thyroid stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3). 
t 
A blood sample will be collected for the assessment of complement Bb immediately (within 10 minutes) pre-dose, and 30 (±5) minutes, and 2 (± 15 minutes) and 24 hours 
(±120 minutes) post infusion.  If the patient experiences an infusion reaction, a blood sample for analysis of complement factors should be obtained within 1 hour of the start 
of the reaction. 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
18 
u 
A blood sample for the assessment of tryptase and C3a is to be collected only in the event of an acute infusion reaction: at time of event or as soon as possible after onset, 
1 hour, and 24 hours after the event. 
v 
Premedications include dexamethasone (8 mg, or equivalent), paracetamol (500 mg, or equivalent), H2 blocker (e.g., 150 mg ranitidine or 20 mg famotidine, or equivalent 
other H2 blocker dose), and H1 blocker (10 mg cetirizine, 25 mg hydroxyzine, fexofenadine or equivalent may be substituted) will be self-administered per os (PO) the 
evening before study drug administration.  Thirty to 60 minutes prior to the start of study drug infusion, dexamethasone (20 mg PO, or equivalent), paracetamol (500 mg PO, 
or equivalent), an H2 blocker (PO), and an H1 blocker (PO) will be administered by study site personnel.  Patients enrolled in an optional cohort evaluating the use of an 
alternative premedication regimen, as agreed upon by the SRC, will receive the following medications at least 60 minutes prior to the start of infusion of ALN-TTR02:  
dexamethasone (10 mg IV, or equivalent), paracetamol (PO 500 mg; or equivalent), IV H2 blocker (e.g. ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 blocker 
dose), and IV H1 blocker (e.g., diphenhydramine 50 mg or equivalent; hydroxyzine or fexofenadine 25 mg PO or cetirizine 10 mg PO may be substituted for any patient who 
does not tolerate IV diphenhydramine or other IV H1 blockers).  These patients will not receive any premedications the evening prior to ALN-TTR02 dosing. 
w 
Site personnel are to call patients the day before dosing to remind them to take premedications that evening (the day before dosing).  This reminder will not be needed for 
patients enrolled in optional cohorts evaluating the alternative premedication regimen. 
x 
The infusion site will be assessed for any localized reaction pre-dose, during infusion, and for 30 minutes after the infusion. 
y 
A blood sample for the assessment of cytokines and C-reactive protein (CRP) will be collected immediately (within 10 minutes) pre-dose, and 2 (±15 minutes), 6 (±15 
minutes), and 24 hours (±120 minutes) post infusion.  If the patient experiences an infusion reaction, a blood sample for analysis of cytokines should be obtained within 
1 hour of the start of the reaction. 
z 
For each dose, plasma PK samples (siRNA and lipids) will be collected pre-dose (within 1 hour of planned dosing start), EOI, and then 5, 10, and 30 minutes, and 1, 2, 4, 6, 
24 and 48 hours post infusion.  Samples will also be collected on Days 7, 14, 21, 35, 42, 49, 56, 112, and 208.  Plasma PK on Day 0 at EOI and then 2 hours post-infusion will 
be analyzed for both free and encapsulated siRNA for cohort 3 and onward, including any optional cohorts.  For each post dose PK blood draw, the following sampling 
windows are allowed: ±1 minute for the 5- and 10-minute draws; ±2 minutes for the 30-minute draws; ±5 minutes for the 1-, 2-, 4-, and 6-hour draws; and ±120 minutes for 
the 24- and 48-hour draws. 
aa 
For each dose, urine PK samples will be collected pre-dose (within 1 hour of planned dosing start), and from 0-6 hours post-infusion (pooled).  Samples will also be collected 
on Days 7, 14, 21, 35, 42, 49, 56, 112, and 208. 
bb Pre-dose samples should be collected prior to infusion, but after premedications have been administered. 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
19 
Table 1-2 
Schedule of Assessments for Optional Cohorts Administered ALN-TTR02 Once Every 3 Weeks (from Protocol 
version 2.1 dated 16 January 2013) 
 
Screening 
Pre-Dosing 
Dosing Cycles 
Follow-Up 
 
 
D -1 
D 0 
D 0 
D 1 
D 2 
D 7 
(±1 D) 
D 10 
(±2 D) 
D 14 
(±3 D) 
 
 
 
 
 
Procedures 
D -45  
to D -3 
D 20 
D 21 
(+2 D) 
D 21 
(+2 D) 
D 22 
D 23 
D 28 
(±1 D) 
D 31 
(±2 D) 
D 35 
(±3 D) 
D 42 
(±3 D) 
D 49 
(±3 D) 
D 56a 
(±3 D) 
D 112 
(±10 D) 
D 208a 
(±2 W) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination, 
excluding weight 
X 
 
Xc 
 
Xc 
Xc 
 
 
Xc 
 
 
X 
 
 
Weight 
X 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Mass Index (BMI) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signse 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital Signs (Serial)f 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Echocardiogramg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG (Serial)h 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Inpatient at Study Site 
 
 
X 
X 
Xi 
 
 
 
 
 
 
 
 
 
Cardiac Monitoring 
(Telemetry)j 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pulse Oximetry (Serial)f 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
(females only) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine Pregnancy Test 
(females only)k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C Statusl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
20 
 
Screening 
Pre-Dosing 
Dosing Cycles 
Follow-Up 
 
 
D -1 
D 0 
D 0 
D 1 
D 2 
D 7 
(±1 D) 
D 10 
(±2 D) 
D 14 
(±3 D) 
 
 
 
 
 
Procedures 
D -45  
to D -3 
D 20 
D 21 
(+2 D) 
D 21 
(+2 D) 
D 22 
D 23 
D 28 
(±1 D) 
D 31 
(±2 D) 
D 35 
(±3 D) 
D 42 
(±3 D) 
D 49 
(±3 D) 
D 56a 
(±3 D) 
D 112 
(±10 D) 
D 208a 
(±2 W) 
Serum Chemistry, 
Hematology, Urinalysis 
X 
 
Xm 
 
X 
 
 
 
X 
 
 
X 
 
 
Liver Function Testsn 
X 
 
Xm 
 
X 
X 
X 
 
X 
 
 
X 
 
 
Coagulation Studieso 
X 
 
Xm 
 
X 
 
 
 
 
 
 
 
 
 
Lipid Panelp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
TTR protein, Vitamin A, 
and RBP in serum 
X 
 
Xq 
 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
TTR mRNA in serum 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Thyroid Function Testss 
X 
 
Xm 
 
 
 
 
 
X 
 
 
X 
 
 
Complement Bbt 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
If infusion reaction:  
Tryptase and C3au 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Premedicationv 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Premedication reminderw 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Administration 
 
