Conditions: Transthyretin (TTR) Amyloid Cardiomyopathy
Keywords: amyloidosis amyloid transthyretin TTR
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 441
Healthy volunteers: no

Brief summary:
This Phase 3 study will investigate the efficacy, safety and tolerability of an oral daily dose of 20 mg or 80 mg tafamidis meglumine capsules compared to placebo in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy.

Detailed description:
Phase 3, multicenter, global, three-arm, parallel design, placebo-controlled, double-blind, randomized study to determine efficacy, safety and tolerability of tafamidis on clinical outcomes (all-cause mortality and frequency of cardiovascular-related hospitalizations) in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy.

Arms:
arm 1: Active Treatment-Low dose arm 2: Active Treatment-High Dose arm 3: Placebo control

Interventions: intervention 1: Tafamidis intervention 2: Tafamidis intervention 3: Placebo
Intervention descriptions: intervention 1: Tafamidis 20 mg in soft gel capsules administered once a day for 30 months intervention 2: Tafamidis 80 mg in soft gel capsules administered once a day for 30 months intervention 3: Placebo in soft gel capsules administered once a day for 30 months

Protocol document:
Prot_000.pdf: 
PF-06291826 Tafamidis Meglumine
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Final Protocol Amendment 3, 24 May 2016
Page 1
FOLDRX PHARMACEUTICALS, A PFIZER COMPANY
A MULTICENTER, INTERNATIONAL, PHASE 3, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF DAILY ORAL DOSING OF 
TAFAMIDIS MEGLUMINE (PF-06291826) 20 MG OR 80 MG IN COMPARISON TO 
PLACEBO IN SUBJECTS DIAGNOSED WITH TRANSTHYRETIN 
CARDIOMYOPATHY (TTR-CM)
Compound:
PF-06291826
Compound Name:
tafamidis
US IND Number:
IND 71,880
European Clinical Trial Database 
(EudraCT) Number:
2012-002465-35
Protocol Number:
B3461028
Phase:
3


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Document History
Document
Version Date
Summary of Changes
Original protocol
31 Jul 2013
N/A
Amendment 1
16 Apr 2014
Following initiation of the study the following 
changes were made to the study protocol:
1.
Typographical corrections and clarifications.
2.
Added the results of the B3461031 study 
indicating a lack of tafamidis effect on QTc.
3.
Clarified the target sample size as 400 subjects.
4.
Added “Smoking and Alcohol Classification” 
to the Schedule of Activities.
5.
Removed Serum Amyloid A from required 
Screening analysis as it is an indicator of an 
active inflammatory process and does not 
contribute to defining an appropriate subject for 
this study.
6.
Amended the Week 2 follow-up to allow for 
flexibility in scheduling a visit to either the 
investigator’s clinic or their primary care 
physician’s office or a visit to a local laboratory 
for blood collection (which would also include, 
a phone call).
7.
The second 6MWT during Screening was 
removed in order to ease the burden of site 
visits.
8.
Removed chest x-ray as a required Screening 
test.
9.
Clarified the duration of a Screening extension 
as being 2 weeks.
10. Clarified language for eligibility requirements 
for the extension study that include completion 
of at least 896 days in this study.
11. Change to provide additional diagnostic 
evaluations via IHC and scintigraphy to support 
diagnosis of TTR-CM.


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Final Protocol Amendment 3, 24 May 2016
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12. Added procedures for confirming TTR 
cardiomyopathy in TTR genotype positive 
subjects with elevated kappa and lambda light 
chain values.
13. Removed the 5 year limitation on biopsies for 
TTR determination.
14. Added examples of calcium channel blockers 
that should be excluded from use in this study 
(eg verapamil, diltiazem).
15. Updated the method of determining glomerular 
filtration.
16. Added tauroursodeoxycholate and doxycycline 
to the list of excluded medications.
17. Added that the discontinuation of NSAIDs 
must be 30 days before the Baseline visit.
18. Expanded 30 month Vital Status determination 
to include Transplant Status.
19. Added diflunisal assay.
20. Changed exclusion language for “prior 
myocardial infarction” to exclude subjects who 
in the opinion of the investigator do not have 
heart failure caused by TTR cardiomyopathy.
21. Added 30 day exclusion for use of 
tauroursodeoxycholate and doxycycline prior to 
enrollment and their exclusion from use during 
the study.
22. Clarified that all follow-up visits need to be 
referenced to the date of the Baseline visit and 
that the anticipated study duration is 910 days.
23. Added language clarifying the term 
“down-titration”.
24. Removed the Endocrine, Immunologic / 
Allergic, and Hematologic / Lymphatic systems 
from the Screening physical examination
because they had been entered in error.


PF-06291826 Tafamidis Meglumine
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Final Protocol Amendment 3, 24 May 2016
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25. Entered echocardiographic parameters for the 
assessment of Longitudinal, Circumferential 
and Radial Echo Strain.
26. Clarified that coagulation variables will be 
measured in the local laboratory.
27. Removed the “Total Blood Volumes ” chart 
and indicated the central lab manual as the 
source of the blood volumes at each visit.
28. Removed the 15 month time frame from the 
enrollment period.
29. Clarified the wording for “censoring” of 
subjects in the statistical section.
30. Added supportive references,
31. Removed the “6 Minute Walk Test Worksheet” 
as it doesn’t match the eCRF.
32. Replaced “appointment card” with “Subject 
Daily Dosing Diary”.
33. Replaced “study medication card” and “blister 
pack” with “study medication wallet”.
34. Added TTR oligomer concentration as an 
exploratory endpoint.
35. Needed to add and rearrange language because 
of a company global change to the protocol 
template.
Amendment 2
26 Feb 2015
1.
Added contraception discussion to schedule of 
activities, as described in the protocol (section 
4.3.1).
2.
Added subjects who undergo surgery for 
Implantation of a cardiac mechanical assist 
device will be treated in the analysis similarly 
to subjects receiving a heart transplant.
3.
Added conversion of NT proBNP to SI units.
4.
Added clarification for Hepatitis and HIV 
exclusion.


PF-06291826 Tafamidis Meglumine
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Final Protocol Amendment 3, 24 May 2016
Page 5
5.
Added clarifying text to Contraindicated 
Therapies (section 5.8.1).
6.
Added language to comply with the new Pfizer 
protocol template (Endpoint Adjudication and 
Communication of Results by Pfizer).
Amendment 3
24 May 2016
1.
Clarified the term “down-titration” to “dose 
reduction” to more accurately represent the 
change in dose that may occur when a subject 
is unable to tolerate the randomized dose.
2.
Removed reference to the color of the capsules 
under ‘Appearance’ in tabular summary of the 
investigational product (active and matching 
placebo), to eliminate confusion with a change 
in investigational product manufacture
(implemented in protocol administrative 
change letter dated 11 Apr 2016).
3.
Added the collection of urine samples at 
Months 12, 18, 24, and 30 or (Early Study 
Discontinuation) to be used in assay 
development for measurement of TTR 
oligomer concentrations in urine to be 
performed at selected centers.
4.
Added the collection of blood samples for 
testing of tafamidis concentrations in subjects 
who require dialysis or hemofiltration after 
randomization and while on study treatment.
5.
Removed the requirement for blood samples at 
Months 12 and 24 for testing of diflunisal
concentrations.
6.
Clarified that subjects who do not enroll in the 
extension study will be followed for 28 
calendar days after the last dose of study 
medication for collection of adverse events.  
Subjects who enroll in the extension study will 
continue to be monitored for adverse events 
within the extension study.
7.
Clarified that the Endpoint Adjudication 
Committee (EAC) Guidelines have been 
incorporated into the updated EAC Charter.
8.
Better delineated the analysis planned for 
Kansas City Cardiomyopathy Questionnaire 
(KCCQ) scores related to subject symptoms.


PF-06291826 Tafamidis Meglumine
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9.
Incorporated the discontinuation of enrollment 
of subjects with wild-type genotype in order to 
increase the numbers of subjects with variant 
genotype (implemented in protocol 
administrative change letter dated 30 Jun 
2015).
10. Provided the study number for the extension 
study and clarified that all subjects in the 
extension study will receive tafamidis; 
however, the dose will be blinded in order to 
maintain blinding in the B3461028 study.
11. Clarified that dosing is permitted in the PM 
when the timing of pharmacokinetic samples is 
prohibitive for adherence with AM dosing.
12. Added the requirement that urine should be 
sent for microscopic evaluation following any 
positive test on urine dipstick, not just a 
positive test for blood or protein.
13. Removed inconsistent information found in
Section 7.8 Hospitalization Determination on 
the follow-up required for Month 30 vital status 
/ transplant / cardiac mechanical assist device
to reflect what is being collected.  Follow-up at 
Month 30 for this information is still included 
in Section 6.3 Subject Withdrawal and Vital 
Status / Transplant / Cardiac Mechanical Assist 
Device Status Follow-up.
14. Clarified that events resulting in organ 
transplantation or cardiac mechanical assist 
device should be considered “medically 
important” and, therefore, reported as serious 
adverse events.
15. Redefined the baseline groupings for New 
York Heart Association (NYHA) Functional 
Classification that will be used for efficacy 
analyses, grouping subjects with NYHA Class I 
and II together to be compared against NYHA 
Class III
16. Amended the description and frequency of data 
review by the External Data Monitoring 
Committee (E-DMC) to be consistent with the 
E-DMC charter.


PF-06291826 Tafamidis Meglumine
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Final Protocol Amendment 3, 24 May 2016
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17. Added or revised language to comply with the 
updated Pfizer protocol template (Section 4.3.1 
Contraception, Section 5.6 Drug Storage, 
Section 5.7.1 Destruction of Investigational 
Product Supplies, Section 10 Quality Control 
and Quality Assurance, Section 12.3 Subject 
Information and Consent).
18. Deleted Section 12.4 Subject Recruitment as 
this language is now included in revised Pfizer 
protocol template language under Section 12.3 
Subject Information and Consent.
19. Several typographical and formatting errors 
were corrected.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.


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This is a list of abbreviations 
Abbreviation
Term
6MWT
6 Minute Walk Test
99mTC-DPD
Technetium-99m-3,3-diphosphono-1,2-propano-dicarboxylic 
acid
99mTC- PYP
Technetium-99m - Pyrophosphate
99mTC-HMDP
Technetium-99m - hydroxymethylene diphosphonate
AE
adverse event
AL
immunoglobulin light chain amyloidosis
ALT
alanine transaminase
ANOVA
analysis of variance
anti-HCV
Serology for hepatitis C
AST
aspartate transaminase
AV
atrioventricular
BUN
blood urea nitrogen
CDS
core data sheet
Cmax
Maximum drug concentration
Cmax,ss
Maximum drug concentration at steady state
CMH
Cochran-Mantel-Haenszel
Cmin,ss
Minimum drug concentration at steady state
CRF
case report form
CSA
clinical study agreement
CTA
clinical trial application
DNA
deoxyribonucleic acid
EAC
Endpoint Adjudication Committee
EC
ethics committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EQ-5D-3L
EuroQoL-5 Dimensions
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
Database
FAPWTR
Familial Amyloidotic Polyneuropathy World Transplant 
Registry
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act of 2007 
(United States)
free Hb
Free hemoglobin
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate


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Final Protocol Amendment 3, 24 May 2016
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HBsAg
serology for hepatitis B
hCG
human chorionic gonadotropin
HF
Heart Failure
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
ID
identification
IHC
immunohistochemistry
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
ITT
intent-to-treat
IUD
intrauterine device
KCCQ-OS
Kansas City Cardiomyopathy Questionnaire – Overall 
Summary
LFT
liver function test
LSLV
last subject last visit 
LV
left ventricle
mBMI
modified Body Mass Index
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MGUS
monoclonal gammopathy of undetermined significance
MHLW
Ministry of Health, Labor and Welfare
MMRM
mixed model repeated measures ANCOVA
MR
molar ratio of tafamidis:TTR plasma concentration
MRI
magnetic resonance imaging
N/A
not applicable
NSAID
Non-Steroidal Anti-Inflammatory Drug
NT-proBNP
N-Terminal prohormone B-type Natriuretic Peptide 
(NT-proBNP)
NYHA
New York Heart Association
PA
posterior-anterior
PGA
Patient Global Assessment
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/Pharmacodynamic
PP
per protocol
PR
PR interval on the ECG
PT
prothrombin time
QD
once daily dosing
QRS
QRS duration on the ECG
QT
QT duration on the ECG


PF-06291826 Tafamidis Meglumine
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QTc
Corrected ECG QT Interval
QTc (B and F)
Corrected ECG QT Interval using the Bazett’s or Fridericia’s
correction
RNA
ribonucleic acid
RR
RR interval on the ECG
SA
sinoatrial
SAE
serious adverse event
SAP
statistical analysis plan
SI units
Standard International units
SOP
standard operating procedure
SRSD
single reference safety document
TEAE
Treatment Emergent Adverse Events
TRACS
Transthyretin Amyloid Cardiac Study
TTR
Transthyretin
TTR-CM
Transthyretin Cardiomyopathy
TTR-FAP
Transthyretin Familial Amyloid Polyneuropathy
ULN
upper limit of normal
US
United States
USPI
United States package insert
UTN
Universal Trial Number


PF-06291826 Tafamidis Meglumine
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PROTOCOL SUMMARY
Background and Rationale:
Transthyretin amyloid disease is a rare and fatal condition characterized by the deposition of 
amyloid derived from transthyretin (a plasma protein) in various organs and tissues. 
Deposition of TTR amyloid is associated with two distinct clinical presentations: 
transthyretin familial amyloid polyneuropathy (TTR-FAP) when the peripheral nerves are 
primarily affected and transthyretin amyloid cardiomyopathy (TTR-CM) when the heart is 
primarily affected. Both TTR-FAP and TTR-CM are associated with genetic variants of 
transthyretin but TTR-CM may also occur in the absence of any genetic mutation and may be 
due to wild-type TTR amyloid deposition.  At this time, with the exception of the approval of 
tafamidis for TTR-FAP in the European Union (EU) and Japan, there are no approved 
pharmacotherapies for these conditions.
TTR-CM occurs when TTR amyloid fibrils infiltrate the myocardium, leading to deposits of 
extracellular amyloid. Deposition of transthyretin fibrils occurs between the myocardial cells 
and produces a thickening and stiffening of the myocardial tissue. This infiltration of the 
myocardium results in diastolic dysfunction progressing to restrictive cardiomyopathy, 
congestive heart failure, and ultimately death.
Pfizer is developing tafamidis, an oral small molecule, for the treatment of transthyretin 
amyloid diseases.  It has been demonstrated to bind selectively to TTR in human blood and 
slow fibril formation in vitro (Razavi 2003).40  It binds to the 2 thyroxine binding sites with 
negative cooperativity, exhibiting dissociation constants of 2 nM [Kd1] and 154 nM [Kd2] 
(DeVit 2006)11 and kinetically stabilizing the TTR tetramer when bound (Sekijima 2009).46
TTR stabilization has been hypothesized to lead to slowing or halting of disease progression.  
This hypothesis was confirmed in a double-blind, placebo-controlled, 18-month study in 
subjects with TTR-FAP, in which those subjects receiving tafamidis had better neurologic 
outcomes compared with those receiving placebo. In order to improve the understanding of 
the natural history of TTR-CM, a longitudinal, observational clinical study of 29 subjects 
with either the V122I genetic variant (11 subjects) or wild-type (18 subjects) associated 
TTR-CM (Transthyretin Amyloid Cardiac Study; TRACS) was undertaken.  A follow-up 
Phase 2 open-label interventional study (Study Fx1B-201) demonstrated TTR stabilization in 
subjects with V122I and wild-type TTR-CM and an acceptable safety profile following 
12 months of tafamidis 20 mg given once daily.
Study B3461031 was designed to evaluate the effect of tafamidis on the corrected QT (QTc) 
interval in healthy volunteers.  The primary objective was to characterize the effect of a 
supra-therapeutic tafamidis concentration (~20 μg/mL) on the QTc interval relative to 
placebo in healthy volunteers.  A supra-therapeutic, single, 400 mg oral-dose of tafamidis 
solution in healthy volunteers demonstrated a lack of an effect on QTc interval prolongation.  
Single doses of moxifloxacin 400 mg established that the study had adequate sensitivity to 
detect increases in the QTc interval.