 
 
Xx 
 
 
 
 
 
 
 
 
 
 
Anti-PEG Antibody 
Testing (IgG, IgM) 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Cytokines and CRPy 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Plasma PK Samplingz 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Urine PK Samplingaa 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Exploratory Biomarkers 
X 
 
Xbb 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Medications 
X 
 
 
 
Continuous Monitoring 
 
 
Review/Record AEs 
 
 
 
 
 
 
Study Completion 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Footnotes on following pages. 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
21 
a 
Early termination procedures: if a patient withdraws prior to Day 56, then the Days 56 and 208 visits should be performed.  If a patient is withdrawn/withdraws after Day 56 
and prior to Day 208, then the Day 208 visit should be performed. 
b 
Interval medical history. 
c 
Focused physical examination (includes head/ears/eyes/nose/throat [HEENT], cardiovascular, respiratory, abdominal, and hepatic assessments).  If the screening physical 
examination was performed within 72 hours of Day 0, then the pre-dose (Day 0) physical examination does not need to be repeated; however, the patient’s weight will be 
obtained. 
d 
Weight measured on Day 0 and Day 21 will be used for calculating first and second dose, respectively. 
e 
Vital signs to include: blood pressure, pulse rate, oral body temperature, and respiratory rate.  Parameters are to be measured in the supine position using an automated 
instrument after the patient has rested comfortably for 10 minutes. 
f 
Serial measures (vital signs and pulse oximetry) are to be measured within 30 minutes pre-dose; at the end of infusion (EOI); and 30 (±5) minutes; 1, 2, and 3 (±15 minutes) 
hours; 6, 12, and 18 (±30 minutes) hours; and 24 (+30 minutes) hours post-infusion. 
g 
Not needed if a normal echocardiogram has been obtained within the past 90 days. 
h 
Serial electrocardiograms (ECGs) will be collected in 3 replicates within 30 minutes pre-dose, EOI, and 30 (±5) minutes, 2 and 4 (±15 minutes) hours, and 24 (+30 minutes) 
hours post-infusion. 
i 
Patients will be hospitalized at the study site for at least 24 hours after the end of infusion of study drug.  Patients may be discharged upon completion of review by the 
Investigator of ECG, sodium, potassium, creatinine, albumin, calcium, glucose, phosphate, and LFTs results obtained at 24-hours post-infusion, if results are deemed not 
clinically significant.  Any clinically significant findings must be discussed with the medical monitor to determine whether patient can be discharged and to formulate plans 
for patient follow-up. 
j 
Continuous cardiac monitoring will be performed via telemetry starting no later than 30 minutes prior to dosing and continuing through 24 hours (+1 hour) post-dose. 
k 
Day 0 pre-dose only, not performed on Day 21. 
l 
Serologies include hepatitis B surface antibody (HbsAb), hepatitis B surface antigen (HbsAg), and anti–hepatitis C virus antibody (anti-HCV Ab). 
m 
If the parameter was assessed and meets eligibility requirements within 72 hours of Days 0 and 21, then it does not need to be repeated pre-dose (Days 0 and 21, respectively). 
n 
Liver function tests include aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and bilirubin (total and direct). 
o 
Coagulation studies include prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR). 
p 
Lipid panel (non-fasting) includes total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), and triglycerides 
will be collected on Day 0 only. 
q 
Pre-dose samples for TTR protein, vitamin A, and RBP measurements will be drawn immediately (within 10 minutes) prior to the premedications and immediately prior to 
dosing. 
r 
A patient will be followed approximately every 2 weeks after Day 56 if their TTR level continues to recover but is not found to have returned to within at least 80% of the 
baseline value.  If this occurs, the patient will be followed and discussed at each SRC meeting until the TTR level returns to within at least 80% of the baseline value. 
s 
Thyroid function tests include thyroid stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3). 
t 
A blood sample will be collected for the assessment of complement Bb immediately (within 10 minutes) pre-dose, and 30 (±5) minutes, and 2 and 24 hours (±120 minutes) 
post infusion.  If the patient experiences an infusion reaction, a blood sample for analysis of complement factors should be obtained within 1 hour of the start of the reaction. 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
22 
u 
A blood sample for the assessment of tryptase and C3a is to be collected only in the event of an acute infusion reaction: at time of event or as soon as possible after onset, 
1 hour, and 24 hours after the event. 
v 
Premedications include dexamethasone (8 mg, or equivalent), paracetamol (500 mg, or equivalent), H2 blocker (e.g. 150 mg ranitidine or 20 mg famotidine, or equivalent 
other H2 blocker dose), and H1 blocker (10 mg cetirizine, 25 mg hydroxyzine, fexofenadine or equivalent may be substituted) will be self-administered per os (PO) the 
evening before study drug administration.  Thirty to 60 minutes prior to the start of study drug infusion, dexamethasone (20 mg PO, or equivalent), paracetamol (500 mg PO, 
or equivalent), an H2 blocker (PO), and an H1 blocker (PO) will be administered by study site personnel.  Patients enrolled in an optional cohort evaluating the use of an 
alternative premedication regimen, as agreed upon by the SRC, will receive the following medications at least 60 minutes prior to the start of infusion of ALN-TTR02:  
dexamethasone (10 mg IV, or equivalent), paracetamol (PO 500 mg; or equivalent), IV H2 blocker (e.g. ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 blocker 
dose), and IV H1 blocker (e.g., diphenhydramine 50 mg or equivalent; hydroxyzine or fexofenadine 25 mg PO or cetirizine 10 mg PO may be substituted for any patient who 
does not tolerate IV diphenhydramine or other IV H1 blockers).  These patients will not receive any premedications the evening prior to ALN-TTR02 dosing. 
w 
Site personnel are to call patients the day before dosing to remind them to take premedications that evening (the day before dosing).  This reminder will not be needed for 
patients enrolled in optional cohorts evaluating the alternative premedication regimen. 
x 
The infusion site will be assessed for any localized reaction pre-dose, during infusion, and for 30 minutes after the infusion. 
y 
A blood sample for the assessment of cytokines and C-reactive protein (CRP) will be collected immediately (within 10 minutes) pre-dose, and 2 (±15 minutes), 6 
(±15 minutes), and 24 hours (±120 minutes) post infusion.  If the patient experiences an infusion reaction, a blood sample for analysis of cytokines should be obtained within 
1 hour of the start of the reaction. 
z 
For each dose, plasma PK samples (siRNA and lipids) will be collected pre-dose (within 1 hour of planned dosing start), EOI, and then 5, 10, and 30 minutes, and 1, 2, 4, 6, 
24 and 48 hours post infusion.  Samples will also be collected on Days 7, 14, 28, 35, 42, 49, 56, 112, and 208.  Plasma PK on Day 0 at EOI and then 2 hours post-infusion will 
be analyzed for both free and encapsulated siRNA for cohort 3 and onward, including any optional cohorts.  For each post dose PK blood draw, the following sampling 
windows are allowed: ±1 minute for the 5- and 10-minute draws; ±2 minutes for the 30-minute draws; ±5 minutes for the 1-, 2-, 4-, and 6-hour draws; and ±120 minutes for 
the 24- and 48-hour draws. 
aa 
For each dose, urine PK samples will be collected pre-dose (within 1 hour of planned dosing start), and from 0-6 hours post-infusion (pooled).  Samples will also be collected 
on Days 7, 14, 28, 35, 42, 49, 56, 112, and 208. 
bb Pre-dose samples should be collected prior to infusion, but after premedications have been administered. 
 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
23 
1.2.5. 
Pharmacodynamic and Safety Parameters 
1.2.5.1. 
Pharmacodynamic Parameters 
The PD evaluation will include assessment of effects of ALN-TTR02 on serum total TTR 
levels.  Exploratory PD effects of ALN-TTR02 will be evaluated by: 
 Serial measurement of circulating mutant and wild type TTR levels. 
 Serial measurement of serum TTR mRNA levels. 
 Serial measurement of circulating vitamin A and retinol binding protein (RBP) levels. 
1.2.5.2. 
Safety Parameters 
Safety monitoring will include assessment of adverse events (AEs), 12-lead ECGs, cardiac 
monitoring (telemetry), arterial oxygen saturation (SaO2) using pulse oximetry, vital signs 
(blood pressure, pulse rate, oral body temperature, and respiratory rate), clinical laboratory 
safety tests (hematology, serum chemistry, LFTs, thyroid function parameters, serology, 
coagulation parameters, urinalysis, cytokines, c-reactive protein [CRP], and complement 
factors), and physical examinations.  Patients will be closely monitored for both acute and 
delayed IRRs.  All IRRs will be recorded as AEs. 
The safety of ALN-TTR02 will be evaluated by: 
 The proportion of subjects experiencing AEs, serious adverse events (SAEs), DLTs, 
infusion-related AEs, and AEs leading to study drug discontinuation. 
 Infusion tolerability, as assessed by serial ECGs, measurement of SaO2 by pulse 
oximetry, and blood pressure. 
 Change from baseline in clinical laboratory test results, including hematology, serum 
chemistries, LFTs, and coagulation parameters. 
 Change from baseline in measures of thyroid function (thyroid stimulating hormone 
[TSH], T4, and triiodothyronine [T3]. 
 Change from baseline in CRP, cytokines, and complement. 
 Vital sign measurements. 
 Physical examination findings. 