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Objectives and Endpoints:
The objective of this study is to determine the efficacy, safety, and tolerability of tafamidis in 
subjects with transthyretin cardiomyopathy
The primary objective is to assess the efficacy, safety, and tolerability of an oral dose of 
20 mg or 80 mg tafamidis meglumine soft gel capsules in comparison to placebo and given 
once daily, in addition to standard of care, for 30 months in subjects diagnosed with either a 
TTR variant or wild-type TTR-CM.  The study is designed to assess the potential for benefit 
from treatment with tafamidis relative to placebo based on all-cause mortality and frequency
of cardiovascular-related hospitalizations (including heart failure, arrhythmia, myocardial 
infarction, and stroke as well as other cardiovascular-related events).
Primary Analysis:
The primary analysis uses a hierarchical combination applying the method of 
Finkelstein-Schoenfeld (Finkelstein 1999)16 to all-cause mortality and frequency of 
cardiovascular-related hospitalizations, which is defined as the number of times a subject is 
hospitalized (ie, admitted to a hospital) for cardiovascular-related morbidity.
Secondary Endpoints:
Analysis of the following key secondary endpoints will follow an alpha conserving strategy:
1. Change from Baseline to Month 30 on the distance walked during the 6-Minute Walk 
Test (6MWT) (Appendix 4).
2. Change from Baseline to Month 30 on the Kansas City Cardiomyopathy 
Questionnaire Overall Summary score (KCCQ-OS) (Appendix 1.1).
The following additional secondary endpoints will be analyzed without an alpha conserving 
strategy for multiple comparisons:
1. Cardiovascular-related mortality,
2. Frequency of cardiovascular-related hospitalization,
3. All-cause mortality,
4. TTR Stabilization at Month 1.
Study Design:
This is an international, multicenter, double-blind, placebo-controlled, randomized, 3-arm 
study with a 30-month treatment phase wherein subjects with transthyretin cardiomyopathy, 
due to either variant or wild-type TTR, will receive either 20 mg (n= 80) or 80 mg (n = 160) 
tafamidis or matching placebo (n = 160) once daily, in addition to standard of care.  The 


PF-06291826 Tafamidis Meglumine
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Final Protocol Amendment 3, 24 May 2016
Page 13
study includes a provision for sites to implement a blinded dose reduction to 40 mg once 
daily for subjects who experience adverse events that may be associated with the tolerability 
of treatment with tafamidis.
Selection of Subjects:
Subjects that will be included into the protocol must meet specific inclusion criteria that 
include but is not limited to the following:
1. A medical history of Heart Failure (HF) with at least 1 prior hospitalization for HF or 
clinical evidence of HF (without hospitalization) manifested by signs or symptoms of 
volume overload or elevated intracardiac pressures (eg, elevated jugular venous 
pressure, shortness of breath or signs of pulmonary congestion on x-ray or 
auscultation, peripheral edema) that required/requires treatment with a diuretic for 
improvement.
2. Evidence of cardiac amyloid by echocardiography with an end-diastolic 
interventricular septal wall thickness > 12 mm.
3. Presence of amyloid deposits in biopsy tissue and TTR precursor protein 
identification by mass spectrometry, immunohistochemistry or scintigraphy.
4. An NT-proBNP concentration > 600 pg/mL.
5. A 6-Minute Walk Test distance > 100 meters.
Subjects will be excluded if they have:
1. A New York Heart Association (NYHA) classification of IV.
2. Glomerular filtration rate (eGFR) of < 25 mL/min./1.73 m2.
3. Use of certain non-steroidal anti-inflammatory drugs (NSAIDs), see Section 5.8.1.
4. Modified Body Mass Index (mBMI) below 600.
Study Treatment:
Investigators will confirm the eligibility of each subject to meet inclusion/exclusion criteria.
An Interactive Response Technology (IRT) system will assign a unique subject identification 
number sequentially to each subject who has signed the informed consent document (ICD).  
This identifying number will be retained throughout the duration of study participation.
Subject eligibility for participation in the treatment phase of the protocol will be determined 
following the assessments at the Screening and Baseline visits. Subjects will be screened for 
eligibility and those who meet the inclusion criteria and do not meet the exclusion criteria,
will be randomized. There will be a treatment assignment stratification by TTR genotype 


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Page 14
(variant or wild-type) as well as by Baseline severity (NYHA Class I and NYHA Classes II
and III combined).  Subjects will receive either 20 mg (n= 80) or 80 mg (n = 160) tafamidis 
or matching placebo (n = 160) once daily, in addition to standard of care (eg, diuretics) for
30 months. Tafamidis is available in 20 mg soft gel capsules, and subjects will take 
4 capsules per day of blinded therapy.  The study includes a provision for sites to implement 
a blinded dose reduction to 40 mg once daily for subjects who experience adverse events that 
may be associated with the tolerability of treatment with tafamidis.
Dosage Level
Compound
Appearance
Number of Capsules Per Day 
(Dose)
Tafamidis 
meglumine 20 mg
PF-06291826
Oblong soft gelatin 
capsules
1 (Tafamidis 20 mg capsule)
3 (Placebo capsules)
Tafamidis 
meglumine 40 mg 
(in the event of 
blinded dose 
reduction for the 
80 mg dose)
PF-06291826
Oblong soft gelatin 
capsules
2 (Tafamidis 20 mg capsules)
2 (Placebo capsules)
Tafamidis 
meglumine 80 mg
PF-06291826
Oblong soft gelatin 
capsules
4 (Tafamidis 20 mg capsules)
Placebo for 
Tafamidis
Oblong soft gelatin 
capsules
4 (Placebo capsules)
The study will use an External Data Monitoring Committee (E-DMC) that will be 
responsible for ongoing monitoring of the safety of subjects in the study according to the 
E-DMC Charter.
Statistical Method:
Sample Size
The target sample size is 400 subjects.  Sample size estimation assumptions include an
all-cause mortality rate of 12.5% for the tafamidis group and 25% for the placebo group and 
1.5 cardiovascular-related hospitalizations for the tafamidis group and 
2.5 cardiovascular-related hospitalizations for the placebo group (Connors 2011).9  With a 
treatment duration of 30 months and a significance level (alpha) of 0.05 (two-sided test), a
sample size of 300 (n=120 for placebo, n=60 for 20 mg, and n=120 for 80 mg) yields a 
power over 90% (for the primary comparison), which assumes pooling of the tafamidis 
20 mg and 80 mg dose groups.  An alternative assumption of 30% reduction in mortality 
(17.5 % for tafamidis and 25% for placebo) yields a power of approximately 80%.  Sample 
size estimation was performed based on simulations, given that no closed-form sample size 
estimation solution is available for the primary analysis method.


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In this rare disease area, prior information on treatment response is limited.  A sample size of 
300 subjects would provide over 90% power with 50% treatment effect (reduction in 
mortality).  That assumption is based on open-label, uncontrolled data with tafamidis and 
represents a large effect in the area of cardiovascular studies.  Based on the uncertainty of the 
assumptions due to limited data, the target sample size is 400 subjects
(n=160 for placebo, n=80 for 20 mg, and n=160 for 80 mg).
Analysis Populations
The intent-to-treat (ITT) analysis set will include all subjects in the safety population who 
had at least 1 post-Baseline efficacy evaluation (ie, post-Baseline hospitalization, study visit, 
or date of death). The per protocol (PP) analysis set will include all subjects in the ITT set 
who did not violate any inclusion/exclusion criteria and who did not have protocol violations 
considered to impact the interpretation of the primary efficacy analysis. The safety analysis 
set will include all subjects who are enrolled (randomized) and received at least 1 dose of 
double-blind medication.
Primary Efficacy Analysis
The primary analysis will be based on the ITT analysis set and will combine the subjects in 
the tafamidis 20 mg and tafamidis 80 mg groups (including subjects in the 80 mg group that 
may have had a dose reduction to 40 mg) into one pooled group. This pooled group 
(tafamidis) will be compared with the placebo group using the Finkelstein-Schoenfeld 
method. The test is based on the principle that each subject in the clinical study is compared 
to every other subject within strata in a pair-wise hierarchical fashion using all-cause
mortality first, assigning a +1 to the “better” subject and a -1 to the “worse” subject. The 
stratified test statistic is based on the sum of these scores within strata.  The null hypothesis 
for the primary analysis is that neither all-cause mortality nor frequency of 
cardiovascular-related hospitalizations is different between the tafamidis and placebo 
treatment groups. The corresponding alternative hypothesis is that at least one and possibly 
both all-cause mortality and frequency of cardiovascular-related hospitalizations are different 
between the tafamidis and placebo treatment groups.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, for dispensing drug and 
dose reduction as well as to conduct evaluations or assessments required to protect the well-being of the subject.
Protocol Activity
Screening
Period
Base
Line
Month
Day -45 to 
Day -10
Day
1
Week 
2a
1
3
6
9
12
15
18
21
24
27
30 (Day 910)
(or Early Study 
Discontinuation)
Visit Window (weeks)
1
1
2
2
2
2
2
2
2
2
2
2
Informed Consent and Release of 
Medical Information Form
X
Medical History 
X
X
Smoking and Alcohol 
Classification
X
Review entrance criteria
X
Randomization
X
Physical examination (full)
X
X
Brief physical examination
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
12 Lead ECG
X
Xb
X
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram
X
X
X
X
Tissue biopsyd
X
Laboratory samples


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Protocol Activity
Screening
Period
Base
Line
Month
Day -45 to 
Day -10
Day 
1
Week 
2a
1
3
6
9
12
15
18
21
24
27
30 (Day 910)
(or Early Study 
Discontinuation)
Hematology
X
X
X
X
X
X
X
X
X
Serum Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (INR, PT –
Local)e
X
X
X
X
X
X
X
X
Retinol Binding Protein
X
X
X
X
X
X
X
Serology (HBsAg, 
anti-HCV, and HIV)
X
Serum/urine test for primary 
(light chain) amyloidosis 
(AL) 
X
Urinalysis
X
X
X
X
X
X
X
X
Genotyping
X
Pregnancy test f
X
X
X
X
X
X
X
X
TTR stabilization, TTR oligomer 
concentration, and TTR 
concentrationg
X
X
X
X
X
X
X
Urine TTR oligomer 
concentrationh
X
X
X
X
Tafamidis Concentrations i
X
X
X
X
X
X
X
Tafamidis concentrations (for 
subjects receiving dialysis or 
hemofiltration)j
------------------------------------Any time during the study---------------------------------------------
Diflunisal concentrationk
X
X
X
X
X
X
Pharmacogenetic sample
X
NT – proBNP, troponin I
X
X
X
X
6MWT
X
X
X
X
X
X
X
KCCQ l
X
X
X
X
X
X
EQ-5D-3Lm
X
X
X
X
X
X
PGAn
X
X
X
X
X
X
NYHA classificationo
X
X
X
X
X
X
X


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Protocol Activity
Screening
Period
Base
Line
Month
Concomitant medicationsp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record time of dosing
X
X
X
X
X
X
Record dosing adherence
X
X
X
X
X
X
X
X
X
X
X
Adverse Events reporting
X
X
X
X
X
X
X
X
X
X
X
X
Xq
Hospitalization determination
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense blinded medication
X
X
X
X
X
X
X
X
X
X
Documentation of vital 
transplant and implant statusr
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception  Discussions
X
X
X
X
X
X
X
X
X
X
X
X
a.
The Week 2 “visit” will allow the subject to either come to the clinic, or consist of a telephone call to the subject for specified data determination and 
having the subject go to a local laboratory or local physician’s office to have their needed laboratory samples collected and shipped to the central 
laboratory.
b.
Baseline (Day 1) ECG pre-dose.
c.
Systolic and diastolic blood pressure and pulse rate (supine at least 3 minutes and standing at least 2 minutes prior to assessment), respiration rate and 
body temperature
d.
Biopsy must be performed at Screening or have been performed and documented previously.
e.
INR and PT will be determined at the site’s local laboratory.
f.
For women of childbearing potential.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.
g.
TTR stabilization, TTR oligomer concentration, and TTR concentration:  Baseline (Day 1) sample: collect at any time pre-dose during the clinic visit.
Month 1 sample: collect pre-dose and at 3 hours (± 1.5 hours) post-dose; Month 6 sample: collect at 7 hours (+ 2.5 hours) post-dose; Month 12 sample:
collect at 7 hours (± 2.5 hours) post-dose; Month 18 sample: collect at 1 hour (± 30 minutes) post-dose; Month 24 sample: collect at 1 hour 
(±30 minutes) post-dose; Month 30 sample: at any time during clinic visit.
h.
Subjects at selected centers will provide a urine sample to be used in assay development for measurement of TTR oligomer concentrations in urine. For 
those subjects who provide consent, a 10 mL aliquot of urine will be collected (starting at the earliest possible prospective visit for the subject) at
Months 12, 18, 24, and 30 (or Early Study Discontinuation); this aliquot will be obtained from the urine sample already collected for urinalysis at these 
visits.   
i.
Baseline (Day 1) tafamidis concentration sample: collect at any time pre-dose during the clinic visit. Month 1 tafamidis concentration sample: collect 
pre-dose and at 3 hours (±1.5 hours) post-dose; Month 6 tafamidis concentration sample: collect at 7 hours (± 2.5 hours) post-dose; Month 12 tafamidis 
concentration samples: collect at 7 hours (± 2.5 hours) post-dose; Month 18 tafamidis concentration sample: collect at 1 hour (± 30 minutes) post-dose; 
Month 24 tafamidis concentration sample: collect at 1 hour (± 30 minutes) post-dose; Month 30 tafamidis concentration: collect at any time during the 
clinic visit.


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j.
Should a subject require dialysis or hemofiltration at any time after randomization while on study treatment, the subject should have blood samples
collected for tafamidis concentrations around the time of renal replacement therapy.  The timing of the sample collection will depend on the type of 
renal replacement therapy administered.  For hemodialysis or hemofiltration, samples should be collected on the date of the renal replacement therapy 
both prior to administration and after administration.  When peritoneal dialysis is administered, the first sample should be collected at initiation of the 
first exchange.  The second sample should be collected after the first exchange is completed (if performed outside of the home) or at least 24 hours after 
the initiation of the first exchange (if administered at home).  Every effort should be made to collect these samples on the date of the subject’s first 
administration of renal replacement therapy in the study; however, if this is not possible, the samples should be obtained as soon as possible on the date 
of a renal replacement therapy treatment.  If necessary, the sample collection can be obtained using the guidelines for lab sample collection in the
Guidance for Remotely Conducted Study Visits provided for the study. At the time of sample collection, the date and time of the last dose and the date 
and time of sample collection must be recorded.
k.
Diflunisal concentration to determine if there is evidence of exposure to diflunisal prior to or during the study.  Sample can be collected at any time 
during the clinic visit, after the ECG blood pressure and vital signs.
l.
Kansas City Cardiomyopathy Questionnaire (KCCQ) (Appendix 1.1) should be completed before the EQ-5D-3L (Appendix 2) and PGA (Appendix 3).
m. EuroQoL-5 Dimensions (EQ-5D-3L) (Appendix 2) to be completed after the KCCQ (Appendix 1.1).
n.
Patient Global Assessment (PGA) should be completed after the KCCQ (Appendix 1.1) and EQ-5D-3L (Appendix 2).
o.
NYHA – New York Heart Association classification.
p.
At the Screening visit, this will be Prior Medications.
q.
Except for subjects who are randomized into the extension study (Study B3461045), all other subjects will have a 4-week (28 calendar days) safety 
follow-up visit after the last dose of the study medication for collection of adverse events.  This visit can be completed by telephone.
r.
When the Vital Status is determined, the subject should be asked if they have undergone a heart and/or liver transplant or implantation of cardiac 
mechanical assist device.  This is especially important at the 30 month visit.  If a subject indicates that they have had a transplant and they are still 
enrolled in the study, they should be removed from the study.
s.
For all subjects who, in the opinion of the investigator, are biologically capable of having children and are sexually active; at each study visit, discuss 
with the subject the need to use highly effective contraception consistently and correctly, instruct the subject to call immediately if a selected birth 
control method is discontinued or if pregnancy is known or suspected and document such conversation in the patient chart. 


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TABLE OF CONTENTS
LIST OF FIGURES .................................................................................................................24
APPENDICES .........................................................................................................................24
1. INTRODUCTION ...............................................................................................................25
1.1. Indication.................................................................................................................25
1.2. Background and Rationale ......................................................................................25
1.2.1. Studies TRACS and Fx1B-201...................................................................29
1.2.2. Dose Rationale............................................................................................32
1.2.3. Study Rationale...........................................................................................32
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................32
2.1. Objectives................................................................................................................32
2.2. Endpoints.................................................................................................................32
2.2.1. Primary Analysis ........................................................................................33
2.2.2. Key Secondary Endpoints: .........................................................................33
2.2.3. Secondary Endpoints:.................................................................................33
2.2.4. Exploratory Endpoints:...............................................................................33
3. STUDY DESIGN.................................................................................................................35
4. SUBJECT SELECTION......................................................................................................36
4.1. Inclusion Criteria.....................................................................................................36
4.2. Exclusion Criteria....................................................................................................38
4.3. Life Style Guidelines...............................................................................................39
4.3.1. Contraception..............................................................................................39
4.4. Sponsor Qualified Medical Personnel.....................................................................40
5. STUDY TREATMENTS.....................................................................................................41
5.1. Allocation to Treatment ..........................................................................................41
5.2. Breaking the Blind ..................................................................................................41
5.3. Dosing Adherence...................................................................................................42
5.4. Drug Supplies..........................................................................................................42
5.4.1. Dosage Form and Packaging ......................................................................43
5.4.2. Preparation and Dispensing........................................................................43
5.5. Administration.........................................................................................................43
5.6. Drug Storage ...........................................................................................................44


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5.7. Drug Accountability................................................................................................45
5.7.1. Destruction of Investigational Product Supplies ........................................46
5.8. Concomitant Treatments .........................................................................................46
5.8.1. Contraindicated Therapies..........................................................................46
6. STUDY PROCEDURES .....................................................................................................47
6.1. Screening Period .....................................................................................................47
6.2. Study Period ............................................................................................................49
6.2.1. Baseline (Day 1) .........................................................................................49
6.2.2. Week 2 Follow-up ......................................................................................51
6.2.3. Month 1 Visit..............................................................................................51
6.2.4. Month 3 Visit..............................................................................................53
6.2.5. Month 6 Visit..............................................................................................53
6.2.6. Month 9 Visit..............................................................................................55
6.2.7. Month 12 Visit............................................................................................56
6.2.8. Month 15 Visit............................................................................................57
6.2.9. Month 18 Visit............................................................................................58
6.2.10. Month 21 Visit..........................................................................................59
6.2.11. Month 24 Visit..........................................................................................60
6.2.12. Month 27 Visit..........................................................................................61
6.2.13. Month 30 Visit or Early Study Discontinuation.......................................62
6.2.14. Dialysis or Hemofiltration Treatments and Tafamidis 
Concentrations .................................................................................................64
6.3. Subject Withdrawal and Vital Status / Transplant / Cardiac Mechanical 
Assist Device Status Follow-up.................................................................................64
6.3.1. Subject Withdrawal for Heart or Liver Transplantation or
Implantation of Cardiac Mechanical Assist Device.........................................65
7. ASSESSMENTS..................................................................................................................65
7.1. Biopsy Documentation of Amyloid Deposition......................................................66
7.2. TTR Genotyping .....................................................................................................66
7.3. Renal Function Assessment ....................................................................................66
7.4. Modified Body Mass Index.....................................................................................66
7.5. Pharmacogenomic Biomarker.................................................................................67
7.5.1. Markers of Drug Response.........................................................................67


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7.5.2. Additional Research....................................................................................68
7.6. Safety Assessments .................................................................................................68
7.6.1. Medical History ..........................................................................................68
7.6.2. Physical Examinations and Height and Weight Measurements .................68
7.6.3. Vital Signs ..................................................................................................69
7.6.4. Electrocardiograms.....................................................................................69
7.6.5. Echocardiograms ........................................................................................69
7.6.6. Clinical Laboratory Tests ...........................................................................71
7.6.7. Pregnancy Testing ......................................................................................72
7.6.8. Testing for Light Chain Amyloid ...............................................................72
7.6.9. N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) 
and Troponin I..................................................................................................72
7.6.10. Serology....................................................................................................73
7.7. Efficacy Assessments..............................................................................................73
7.7.1. Patient Reported Outcomes ........................................................................73
7.7.1.1. Kansas City Cardiomyopathy Questionnaire ............................73
7.7.1.2. EQ-5D-3L..................................................................................73
7.7.1.3. Patient Global Assessment (PGA) ............................................74
7.7.2. TTR Stabilization, TTR Oligomer Concentration, and TTR 
Concentration Measurements...........................................................................74
7.7.3. Diflunisal Concentration.............................................................................74
7.7.4. 6-Minute Walk Test (6MWT) ....................................................................75
7.7.5. New York Heart Association Classification...............................................75
7.7.6. Pharmacokinetic Measurements .................................................................76
7.8. Hospitalization Determination ................................................................................77
7.9. Total Blood Volumes ..............................................................................................78
8. ADVERSE EVENT REPORTING......................................................................................78
8.1. Adverse Events........................................................................................................78
8.2. Reporting Period .....................................................................................................78
8.3. Definition of an Adverse Event...............................................................................79
8.4. Medication Errors....................................................................................................80
8.5. Abnormal Test Findings..........................................................................................80


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8.6. Serious Adverse Events...........................................................................................80
8.6.1. Protocol-Specified Serious Adverse Events...............................................81
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................81
8.7. Hospitalization ........................................................................................................82
8.8. Severity Assessment................................................................................................84
8.9. Causality Assessment..............................................................................................84
8.10. Exposure During Pregnancy..................................................................................84
8.11. Occupational Exposure .........................................................................................86
8.12. Withdrawal Due to Adverse Events (see also Section on Subject 
Withdrawal and Vital Status / Transplant/Cardiac Mechanical Assist Device 
Status Follow-up........................................................................................................86
8.13. Eliciting Adverse Event Information ....................................................................86
8.14. Reporting Requirements........................................................................................86
8.14.1. Serious Adverse Event Reporting Requirements .....................................86
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................87
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................87
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................87
9.1. Sample Size Determination.....................................................................................87
9.2. Analysis Populations...............................................................................................88
9.2.1. Primary Efficacy Analysis..........................................................................89
9.2.2. Analysis of Key Secondary Endpoints .......................................................90
9.3. Analysis of Secondary Endpoints ...........................................................................91
9.4. Analysis of Exploratory Endpoints .........................................................................92
9.4.1. Pharmacokinetic Data.................................................................................94
9.4.2. Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling...........................94
9.5. Safety Analysis........................................................................................................94
9.6. Data Monitoring Committee ...................................................................................95
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................96
11. DATA HANDLING AND RECORD KEEPING .............................................................96
11.1. Case Report Forms/Electronic Data Record .........................................................96
11.2. Record Retention...................................................................................................97
12. ETHICS..............................................................................................................................97


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12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............97
12.2. Ethical Conduct of the Study ................................................................................98
12.3. Subject Information and Consent..........................................................................98
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................99
13. DEFINITION OF END OF TRIAL...................................................................................99
13.1. End of Trial in a Member State.............................................................................99
13.2. End of Trial in all other Participating Countries...................................................99
14. SPONSOR DISCONTINUATION CRITERIA ................................................................99
15. PUBLICATION OF STUDY RESULTS..........................................................................99
15.1. Communication of Results by Pfizer ....................................................................99
15.2. Publications by Investigators ..............................................................................100
16. REFERENCES ................................................................................................................102
LIST OF FIGURES
Figure 1.
Scatter Plot of TTR Percent Stabilization vs Tafamidis:TTR Molar Ratio 
by Treatment in Study B3461040.........................................................................28
APPENDICES
Appendix 1. Patient Reported Outcomes...............................................................................106
Appendix 1.1. KCCQ.............................................................................................................106
Appendix 2. EQ-5D-3L .........................................................................................................110
Appendix 3. PGA...................................................................................................................112
Appendix 4. 6-Minute Walk Test ..........................................................................................113


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1. INTRODUCTION
1.1. Indication
Tafamidis is a small molecule that has been demonstrated to stabilize transthyretin and is 
being developed for the treatment of TTR-CM.  Tafamidis has already been approved in the 
European Union for the treatment of Transthyretin Familial Amyloid Polyneuropathy 
(TTR-FAP) in adult patients with stage 1 symptomatic polyneuropathy.  It has also been 
approved in Japan by the Ministry of Health, Labor and Welfare (MHLW) to delay the 
peripheral neurological impairment of transthyretin familial amyloid polyneuropathy.
1.2. Background and Rationale
Amyloidosis is a severely debilitating condition induced by the accumulation of various
insoluble fibrillar proteins, or amyloid, within the tissues in amounts sufficient to impair
normal function. Different precursor proteins have been associated with amyloid
cardiomyopathy, including immunoglobulin light chains (associated with primary or AL 
amyloidosis), serum amyloid A (associated with secondary or AA amyloidosis) and
transthyretin (TTR) representing the most common inherited amyloidosis. Transthyretin 
(also referred to as pre-albumin), a 127-amino acid, 55 kDa protein that is primarily 
synthesized in the liver, is a transport protein of thyroxine and retinol-binding protein-retinol 
(vitamin A) complex (Blake 1978, Monaco 1995).3,34  A mutation in TTR accelerates the 
process of fibrillogenesis whereby the tetrameric structure of the TTR protein dissociates 
leading to amyloid deposition (Nilsson 1975, Saraiva 2001).36,45  Dissociation of the TTR 
tetramer into monomers is the initial and rate-limiting step in amyloidogenesis (Nilsson 
1975, Saraiva 2001).36,45
Transthyretin amyloidosis can present as either a hereditary or an age-related disease. The 
major phenotypic presentations of TTR amyloidosis include transthyretin familial amyloid 
polyneuropathy (TTR-FAP), which can present with sensorimotor and autonomic
polyneuropathy and transthyretin cardiomyopathy (TTR-CM), which can present in either a 
genetic variant or a wild-type form (the latter is also known as senile systemic amyloidosis or 
SSA).
More than 100 TTR single site variants have been identified and associated with TTR 
amyloidosis, and at least 22 mutations as well as wild-type protein are associated with 
transthyretin cardiomyopathy.  The V122I (valine replaced by isoleucine at position 122) 
mutation is the most common, with an estimated prevalence of 3.3% in the African American 
population (Buxbaum 2006)6 with variable clinical penetrance of approximately 
30% (Jacobson 2011).30
In the elderly, wild-type (normal) TTR may become structurally unstable and result in 
deposition of amyloid fibrils, primarily in heart tissue, and may lead to diastolic dysfunction, 
restrictive cardiomyopathy and heart failure (Pages 1973, Saraiva 2001, Hammarström 2002, 
Quintas 2001).45,25,38  The frequency of TTR amyloid deposition in cardiac ventricles 
reported from autopsy studies in subjects >80 years of age range from 1.8% (Jacobson 
1997)29 to 16.5% (Cornwell 1983)10, with a rate of clinical cardiac disease premortem of 
34% (Cornwell 1983).10


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TTR-CM is a late onset disease with symptoms typically occurring in subjects aged 60 years 
or older, though the L111M variant may express TTR-CM in subjects at an earlier age.
Symptoms of TTR-CM are not mutation-type dependent and are typical of restrictive cardiac 
disease, and include dyspnea on exertion, orthostatic hypotension, and syncope, as well as 
conduction abnormalities, including bundle branch block, atrioventricular block, sinoatrial 
block, and atrial fibrillation.  Objective measures of cardiac involvement include abnormal 
electrocardiogram (ECG) with findings including low voltage, left and right ventricular wall 
thickening by echocardiogram, and elevated cardiac biomarkers (Connors 2009).8  These 
findings are non-specific for heart failure, making the diagnosis of cardiac amyloidosis 
difficult and resulting in likely under diagnosis of this condition (Falk 2011).15
Median survival from diagnosis for patients with TTR-CM was 41 months in a study of the 
V122I mutation and median survival was reported as 46 months for wild-type (Connors 
2011).9  Death in most patients with cardiac amyloidosis is from cardiac causes, including 
sudden death, heart failure, and myocardial infarction (Kyle 1996, Smith 1984).31,47
Except for symptom management, such as use of diuretics for symptoms of heart failure and 
pacemaker placement for cardiac arrhythmias, the only treatment option currently available 
for TTR-CM patients is orthotopic liver transplant.  This may be combined with heart 
transplant, depending on organ availability, patient capacity to tolerate the combined 
transplant, and the severity of cardiac amyloidosis at the time of transplant.  Transplantation 
of the liver removes the primary production site of amyloidogenic mutant TTR protein and 
replaces it with the production of wild-type TTR (Lewis 1994, Holmgren 1993).33,27  The 
Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) includes data 
on combined heart and liver transplant that indicates that this procedure is relatively 
infrequent, documenting 6 cases out of 575 transplantations (Herlenius 2004).26  The mean 
age of those undergoing combined heart and liver transplant was older (585 years) than 
those undergoing liver transplant alone (4011 years, p<0.001).
Tafamidis is an oral small molecule, under development by Pfizer, as a disease modifying 
therapy for TTR amyloid diseases.  It binds to the thyroxine binding sites on the TTR 
tetramer, thereby preventing destabilization into the monomeric form.  It has been 
demonstrated to bind selectively to TTR in human blood and slow fibril formation in vitro 
(Razavi 2003).40  It binds to the 2 thyroxine binding sites with negative cooperativity, 
exhibiting dissociation constants of 2 nM [Kd1] and 154 nM [Kd2] (DeVit 2006)11 and 
kinetically stabilizing the TTR tetramer when bound (Sekijima 2009).46
TTR stabilization has been hypothesized to lead to slowing or halting of disease progression.  
This hypothesis was confirmed in study Fx-005, a double-blind, placebo-controlled, 
18-month study in subjects with TTR-FAP, in which those subjects receiving tafamidis had 
better neurologic outcomes compared with those receiving placebo.  In order to improve the 
understanding of the natural history of TTR-CM, a longitudinal, observational clinical study 
of 29 subjects with either the V122I genetic variant (11 subjects) or wild-type (18 subjects) 
associated TTR-CM (Transthyretin Amyloid Cardiac Study; TRACS) was undertaken.  A 
follow-up Phase 2 open-label interventional study (Study Fx1B-201) demonstrated TTR 


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stabilization in subjects with V122I and wild-type TTR-CM, an acceptable safety profile, and 
apparent stabilization of disease following 12 months of tafamidis 20 mg given once daily 
compared with the unmatched historical control cohort (TRACS).  In study Fx1B-201, 
tafamidis effectively stabilized TTR in 34 of 35 (97.1%) subjects, representing both 
wild-type and V122I, at Week 6, with approximately 88% stabilized throughout the 
12 months of the study.  Of note, tafamidis has also been studied in TTR-FAP and effectively 
stabilized TTR in 98% of subjects as well as demonstrating effects relative to placebo on 
clinical measures (Coelho 2012).7
Study Fx-002 was a Phase 1 study designed to evaluate the safety, tolerability, and 
pharmacokinetics of orally administered tafamidis in healthy male and female volunteers at 
single doses up to 120 mg and 3 multiple escalating doses (15, 30 and 60 mg) administered 
as solution in comparison to placebo once daily over 14 days.  Study Fx1A-109 was a 
Phase 1 study in healthy volunteers designed to evaluate the cytochrome P450 induction 
potential of tafamidis 20 mg administered for 14 days.  In Fx-002, the mean (standard 
deviation) Cmax value on Day 14 for the 60 mg solution was 4.40 (1.16) g/mL.  The mean 
(standard deviation) Cmax on Day 14 for the 20 mg capsule was 2.66 (0.55) g/mL in 
Fx1A-109.
There were no dose-limiting safety or tolerability issues noted during the Phase 1 program in 
healthy subjects up to a single dose of 480 mg or multiple doses up to 60 mg.  Further, a 
single oral dose of 20 mg tafamidis was well tolerated by subjects with moderate or mild 
hepatic impairment.  No cases of acute overdose with tafamidis have been reported.
Study B3461040 was a Phase 1, randomized, double-blind, crossover, ascending dose 
escalation study to assess the safety and pharmacokinetics of tafamidis doses greater than 
120 mg as oral solution in healthy subjects.  Single doses of tafamidis up to 480 mg were 
well tolerated in the study population of healthy adult Asian men.
The transthyretin (TTR) % stabilization data from Study B3461040 (Figure 1) suggest that a 
plateau is achieved as the molar ratio of tafamidis: TTR plasma concentration (MR) 
increases.  Based upon the data available prior to conducting Study B3461040, it was 
believed that exposures achieved following a tafamidis dose of 20 mg once daily (QD) were 
sufficient to approach the TTR % stabilization plateau.  The data from Study B3461040 
suggest that doses higher than 20 mg provide a greater degree of stabilization, as measured 
by the urea-based TTR stabilization assay.  While the long-term risk-benefit of doses higher 
than 20 mg QD is unknown, it is reasonable to postulate that greater TTR stabilization has 
the potential to provide additional efficacy.
In order to calculate molar ratios at various tafamidis exposures, a TTR concentration must 
be assumed.  Mean TTR concentrations observed at Baseline in Study Fx-005 (24.7 mg/dL) 
and in patients with V122I mutations in Study Fx1B-201 (13.5 mg/dL) and the Transthyretin 
Amyloid Cardiac Study (TRACS) (14.9 mg/dL) are assumed for the calculations that follow: 
a 20 mg QD tafamidis dose at steady state produces a mean MR in the range of 1.2 to 
3.2 from mean minimum concentration at steady state (Cmin,ss) to maximum concentration at 
steady state (Cmax,ss), which is below the plateau region of the data depicted in (Figure 1). 


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Mean Cmin,ss to Cmax,ss following tafamidis doses of 80 mg are expected to produce MR 
values of 3.5 to 9.6, which are approaching or on the plateau region of TTR % stabilization.
Figure 1.
Scatter Plot of TTR Percent Stabilization vs Tafamidis:TTR Molar Ratio by 
Treatment in Study B3461040
Abbreviations:  TTR= transthyretin; QD = once daily
Source:  B3461040 CSR Figure 14.4.7.2.1
Based upon the TTR % stabilization data, tafamidis doses of 20 and 80 mg will be used in
Study B3461028.  The 20 mg dose will provide additional safety and efficacy data for that 
previously studied dose in TTR-FAP.  The 80 mg dose is approaching maximal TTR % 
stabilization, which has the potential for increased efficacy over the 20 mg dose.
The B3461031 study was a Phase 1 study designed to evaluate the effect of tafamidis on the 
corrected QT (QTc) interval in healthy volunteers.  The primary objective was to characterize 
the effect of a supra-therapeutic tafamidis concentration (~20 μg/mL) on QTc interval 
relative to placebo in healthy volunteers.  The primary analysis was to compare the 
time-matched mean differences in QTc interval using Fridericia’s correction method (QTcF) 
between tafamidis and placebo at each post-dose time.  The secondary ECG endpoint was to 
compare the mean difference in QTcF interval between moxifloxacin and placebo at the 
historical moxifloxacin median Tmax of 3 hours.  A supra-therapeutic, single, 400 mg 
oral-dose of tafamidis solution in healthy volunteers demonstrated a lack of an effect on QTc 


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interval prolongation.  Single doses of moxifloxacin 400 mg established that the study had 
adequate sensitivity to detect increases in QTc interval.
TTR-CM is a rare disease with very little available published information.  Based on this, the 
natural history and disease progression of TTR-CM were prospectively evaluated in a 
non-interventional study involving 29 subjects (Transthyretin Amyloidosis Cardiac Study 
[TRACS]; Study Fx-001; Ruberg 2012).41  In addition, subsequent to the TRACS study, an 
open-label, Phase 2 Study Fx1B-201 was initiated.  This study involved 35 subjects with 
TTR-CM who received open-label tafamidis 20 mg QD for 12 months along with routine 
standard of care. The proportion of patients with the variant genotype was substantially 
lower in Fx1B-201 compared with TRACS.
1.2.1. Studies TRACS and Fx1B-201
In the Fx1B-201 study, 31 subjects had the wild-type genotype and 4 had the V122I 
genotype.  The subjects were elderly (mean age approximately 76 years), with significant 
disease duration (approximately 8 years), and signs and symptoms of mild to moderate 
cardiac dysfunction (94% with NYHA Class I or II) at the time of enrollment.  Age, sex, and 
age at TTR symptom onset were similar between the TRACS and Fx1B-201 studies.  A 
larger percentage of subjects in the TRACS study had an NYHA class of III or higher 
(7/29, 24.1%) than in Study Fx1B-201 (2/35, 5.7%) at Baseline.
Following 12 months treatment with tafamidis, along with routine standard of care, 
2/35 (5.7%) subjects died, 9/35 (25.7%) experienced at least one cardiovascular-related
hospitalization, and 9/35 (25.7%) experienced the composite endpoint of death or 
cardiovascular-related hospitalization.  Results were similar between the TTR genotype 
groups.  A Kaplan-Meier analysis of survival from time of diagnosis for the study 
demonstrated an approximately 87.5% survival rate at 30 months.  These data were 
numerically better than that reported in the TRACS historical control cohort (which it should 
be noted was not a matched cohort and had greater disease severity at Baseline), during 
which the 12-month rate of death, cardiovascular-related hospitalizations and 
death/cardiovascular-related hospitalizations were 6/29 (20.7%), 10/29 (34.5%) and 
13/29 (44.8%), respectively.
Cardiac biomarkers (NT-proBNP, troponin I and T) at Baseline were elevated in study 
Fx1B-201. There were elevations in NT-proBNP over 12 months that were more apparent in 
the V122I than the wild-type population in the study.  Troponin I and T, more specific 
markers of cardiac necrosis, remained relatively stable in the wild-type population, 
suggesting no substantial deterioration of cardiac status over 12 months of tafamidis 
treatment.  These data are supported by the functional assessments of NYHA classification 
and 6-Minute Walk Test (Appendix 4).  At 12 months, 75% of the subjects in Fx1B-201 had 
improved or preserved NYHA classification, with the overall population demonstrating 
minimal change on the 6-Minute Walk Test in distance walked (mean change from Baseline 
of -11 meters).  This maintained functional walking capacity is in contrast to the deterioration 
observed in TRACS at 12 months (mean change from Baseline of -44 meters).