Alnylam Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol ALN-TTR02-002 
23 July 2013, Final Version 1.0 
 
CONFIDENTIAL 
24 
2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following patient populations (i.e., analysis sets) may be evaluated and used for 
presentation of the data: 
 Intent-to-Treat (ITT) Analysis Set:  All patients who were enrolled and received study 
treatment. 
 Per-Protocol (PP) Analysis Set:  All patients in the ITT analysis set who had no major 
protocol violations. 
 Pharmacokinetic (PK) Analysis Set:  All patients in the ITT analysis set who have 
adequate data to determine a full PK profile. 
The ITT analysis set is the primary population for the analysis of PD and safety parameters.  A 
secondary analysis of PD parameters will be performed for the PP analysis set.  The PK analysis 
set is the primary population for the analysis of PK parameters. 
2.2. 
Protocol Violations 
At the discretion of the Sponsor, major protocol violations, as determined by a review of the 
data prior to unblinding of the study results and the conduct of statistical analyses, may result in 
the removal of a subject’s data from the PP analysis set.  Medpace will be responsible for 
producing the final protocol violation file (formatted as a Microsoft Excel file), which will be 
reviewed by Veristat and Alnylam; this file will include a description of the protocol violation 
and clearly identify whether or not this violation warrants exclusion from the PP analysis set.  
This file will be finalized prior to hard database lock. 
All protocol violations will be presented in a data listing. 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
Based on the planned dose escalation scheme, up to 27 patients are expected to be enrolled.  
Three patients are to be enrolled at each of 4 planned dose levels.  An additional 5 cohorts of 3 
patients may be enrolled onto 1 or more of these specified dose levels to further evaluate safety 
and tolerability or PD effects.  The sample size was chosen based on previous experience in 
Phase 2 studies and was not based on power calculations. 
3.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day.  Pre-treatment 
and on-treatment study days are numbered relative to the day of study medication dosing, which 
is designated as Day 0.  For example, the day prior to study medication will be Day -1 and the 
day after study medication will be Day 1. 
All output will be incorporated into Microsoft Word or Excel files, or Adobe Acrobat PDF files, 
sorted and labeled according to the International Conference on Harmonisation (ICH) 
recommendations, and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters.  For categorical variables, summary tabulations of the number and percentage of 
subjects within each category (with a category for missing data) of the parameter will be 
presented.  For continuous variables, the number of subjects, mean, median, standard deviation 
(SD), minimum, and maximum values will be presented. 
All data will be presented in by-subject data listings. 
As this is a Phase 2 dose-escalation trial, formal statistical hypothesis testing will not be 
performed.  Although exploratory confidence intervals (CIs) will be presented as described 
below, no formal statistical conclusions will be made based on these estimates. 
Subjects will be analyzed in the cohort to which they were originally assigned.  Data will be 
tabulated for each dose group (i.e., dose level, regimen, and pre-medication regimen). 
Laboratory data 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. 


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3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software version 9.3 
or higher, unless otherwise noted.  Adverse events will be coded for summarization using the 
Medical Dictionary for Regulatory Activities (MedDRA® version 15.0).  Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary 
(March 2012 version). 
3.4. 
Baseline Definitions 
Unless noted otherwise, baseline will be defined as the Day 0 pre-dose value when non-missing, 
otherwise the latest value from amongst any screening values will be used (i.e., the 
measurement closest to and prior to dosing will be considered baseline).  For PD parameters 
(TTR, RBP, Vitamin A), baseline will be defined as the average of all pre-dose values (i.e., 
Screening and Day 0 pre-dose values). 
3.5. 
Methods of Pooling Data 
Data will be summarized separately for each dose group (i.e., dose level and regimen).  Data 
from expansion cohorts that are dosed at the same level and regimen as a previous cohort will be 
pooled with the previous cohort for presentation by dose group.  In addition, safety data will be 
presented overall. 
Data will be tabulated separately for dose groups dosed 4 weeks apart and dose groups dosed 3 
weeks apart, if applicable. 
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 Phase 2 study with a descriptive interpretation. 
3.8. 
Subpopulations 
Summaries of serial TTR will be presented by genotype (V30M versus other) and use of TTR 
stabilizer (tafamidis or diflunisal use versus none). 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who voluntarily withdraw are termed dropouts.  Dropouts may be replaced following 
discussion with the Investigator and Sponsor. 