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Non-invasive cardiac assessments demonstrated significant cardiac involvement at Baseline
in study Fx1B-201, with substantial ventricular wall thickening on echocardiography and 
cardiac magnetic resonance imaging (MRI) and elevated intra-cardiac filling pressures on 
echocardiography.  There were no consistent clinically relevant changes in the 
echocardiography parameters over time.  For the wild-type subjects, who were the majority 
of subjects in the study, the deterioration in ejection fraction (-4.4%) and stroke volume 
(-1.9 mL) observed in the Fx1B-201 study was less than that observed in TRACS 
(-11.3% and -9.0 mL, respectively) at 12 months.  Similar findings were observed in a subset 
of subjects that underwent cardiac MRI.  In these subjects in the Fx1B-201 study, there was a 
decrease in the percent of left ventricle (LV) mass with amyloid observed at 12 months, 
while there was an increase in LV mass with amyloid observed in TRACS.
Baseline electrocardiogram and 24-hour Holter monitoring demonstrated substantial 
conduction and rhythm abnormalities, including bundle branch blocks and atrial 
fibrillation/flutter.  There were no clinically relevant changes over time in these assessments, 
with perhaps slight improvement in cardiac autonomic function in study Fx1B-201 as 
demonstrated by improved heart rate variability indices.
Over the 12 months of tafamidis treatment in study Fx1B-201, quality of life and functional 
status was maintained, as assessed by the Short Form-36, patient reported health survey 
(SF-36), the Kansas City Cardiomyopathy Questionnaire (KCCQ),(Appendix 1.1) and the 
Patient Global Assessment (PGA) (Appendix 3). The majority of these results were also 
better when compared with TRACS.
Seven subjects participated in both TRACS (median follow-up 12.5 months, with range of 
6-26 months) and Protocol Fx1B-201. All seven subjects completed 12 months of treatment 
with tafamidis. However, given the small number of subjects, it is difficult to assess whether 
disease progression was different during treatment with tafamidis as compared to standard of 
care in TRACS.  The rate of cardiovascular-related hospitalization was similar between the 
two 12-month periods, with some evidence of stabilized cardiac function (ejection fraction 
and fractional shortening) observed following treatment with tafamidis.
The type and incidence of adverse events observed in study Fx1B-201 was not unexpected 
for this elderly subset of subjects with pre-existing cardiac disease related to TTR-CM.  Two 
deaths were reported during the study.  One subject died of a hemorrhagic stroke 
approximately 4 months after study start, while on anticoagulation medication and after 
sustaining a head injury resulting from a fall.  The other subject was diagnosed with primary 
(light chain) amyloid cardiomyopathy, a disease for which tafamidis is not designed to be 
effective, approximately 11 months after starting the study.  He died following complications 
of pleurodesis, for management of recurrent pleural effusions.  The former event was 
unexpected and considered possibly related to study drug and the latter case was considered 
to be unrelated to study drug.  In addition, one subject discontinued participation in 
Fx1B-201 to undergo temporal lobectomy for treatment of a glioblastoma multiforme, 
reported approximately 12 months after starting the study, which was considered unrelated to 
tafamidis and the subject died secondary to an intracranial hemorrhage.  A second subject
with a history of systolic and diastolic heart failure, worsening heart failure, and increasing 


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falls, which were assessed as possibly related to tafamidis, died approximately 2 months after 
study completion of an unknown cause.  The death was assessed as unrelated to tafamidis.
The most frequent adverse events overall were related to symptoms and episodes of heart 
failure (dyspnea, cardiac failure and edema).  Eighteen (51.4%) subjects reported at least one 
Treatment Emergent Adverse Events (TEAE) that was considered at least possibly related to 
study medication.  The most common (>5%) treatment-related TEAEs included urinary tract 
infection (20.5%), balance disorder (14.3%), ageusia (8.6%), constipation, diarrhea, edema 
peripheral, fall, weight increased, decreased appetite and dyspnea (5.7% each). The majority 
(≥85%) of subjects experienced TEAEs considered mild or moderate in severity. One 
adverse event (AE) of hyperkalemia, reported during a hospitalization for decompensated 
heart failure and associated with acute renal failure, was considered life-threatening and not 
related to tafamidis.
In study Fx1B-201, a total of 15 (42.9%) subjects reported 41 treatment-emergent serious 
adverse events (SAEs), with the majority cardiac in nature. Serious adverse events reported 
by more than 1 subject included cardiac failure congestive (reported in 9 patients), atrial 
fibrillation and fall (3 subjects each), cardiac failure, syncope (2 subjects each). The reasons 
for hospitalizations were similar to those reported during TRACS, again primarily cardiac in 
nature (eg, worsening congestive heart failure).
Renal function was abnormal overall at Baseline, and suggestive of pre-renal azotemia with 
blood urea nitrogen (BUN) elevated to a greater degree than creatinine.  BUN remained 
stable in subjects with wild-type disease but there was evidence of progressive worsening in 
the four African-American subjects with V122I.  NT-proBNP and troponin I and T were 
elevated at Baseline, but remained stable through 12 months in subjects with wild-type TTR.  
Although increases over the 12-month study were noted in subjects with V122I in these 
cardiac markers, it is not known if the elevations were related to worsening cardiac or renal 
function.  There were no other clinically relevant changes in mean laboratory parameters 
over time.
There were no clinically relevant changes in vital signs, or in the proportion of subjects with 
orthostatic hypotension on treatment.  There were no apparent adverse effects of tafamidis on 
cardiac rhythm or conduction, including cardiac repolarization.
The adverse events reported for subjects during study Fx1B-201 largely reflect underlying 
disease, co-morbid conditions, and elderly status. Given the caveat that this study did not 
have a control group, there were no apparent safety trends related to drug therapy, suggesting 
that an oral daily dose of 20 mg tafamidis over 12 months was well tolerated in TTR-CM 
subjects.
TRACS and Fx1B-201 have provided not only Baseline data on a variety of cardiac functions 
in this subject population, but change in these functions over time. This current 
interventional study is designed to evaluate whether stabilization of TTR by tafamidis can 
modify clinical outcomes as well as specific cardiac parameters associated with TTR-CM.  
The study medication was referred to in previous study protocols as Fx-1006A. To simplify 


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discussions in the text of this protocol, the term ‘tafamidis’ is used to refer to the study 
medication and dosing regimen.
1.2.2. Dose Rationale
This protocol will employ tafamidis meglumine at 20 mg and 80 mg doses compared with 
placebo.  The 20 mg dose of tafamidis has been used previously in both polyneuropathy and 
cardiomyopathy trials. A range of tafamidis exposures has been assessed in clinical 
pharmacology studies in healthy volunteers that include the concentrations expected with an
80 mg dose.  The addition of the 80 mg dose, which is expected to result in near maximal 
TTR stabilization, will permit exploration of a higher dose to assure that efficacy and safety 
have been explored across a range of adequately separated doses.
1.2.3. Study Rationale
This study is being conducted to evaluate the efficacy and safety of tafamidis in comparison 
to placebo for the treatment of TTR-CM.  Tafamidis is a novel specific stabilizer of both 
wild-type and amyloidogenic variants of TTR. Tafamidis binds to TTR at the thyroxine 
binding sites and inhibits TTR tetramer dissociation, the rate-limiting step in the 
amyloidogenic process. By stabilizing the tetrameric native state of TTR, tafamidis increases 
the activation barrier associated with tetramer dissociation and therefore mimics the 
tetrameric stabilization effect observed with naturally occurring protective trans-suppressor 
variants.  It is hypothesized that tafamidis would stop or slow the progression of TTR-CM
and therefore represent a disease modifying therapy.
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator Brochure (IB).
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
The primary objective of this study is to assess the efficacy of an oral dose of 20 mg or 
80 mg tafamidis meglumine soft-gel capsules based on all-cause mortality and on frequency
of cardiovascular-related hospitalizations as well as to assess safety and tolerability in 
comparison to placebo. Tafamidis or placebo will be administered once daily, in addition to 
standard of care, for 30 months in subjects diagnosed with variant or wild-type TTR 
cardiomyopathy (TTR-CM).
2.2. Endpoints
This protocol will use an independent Endpoint Adjudication Committee (EAC) to determine 
whether certain investigator-reported events meet the definition of disease-related efficacy 
endpoints, using pre-defined endpoint criteria thereby maintaining scientific integrity of the 
study.  Sites will submit a Serious Adverse Event notification for all deaths and 
hospitalizations, as outlined in Section 8.14.1


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The Endpoint Adjudication Committee is the primary group responsible for adjudicating all 
potential endpoint events reported in this study.  This Committee will conduct a review of 
events reported by trial investigators blinded for treatment assignment to determine whether 
they meet protocol-specified criteria for endpoint reporting.  The EAC is independent of 
Pfizer.  Inclusion of an independent EAC is justified in order to comply with regulatory and 
industry standards.  In the event there is insufficient information for the adjudication process 
to classify either a mortality or hospitalization as cardiovascular related or not cardiovascular 
related, then the event will be classified as “indeterminate”.  In the adjudication process, 
cases with at least some information indicating a contributory cardiovascular cause, including 
ambiguous cases, will be adjudicated to the cardiovascular-related category.  Details of the 
actions and responsibilities of the EAC can be found in the EAC Charter and EAC 
Guidelines, the latter of which have been incorporated into the EAC Charter.
2.2.1. Primary Analysis
The primary analysis uses a hierarchical combination, applying the method of 
Finkelstein-Schoenfeld (Finkelstein 1999)16 to:
1. All-cause mortality and
2. Frequency of cardiovascular-related hospitalizations over the duration of the trial, 
which is defined as the number of times a subject is hospitalized (ie, admitted to a 
hospital) for cardiovascular-related morbidity.
2.2.2. Key Secondary Endpoints:
1. Change from Baseline to Month 30 in the distance walked during 6-Minute Walk 
Test (6MWT).(Appendix 4)
2. Change from Baseline to Month 30 in the Kansas City Cardiomyopathy 
Questionnaire Overall Score (KCCQ-OS).(Appendix 1.1)
2.2.3. Secondary Endpoints:
1. Cardiovascular-related mortality.
2. Frequency of cardiovascular-related hospitalization.
3. All-cause mortality.
4. TTR stabilization at Month 1.
2.2.4. Exploratory Endpoints:
1. Frequency of all-cause hospitalization.
2. Cardiovascular-related days hospitalized.
3. All-cause days hospitalized.


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4. All-cause mortality and the frequency of all-cause hospitalization using the 
Finkelstein-Schoenfeld analysis.
5. All-cause mortality and cardiovascular-related days hospitalized using the 
Finkelstein-Schoenfeld analysis.
6. Cardiovascular-related mortality and frequency of cardiovascular-related 
hospitalization using the Finkelstein-Schoenfeld analysis.
7. TTR stabilization at each time point other than Month 1.
8. TTR concentration at each time point.
9. Change from Baseline at time points other than Month 30 in the 6-Minute Walk Test 
(6MWT).(Appendix 4).
10. Change from Baseline at time points other than Month 30 in the Kansas City 
Cardiomyopathy Questionnaire Overall Score (KCCQ-OS).(Appendix 1.1).
11. Change from Baseline at each time point in the Kansas City Cardiomyopathy 
Questionnaire domain scores (Physical limitation, Symptom stability, Symptom
frequency, Symptom burden, Self-efficacy, Social limitation, and Quality of life) and 
domain summary scores (Functional summary and Clinical summary).
12. Change from Baseline at each time point in EuroQoL-5 Dimensions (EQ-5D-3L) 
(Appendix 2) Index Score and visual analog scale (VAS) scores.
13. Patient Global Assessment at each time point (Appendix 3).
14. New York Heart Association classification (NYHA) at each time point.
15. Change from Baseline at each time point in modified Body Mass Index.
16. Change from Baseline at each time point in NT-proBNP concentration.
17. TTR oligomer concentration at each time point.
18. Change from Baseline at each time point in select echocardiographic parameters (See 
Section 7.6.5 for complete list), including:
a.
End-diastolic interventricular septal wall thickness (mm);
b. Left ventricle posterior wall thickness (mm);
c.
Left ventricular ejection fraction (%);
d. Left ventricular stroke volume (mL);


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e.
Global longitudinal strain;
f.
Circumferential strain mid global;
g. Radial strain mid global.
Safety and tolerability will be assessed with adverse event reporting as well as the conduct of 
ECGs, clinical laboratory testing, vital signs, and physical examinations.
3. STUDY DESIGN
This is a Phase 3, multicenter, international, three-arm, parallel design, placebo-controlled, 
randomized study with a 30-month double-blind treatment phase, to determine efficacy,
safety and tolerability of tafamidis on clinical outcomes in subjects with either transthyretin 
genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy (TTR-CM).
There will be approximately 400 subjects enrolled in the study in a 2:1:2 ratio 
(placebo:20 mg:80 mg).  The subjects will be allocated to the 3 arms of the study in the 
following manner: n=160 in the placebo arm, n=80 in the 20 mg arm, and n=160 in the 
80 mg arm.  Subjects who experience adverse events that may be associated with poor 
tolerability to treatment with tafamidis that may impact dosing adherence have the option of 
blinded treatment re-assignment and potential dose reduction (see Section 5.5). Subjects will 
be stratified during enrollment by TTR genotype (variant and wild-type) and structured such 
that greater than 30% of randomized subjects have a TTR mutation and greater than 30% of 
subjects have a diagnosis of wild-type TTR cardiomyopathy, with the intent to enroll
comparable numbers between the variant and wild-type groups.  
Enrollment may be closed for either wild-type or variant stratum in order to enroll at least 
30% of subjects with each TTR genotype (wild-type and variant).
Additionally, stratification to treatment assignment will be done for Baseline severity of 
disease based on NYHA classification (NYHA Class I and NYHA Classes II and III
combined).  Stratification will be implemented in order to maintain a balance of both TTR 
genotype and disease severity across the treatment assignments. The site will ensure a 
Month 30 follow-up contact to determine the subject’s vital status and whether the subject 
has had a heart and / or liver transplant or implantation of cardiac mechanical assist device.  
Upon completion of the study at the Month 30 visit, subjects may be eligible for -treatment 
with tafamidis in a separate extension study (B3461045), which will permit the collection of 
additional safety and efficacy data, and may include the assessment of hospitalizations, 
mortality, and other outcomes relating to disease progression.  For the purpose of this study, 
30 months is defined as 910 days.  Eligibility for the extension study (B3461045) requires 
subject participation in this study at least through Day 896 (Month 30 minus 2 weeks).


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4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team, before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated Informed Consent Document indicating 
that the subject (or a legal representative) has been informed of all pertinent aspects 
of the study and evidence of a personally signed and dated Release of Medical 
Information Form regarding access to medical records as well as vital status / 
transplant status follow-up by the site with the subject or the subject’s caregivers 
30 months after study randomization.  In some cases, sites may combine these two 
forms into one form, as is their standard practice.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures,
3. Age greater than or equal to 18 and less than or equal to 90 years old at the time of 
randomization,
4. Medical history of Heart Failure (HF) with at least 1 prior hospitalization for HF or 
clinical evidence of HF (without hospitalization) manifested by signs or symptoms of 
volume overload or elevated intracardiac pressures (eg, elevated jugular venous 
pressure, shortness of breath or signs of pulmonary congestion on x-ray or 
auscultation, peripheral edema) that required/requires treatment with a diuretic for 
improvement,
5. Subject has documented TTR amyloid cardiomyopathy in accordance with 
institutional site standard of care, which is defined as:
a.
Variant TTR amyloid cardiomyopathy defined by all of the following:

presence of a variant TTR genotype associated with cardiomyopathy and 
presenting with a cardiomyopathy phenotype (eg, a history of congestive heart 
failure),
1. TTR genotyping is required at Screening unless documentation (ie,
original laboratory result, or copy) of a prior determination of a TTR 
genotype is produced,


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2. Subjects with a confirmed diagnosis of mutant (variant genotype)
TTR-CM with concurrent monoclonal gammopathy of undetermined 
significance (MGUS) based on serum or urine light chain determinations, 
should be tested in the same manner as in the case of equivocal 
immunohistochemistry for subjects with wild type TTR-CM below,

Evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness > 12 mm,

Presence of amyloid deposits in biopsy tissue, such as fat aspirate, salivary 
gland, median nerve connective tissue sheath, or cardiac (amyloid 
demonstrated per appropriate stain such as Congo red or alcian blue stain).
b. Wild-type TTR amyloid cardiomyopathy defined by all of the following:

absence of a variant TTR genotype,

evidence of cardiac involvement by echocardiography with an end-diastolic 
interventricular septal wall thickness > 12 mm,

presence of amyloid deposits in biopsy tissue, such as fat aspirate, salivary 
gland, median nerve connective tissue sheath, or cardiac (amyloid 
demonstrated per appropriate stain such as Congo red or alcin blue stain),

TTR precursor protein identification by immunohistochemistry, scintigraphy 
or mass spectrometry (Ruberg and Berk 2012, Dungu et al, 2012).41,13  
1. In the case where immunohistochemistry (IHC) outcome is equivocal such 
as staining suggestive of lambda or kappa light chains, additional 
confirmatory testing is required to confirm the diagnosis of TTR 
cardiomyopathy.  This confirmatory test may be performed using one of 
the following: (a) mass spectrometry (b) immunohistochemistry with 
electron microscopy or immunoelectron microscopy or immune-gold
microscopy (c) scintigraphy with tracer eg 99mTC-DPD 
[99mTC-3,3-diphosphono-1,2-propano-dicarboxylic acid], 99mTC- PYP 
[Pyrophosphate] and also 99mTC-HMDP [hydroxymethylene 
diphosphonate](Ando Y 2013, Glaudemans 2014, Bokhari S 2014, 
Bokhari S 2013).2,18,5,4
6. Biopsy, used to determine the presence of amyloid and demonstration of TTR 
precursor protein, must be done during Screening or documented as having been 
performed previously,
7. Subject must be able to read in native language and complete self-administered 
questionnaires independently,


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8. Subject’s symptoms of HF are optimally managed and clinically stable with no 
cardiovascular-related hospitalizations within 2 weeks prior to Baseline, as assessed 
by the Principal Investigator,
9. Male and female subjects of childbearing potential and at risk for pregnancy must 
agree to use two highly effective methods of contraception throughout the study and 
for at least 28 days after the last dose of assigned treatment.  A subject is of 
childbearing potential if, in the opinion of the investigator, he/she is biologically 
capable of having children and is sexually active,
10. Subject must have a Screening visit NT-proBNP concentration > 600 pg/mL (the 
conversion factor from conventional pg/mL to SI units is to divide by 8.45),
11. Subjects must be able to complete > 100 m on the 6-Minute Walk Test at Screening,
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Subjects with echocardiogram assessment at Screening that is not deemed 
interpretable by the central echocardiogram reader for the measurement of wall 
thickness.
2. Subjects using non-steroidal anti-inflammatory drugs (NSAIDs) that are not 
allowable in the protocol within 30 days prior to the Baseline visit (see Section 5.8.1).
3. Subjects with an mBMI below 600.
4. Subjects with a history of drug or alcohol abuse within the past 5 years that in the 
opinion of the investigator would interfere with compliance with study procedures or 
follow-up visits.
5. Subjects taking or have previously taken tafamidis.
6. Subjects requiring treatment with calcium channel blockers (eg verapamil, diltiazem)
or digitalis.
7. Subjects with primary (light chain) amyloidosis.
8. Subjects who have prior liver or heart transplantation, or implanted cardiac 
mechanical  assist device.
9. Subject has known or suspected hepatitis B, C, Human Immunodeficiency Virus 
(HIV) infection or positive serology for hepatitis B (HBsAg), hepatitis C (anti-HCV), 
or HIV.
10. Subjects with renal failure requiring dialysis and/or have an estimated glomerular 
filtration rate (eGFR) of < 25 mL/min./1.73 m2.


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11. Subjects with urinary retention requiring self-catheterization.
12. Subjects who are investigational site staff members directly involved in the conduct 
of the trial and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the trial.
13. Subjects who have symptoms indicative of New York Heart Association 
Classification IV at the Screening or Baseline visit.
14. Subjects with liver function test abnormalities (alanine transaminase and/or aspartate 
transaminase) greater than 2 times the upper limit of normal that are considered to be 
due to reduced liver function or active liver disease.
15. Subjects with participation in studies involving investigational drug(s) (Phases 1-4) 
within 30 days before the current study begins and/or during study participation. For 
diflunisal, tauroursodeoxycholate and doxycycline, this time period will also be 
within 30 days before the Baseline visit and/or any time during study participation.
16. Subjects with other severe acute or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with study participation 
or investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study.
17. Subjects who are pregnant females; breastfeeding females; male subjects with 
partners currently pregnant, males and females of childbearing potential who are 
unwilling or unable to use two (2) highly effective method of contraception as 
outlined in this protocol for the duration of the study and for at least 28 days, after last 
dose of investigational product.
18. Subjects with a history of sustained ventricular tachycardia or aborted ventricular 
fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal 
dysfunction for which a pacemaker is indicated but will not be placed.
19. Subjects with heart failure that in the opinion of the investigator is on the basis of 
ischemic heart disease (eg prior myocardial infarction with documented history of 
cardiac enzymes and ECG changes), or uncorrected valvular disease and not 
primarily due to transthyretin amyloid cardiomyopathy.
4.3. Life Style Guidelines
4.3.1. Contraception
In this study, fertile male subjects and female subjects who are of childbearing potential will 
receive tafamidis, which has been associated with teratogenic risk.  Subjects who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 
must agree to use 2 methods of highly effective contraception throughout the study and for 


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28 days after the last dose of investigational product.  The investigator or his or her designee, 
in consultation with the subject, will confirm that the subject has selected 2 appropriate 
methods of contraception for the individual subject and his/her partner(s) from the list of 
permitted contraception methods (see below) and will confirm that the subject has been 
instructed in their consistent and correct use.  At time points indicated in the Schedule of 
Activities, the investigator or designee will inform the subject of the need to use 2 highly 
effective methods of contraception consistently and correctly and document the conversation, 
and the subject’s affirmation, in the subject’s chart.  In addition, the investigator or designee 
will instruct the subject to call immediately if 1 or both of the selected contraception methods
is discontinued or if pregnancy is known or suspected in the subject or partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s partner plans to remain on the same treatment throughout the entire 
study and has been using that hormonal contraceptive for an adequate period of time 
to ensure effectiveness,
2. Correctly placed copper-containing intrauterine device (IUD),
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate,
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate,
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the coordinator’s manual.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study number, 
contact information for the investigational site and contact details for a help desk in the event 
that the investigational site staff cannot be reached to provide advice on a medical question 
or problem originating from another healthcare professional not involved in the subjects 
participation in the study.  The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 


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the study team are not available.  It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the subject directly and if a subject calls that number they 
will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
Investigators will confirm the eligibility of each subject to meet inclusion/exclusion criteria. 
An Interactive Response Technology (IRT) system will assign a unique subject identification 
number sequentially to each subject who has signed the informed consent document (ICD).  
This identifying number will be retained throughout the duration of the study participation.
Subject eligibility for participation in the treatment phase of the protocol will be determined 
following the assessments during the Screening period and at the Baseline (Day 1) visit.
Subjects will be screened for eligibility and those, in the judgment of the investigator, who 
meet the inclusion criteria and do not meet the exclusion criteria, will be randomized. There 
will be a treatment assignment stratification by TTR genotype (variant or wild-type) as well 
as by Baseline severity (NYHA Class I and NYHA Classes II and III combined). Subjects 
will be assigned to blinded treatment with either tafamidis 20 mg or 80 mg or matching 
placebo once daily, in addition to standard of care (eg, diuretics) for 30 months. Other than 
Week 2, Month 1 and Month 3, study visits will be at 3-month intervals (Month 6, 9, 12, 
etc.).  Subjects must return for their appointment before their blinded study drug supply is 
exhausted.  Subjects must bring all of their study medication wallets and their Subject Daily 
Dosing Diary to each appointment.  The site will collect all study medication wallets
dispensed at the previous visit and dispense a new set of study medication wallets and a 
Subject Daily Dosing Diary to the subject.
5.2. Breaking the Blind
The reason for breaking the blind for an individual subject may include the following:
1. A serious, unexpected/unlisted, treatment-related event for reasons of subject safety.
2. An urgent safety measure taken by the investigator or Pfizer to protect subjects 
against immediate hazard to health.
3. A potentially life threatening drug interaction.
4. Ethical considerations such as a medical emergency where understanding the 
treatment allocation is necessary to adequately manage the subject’s condition.  In 
this case, an attempt should be made to contact the study clinician or another member 
of the study team.


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Whenever possible, the investigator or sub-investigator should consult with a member of the 
study team (eg, the clinical trial manager or the monitor) prior to breaking the blind for an 
individual subject.  After reviewing and approving the investigator’s request, the study 
clinician will provide written authorization (email) to the investigator to break the blind.
If unable to contact a member of the study team, the investigator may break the blind for a 
given subject experiencing an SAE or other medical emergency where knowledge of the 
treatment assignment will affect treatment decisions.
Breaking the blind will be done electronically and instructions will be given at a training 
session for the protocol.
5.3. Dosing Adherence
Subjects will be instructed to take the medication on a daily basis.  They will also be 
instructed to bring all of their study medication back to the study site, including used and 
unused study medication wallets, at each scheduled study visit so that the total amount of 
drug taken can be determined and unused medication collected by site personnel.  Study drug 
capsule count will be performed at each scheduled visit for all subjects or as per local 
regulations.  The need for adherence with study drug administration will be reinforced at 
each study visit.
For the purpose of promoting dosing adherence, the sites will calculate the number of days 
dosed divided by the number of days participating in the study for each study visit to provide 
a measure of treatment adherence.  As part of study data analysis, subjects will be considered 
to be adherent to the dosing requirements of the study if they have taken 4 capsules of study 
medication per day on at least 80% of the days of study participation.  Subjects with less than 
80% dosing adherence will be excluded from the per protocol analysis set.
Subjects will be randomized to blinded therapy with either 20 mg or 80 mg of tafamidis or 
placebo.  Individual subjects with tolerability issues that could impact dosing adherence will 
have the option to receive blinded dose reduction of their dose.  See Section 5.5 regarding the 
decision and procedures for blinded dose reduction due to poor tolerability.
5.4. Drug Supplies
In order to achieve the proper dosage and maintain the blind in the study, capsules will be 
dispensed in a blinded fashion to achieve a daily dose of 4 capsules.  Each dose of 4 capsules 
will consist of either 3 capsules of blinded placebo and 1 capsule of blinded tafamidis 20 mg, 
4 capsules of blinded tafamidis 20 mg, or 4 capsules of blinded placebo.


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Dosage Level
Compound
Appearance
Number of Capsules Per Day 
(Dose)
Tafamidis meglumine
20 mg
PF-06291826
Oblong soft gelatin 
capsules
1 (Tafamidis 20 mg capsule)
3 (Placebo capsules)
Tafamidis meglumine 
40 mg (in the event of 
blinded dose reduction
for the 80 mg dose)
PF-06291826
Oblong soft gelatin 
capsules
2 (Tafamidis 20 mg capsules)
2 (Placebo capsules)
Tafamidis meglumine
80 mg
PF-06291826
Oblong soft gelatin 
capsules
4 (Tafamidis 20 mg capsules)
Placebo for Tafamidis
Oblong soft gelatin 
capsules
4 (Placebo capsules)
5.4.1. Dosage Form and Packaging
Tafamidis meglumine 20 mg (and matching placebo) in soft gel capsules will be packaged as 
7 tri-fold study medication wallets in each carton with each wallet labeled 1 through 7.  Each 
of the study medication wallets will be packaged with enough medication for 15 days of 
dosing.  Subjects will be dispensed 1 carton containing 7 study medication wallets.  This will 
provide enough study medication for each 3-month dosing period plus 1 extra study 
medication wallet to allow for flexibility in clinic visit scheduling (total of 105 days’ supply).  
Written dosing instructions will be supplied to subjects.  Subjects should be instructed to 
only dose from 1 study medication wallet each day.  Subjects should take 4 capsules one time 
a day with water.  Each 4-capsule daily dose is packaged on a separate row in the study 
medication wallet with “Date ____” printed beside each daily dose.  Subjects should be 
instructed to dose each day from a single row, and write in the date that the dose was taken.  
Subjects should be instructed to complete dosing from one study medication wallet prior to 
starting dosing from the next consecutively numbered study medication wallet.
5.4.2. Preparation and Dispensing
Drug (or matching placebo) will be dispensed at Baseline (Day 1), Month 3, and at every 
3-month visit thereafter using an IRT system.
5.5. Administration
Subjects will be instructed to take 4 capsules per day from an individual row on the 
dispensed study medication wallet and to take the capsules with a glass of water.  Subjects 
will swallow the study medication whole, and will not manipulate or chew the medication 
prior to swallowing. Subjects will be instructed to dose at a consistent time of day. Subjects 
will be instructed to start taking their medication each day in the morning (AM dosing); 
however, it is permitted for subjects to take his/her medication in the PM prior to a clinic 
visit when the timing of pharmacokinetic (PK) sample collection is prohibitive for adherence 
with AM dosing.  Subjects should not take an extra dose of medication in the event that a 
dose from a previous day is missed and should resume dosing 4 capsules per day from an 
individual row on the study medication wallet at the next planned dosing time.  Similarly, if 
multiple doses are missed in succession, the subject should resume dosing at the next planned 
dosing time without taking additional doses to make up for those doses that were missed.  
Instructions on dosing are provided on the Subject Daily Dosing Diary.


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At the end of each visit, sites will instruct subjects, in writing on the front of the Subject 
Daily Dosing Diary, when to take their medication prior to their next study visit. This is 
especially important if the next visit has a collection of blood sample(s) for PK analysis.  
Knowing the actual time of dosing is essential for appropriate analysis of samples for TTR 
stabilization, TTR and oligomer concentration, and for tafamidis pharmacokinetic 
measurements, as required and specified in Section 7.7.2 and Section 7.7.6. On the day of 
the study visit, subjects will write the actual time that they took their medication in the 
Subject Daily Dosing Diary and the site staff will record this dosing time in the case report 
form (CRF).  On specified study days (Months 1, 18, and 24), subjects will take their 
medication during the clinic visit and subjects will be reminded to not take their daily dose 
on those days until instructed by clinic staff.
Subjects should be instructed not to take more than 4 capsules when taking their daily 
blinded therapy.  It should also be noted that at Month 6 and Month 12 visits, dosing should 
take place 7 hours (± 2.5 hours) prior to the timing of PK sample.  On the day prior to Month 
6 and Month 12 visits, subjects are permitted to take their usual AM dose and then take the 
next day’s dose in the PM if necessary to adhere to the PK sampling schedule.  
In the event that subjects experience adverse events that may be associated with the
tolerability of treatment with tafamidis that may impact dosing adherence, they should return 
to the clinic with their medication.  If the investigator assesses that the tolerability issue is 
persistent and anticipated to impact dosing adherence and that the subject’s safety is not 
compromised by continuing treatment, then the subject may receive blinded treatment 
re-assignment and potential dose reduction.
Prior to blinded dose reduction, the site should collect a PK sample, noting the actual time of 
last dosing and the actual time of PK sample collection.  The site personnel will enter the 
subject’s study-specific identification (SSID) number into the IRT system and request 
blinded dose reduction.  The IRT system will provide a new container number for blinded 
treatment re-assignment for this subject.  If the subject was receiving the 80 mg dose, then 
the re-assignment will be to 40 mg.  If subject was receiving placebo or the 20 mg dose, they 
will be maintained on that dose but will still receive a new container number in order to 
maintain the blind.  If poor tolerability continues following the blinded re-assignment, the 
site has the option to discontinue dosing for this subject and to terminate study participation.  
In the event of early study discontinuation, the site staff will follow-up on the subject’s vital 
status / transplant status 30 months after randomization.
5.6. Drug Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products, are stored in a secured area with controlled access under required
storage conditions and in accordance with applicable regulatory requirements.  All 
investigational product should be stored at controlled room temperature 15-25° C (59-77° F). 
Investigational products should be stored in their original container and in accordance with 
the label.


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Any storage conditions stated in the SRDS will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational product.
5.7. Drug Accountability
At each scheduled clinic visits starting at Month 1; subjects will bring their Subject Daily 
Dosing Diary and their study medication wallets with them to the site.  Beginning at the 
Month 3 visit, subjects will return used Subject Daily Dosing Diary and study medication 
wallets and site personnel will collect any unused medicine, determine dosages taken, and 
store returned drug for disposition.  See Section 5.3 for documentation of dosing adherence.
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies as outlined in the in the monitoring plan.
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).


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5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatments
Medications taken within 28 days before the first dose of trial medication will be documented 
as a prior medication. Medications taken after the first dose of trial medication will be 
documented as concomitant medications.
Concomitant Treatment is defined as ongoing or initiated at any time on or after Baseline 
(Day 1) of the study through the final study visit. Concomitant treatments include any 
substance ingested, injected, absorbed, inhaled, or otherwise enters the body for a therapeutic
purpose regardless of number of doses taken. This includes prescription and 
over-the-counter medicines, vitamins, and herbal remedies.
Subjects may use supplements and medications during the course of the study with the 
exception of those listed in Section 4.2 and Section 5.8.1.  Medication considered to be 
standard of care are permitted but should be recorded on the CRF.
Standard of Care: Medications indicated as standard of care should be stabilized for at least 
4 weeks of therapy (other than diuretics) prior to Baseline.
Changes in diuretic dose are permitted within 4 weeks of the Baseline visit.
5.8.1. Contraindicated Therapies
Use of NSAIDs other than those noted below is prohibited.  Some NSAIDs, like diflunisal,
can bind to the thyroxine binding sites on transthyretin (Almeida 2004).1  Subjects must 
discontinue use of diflunisal at least 30 days prior to the Baseline visit (Day 1). Permitted 
NSAIDs include: acetylsalicylic acid, etodolac, ibuprofen, indomethacin, ketoprofen, 
nabumetone, naproxen, nimesulide, piroxicam, and sulindac.  Use of any other NSAIDS 
requires agreement with the Sponsor’s clinician or medical monitor.
1. Use of any investigational therapy during the study is not permitted.
2. Use of diflunisal or any other investigational therapy during the study is prohibited.
The presence of diflunisal in the blood will be measured at Screening and at various 
times throughout the study in order to document whether the subjects are taking a 
contraindicated medication so that they can be appropriately counselled. Such 
subjects will be handled as protocol violators in the analysis as described in the 
Statistical Analysis Plan.
3. Additionally, the use of tauroursodeoxycholate and doxycycline is not permitted.


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4. Digitalis and calcium channel blockers (eg verapamil, diltiazem) are prohibited 
concomitant medications because they bind to amyloid fibrils and may lead to 
increased toxicity (Gertz 1985, Rubinow 1981, Rapezzi 2010).17,44,39  If the agent is to 
be stopped, it must be at least 30 days before Baseline.
6. STUDY PROCEDURES
Every effort should be made to ensure that scheduled visits are completed according to the 
Schedule of Activities on the prescribed days and protocol required tests and procedures are 
completed as described.  From time to time there may be circumstances, such as a constraint 
on travel for health-related reasons, that a clinic visit may not be possible.  In these cases, 
with prior discussion and approval from the sponsor, alternative options for completing the 
visit may be considered.  Additionally, visits should be completed as close to the scheduled 
timeframe as possible but not to exceed 1 week of the target date for the Month 1 visit and
2 weeks of the target dates for subsequent visits.  
The duration of this study is 30 months.  Follow-up visit dates should be based on the date of 
the Baseline visit, not the date of the previous follow-up visit.  If the Baseline visit, for 
example, is on the 15th of the month, the Month 1 visit is to be scheduled on the 15th of the 
next month 1 week).  The Month 3 visit is to be scheduled on the 15th of the 3rd month from 
the Baseline visit 2 weeks).
The Month 30 visit is to be scheduled 910 days following the Baseline visit (2 weeks), and 
can be determined by the use of the Visit Calculator, located in Firecrest.
6.1. Screening Period
The following evaluations will be performed and laboratory samples collected for all subjects 
during the Screening Period prior to starting drug (eg, Day -45 to Day -10).  If tests cannot be 
performed, if tests need to be repeated or if there are extenuating circumstances the 
Screening period may be extended following written authorization from the study clinician. 
The duration of the Screening extension will be no more than 2 weeks.
At the discretion of the investigator, isolated abnormal tests can be repeated for confirmation.
However, the entire panel should not be repeated. In the event the repeated test confirms an
abnormal value, no further testing is necessary. The abnormal test value from the 
confirmatory test will be entered into the database and the subject will be considered a 
Screen failure. If the repeat test does not confirm the abnormal value (ie, it is within the 
normal range), the investigator is required to again repeat the specific laboratory test. If this 
further repeat test confirms a value within the normal range, the last repeated normal value is 
entered into the database.  If the further repeat test value is abnormal, this value will be 
entered into the database and the subject will be considered a Screen failure.
Written subject informed consent will be obtained prior to any study-related procedures.


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The sites will assure that laboratory procedures are performed to allow sufficient time for 
returning results to the site for evaluation.  The following procedures will be conducted 
during the Screening Period:
1. Medical History (including history of heart failure),
2. Smoking and alcohol classification,
3. Full physical examination including weight and height,
4. Single 12-lead ECG - perform ECGs prior to any blood collection or blood pressure 
measurements,
5. Echocardiogram (must have an end-diastolic interventricular septal wall thickness of 
>12 mm and assessment for study eligibility will be based on a central laboratory
reading).  See Section 7.6.5 for required measurements,
6. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature),
7. Tissue biopsy (repeat not required if there is documentation by mass spectrometry, 
immunohistochemistry or scintigraphy of amyloid deposition from a prior biopsy).  
The original laboratory result, or copy will be part of the source documentation,
8. Collect blood, and urine samples for the following clinical laboratories:
a.
Hematology;
a.
Serum Chemistry;
b. Coagulation (INR, PT);
c.
Serology for Hepatitis B (HBsAg), Hepatitis C (anti-HCV), and HIV;
d. Serum and urine test for primary light chain amyloidosis (AL) Section 7.6.8;
e.
Urinalysis;
f.
Genotyping - not needed for subjects with prior documented genotyping.  In such 
instances, the original laboratory result, or copy will be filed as source 
documentation;
g. Urine pregnancy test – for women of childbearing potential.
9. Collect blood samples for NT-proBNP and troponin I.
10. Collect blood sample for diflunisal concentration (Section 7.7.3).