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Subjects who are withdrawn due to AEs during infusion of the ALN-TTR02 will not be 
replaced. 
If a subject is withdrawn/withdraws, the discharge procedures should be performed and an early 
termination (ET) visit scheduled as follows: 
 If a subject is withdrawn/withdraws prior to Day 56, then the Day 56 assessments should 
be completed; 
 If a subject is withdrawn/withdraws after Day 56 and prior to Day 208, then the Day 208 
assessments should be completed. 
Data collected at an ET visit will be included in Day 56 or Day 208 tabular summaries.  That is, 
the Day 28 summary will include actual observed values from Day 56 along with data collected 
from any ET visits prior to Day 56.  Similarly, the Day 208 summary will include data from 
subjects completing the study, along with any data collected at ET visits between Day 56 and 
Day 208. 
3.10. 
Missing, Unused, and Spurious Data 
In general, there will be no substitutions made to accommodate missing data points.  All data 
recorded on the case report form (CRF) will be included in data listings that will accompany the 
CSR.  Data collected at multiple time points throughout the study will be presented in 
chronological order in the data listings according to assessment date/time. 
Handling of partial dates for determining whether an AE is treatment-emergent is discussed in 
Section 4.5.2.  Handling of partial dates for determining concomitant medication is discussed in 
Section 4.5.6. 
3.11. 
Visit Windows 
It is expected that all visits will occur according to the protocol schedule of assessments.  All 
data will be tabulated per the evaluation visit as recorded on the CRF even if the assessment is 
outside of the window for that study visit.  In data listings, the study day relative to Day 0 (day 
of first dose) will be presented. 
Unscheduled visits will be included in data listings, but no assignment to a study visit will be 
made for the purpose of summary tabulations. 
3.12. 
Interim Analyses 
No interim analyses are planned for this study. 


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4. 
STUDY ANALYSES 
4.1. 
Subject Disposition 
Subject disposition will be tabulated and include the number enrolled, the number dosed, the 
number in each subject population for analysis, the number who completed the study (as 
indicated on the Study Completion CRF), the number who withdrew prior to completing the 
study and reason(s) for withdrawal.  Summary data will be presented by dose group and overall. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. 
4.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and presented by dose group and 
overall for the ITT population. 
Age, height, weight, and BMI will be summarized using descriptive statistics (number of 
subjects, mean, SD, median, minimum, and maximum).  Sex, race, ethnicity, and country will 
be summarized by presenting the numbers and percentages of subjects in each category. 
Baseline disease characteristics will be summarized by presenting the numbers and percentages 
of subjects with or without the V30M mutation and with or without prior exposure to TTR02.  
Concurrent use of TTR stabilizer (Tafamidis or Diflunisal) will also be summarized. 
All demographic and baseline data will be provided in data listings. 
Medical history and prior surgeries will be presented in a data listing.  Pregnancy and virology 
test results will be presented in data listings. 
4.3. 
Pharmacodynamic Evaluation 
4.3.1. 
Total Serum TTR (ELISA) 
Serial measurements and changes from baseline of serum TTR through Day 208 will be 
summarized for each scheduled time point using descriptive statistics.  Percent change from 
baseline will also be summarized.  Ninety-five percent CIs for percent change will be presented.  
An overall summary of percent reduction in TTR will include the maximum percent reduction 
per dose group, dose group means (SD) at individual and group nadirs (defined below), and 
dose group means (SD) at Day 28 and Day 56 (Day 21 and Day 42 for optional cohorts dosed 
every 3 weeks). 
The individual nadir TTR value, defined as the lowest observed TTR value from Day 1 to the 
Day 28 premedication assessment (Day 21 for optional cohorts dosed every 3 weeks), will be 


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determined for each subject.  The nadir value will be plotted for each subject, grouped by dose 
group.  Dose group means will be indicated on the plot.  The value of the percent reduction 
associated with the nadir will be plotted similarly.  The nadir value from the Day 29 to Day 56 
interval (Day 22 to Day 42 for optional cohorts dosed every 3 weeks) will also be determined 
and plotted. 
The group nadir TTR value, defined as the lowest observed mean percent TTR reduction from 
baseline from Day 1 to the Day 28 premedication assessment (Day 21 for optional cohorts dosed 
every 3 weeks), will be determined for each dose/regimen group.  The group nadir value will be 
plotted for each group, along with standard error bars.  The group nadir value from the Day 29 
to Day 56 interval (Day 22 to Day 42 for optional cohorts dosed every 3 weeks) will also be 
determined and plotted. 
The area under the concentration-time curve (AUC) will be calculated for serum TTR.  The 
AUC will be calculated using the daily TTR concentrations starting from baseline, defined as 
the average of all pre-dose values, and continuing to the Day 28 premedication assessment 
(Day 21 for optional cohorts dosed every 3 weeks).  The trapezoidal rule will be used for the 
calculation of AUC.  For the purpose of this AUC calculation, it is assumed that the collection 
times are in multiples of equal 24 hour intervals.  For example, the interval from Day 2 to Day 4 
will be 48 hours, irrespective of actual assessment times.  AUC will be summarized using 
descriptive statistics.  A similar calculation and summary will be performed for the AUC 
calculated from Day 28 to Day 56 (Day 21 to Day 42 for optional cohorts dosed every 3 weeks). 
TTR levels over time will be plotted.  Each subject’s TTR levels will be joined by a line, and 
each subject within a dose group will have a different symbol.  A separate plot will be produced 
for each dose group.  In addition, the average of each dose group (with standard error bars) will 
be plotted versus time.  Dose group means (with standard error bars) for percent change from 
baseline will be plotted over time. 
The pharmacodynamics assessment for use in the PK/PD analysis will be similar to that 
described above, but may include additional PD analyses which will be used for the purpose of 
PK/PD analysis.  The methods for the PK/PD analysis will be described in the PK and PK/PD 
analysis plans and the analysis result will be reported in the separate PK and PK/PD report 
which will be appended to the CSR. 