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11. 6-Minute Walk Test (Appendix 4).
12. NYHA classification.
13. Documentation of prior medications.
6.2. Study Period
For the trial period discussed below, where multiple procedures are scheduled at the same 
nominal time point(s) relative to dosing, the following chronology of events is suggested:
1. ECGs – ECGs should be obtained prior to vital sign and blood specimen collection.
2. Blood pressure/pulse rate –obtain prior to the blood specimen collection.
3. Blood sample collection for clinical laboratories and diflunisal concentration.
4. Blood specimens for Tafamidis concentration, TTR stabilization, TTR oligomer 
concentration, and TTR concentration – obtain within the specified time windows.
All other procedures should be obtained after blood specimen collections, unless sampling is 
determined by the study personnel to potentially impact the results.  For Patient Reported 
Outcome measures (Appendix 1), the following order should be adhered to: Kansas City 
Cardiomyopathy Questionnaire, (Appendix 1.1) EuroQoL-5 Dimensions, (EQ-5D-3L),
(Appendix 2) and then the Patient Global Assessment (Appendix 3).
6.2.1. Baseline (Day 1)
Prior to dosing, the following procedures will be completed at the Baseline visit:
1. Review entrance criteria.
2. Randomization.
3. Medical history (updated for changes since Screening visit).
4. Brief Physical Examination with weight.
5. Single 12-lead ECG - prior to any blood pressure measurement or blood collection.
6. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
7. Blood and urine sample collection for the following clinical laboratories:
a.
Hematology;
b. Serum Chemistry;


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c.
Coagulation (INR, PT);
d. Retinol Binding Protein;
e.
Urinalysis;
f.
Urine Pregnancy test – for women of childbearing potential.
8. Collect blood sample for TTR stabilization, TTR oligomer concentration, and TTR 
concentration assays pre-dose.
9. Collect blood sample for diflunisal concentration (Section 7.7.3).
10. Collect Baseline pre-dose blood sample as control for tafamidis concentration.
11. Collect pharmacogenomic sample.
12. Collect blood sample for NT-proBNP and troponin I.
13. 6-Minute Walk Test (Appendix 4).
14. Kansas City Cardiomyopathy Questionnaire (Appendix 1.1).
15. EQ-5D-3L (Appendix 2).
16. Patient Global Assessment (Appendix 3).
17. NYHA classification.
18. Documentation of concomitant medications.
19. Adverse event reporting.
20. Hospitalization determination.
21. Documentation of vital status and transplant or cardiac mechanical assist device
status.
22. Dispense blinded medication.
Subjects will be instructed to take their first tafamidis daily dose of 4 capsules after the 
completion of the Baseline procedures and to continue dosing 4 capsules each day in the 
morning until the next study visit.
At the end of the visit, a time will be scheduled for the Week 2 phone call along with the 
Month 1 appointment. The subject will be instructed not to take their medication at home on 
the day of the Month 1 visit, but rather wait and take the medication when instructed by the 
site staff when they arrive at the clinic. A Subject Daily Dosing Diary stating the date and 


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time of the Month 1 visit will be issued to the subject. The subject will be reminded to return 
to the clinic with all dispensed study medication wallets.
6.2.2. Week 2 Follow-up
1. Subjects required to have their labs drawn either at a local laboratory, at their primary 
physician’s office or at the Investigator’s site and have the samples sent to the central 
laboratory.  The results will be sent to the investigator site.  The clinical site will 
arrange a telephone call with the subject to inquire about any adverse effects and their 
health status for the Week 2 follow-up (see below).
2. Whether using the clinical site, a local laboratory or primary physician’s office, the 
following specimens will be collected.
a.
Hematology;
b. Serum Chemistry.
3. The site will contact the subject by phone at the time agreed with the subject at the 
baseline visit to collect the following information since the last visit:
a.
Documentation of concomitant medications;
b. Adverse events reporting;
c.
Hospitalization determination;
d. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the clinic visit or phone call, the Month 1 appointment will be confirmed and
the subject will be reminded to take their medication in the clinic, rather than at home, on the 
day of the next visit, as indicated on the Subject Daily Dosing Diary.  The subject will be 
reminded to return to the clinic with all dispensed study medication wallets.
6.2.3. Month 1 Visit
On the day of the Month 1 study visit, subjects will NOT take their study medication at home 
prior to the Month 1 clinic visit. Study medication on the day of the Month 1 visit will be 
taken in the clinic in order to accurately and conveniently time the tafamidis concentration 
blood sample, which is to be pre-dose as well as 3 hours (1.5 hours) after the actual time of 
dosing.
Study site personnel will also record in the CRF the time of dosing on the day before the 
Month 1 visit as recorded by the subject on their Subject Daily Dosing Diary.
Prior to dosing, the following procedures will be completed at the Month 1 visit:


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1. Brief physical examination with weight.
2. Single 12-lead ECG -prior to any blood collection or blood pressure measurements.
3. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
4. Collect blood sample for TTR stabilization, TTR oligomer concentration, and TTR 
concentration assays.
5. Collect pre-dose sample for tafamidis concentrations.
6. Collect blood sample for diflunisal concentration (Section 7.7.3).
The subject is to administer the dose of blinded study medication at the clinic and the actual 
time of dosing will be recorded by the study site personnel.
After dosing, the following procedures will be completed:
1. Blood and urine sample collection for the following clinical laboratories:
a.
Hematology;
b. Serum Chemistry;
c.
Coagulation (INR, PT);
d. Retinol Binding Protein;
e.
Urinalysis;
f.
Urine pregnancy test – for women of childbearing potential.
2. Collect blood sample for TTR stabilization, TTR oligomer concentration, and TTR 
concentration assays at 3 hours (1.5 hours) after dosing,
3. Collect blood sample for tafamidis concentration at 3 hours (1.5 hours) after dosing
and record the actual time of the blood sample as well as the actual time of drug 
dosing,
4. Documentation of concomitant medications,
5. Record dosing adherence,
6. Adverse events reporting,
7. Hospitalization determination,


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8. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit the next appointment is to be scheduled and subject will be instructed 
to take their medication at home prior to the next visit.  A Subject Daily Dosing Diary stating 
the date and time of the next visit will be issued to the subject.  The subject will be reminded
to return to the clinic with all dispensed study medications wallets.
6.2.4. Month 3 Visit
The following procedures will be completed at the Month 3 visit:
1. Brief physical examination with weight.
2. Vital Signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
3. Blood sample collection for Serum Chemistry.
4. Documentation of concomitant medications.
5. Record dosing adherence.
6. Adverse event reporting.
7. Hospitalization determination.
8. Dispense blinded study medication.
9. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit, the next appointment is to be scheduled and subject will be instructed 
to take their medication at home prior to the next clinic visit.  Visit scheduling and dosing 
time instructions for subjects must consider that the tafamidis concentration sample is to be 
collected 7 hours (± 2.5 hours) after dosing.  A Subject Daily Dosing Diary stating the date 
and time of the next visit will be issued to the subject.
Subjects will be instructed to accurately record on the Subject Daily Dosing Diary the actual 
time at which they took their prior 2 doses of blinded medication at home on the day before 
and the day of the Month 6 visit.  The subject will be reminded to return to the clinic with all 
dispensed study medication wallets.
6.2.5. Month 6 Visit
Subjects will take their scheduled dose at home prior to the clinic visit and record the actual 
time of dosing on their Subject Daily Dosing Diary.  Study site personnel will record in the 
CRF the time of dosing the day before and the day of the Month 6 visit as recorded by the 


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subject on their Subject Daily Dosing Diary.  Dosing at this visit should take place 7 hours 
(2.5 hours) prior to the timing of the tafamidis concentration blood collection.
The following procedures will be completed at the Month 6 visit:
1. Brief physical examination with weight.
2. Single 12-lead ECG.
3. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
4. Blood and urine sample collection for the following clinical laboratories:
a.
Hematology;
b. Serum Chemistry;
c.
Coagulation (INR, PT);
d. Retinol Binding Protein;
e.
Urinalysis;
f.
Urine pregnancy test – for women of childbearing potential.
5. Collect blood sample for TTR stabilization, TTR oligomer concentration, and TTR 
concentration assays at 7 hours (± 2.5 hours) post-dose.
6. Collect blood sample for diflunisal concentration (Section 7.7.3).
7. Collect blood sample for tafamidis concentration at 7 hours (± 2.5 hours) after dosing 
and record the actual time of the blood sample as well as the time of drug dosing from 
the subject’s Subject Daily Dosing Diary.
8. Echocardiogram.
9. 6-Minute Walk Test (Appendix 4).
10. Kansas City Cardiomyopathy Questionnaire (Appendix 1.1).
11. EQ-5D-3L (Appendix 2).
12. Patient Global Assessment (Appendix 3).
13. NYHA classification.
14. Documentation of concomitant medications.


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15. Record dosing adherence.
16. Adverse event reporting.
17. Hospitalization determination.
18. Dispense blinded study medication.
19. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit the next appointment is to be scheduled. A Subject Daily Dosing 
Diary stating the date and time of the next visit will be issued to the subject.  The subject will 
be reminded to return to the clinic with all dispensed study medication wallets.
6.2.6. Month 9 Visit 
The following evaluations will be performed for all subjects at the Month 9 visit.
1. Brief physical examination with weight.
2. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
3. Blood sample collection for Serum Chemistry.
4. Documentation of concomitant medications.
5. Record dosing adherence.
6. Adverse event reporting.
7. Hospitalization determination.
8. Dispense blinded study medication.
9. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit, the next appointment is to be scheduled and subject will be instructed 
to take their medication at home prior to the next clinic visit. Visit scheduling and dosing 
time instructions for subjects must consider that the tafamidis concentration sample is to be 
collected 7 hours (± 2.5 hours) after dosing.  A Subject Daily Dosing Diary stating the date 
and time of the next visit will be issued to the subject. Subjects will be instructed to 
accurately record on the Subject Daily Dosing Diary the actual time at which they took their 
prior 2 doses of blinded medication at home on the day before and the day of the Month 12
visit.  The subject will be reminded to return to the clinic with all dispensed study medication 
wallets.


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6.2.7. Month 12 Visit 
Subjects will take their scheduled dose at home prior to the clinic visit and record the actual 
time of dosing on their Subject Daily Dosing Diary.  Study site personnel will record in the 
CRF the time of dosing the day before and the day of the Month 12 visit as recorded by the 
subject on their Subject Daily Dosing Diary.  Dosing at this visit should take place 7 hours 
(2.5 hours) prior to the timing of the tafamidis concentration blood collection.
The following procedures will be completed at the Month 12 visit:
1. Brief physical examination with weight.
2. 12-Lead ECG.
3. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
4. Blood and urine sample collection for the following clinical laboratories:
a.
Hematology;
b. Serum Chemistry;
c.
Coagulation (INR, PT);
d. Retinol Binding Protein;
e.
Urinalysis;
f.
Urine pregnancy test – for women of childbearing potential.
5. Collect blood sample for TTR stabilization, TTR oligomer concentration, and TTR 
concentration assays at 7 hours (2.5 hours) post-dose.
6. Collect blood sample for tafamidis concentration at 7 hours (± 2.5 hours) after dosing 
and record the actual time of the blood sample as well as the time of drug dosing from 
the subject’s Subject Daily Dosing Diary.
7. At selected centers only, collect urine sample for assay development of TTR oligomer 
concentration.
8. Collect blood sample for NT-proBNP and troponin I.
9. 6-Minute Walk Test.
10. Kansas City Cardiomyopathy Questionnaire (Appendix 1.1).
11. EQ-5d-3L (Appendix 2).


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12. Patient Global Assessment (Appendix 3).
13. NYHA classification.
14. Documentation of concomitant medications.
15. Record dosing adherence.
16. Adverse event reporting.
17. Hospitalization determination.
18. Dispense blinded study medication.
19. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit the next appointment is to be scheduled.  A Subject Daily Dosing 
Diary stating the date and time of the next visit will be issued to the subject. The subject will 
be reminded to return to the clinic with all dispensed study medication wallets.
6.2.8. Month 15 Visit 
The following evaluations will be performed for all subjects at the Month 15 visit:
1. Brief physical examination with weight.
2. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate and body temperature).
3. Blood sample collection for Serum Chemistry.
4. Documentation of concomitant medications.
5. Record dosing adherence.
6. Adverse event reporting.
7. Hospitalization determination.
8. Dispense blinded study medication.
9. Documentation of vital status and transplant or cardiac mechanical assist device
status.


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At the end of the visit, the next appointment is to be scheduled and subject will be instructed 
to take their medication in the clinic, rather than at home, on the day of the next visit.  A 
Subject Daily Dosing Diary stating the date and time of the next visit will be issued to the 
subject. Subjects will be instructed to accurately record on the Subject Daily Dosing Diary
the actual time at which they took their dose of blinded medication at home on the day before 
the Month 18 visit. The subject will be reminded to return to the clinic with all dispensed 
study medication wallets.
6.2.9. Month 18 Visit
On the day of the Month 18 study visit, subjects will NOT take their study medication at 
home prior to the Month 18 clinic visit. Study medication on the day of the Month 18 visit 
will be taken in the clinic in order to accurately and conveniently time the tafamidis 
concentration blood sample, which is to be 1 hour (± 30 minutes) after the actual time of 
dosing.
Study site personnel will also record in the CRF the time of dosing on the day before the 
Month 18 visit as recorded by the subject on their Subject Daily Dosing Diary.
After dosing, the following procedures will be completed at the Month 18 visit:
1. Brief physical examination with weight.
2. Single 12-Lead ECG.
3. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
4. Echocardiogram.
5. Blood and urine sample collection for the following clinical laboratories:
a.
Hematology;
b. Serum Chemistry;
c.
Coagulation (INR, PT);
d. Retinol Binding Protein;
e.
Urinalysis;
f.
Urine pregnancy test – for women of childbearing potential.
6. Collect blood sample for TTR stabilization, TTR oligomer concentration, and TTR 
concentration assays at 1 hr (± 30 minutes) post-dose.


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7. Collect blood sample for tafamidis concentration at 1 hour (30 minutes) after 
dosing and record the actual time of the blood sample as well as the actual time of 
drug dosing.
8. At selected centers only, collect urine sample for assay development of TTR oligomer 
concentration.
9. Collect blood sample for diflunisal concentration (Section 7.7.3).
10. 6-Minute Walk Test (Appendix 4).
11. Kansas City Cardiomyopathy Questionnaire (Appendix 1.1).
12. EQ-5D-3L (Appendix 2).
13. Patient Global Assessment (Appendix 3).
14. NYHA classification.
15. Documentation of concomitant medications.
16. Record dosing adherence.
17. Adverse event reporting.
18. Hospitalization determination.
19. Dispense blinded study medication.
20. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit, the next appointment is to be scheduled.  A Subject Daily Dosing 
Diary stating the date and time of the next visit will be issued to the subject.  The subject will 
be reminded to return to the clinic with all dispensed study medication wallets.
6.2.10. Month 21 Visit 
The following procedures will be performed for all subjects at the Month 21 visit:
1. Brief physical examination with weight.
2. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
3. Blood sample collection for Serum Chemistry.
4. Documentation of concomitant medications.


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5. Record dosing adherence.
6. Adverse event reporting.
7. Hospitalization determination.
8. Dispense blinded study medication.
9. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit, the next appointment is to be scheduled and subject will be instructed 
to take their medication in the clinic, rather than at home, on the day of the next visit.  A 
Subject Daily Dosing Diary stating the date and time of the next visit will be issued to the 
subject. Subjects will be instructed to accurately record on the Subject Daily Dosing Diary 
the actual time at which they took their dose of blinded medication at home on the day before 
the Month 24 visit.  The subject will be reminded to return to the clinic with all dispensed 
study medication wallets.
6.2.11. Month 24 Visit 
On the day of the Month 24 study visit, subjects will NOT take their study medication at 
home prior to the Month 24 clinic visit. Study medication on the day of the Month 24 visit 
will be taken in the clinic in order to accurately and conveniently time the tafamidis 
concentration blood sample, which is to be 1 hour (± 30 minutes) after the actual time of 
dosing.
Study site personnel will also record in the CRF the time of dosing on the day before the 
Month 24 visit as recorded by the subject on their Subject Daily Dosing Diary.
After dosing, the following procedures will be completed at the Month 24 visit:
1. Brief physical examination with weight.
2. Single 12-Lead ECG.
3. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate
supine and standing, respiration rate, and body temperature).
4. Blood and urine sample collection for the following clinical laboratories.
a.
Hematology;
b. Serum Chemistry;
c.
Coagulation (INR, PT);
d. Retinol Binding Protein;


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e.
Urinalysis;
f.
Urine pregnancy test – for women of childbearing potential.
5. Collect blood sample for TTR stabilization, TTR oligomer concentration, and TTR 
concentration assays at 1 hour (± 30 minutes) post-dose.
6. Collect blood sample for tafamidis concentration at 1 hour (± 30 minutes) after 
dosing and record the actual time of the blood sample as well as the actual time of 
drug dosing.
7. At selected centers only, collect urine sample for assay development of TTR oligomer 
concentration.
8. .6-Minute Walk Test (Appendix 4).
9. Kansas City Cardiomyopathy Questionnaire (Appendix 1.1).
10. EQ-5D-3L (Appendix 2).
11. Patient Global Assessment (Appendix 3).
12. NYHA classification.
13. Documentation of concomitant medications.
14. Record dosing adherence.
15. Adverse event reporting.
16. Hospitalization determination.
17. Dispense blinded study medication.
18. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit, the next appointment is to be scheduled.  A Subject Daily Dosing 
Diary stating the date and time of the next visit will be issued to the subject.  The subject will 
be reminded to return to the clinic with all dispensed study medication wallets.
6.2.12. Month 27 Visit 
The following procedures will be performed for all subjects at the Month 27 visit:
1. Brief physical examination with weight.


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2. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
3. Blood sample collection for Serum Chemistry.
4. Documentation of concomitant medications.
5. Record dosing adherence.
6. Adverse event reporting.
7. Hospitalization determination.
8. Dispense blinded study medication.
9. Documentation of vital status and transplant or cardiac mechanical assist device
status.
At the end of the visit, the next appointment is to be scheduled and subject will be instructed 
to take their medication at home prior to the next clinic visit.  A Subject Daily Dosing Diary 
stating the date and time of the next visit will be issued to the subject. Subjects will be 
instructed to accurately record on the Subject Daily Dosing Diary the actual time at which 
they took their dose of blinded medication at home on the day before and the day of the 
Month 30 visit.  The subject will be reminded to return to the clinic with all dispensed study 
medication wallets.
6.2.13. Month 30 Visit or Early Study Discontinuation
Subjects will take their scheduled dose at home on the day of the clinic visit and record the 
actual times of dosing for the 2 doses prior to the visit on their Subject Daily Dosing Diary.  
Study site personnel will record in the CRF the time of dosing the time of dosing the day 
before and the day of the Month 30 visit as recorded by the subject on their Subject Daily 
Dosing Diary.  The following procedures will be performed for all subjects at the Month 30
visit or at the time of Early Study Discontinuation:
1. Full physical examination with weight.
2. Single 12-Lead ECG.
3. Vital signs (systolic and diastolic blood pressure supine and standing, pulse rate 
supine and standing, respiration rate, and body temperature).
4. Echocardiogram.
5. Blood and urine sample collection for the following clinical laboratories:
a.
Hematology;


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b. Serum Chemistry;
c.
Coagulation (INR, PT);
d. Retinol Binding Protein;
e.
Urinalysis;
f.
Urine pregnancy test – for women of childbearing potential.
6. Collect blood sample for TTR stabilization, TTR oligomer concentration, and TTR 
concentration assays at any time during the clinic visit.
7. Collect blood sample for tafamidis concentration at any time after dosing and record 
the actual time of the blood sample as well as the time of drug dosing from the 
subject’s Subject Daily Dosing Diary.
8. At selected centers only, collect urine sample for assay development of TTR oligomer 
concentration.
9. Collect blood sample for NT-proBNP and troponin I.
10. Collect blood sample for diflunisal concentration (Section 7.7.3).
11. 6-Minute Walk Test (Appendix 4).
12. Kansas City Cardiomyopathy Questionnaire (Appendix 1.1).
13. EQ-5D-3L (Appendix 2).
14. Patient Global Assessment (Appendix 3).
15. NYHA classification.
16. Documentation of concomitant medications.
17. Record dosing adherence.
18. Adverse event reporting.
19. Hospitalization determination.
20. Documentation of vital status, transplant or cardiac mechanical assist device status
(within 2 weeks of the target Month 30 visit).


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Additionally, except for subjects who are randomized into the extension study (Study 
B3461045), subjects will have a 4-week (28 calendar days) safety follow-up visit after the 
last dose of the study medication for collection of adverse events.  This visit can be 
completed by telephone.
6.2.14. Dialysis or Hemofiltration Treatments and Tafamidis Concentrations
Should a subject require dialysis or hemofiltration at any time after randomization while on 
study treatment, the subject should have blood samples collected for tafamidis concentrations 
around the time of renal replacement therapy.  The timing of the sample collection will 
depend on the type of renal replacement therapy administered. For hemodialysis or 
hemofiltration, samples should be collected on the date of the renal replacement therapy both 
prior to administration and after administration.  When peritoneal dialysis is administered, 
the first sample should be collected at initiation of the first exchange.  The second sample 
should be collected after the first exchange is completed (if performed outside of the home) 
or at least 24 hours after the initiation of the first exchange (if administered at home).  Every 
effort should be made to collect these samples on the date of the subject’s first administration 
of renal replacement therapy in the study; however, if this is not possible, the samples should 
be obtained as soon as possible on the date of a renal replacement therapy treatment.  If 
necessary, the sample collection can be obtained using the guidelines for lab sample 
collection in the Guidance for Remotely Conducted Study Visits provided for the study. At 
the time of sample collection, the date and time of the last dose and the date and time of 
sample collection must be recorded.
6.3. Subject Withdrawal and Vital Status / Transplant / Cardiac Mechanical Assist 
Device Status Follow-up
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site.
Due to the inclusion of all-cause mortality in the primary analysis, a Release of Medical 
Information Form will be required of all subjects for the purpose of access to medical records 
as well as for obtaining vital status / transplant / cardiac mechanical assist device status 
follow-up with the subject’s primary physician or with death registries. The signing of this 
Release of Medical Information Form is in addition to the Informed Consent Document.  In 
some cases, sites may combine these two forms into a single form, as is their standard 
practice.
In the situation where the subject or the alternative designated contact (ie, individual 
identified in the Release of Medical Information Form) cannot be reached, attempts will be 
made to ascertain the vital status / transplant / cardiac mechanical assist device status of the 
subject by searching the appropriate national or regional vital status registry or other relevant 
databases, where available and allowable by local law. Depending on the local law, this 
search will be conducted by the enrolling physician, his/her designee at the study site.


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If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The site should make a minimum of 3 documented phone calls followed by a 
registered letter inquiring about the reason for lack of return for the scheduled appointment.  
In any circumstance, every effort should be made to document subject outcome, if possible, 
including the subject’s vital status / transplant / cardiac mechanical assist device status 
through 30 months following the Baseline visit.  The investigator should inquire about the 
reason for withdrawal, request that the subject return for a final study visit (if applicable) and 
return all unused investigational product(s), and follow-up with the subject regarding any 
unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected, except for ascertaining vital status / transplant / cardiac mechanical assist device
status at 30 months after Baseline.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.  Subjects requesting withdrawal should be 
informed that withdrawal of consent for follow-up will jeopardize the public health value of 
the study.  At the time of withdrawal, subjects will be asked about the contribution of 
possible adverse events to their decision to withdraw consent and any adverse event 
information elicited will be documented.  Preferably the subject should withdraw consent in 
writing and, if the subject or the subject’s representative refuses or is physically unavailable, 
the site should document and sign the reason for the subject’s failure to withdraw consent in 
writing.
6.3.1. Subject Withdrawal for Heart or Liver Transplantation or Implantation of 
Cardiac Mechanical Assist Device
Subjects may be on a transplant list at the time of randomization.  However, if a subject 
chooses to accept a donor organ transplant during the study or undergoes implantation of a 
cardiac mechanical assist device, they will stop taking blinded study medication and be 
discontinued from study participation prior to the transplant operation.  Vital status / 
transplant status for the subject will be established through 30 months (910 days) following 
the Baseline visit.  Subjects who discontinue from the study due to transplantation or 
implantation of a cardiac mechanical assist device will be handled in the statistical analysis 
as described in Section 9.2.1.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated, that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform assessments as planned. In these cases, the investigator will take all steps necessary 
to ensure the safety and well-being of the subject.  When a protocol required assessment 
cannot be performed, the investigator will document the reason for this and any corrective 
and preventive actions which he/she has taken to ensure that normal processes are adhered to,
as soon as possible.  The study team will be informed of these incidents in a timely fashion.


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All visits will be scheduled from the Baseline visit on Day 1, so that study participation will 
be for 30 months.  In the event that an actual clinic visit day differs from the scheduled clinic 
visit day, the next visit will be scheduled according to the original timing relative to Baseline 
so that the study schedule is maintained.
7.1. Biopsy Documentation of Amyloid Deposition
In the event that there is no documentation of prior biopsy and demonstration of TTR 
amyloid deposition by either mass spectrometry, immunohistochemistry or scintigraphy [See 
Section 4.1], cardiac or non-cardiac tissue will be biopsied and tested by the investigational 
site as per the site’s standard of care and evaluated with Congo red stain or alcian blue stain. 
Stained tissue will be viewed under polarized light used to demonstrate amyloid 
characteristic ‘apple-green’ birefringence.  For subjects without identification of a TTR 
variant and demonstration of amyloid deposition who may have a diagnosis of wild-type 
TTR-CM (SSA), analysis will be performed to confirm the precursor protein basis for 
amyloid deposition, by either: mass spectrometry, immunohistochemistry or scintigraphy
[see Section 4.1].
7.2. TTR Genotyping
Subjects with a documented prior genotyping and the original laboratory result or copy for 
source documentation will not require additional genotyping.  Subjects without prior 
genotyping will require collection of a blood sample for TTR genotype testing.  The sample 
will be sent to a reference laboratory for complete genomic sequencing.
Complete information on sample collection, storage, and sample transport for genotype
confirmation are detailed in a separate laboratory manual.
7.3. Renal Function Assessment
Renal function will be assessed using the modified Modification of Diet in Renal Disease 
(MDRD) equation for estimated glomerular filtration rate (eGFR).
eGFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
African-American) [from http://nkdep.nih.gov/lab-evaluation/gfr/estimating.shtml].
7.4. Modified Body Mass Index
Transthyretin, in the monomeric form, can enter cardiac and neural tissues.  As part of the 
polyneuropathy, TTR can cause severe gastrointestinal problems resulting in wasting.  A 
means of determining if there is gastrointestinal involvement in subjects is to calculate their 
mBMI.  Body Mass Index (BMI) is calculated as weight (kg) / [height (meters)]2.  The 
mBMI is calculated by multiplying BMI by serum albumin concentration (g/L).


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7.5. Pharmacogenomic Biomarker
7.5.1. Markers of Drug Response
Variation in genetic markers and other biomarkers may help to explain some of the 
variability in response seen with some drugs among different individuals.  This is referred to 
as pharmacogenomic/biomarker research.  Comparing the DNA, RNA, protein, and 
metabolite variation patterns of subjects who respond well and those who respond poorly to 
treatment may help to better define the most appropriate group of patients in which to target a 
given treatment.  Collecting biospecimens for exploratory pharmacogenomic/biomarker 
analyses and retaining them in the Pfizer BioBank makes it possible to better understand the 
drug’s mechanism of action and to seek explanations for differences in, for example, 
exposure, efficacy, tolerability, or safety not anticipated prior to the beginning of the study.  
Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited as such by local regulations or ethics committee decision.
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study ID number.  Samples will be kept in a facility 
accessible only by badge-swipe.  Data will be stored on password-protected computer 
systems.  The key between the code and the subject’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
have access to the key nor any personally identifying information.  Biospecimens will only 
be used for the purposes described here and in the informed consent document/patient 
information sheet; any other uses require additional ethical approval.  Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored indefinitely to allow for future research on the topics described here, including 
research conducted during the lengthy drug development process and also post-marketing 
research.  Subjects can withdraw their consent for the use of their biospecimens at any time 
by making a request to the investigator, in which event any remaining biospecimen will be 
destroyed; data already generated from the biospecimens will continue to be stored to protect 
the integrity of existing analyses.  It is very unlikely that results generated from the 
biospecimens will have any clinical, diagnostic, or therapeutic implications for the individual 
study participants.  Subjects are notified in the informed consent document/patient 
information sheet that their results will not be given to them, unless required by local laws or 
regulations, in which case results will be returned via the investigator.  Results will not be 
provided to family members or other physicians; nor will they be recorded in the subject’s 
medical record.  There is no intention to contact subjects after completion of the clinical trial.
A blood biospecimen Prep D1 (K2 EDTA whole blood collection optimized for DNA 
analysis) will be collected at the Baseline visit to be retained for potential 
pharmacogenomic/biomarker analyses related to drug response, unless prohibited by local 
regulations or ethics committee decision.  Putative safety biomarkers, drug metabolizing 
enzyme genes, drug transport protein genes, or genes thought to be related to the mechanism 
of drug action may be examined.


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The Banked Biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage and 
shipment instructions are provided in the central laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/patient information sheet that 
they will not be compensated in this event.
7.5.2. Additional Research
Unless prohibited by local regulations, subjects will be asked to indicate on a consent form 
whether they will allow the Banked Biospecimens to also be used for the following research:

Investigations of the disease under study in the clinical trial, and related conditions,

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to Pharmacogenomics/biomarkers.
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in Section 7.5.1 will be used.  Subjects may still participate in the 
clinical trial if they elect not to allow their Banked Biospecimens to be used for the additional 
purposes described in this section.
7.6. Safety Assessments
7.6.1. Medical History
A complete medical history is to be documented for all subjects during the Screening Period.
This medical history will document the specific symptoms the subject reports associated with 
TTR-CM, as well as any additional co-morbid conditions or symptoms.  Medical history will 
be updated at the Baseline visit for changes since the Screening visit.
7.6.2. Physical Examinations and Height and Weight Measurements
All subjects will undergo a physical examination during the Screening Period and the Month 
30 visit or Early Study Discontinuation, including assessment of the following body systems:
General appearance 
Neurological
Head and neck 
Cardiovascular
Eyes 
Abdomen
Ears 
Skin
Nose 
Musculoskeletal
Throat 
Respiratory
Genitourinary 
Brief physical examinations, including assessment of general appearance, cardiovascular, 
respiratory, and gastrointestinal system, are to be performed at all other study visits.  


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Measurement of height in centimeters (cm) will be collected at the Screening visit only.  
Weight in kilograms (kg) will be collected at each study clinic visit.
7.6.3. Vital Signs
Vital signs will be recorded at each study visit.
Supine and standing blood pressure will be measured with the subject’s arm supported at the 
level of the heart, and recorded to the nearest mm Hg.  The same arm (preferably the 
dominant arm) will be used throughout the trial.  The subject should be supine for at least 
3 minutes before the supine blood pressure is obtained.  Standing blood pressure should then 
be measured approximately 2 minutes after the subject assumes the standing position.  The 
same size blood pressure cuff, which has been properly calibrated, will be used to measure 
blood pressure at each time point.  The use of automated devices for measuring BP and pulse 
rate are acceptable, although, when done manually, pulse rate will be measured in the 
brachial/radial artery for at least 30 seconds.  When the timing of these measurements 
coincides with a blood collection, blood pressure and pulse rate should be obtained prior to 
the nominal time of the blood collection.
7.6.4. Electrocardiograms
A 12-lead electrocardiogram (ECG) will be performed for all subjects at Screening, Baseline, 
Months 1, 6, 12, 18, 24, and 30.  Where possible, ECGs will be performed before blood 
pressure or pulse measurements or blood collection.  For ECG recordings, the subjects will 
remain supine for about 5 minutes before recording the ECG.
The following ECG parameters will be assessed: PR, RR, QRS, QT, and QTc (B and F) 
interval, heart rate, and overall interpretation, with recording of any abnormal findings. 
Ten-second rhythm strips will accompany each ECG. For subject entry into the study, each 
ECG will be recorded and read locally by the clinical site, and the clinical significance of 
ECG findings will be assessed by the investigator.
In addition, for overall analysis of the ECG parameters, each ECG will be digitalized and 
sent to an independent ECG laboratory that will conduct a centralized review of the results 
for confirmation by an independent cardiologist.
Detailed instructions for performing ECGs are provided in a separate study laboratory 
manual (Centralized ECG Procedure Manual).
7.6.5. Echocardiograms
Echocardiography (2D Doppler) will be performed for all subjects at Screening and Months 
6, 18, and 30 (or Early Study Discontinuation).  The assessment of end-diastolic 
interventricular septal thickness for study entry will be based on the echocardiogram 
performed at the Screening visit as interpreted by the independent central laboratory. If the 
Screening echocardiographic recording is not clear enough to accurately determine the 
end-diastolic interventricular septal wall thickness, it must be repeated.  Each 
echocardiogram will be recorded and reviewed locally by the clinical site, and the clinical 


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significance of echocardiogram findings will be assessed by the Investigator.  Each 
echocardiogram will also be sent to an independent central laboratory that will conduct a 
centralized review of the results.  The central reading of the Screening echocardiogram must 
be completed prior to subject randomization at the Baseline visit.
The following parameters will be included in the assessment:
1. End-diastolic interventricular septal wall thickness (mm).
2. Left ventricle posterior wall thickness (mm).
3. Left ventricular ejection fraction (%).
4. Left ventricular stroke volume (mL).
5. Fractional shortening (%).
6. Left atrial diameter, anterior-posterior (mm).
7. Left atrial diameter, medio-lateral (mm).
8. Left atrial diameter, superior-inferior (mm).
9. Left ventricular end systolic diameter (mm).
10. Left ventricular end systolic volume (mL).
11. Left ventricular end-diastolic diameter (mm).
12. Left ventricular end-diastolic volume (mL).
13. Left ventricular mass (g).
14. E/A Ratio.
15. E/E’ Ratio.
16. Global longitudinal strain.
a.
Basal septal;
b. Mid septal;
c.
Apical septal;
d. Basal lateral;
e.
Mid lateral;


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f.
Apical lateral.
17. Circumferential strain basal global.
18. Circumferential strain mid global.
19. Circumferential strain apical global.
20. Radial strain basal global.
21. Radial strain mid global,
22. Radial strain apical global.
Detailed instructions for performing echocardiography are provided in a separate study 
laboratory manual (Echocardiography Imaging Manual).
7.6.6. Clinical Laboratory Tests
Blood and urine samples will be collected at Screening, Baseline, Week 2 (no urine), and at 
Months 1, 6, 12, 18, 24, and 30 as well as in the event of Early Study Discontinuation.  
Serum chemistry will be collected at each study visit.
The following clinical laboratory parameters will be assessed:
Serum Chemistry
Sodium
Inorganic Phosphorus
Aspartate aminotransferase 
(AST)
Potassium
Glucose
Gamma glutamyl transferase
Chloride
Total bilirubin
Cholesterol
Bicarbonate
Total protein
Uric acid
Blood Urea Nitrogen
Albumin
Thyroid-stimulating hormone
Creatinine
Globulin
Total thyroxine (T4)
Calcium
Alanine aminotransferase (ALT)
Free T4
Retinol binding 
protein
Alkaline Phosphatase
Coagulation (to be measured in site’s local laboratory)
International normalized ratio (INR)
Prothrombin time (PT)
Hematology
Hemoglobin
White blood cell count
Hematocrit
Neutrophils
Red blood cell count
Lymphocytes
Mean corpuscular volume
Monocytes


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Mean corpuscular hemoglobin 
Eosinophils
Mean corpuscular hemoglobin 
concentration 
Basophils
Platelets 
Urinalysis
pH
Blood (free Hb)
Protein
Nitrite
Glucose
Urobilinogen
Ketones
Specific gravity
Bilirubin
Urinalysis will be a qualitative determination by dipstick at the site.  If the urine dipstick 
demonstrates a positive result for any test, the specimen will be sent to the Central 
Laboratory for microscopic evaluation.  
Specifications for sample collection are provided in the study laboratory manual.
7.6.7. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at the Screening and Baseline visits before 
investigational product administration and at the end of treatment visit.  A negative 
pregnancy result is required before the subject may receive the investigational product.  
Pregnancy tests will also be done whenever one menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected), repeated at and 
Months 1, 6, 12, 18, 24, and 30 (or Early Study Discontinuation) to confirm that the subject 
has not become pregnant during the study.  In the case of a positive hCG test, the subject will 
be discontinued from the study.  Pregnancy tests may also be repeated as per request of 
IRB/IECs or if required by local regulations.
7.6.8. Testing for Light Chain Amyloid 
Specifications for testing samples are provided in the study laboratory manual.
Elderly subjects with reduced renal function may experience elevations in levels of free 
kappa light chains and free lambda light chains with no change in the kappa/lambda ratio.  
Subjects with elevated serum / urine levels of free kappa light chain, free lambda light chain 
and a free kappa / lambda ratio indicative of light chain amyloidosis (MGUS) will require 
confirmatory test using mass spectrometry or immunohistochemistry with electron
microscopy or scintigraphy [See Section 4.1].
7.6.9. N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) and 
Troponin I
Specifications for sample collection can be found in the study laboratory manual.


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7.6.10. Serology
All subjects will be tested for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(anti-HCV), and human immunodeficiency virus (HIV) during the Screening period. 
Subjects with positive findings on these serologies will be excluded from study participation.
7.7. Efficacy Assessments
7.7.1. Patient Reported Outcomes
Sites will be provided with an approved translated version of each questionnaire that will be 
required for use in the study.
7.7.1.1. Kansas City Cardiomyopathy Questionnaire
The KCCQ (Appendix 1.1) (Green 2000)19 is a 23-item subject-completed questionnaire that 
assesses health status and health-related quality of life in subjects with heart failure. Items 
assess the ability to perform activities of daily living, frequency and severity of symptoms, 
the impact of these symptoms, and health-related quality of life. Response options vary by 
question. Scoring yields scores for 6 domains (Physical limitation, Symptom stability, 
Symptoms, Self-efficacy, Social limitation, and Quality of life), two summary scores 
(Functional summary and Clinical summary), as well as an Overall Summary score. Domain 
scores are transformed to a 0 to 100 range; higher scores indicate better health status. It takes 
approximately 4-6 minutes for a subject to complete the KCCQ.
Subjects will complete the KCCQ at the Baseline visit and at Months 6, 12, 18, 24, and 
30 (or Early Study Discontinuation) as listed in the Schedule of Activities. In each instance 
of administration, the KCCQ should be completed by subjects before completing the 
EQ-5D-3L (Appendix 2) and PGA assessments(Appendix 3).
The KCCQ can be found in Section Appendix 1.1.
7.7.1.2. EQ-5D-3L
The EQ-5D-3L Appendix 2 (3 levels version) is a brief, self-administered generic health 
status instrument that takes about 5 minutes to complete (Euroqol Group 1990).14  The 
instrument consists of two parts.  In the first part, respondents are asked to rate their current 
health state on 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and 
anxiety or depression) with each dimension having three levels of function (1=no problem, 
2=some problem, and 3=extreme problem).  The second part is a subject’s self-rating of 
current health state on a Visual Analog Scale (EQ-5D VAS) with endpoints labeled ‘best 
imaginable health state’ (score of 100) and ‘worst imaginable health state’ (score of 0). The 
scores from the 5 dimensions may be used to calculate a single index value, also known as a 
utility score.
Subjects will complete the EQ-5D-3L (Appendix 2) at the Baseline visit and at visit Months 
6, 12, 18, 24, and 30 (or Early Study Discontinuation) as listed in the Schedule of Activities.
Subjects should complete the EQ-5D-3L after the KCCQ (Appendix 1.1).