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4.3.2. 
Vitamin A and Retinol Binding Protein 
Observed values and changes from baseline in vitamin A through Day 208 will be summarized 
for each scheduled time point using descriptive statistics.  Percent change from baseline will 
also be summarized.  Ninety-five percent CIs for percent change will be presented. 
Vitamin A levels over time will be plotted.  Each subject’s vitamin A levels will be joined by a 
line, and each subject within a dose group will have a different symbol.  A separate plot will be 
produced for each dose group.  In addition, the average of each dose group (with standard error 
bars) will be plotted versus time.  Dose group means (with standard error bars) for percent 
change from baseline will be plotted over time.  Percent reduction from baseline at individual 
and group nadirs will be plotted as described above for serum TTR. 
The above summaries will also be performed for RBP. 
A scatter plot of total serum TTR protein versus vitamin A and RBP, all normalized to their 
respective baseline values, will be produced.  The plot will include Spearman’s correlation 
coefficients (ρ) and the p-values from the tests of ρ = zero, to assess the strength of the 
correlations between serum TTR and vitamin A and between serum TTR and RBP. 
4.4. 
Pharmacokinetic Evaluations 
All tabulations of PK data will be presented in a separate report appended to the CSR. 
4.5. 
Safety Analyses 
Safety analyses will be conducted using the ITT analysis set. 
4.5.1. 
Study Drug Exposure 
Duration of infusion will be summarized using descriptive statistics.  A summary of the 
numbers and percentages of subjects with a dose interruption will be provided.  Duration of 
interruption will be summarized using descriptive statistics.  Summary statistics will be 
provided for the total drug amount received by the subject and the total volume infused. 
All data related to study medication administration, including details on inpatient hospitalization 
for dosing, will be presented in a data listing. 
4.5.2. 
Adverse Events 
Adverse events will be displayed in tables and data listings using MedDRA system organ class 
(SOC) and preferred term. 


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Analyses 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 
administration of study medication through 28 days after dosing, or any event that was present 
pre-infusion but worsened in intensity or was subsequently considered drug-related by the 
Investigator. 
When determining whether an AE is treatment-emergent, partial dates will be handled as 
follows.  If the day of the month is missing, the onset day will be set to the first day of the 
month unless it is the same month and year as study treatment.  In this case, in order to 
conservatively report the event as treatment-emergent, the onset date will be assumed to be the 
date of treatment.  If the onset day and month are both missing, the day and month will be 
assumed to be January 1, unless the event occurred in the same year as the study treatment.  In 
this case, the event onset will be imputed as the day of treatment, in order to report the event 
conservatively as treatment-emergent.  A missing onset date will be imputed as the day of 
treatment.  If the resulting imputed onset date is later than a non-missing date of resolution, then 
the imputed onset date will be set to the resolution date.  The imputed data is used solely for the 
purpose of determining whether an AE is treatment-emergent; actual dates as recorded on the 
eCRF will be presented in subject listings. 
Adverse events are summarized by subject incidence rates; therefore, in any tabulation, a subject 
contributes only once to the count for a given SOC or preferred term. 
The numbers and percentages of subjects with any treatment-emergent adverse event (TEAE), 
with any TEAE assessed by the Investigator as related to treatment (definitely or possibly 
related), with any TEAE that is severe in intensity, with any serious TEAE, with any TEAE 
leading to discontinuation of study medication, or with any TEAE considered a DLT will be 
summarized by dose group and overall. 
Tabulations by SOC and preferred term will be produced for all TEAEs, for all related TEAEs, 
all TEAEs of severe intensity, all treatment-emergent IRRs, and for all serious TEAEs.  In these 
tabulations, each subject will contribute only once (i.e., the most related occurrence or the most 
intense occurrence) to each of the incidence rates in the descriptive analysis, regardless of the 
number of episodes of a given event (preferred term).  The most commonly occurring TEAEs, 
defined as those events experienced by at least 10% of all subjects, will be tabulated by 
preferred term in decreasing order in frequency. 


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Separate tables will present AE incidence rates by maximum relationship to study drug and by 
maximum severity.  Subjects who report multiple occurrences of the same AE (preferred term) 
will be classified according to the most related or most severe occurrence, respectively. 
No formal hypothesis-testing of AE incidence rates will be performed. 
All reported AEs will be provided in data listings, including AEs that are not treatment-
emergent. 
By-subject listings also will be provided for the following:  subject deaths, SAEs, AEs leading 
to drug discontinuation, and DLTs. 
4.5.3. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. 
Descriptive statistics will be provided for the actual values and changes from baseline to each 
on-study evaluation for each clinical laboratory parameter, including hematology, clinical 
chemistry, LFTs, thyroid function tests, and coagulation studies.  Percent change from baseline 
will also be summarized. 
Descriptive statistics will be provided for CRP and cytokines at pre-dose and 2, 6, and 24 hours 
post-dose.  Change from pre-dose will also be summarized.  Fold change, as defined below, will 
be summarized for CRP.  Complement factor (Bb) will be summarized at pre-dose, and 
30 minutes, 2 hours and 24 hours post-dose.  Change and fold change from pre-dose will also be 
summarized.  Separate summaries will be presented for Dose 1 and Dose 2. 
Fold change from pre-dose is defined as the ratio of the post-dose value to the pre-dose value.  
Maximum fold change is defined as the ratio of the maximum post-dose value to the pre-dose 
value.  Maximum fold change from pre-dose for cytokines, complement factor (Bb), and CRP 
will be represented graphically in the form of a semi-log10 plot.  Maximum fold change will be 
plotted for each subject, grouped by dose level.  Data recorded as below the limit of detection 
will be set equal the lower limit of detection for the calculation of fold change.  Separate plots 
will be presented for Dose 1 and Dose 2. 
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 pre-dose 
category versus the post-dose category, where the post-dose category will be based on the 
maximum observed value (in absolute value) subsequent to each dose.  For dose 1, the 
maximum value shall be selected from assessments performed through the Day 28 pre-dose 


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value (Day 21 for the 3-week regimen).  All out-of-range and clinically significant laboratory 
results will be identified in subject data listings. 
Figures will be produced for each dose group that display each subject’s AST, ALT, alkaline 
phosphatase, and bilirubin (total and direct) results over time; 1 figure will be produced for each 
dose group and liver function test parameter, with lines presenting subject results over time.  In 
addition, treatment group means, with standard error bars, will be plotted over time.  Similar 
plots will be produced for complement factor (Bb) and cytokines.  A vertical reference line will 
identify the nominal Dose 2 dosing day (i.e., Day 28 for the 4-week regimen or Day 21 for the 
3-week regimen). 
Urinalysis results will be included in subject listings but will not be included in summary tables. 
Tryptase and C3a will be included in subject listings for any subjects experiencing an IRR. 
Results of anti-PEG antibody testing will be listed if any positive results are reported. 
All laboratory data, including the Day 0 fasting lipid panel, will be provided in data listings.  
Laboratory values outside of the normal ranges will be listed separately, together with 
comments as to their clinical significance. 
4.5.4. 
Vital Signs and Physical Examination 
Descriptive statistics will be provided for serial vital signs collected on each dosing day, 
including blood pressure, pulse rate, oral body temperature and respiration rate.  Pulse oximetry 
(SaO2) will be included with serial vital sign summaries.  Change from pre-dose to each 
post-dose assessment will also be summarized.  Treatment group means with standard error bars 
will be plotted over time for each serial vital sign assessment.  Separate plots will be presented 
for Dose 1 and Dose 2.  Routine vital signs will be included in subject listings but will not be 
summarized. 
Vital sign measurements will be presented for each subject in a data listing.  All physical 
examination findings will be presented in a data listing. 
4.5.5. 
Electrocardiogram 
Descriptive statistics will be provided for serial ECGs collected on each dosing day, including 
ventricular rate, PR interval, QRS duration, and QT interval.  Bazett’s formula will be used to 
calculate the heart rate corrected QT interval (QTcB).  The mean of the triplicate values will be 
used for calculating summary statistics.  Change from pre-dose to each post-dose assessment 


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will also be summarized.  Routine 12-lead ECGs will be included in subject listings but will not 
be summarized. 
Electrocardiogram data for each subject will be provided in a data listing. 
4.5.6. 
Concomitant Medications 
Concomitant medications will be defined as those medications that were initiated after first 
study drug administration or those that were ongoing at the time of the first study drug 
administration.  If a start date of a medication is missing, the drug will be assumed to be 
concomitant, unless an end date indicates otherwise.  If an end date is missing or the medication 
is ongoing, the medication will be considered concomitant. 
Concomitant medications will be coded using the WHO Drug Dictionary.  Subject incidence 
will be tabulated by Anatomic Therapeutic Class (ATC) and preferred term for each dose group 
and overall; subjects will only count once for each ATC or preferred term in the event that they 
have multiple records of the same ATC or preferred term in the database.  Medications taken as 
protocol specified premedications will be summarized separately. 
The use of concomitant medications, including protocol-specified premedications, will be 
included in a by-subject data listing.  Premedications will also be listed separately. 


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5. 
CHANGES TO PLANNED ANALYSES 
As of this date, there have been no changes between the protocol-defined statistical analyses and 
those presented in this SAP. 
 


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6. 
REFERENCES 
 
1  
Liz MA, Mar FM, Franquinho F, Soursa MM. Aboard transthyretin: from transport to 
cleavage. IUBMB Life. 2010;62:429-435. 
2  
Hou X, Aguilar MI, Small DH. Transthyretin and familial amyloidotic polymeutopathy. 
Recent progress in understanding the molecular mechanism of neurodegeneration. FEBS 
Journal. 2007;274:1637-1650. 
3  
Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE. Tabulation of human 
transthyretin (TTR) variants. Amyloid. 2003;10:160-184. 
4  
Araki S. [Amyloidosis and amyloid protein]. Tanpakushitsu Kakusan Koso. 
1984;29:1770-1782. 
5  
Okamoto S, Wixner J, Obayashi K, et al. Liver transplantation for familial amyloidotic 
polyneuropathy: impact on Swedish patients' survival. Liver Transpl. 2009;15:1229-
1235. 
6  
European Medicines Agency. Vyndaqel: EPAR-Product Information. 2011. Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002294/huma
n med 001498.jsp&mid=WC0b01ac058001d124.  Last accessed on 8 December 2011. 
7  
Vaishnaw AK, Gollob J, Gamba-Vitalo C, et al. A status report on RNAi therapeutics. 
Silence. 2010;1(1):14. 
8  
Elbashir SM, Lendeckel W, Tuschi T. RNA interference is mediated by 21- and 22-
nucleotide RNAs. Genes Dev. 2001;15:188-200. 


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7.
CLINICAL STUDY REPORT APPENDICES 
7.1. 
Statistical Tables to be Generated 
Table 14.1.1 
Subject Enrollment and Disposition, Overall and by Dose Group 
Table 14.1.2 
Demographic and Baseline Characteristics (Intent-to-Treat Analysis Set) 
Table 14.1.3 
Baseline Disease Characteristics (Intent-to-Treat Analysis Set) 
Table 14.2.1.1A Summary of Serial TTR [ELISA] (ug/mL) Measurements by Time Point – 
Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.1.1B 
Summary of Serial TTR [ELISA] (ug/mL) Measurements by Time Point – 
Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.1.2A Summary of Serial Vitamin A (umol/L) Measurements by Time Point - Q4W 
Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.1.2B 
Summary of Serial Vitamin A (umol/L) Measurements by Time Point - Q3W 
Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.1.3A Summary of Serial Retinol Binding Protein (umol/L) Measurements by Time 
Point – Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.1.3B 
Summary of Serial Retinol Binding Protein (umol/L) Measurements by Time 
Point – Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.2.1A Summary of Serial TTR [ELISA] (ug/mL) Measurements by Genotype – 
Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.2.1B 
Summary of Serial TTR [ELISA] (ug/mL) Measurements by Genotype – 
Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.2.2A Summary of Serial TTR [ELISA] (ug/mL) Measurements by Mutation – 
Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.2.2B 
Summary of Serial TTR [ELISA] (ug/mL) Measurements by Mutation – 
Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.2.3A Summary of Serial TTR [ELISA] (ug/mL) Measurements by TTR Stabilizer 
Use – Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.2.3B 
Summary of Serial TTR [ELISA] (ug/mL) Measurements by TTR Stabilizer 
Use – Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.3.1A Summary of Percent Reduction in Serum TTR (ELISA) by Dose Group – 
Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.3.1B 
Summary of Percent Reduction in Serum TTR (ELISA) by Dose Group – 
Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.3.2A Summary of Percent Reduction in Serum Wild Type TTR (LCMS/MS) by 
Dose Group – Q4W Cohorts (Intent-to-Treat Analysis Set – V30M Subjects) 
Table 14.2.3.2B 
Summary of Percent Reduction in Serum Wild Type TTR (LCMS/MS) by 
Dose Group – Q3W Cohorts (Intent-to-Treat Analysis Set – V30M Subjects) 


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Table 14.2.3.3A Summary of Percent Reduction in Serum Mutant TTR (LCMS/MS) by Dose 
Group – Q4W Cohorts (Intent-to-Treat Analysis Set – V30M Subjects) 
Table 14.2.3.3B 
Summary of Percent Reduction in Serum Mutant TTR (LCMS/MS) by Dose 
Group – Q3W Cohorts (Intent-to-Treat Analysis Set – V30M Subjects) 
Table 14.2.4.1A Summary of Area under the TTR (ELISA) Concentration Time Curve – Q4W 
Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.4.1B 
Summary of Area under the TTR (ELISA) Concentration Time Curve – Q3W 
Cohorts (Intent-to-Treat Analysis Set) 
Table 14.2.4.2A Summary of Area under the Wild Type TTR (LCMS/MS) Concentration 
Time Curve – Q4W Cohorts (Intent-to-Treat Analysis Set – V30M Subjects) 
Table 14.2.4.2B 
Summary of Area under the Wild Type TTR (LCMS/MS) Concentration 
Time Curve – Q3W Cohorts (Intent-to-Treat Analysis Set – V30M Subjects) 
Table 14.2.4.3A Summary of Area under the Mutant TTR (LCMS/MS) Concentration Time 
Curve – Q4W Cohorts (Intent-to-Treat Analysis Set – V30M Subjects) 
Table 14.2.4.3B 
Summary of Area under the Mutant TTR (LCMS/MS) Concentration Time 
Curve – Q3W Cohorts (Intent-to-Treat Analysis Set – V30M Subjects) 
Table 14.3.1.1 
Summary of Treatment-Emergent Adverse Events, Overall and by Dose 
Group (Intent-to-Treat Analysis Set) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events, Overall and by Dose Group (Intent-to-
Treat Analysis Set) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events Related to Study Drug, Overall and by 
Dose Group (Intent-to-Treat Analysis Set) 
Table 14.3.1.4 
Severe Treatment-Emergent Adverse Events, Overall and by Dose Group 
(Intent-to-Treat Analysis Set) 
Table 14.3.1.5 
Severe Treatment-Emergent Adverse Events Related to Study Drug, Overall 
and by Dose Group (Intent-to-Treat Analysis Set) 
Table 14.3.1.6 
Serious Treatment-Emergent Adverse Events, Overall and by Dose Group 
(Intent-to-Treat Analysis Set) 
Table 14.3.1.7 
Treatment-Emergent Infusion Related Reaction Signs and Symptoms, 
Overall and by Dose Group (Intent-to-Treat Analysis Set) 
Table 14.3.1.8 
Most Common (≥10% of All Subjects) Treatment-Emergent Adverse Events, 
Overall and by Dose Group (Intent-to-Treat Analysis Set) 
Table 14.3.1.9 
Treatment-Emergent Adverse Events by Maximum Relationship to Study 
Drug, Overall and by Dose Group (Intent-to-Treat Analysis Set) 
Table 14.3.1.10 
Treatment-Emergent Adverse Events by Maximum Severity, Overall and by 
Dose Group (Intent-to-Treat Analysis Set) 
Table 14.3.2.1 
Subject Listing of Deaths 
Table 14.3.2.2 
Subject Listing of Serious Adverse Events 


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Table 14.3.2.3 
Subject Listing of Discontinuations Due to Adverse Events 
Table 14.3.2.4 
Subject Listing of Dose Limiting Toxicities 
Table 14.3.4 
Listing of Abnormal Laboratory Values 
Table 14.3.5.1A Summary and Change from Baseline for Hematology Parameters by Visit, 
Overall and by Dose Group – Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.1B 
Summary and Change from Baseline for Hematology Parameters by Visit, 
Overall and by Dose Group – Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.2A Summary and Change from Baseline for Chemistry Parameters by Visit, 
Overall and by Dose Group – Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.2B 
Summary and Change from Baseline for Chemistry Parameters by Visit, 
Overall and by Dose Group – Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.3A Summary and Change from Baseline for Liver Function Tests by Visit, 
Overall and by Dose Group – Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.3B 
Summary and Change from Baseline for Liver Function Tests by Visit, 
Overall and by Dose Group – Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.4A Summary and Change from Baseline for Coagulation Studies by Visit, 
Overall and by Dose Group – Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.4B 
Summary and Change from Baseline for Coagulation Studies by Visit, 
Overall and by Dose Group – Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.5A Summary and Change from Baseline for Thyroid Function Tests by Visit, 
Overall and by Dose Group – Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.5B 
Summary and Change from Baseline for Thyroid Function Tests by Visit, 
Overall and by Dose Group – Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.6A Summary and Change from Pre-Dose for Cytokines and CRP by Time Point, 
Overall and by Dose Group – Q4W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.6B 
Summary and Change from Pre-Dose for Cytokines and CRP by Time Point, 
Overall and by Dose Group – Q3W Cohorts (Intent-to-Treat Analysis Set) 
Table 14.3.5.7A Summary and Change from Pre-Dose for Complement Factors by Time 
Point, Overall and by Dose Group – Q4W Cohorts (Intent-to-Treat Analysis 
Set) 
Table 14.3.5.7B 
Summary and Change from Pre-Dose for Complement Factors by Time 
Point, Overall and by Dose Group – Q3W Cohorts (Intent-to-Treat Analysis 
Set) 
Table 14.3.5.8 
Shifts from Pre-Dose in Laboratory Parameters, by Dose Group (Intent-to-
Treat Analysis Set) 
Table 14.3.5.9 
Summary and Change from Pre-Dose for Serial Vital Signs and SaO2 by 
Time Point, by Dose Group (Intent-to-Treat Analysis Set) 
Table 14.3.5.10 
Summary and Change from Pre-Dose for Electrocardiogram Results by Visit 
(Intent-to-Treat Analysis Set) 


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Table 14.4.1 
Study Drug Exposure (Intent-to-Treat Analysis Set) 
Table 14.4.2 
Concomitant Medications, Overall and by Dose Group (Intent-to-Treat 
Analysis Set) 
Table 14.4.3 
Premedications, Overall and by Dose Group (Intent-to-Treat Analysis Set) 
7.2. 
Data Listings to be Generated 
Listing 16.2.1 
Subject Disposition 
Listing 16.2.2.1 
Inclusion Criteria 
Listing 16.2.2.2 
Exclusion Criteria 
Listing 16.2.2.3 
Protocol Deviations/Violations 
Listing 16.2.3 
Subjects Excluded From Efficacy Analyses 
Listing 16.2.4.1 
Demographics and Baseline Disease Characteristics 
Listing 16.2.4.2 
Medical/Surgical History 
Listing 16.2.4.3 
Pregnancy Test 
Listing 16.2.4.4 
Viral Serology Tests 
Listing 16.2.5.1 
Study Medication Administration 
Listing 16.2.5.2 
Inpatient Information 
Listing 16.2.6 
Pharmacodynamic Assessments 
Listing 16.2.7.1 
Adverse Events – Sorted By Subject and Onset Date 
Listing 16.2.7.2 
Adverse Events – Sorted by System Organ Class, Preferred Term, Dose 
Group, Subject, and Onset Date 
Listing 16.2.7.3 
Infusion Related Reactions – Sorted by System Organ Class, Preferred 
Term, Dose Group, Subject, and Onset Date 
Listing 16.2.8.1A 
Local Laboratory Assessment – Hematology, Part 1 
Listing 16.2.8.1B 
Local Laboratory Assessment – Hematology, Part 2 
Listing 16.2.8.1C 
Local Laboratory Assessment – Hematology, Part 3 
Listing 16.2.8.2A 
Local Laboratory Assessment – Chemistry, Part 1 
Listing 16.2.8.2B 
Local Laboratory Assessment – Chemistry, Part 2 
Listing 16.2.8.3 
Local Laboratory Assessment – Liver Function 
Listing 16.2.8.4 
Local Laboratory Assessment – Thyroid Function 
Listing 16.2.8.5 
Local Laboratory Assessment – Coagulation 
Listing 16.2.8.6 
Local Laboratory Assessment – C-Reactive Protein 
Listing 16.2.8.7 
Local Laboratory Assessment – Lipid Profile 
Listing 16.2.8.8A 
Local Laboratory Assessment – Urinalysis, Part 1 
Listing 16.2.8.8B 
Local Laboratory Assessment – Urinalysis, Part 2 


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Listing 16.2.8.9 
Complement Factor 
Listing 16.2.8.10A 
Cytokine Sampling, Part 1 
Listing 16.2.8.10B 
Cytokine Sampling, Part 2 
Listing 16.2.8.11 
Anti-PEG Antibody Information (IgG and IgM) 
Listing 16.2.8.12 
C3a 
Listing 16.2.8.13 
Tryptase 
Listing 16.2.8.14 
Vital Signs and Sao2 
Listing 16.2.8.15 
Abnormal Physical Examination Findings 
Listing 16.2.8.16 
Electrocardiogram Results 
Listing 16.2.8.17 
Concomitant Medications 
Listing 16.2.8.18 
Premedications 


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7.3. 
Figures to be Generated 
Figure 14.2.1.1 
Individual TTR (ELISA) Levels over Time 
Figure 14.2.1.2 
Individual Wild Type TTR (LCMS/MS) Levels over Time 
Figure 14.2.1.3 
Individual Mutant TTR (LCMS/MS) Levels over Time 
Figure 14.2.2.1 
Mean TTR (ELISA) Levels by Dose Group over Time 
Figure 14.2.2.2 
Mean Wild Type TTR (LCMS/MS) Levels by Dose Group over Time 
Figure 14.2.2.3 
Mean Mutant TTR (LCMS/MS) Levels by Dose Group over Time 
Figure 14.2.3.1 
Mean Percent Change from Baseline in TTR (ELISA) by Dose Group 
over Time 
Figure 14.2.3.2 
Mean Percent Change from Baseline in Wild Type TTR (LCMS/MS) by 
Dose Group over Time 
Figure 14.2.3.3 
Mean Percent Change from Baseline in Mutant TTR (LCMS/MS) by 
Dose Group over Time 
Figure 14.2.4.1.1 
TTR (ELISA) at Individual Nadir by Dose Group 
Figure 14.2.4.1.2 
Mean Percent Change from Baseline in TTR (ELISA) at Individual Nadir 
by Dose Group 
Figure 14.2.4.2.1 
Wild Type TTR (LCMS/MS) at Individual Nadir by Dose Group 
Figure 14.2.4.2.2 
Mean Percent Change from Baseline in Wild Type TTR (LCMS/MS) at 
Individual Nadir by Dose Group 
Figure 14.2.4.3.1 
Mutant TTR (LCMS/MS) at Individual Nadir by Dose Group 
Figure 14.2.4.3.2 
Mean Percent Change from Baseline in Mutant TTR (LCMS/MS) at 
Individual Nadir by Dose Group 
Figure 14.2.5.1 
Mean Percent Change from Baseline in TTR (ELISA) at Group Nadir by 
Dose Group 
Figure 14.2.5.2 
Mean Percent Change from Baseline in Wild Type TTR (LCMS/MS) at 
Group Nadir by Dose Group 
Figure 14.2.5.3 
Mean Percent Change from Baseline in Mutant TTR (LCMS/MS) at 
Group Nadir by Dose Group 
Figure 14.2.6 
Mean Percent Change from Baseline in TTR (ELISA) at Individual Nadir 
by Dose Group and Stabilizer Use – 300 μg/kg Subjects 
Figure 14.2.7.1 
Area under the TTR (ELISA) Concentration-Time Curve 
Figure 14.2.7.2 
Area under the Wild Type TTR (LCMS/MS) Concentration-Time Curve 
Figure 14.2.7.3 
Area under the Mutant TTR (LCMS/MS) Concentration-Time Curve 
Figure 14.2.8 
Individual Vitamin A Levels over Time 
Figure 14.2.9 
Mean Vitamin A Levels by Dose Group over Time 


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Figure 14.2.10 
Mean Percent Change from Baseline in Vitamin A by Dose Group over 
Time 
Figure 14.2.11 
Mean Percent Change from Baseline in Vitamin A at Individual Nadir by 
Dose Group over Time 
Figure 14.2.12 
Mean Percent Change from Baseline in Vitamin A at Group Nadir by 
Dose Group over Time 
Figure 14.2.13 
Individual Relative Retinol Binding Protein Levels over Time 
Figure 14.2.14 
Mean Retinol Binding Protein Levels by Dose Group over Time 
Figure 14.2.15 
Mean Percent Change from Baseline in Retinol Binding Protein by Dose 
Group over Time 
Figure 14.2.16 
Mean Percent Change from Baseline in Retinol Binding Protein at 
Individual Nadir by Dose Group over Time 
Figure 14.2.17 
Mean Percent Change from Baseline in Retinol Binding Protein at Group 
Nadir by Dose Group over Time 
Figure 14.3.1 
Individual Liver Function Tests over Time 
Figure 14.3.2 
Mean Liver Function Tests by Dose Group over Time 
Figure 14.3.3 
Individual Cytokines and CRP over Time 
Figure 14.3.4 
Mean Cytokines and CRP by Dose Group over Time 
Figure 14.3.5 
Individual Complement Factor (Bb) over Time 
Figure 14.3.6 
Mean Complement Factor (Bb) by Dose Group over Time 
Figure 14.3.7 
Maximum Fold Change from Baseline for CRP  
Figure 14.3.8 
Maximum Fold Change from Baseline for Complement Factor (Bb)  
Figure 14.3.9 
Maximum Fold Change from Baseline for Cytokines