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The EQ-5D-3L can be found in (Appendix 2).
7.7.1.3. Patient Global Assessment (PGA)
The subject’s overall health status will be assessed by the PGA. At Baseline, subjects will be 
asked to rate their current health on the PGA using seven response options that range from 
“Normal, not at all ill” to “Among the most extremely ill”. At follow-up visits subjects will 
be asked to rate the change in their health status since Baseline.
Subjects will complete the PGA at the Baseline visit and at Months 6, 12, 18, 24, and 
30 (or Early Study Discontinuation) as listed in the Schedule of Activities. Subjects should 
complete the PGA after the KCCQ (Appendix 1.1) and EQ-5D-3L (Appendix 2).
The PGA can be found in Section Appendix 3.
7.7.2. TTR Stabilization, TTR Oligomer Concentration, and TTR Concentration 
Measurements
One (1) whole blood sample will be collected at Baseline and Months 1, 6, 12, 18, 24, and 
30 (or Early Study Discontinuation) at times of sampling for tafamidis concentration, to test 
for stabilization of TTR and TTR concentration.  These samples will be analyzed using 
validated analytical methods in compliance with Pfizer standard operating procedures.  
Detailed instructions for collection, storage, labeling, and shipment of all samples are 
provided in a separate study laboratory manual.
These samples may also be used to validate and implement an assay to measure TTR 
oligomer concentration.  Subjects at selected centers will be asked to provide a urine sample 
to be used in assay development for measurement of TTR oligomer concentrations in urine.  
For those subjects who provide consent, a 10 mL aliquot of urine will be collected (starting at 
the earliest possible prospective visit for the subject) at Months 12, 18, 24, and 30 (or Early 
Study Discontinuation); this aliquot will be obtained from the urine sample already collected 
for urinalysis at these visits.  
Additional instructions for collection, storage, labeling, and shipment of all samples are
provided in the study laboratory manual.
7.7.3. Diflunisal Concentration
After the recording of ECGs, Echocardiograms and blood pressure, a blood sample will be 
collected to determine if the subject has taken diflunisal.  The blood sample for this 
assessment will be taken at Screening, Baseline and Months 1, 6, 18, and 30.  Use of 
diflunisal during the study is not permitted.  Subjects taking diflunisal will be appropriately 
counselled. Such subjects will be handled as protocol violators in the analysis as described in 
the Statistical Analysis Plan.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.


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Detailed instructions for collection, storage, labeling, and shipment of all samples are 
provided in a separate study laboratory manual.
7.7.4. 6-Minute Walk Test (6MWT)
A 6MWT will be conducted during the Screening period and at the Baseline visit and at 
Month 6, 12, 18, 24, and 30 visits (or Early Study Discontinuation). There will be one 
6MWT during the Screening period.  Subjects who are unable to walk 100 meters at 
Screening will be considered a Screen Failure.
The test will be conducted in accordance with guidelines established by the American 
Thoracic Society.
Detailed instructions for conducting the 6MWT are provided in Section Appendix 4.
7.7.5. New York Heart Association Classification
Subjects will be evaluated using the New York Heart Association (NYHA) classification at
Screening, Baseline, and at Month 6, 12, 18, 24, and 30.
New York Heart Association (NYHA) Classification:
Class I
Subjects with cardiac disease but without resulting limitations of physical activity.  Ordinary
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II
Subjects with cardiac disease resulting in slight limitation of physical activity. They are
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
angina pain.
Class III
Subjects with cardiac disease resulting in marked limitation of physical activity. They are
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, 
or anginal pain.
Class IV
Subjects with cardiac disease resulting in inability to carry on any physical activity without
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort is increased.


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7.7.6. Pharmacokinetic Measurements
Pharmacokinetic samples, to determine the tafamidis concentration, will be collected at 
Baseline (pre-dosing) and at Months 1, 6, 12, 18, 24, and 30 (or Early Study 
Discontinuation).  For the Month 1, 18, and 24 visits, subjects will be instructed to not take 
their daily dose at home but rather to bring the dose to the clinic and they will be instructed at 
the clinic when to take their dose. Subjects will be instructed by clinic staff when to take 
their dose prior to arriving for the clinic visit at Months 6 and 12. The dosing time provided 
to each subject for each visit should be timed such that the tafamidis concentration sampling 
time occurs during the clinic visit. This determination must consider travel time to clinic and 
other procedures to be performed at that visit. It is imperative that the actual clock time of 
dosing on the specified days and the actual clock time of tafamidis concentration sample 
collection on the day of each clinic visit is recorded.
1. At the Baseline ( Day 1) visit, tafamidis concentration samples will be collected 
pre-dose.
2. At Month 1, a tafamidis concentration sample will be collected pre-dose and at 
3 hours (± 1.5 hours) post-dose.
3. At Month 6, a tafamidis concentration samples will be collected at 7 hours 
(± 2.5 hours) post-dose.
4. At Month 12, a tafamidis concentration sample will be collected at 7 hours 
(± 2.5 hours) post-dose.
5. At Month 18, a tafamidis concentration sample will be collected at 1 hour 
(± 30 minutes) post-dose.
6. At Month 24, a tafamidis concentration sample will be collected at 1 hour 
(±30 minutes) post-dose.
7. At Month 30 (or Early Study Discontinuation), a tafamidis concentration sample can 
be taken at any time during the clinic visit and the actual time of dosing and sample 
collection will be recorded.
In addition, should a subject require dialysis at any time after randomization while on study 
treatment, the subject should have blood samples collected for tafamidis concentrations on 
the date of dialysis both prior to dialysis and after dialysis.  Every effort should be made to 
collect these samples on the date of the subject’s first dialysis treatment in the study; 
however, if this is not possible, the samples should be obtained as soon as possible on the 
date of a dialysis treatment.  If necessary, the sample collection can be obtained using the 
guidelines for lab sample collection in the remote visit guide for the study. At the time of 
sample collection, the date and time of the last dose and the date and time of sample 
collection will be noted.


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Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.  Detailed instructions for collection, storage, labeling, and 
shipment of all samples are provided in a separate study laboratory manual.
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method.  These data will be 
used for internal exploratory purposes and will not be included in the clinical report.  
Samples collected for this purpose will be retained in accordance to local regulations and if 
not used within this timeframe, will be destroyed.
Detailed instructions for storage, labeling, and shipment of all samples are provided in a 
separate study laboratory manual.
7.8. Hospitalization Determination
Sites will determine at each visit whether the subject has been hospitalized (including the 
reason for hospitalization).  -
Hospitalization for endpoint adjudication is defined as a non-elective admission to an acute 
care setting for medical therapy that results in at least a 24-hour stay (or a date change if the 
time of admission/discharge is not available).  Cardiovascular-related hospitalization includes 
hospitalizations with a discharge diagnosis that includes a cardiovascular reason for 
hospitalization.
Hospitalization does not include admission to the following:
1. Rehabilitation facilities.
2. Hospice facilities.
3. Respite care (eg, caregiver relief).
4. Skilled nursing facilities.
5. Nursing homes.
6. Routine emergency room admissions (less than 24 hours).
7. Same-day surgeries (as outpatient/same-day/ambulatory procedures).
The Investigator is responsible for:
1. Ensuring potential study endpoints, including dates of admission and dates of 
discharge, are documented in the source documents.
2. Providing access to source documentation that supports the study endpoints (eg, 
hospital discharge summaries, procedure summaries, death certificates, and autopsy 
reports).


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In addition, for the variables All-Cause Days Hospitalized and Cardiovascular-related Days 
Hospitalized, the cumulative duration of hospitalized days for an entire hospitalization will 
be utilized.  For Cardiovascular-related Days Hospitalized, cardiovascular relatedness for the 
cause of hospitalization will be adjudicated and subsequently, all of the days of that 
hospitalization will be considered to be cardiovascular-related days hospitalized.  
Specifically, within a hospitalization, the days hospitalized will not be allocated to both 
cardiovascular-related and not cardiovascular-related causes.
7.9. Total Blood Volumes
The Laboratory Manual will describe the volume of blood that will be required for each 
specimen.  The only exception is the sample collected for determination of INR and PT, as 
they will be measured at the site’s local laboratory.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
trial.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  Serious adverse events occurring to a subject 
after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all serious adverse events that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product are to be reported to the Sponsor.  AEs (both serious and non-serious) should be 


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recorded on the CRF from the time the subject has taken at least one dose of investigational 
product through the last subject’s last visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject, administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose,

Drug withdrawal,

Drug misuse,

Drug interactions,

Extravasation,

Exposure during pregnancy (EDP) ,

Exposure via breastfeeding,

Medication error,

Occupational exposure.


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8.4. Medication Errors
Medication errors in the study may result from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error case report form (CRF) which is a specific version of the adverse event (AE) page and 
on the SAE form when appropriate.  In the event of medication dosing error, the sponsor 
should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product,

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated adverse event(s) are captured on an 
adverse event (AE) CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:
1. Test result is associated with accompanying symptoms, and/or
2. Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or
3. Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or
4. Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:
1. Results in death.
2. Is life-threatening (immediate risk of death).


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3. Requires inpatient hospitalization or prolongation of existing hospitalization.
4. Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions).
5. Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject, or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
The following events must be considered medically important and have the same reporting 
requirements as SAEs:

Amyloidosis or heart failure resulting in organ transplantation (regardless if the 
subject was pre-planned or on a waiting list for an organ prior to study start);

Amyloidosis or heart failure resulting in cardiac mechanical assist device 
implantation (regardless if the procedure was pre-planned).
8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the sections on Endpoints and on Serious Adverse Event Reporting 
Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels
concurrent with abnormal elevations in total bilirubin levels that meet the criteria outlined 
below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events.
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual Baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:


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
Subjects with AST or ALT and total bilirubin Baseline values within the normal 
range who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin values 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase values 2 X ULN or not available.

For subjects with preexisting ALT or AST or total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above.

For subjects with pre-existing AST or ALT Baseline values above the normal 
range: AST or ALT values 2 times the Baseline values and 3 X ULN, or 8 X
ULN (whichever is smaller).
Concurrent with:

For subjects with pre-existing values of total bilirubin above the normal range:  
Total bilirubin increased from baseline by an amount of at least 1 X ULN or if the 
value reaches ≥3 X ULN (whichever is smaller)
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  In addition to repeating 
measurement of AST and ALT, laboratory tests should include albumin, creatine kinase, total 
bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time
(PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted. All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (LFT) abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in to a hospital or 
equivalent healthcare facility or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.


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Hospitalization does not include the following:

Rehabilitation facilities,

Hospice facilities,

Respite care (eg, caregiver relief),

Skilled nursing facilities,

Nursing homes,

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment lab abnormality),

Social admission (eg, subject has no place to sleep),

Administrative admission (eg, for yearly physical examination,),

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol),

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery),

Hospitalization for observation without a medical AE,

Pre-planned treatments or surgical procedures.  These should be noted in the Baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded as treatment of the AE.


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8.8. Severity Assessment
If required on the AE case report forms (CRFs), the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the AE.  For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see Section 8.134.1 on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records.
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.  An example of environmental exposure 
would be a case involving direct contact with a Pfizer product in a pregnant woman 
(eg, a nurse reports that she is pregnant and has been exposed to chemotherapeutic 
products).


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2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event (AE) report form and 
Exposure in Utero (EIU) Supplemental Form, regardless of whether an SAE has occurred.  In 
addition, the investigator must submit information regarding environmental exposure to a 
Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant and has been 
exposed to a cytotoxic product by inhalation or spillage) using the EIU Form.  This must be 
done irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure. The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EIU reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EIU Form.  In the case of a live birth, the structural integrity of the neonate can 
be assessed at the time of birth.  In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless pre-procedure test findings are 
conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows:
1. Spontaneous abortion includes miscarriage and missed abortion.
2. Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner. The Investigator must document in the source 
document that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner.  


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8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a Case Report Form (CRF), however a copy of the 
completed SAE report form is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (see also Section on Subject Withdrawal and 
Vital Status / Transplant/Cardiac Mechanical Assist Device Status Follow-up
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy exposure via 
breastfeeding and occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.


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For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
The primary comparison of interest is the pooled tafamidis 20 mg and 80 mg treatment 
groups vs. placebo.  The target sample size is 400 subjects.
A sample size of 400 subjects is based on findings from study Fx1B-201 (a 12-month, 
open-label study of tafamidis in TTR-CM subjects), TRACS (an observational study with no 
treatment intervention other than standard of care in TTR-CM subjects), an understanding of 
current clinical outcomes in this population, and the uncertainty of the assumptions derived 
from these limited data.
Given that no closed-form sample size estimation solution is available for the primary 
analysis method, sample size estimation was performed based on simulations.
Sample size assumptions include: 


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1. All-cause mortality rate of 12.5% for the tafamidis group and 25.0% for the placebo 
group (ie, a 50% reduction in mortality with treatment).
2. 1.5 cardiovascular-related hospitalizations for the tafamidis group and 
2.5 cardiovascular-related hospitalizations for the placebo group.
3. Treatment duration of 30 months.
4. Significance level (alpha) of 0.05 (two-sided test).
With these assumptions, 300 subjects (n=120 for placebo, n=60 for 20 mg, n=120 for 80 mg) 
yields a power of over 90% for the primary comparison.  A more conservative assumption of 
30% reduction in mortality (17.5 % for tafamidis and 25% for placebo) yields a power of 
approximately 80%.  With an assumption of 30% reduction in mortality and increasing the 
number of subjects to 400 subjects (n=160 for placebo, n=80 for 20 mg, and n=160 for 
80 mg) yields a power of approximately 90%.
Summary of operating characteristics:
Assumptions
Sample 
Size
Power
50% mortality reduction, hosp frequency 2.5 (pbo), 1.5  (taf) 
N=300
96%
30% mortality reduction, hosp frequency 2.5 (pbo), 1.5  (taf) 
N=300
80%
30% mortality reduction, hosp frequency 2.5 (pbo), 1.5  (taf) 
N=400
90% 
pbo=placebo, taf=tafamidis
The Sponsor notes that a clinically meaningful change in the all-cause mortality component 
of the primary analysis could be considered to be as low as a 10% all-cause mortality 
reduction at 30 months in the comparison between tafamidis and placebo. To power a trial 
utilizing a primary analysis that assumes this magnitude of treatment effect presents 
substantial feasibility challenges to study completion due to the relatively small number of 
subjects identified for potential enrollment in this study.
9.2. Analysis Populations
The intent-to-treat (ITT) analysis set will include all subjects in the safety population who 
had at least 1 post Baseline efficacy evaluation (ie, post Baseline hospitalization, study visit, 
or date of death).  This may also be referred to as a modified intent-to-treat group but for 
simplicity will be referred to throughout the protocol and SAP as ITT.  The per protocol (PP) 
analysis set will include all subjects in the ITT set who did not violate inclusion/exclusion 
criteria and who did not have protocol violations considered to impact the interpretation of 
the primary efficacy analysis.  The safety analysis set will include all subjects who are 
enrolled (randomized) and received at least 1 dose of double-blind medication.


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Both the ITT and PP analysis sets will be used for the primary analysis and for the analyses 
of the key secondary endpoints, with the ITT being primary.  The secondary endpoints and 
the exploratory endpoints will only be analyzed using the ITT analysis set. The Safety 
Analysis Set will be used in the analyses of the safety data.
9.2.1. Primary Efficacy Analysis
The primary analysis uses a hierarchical combination of all-cause mortality and frequency of 
cardiovascular-related hospitalizations (which is defined as the number of times a subject is 
hospitalized [ie, admitted to a hospital] for cardiovascular-related morbidity) over the 
duration of the trial. The primary analysis will combine the subjects in the tafamidis 20 mg 
and tafamidis 80 mg groups (including subjects in the 80 mg group that may have had a dose 
reduction to 40 mg) into one pooled group. This pooled group (tafamidis) will be compared 
with the placebo group using the Finkelstein-Schoenfeld method (Finkelstein 1999).16
The test is based on the principle that each subject in the clinical study is compared to every 
other subject within each stratum in a pair-wise manner.  The method recognizes the higher 
importance of all-cause mortality.  The pair-wise comparison proceeds in hierarchical fashion 
using all-cause mortality first, assigning a +1 to the “better” subject and a -1 to the “worse” 
subject.

If both subjects are dead, then the subject with a longer survival time is assigned +1.

If one subject is alive and the other is not, the live subject receives a +1 and the 
deceased one a -1.

If both subjects are alive, the comparison uses cardiovascular-related hospitalization
to assign scores. The subject with the fewer cardiovascular-related hospitalizations
(frequency) receives a +1 while the other receives -1.
The test statistic is based on the sum of these scores and will be stratified by TTR genotype 
(variant and wild-type) and Baseline severity category (NYHA Classes I and II combined 
and NYHA Class III).
The null hypothesis for the primary analysis is that neither all-cause mortality nor frequency 
of cardiovascular-related hospitalizations is different between the tafamidis and placebo 
treatment groups.  The corresponding alternative hypothesis is that at least one and possibly 
both mortality and frequency of cardiovascular-related hospitalizations are different between 
the tafamidis and placebo treatment groups.
The term “censored” refers to a subject who discontinues from the trial for reasons other than 
death.  For such subjects, there will be additional follow-up to obtain vital status (and 
transplant / cardiac mechanical assist device status) at Month 30 and that information will be 
used in the analysis.  In the case where one subject is censored before a second subject has 
died, and where the vital status of the first subject at Month 30 is missing, then the frequency 
of cardiovascular-related hospitalizations at the shorter of their follow-up times (the shorter 
of the 2 subjects’ study participation) will be used in assigning a +1 or -1.  In the simpler case


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where one subject drops out but both are known to be alive at Month 30, the frequency of 
cardiovascular-related hospitalizations, at the shorter of their follow-up times (the shorter of 
the 2 subjects study participation), will be used in assigning a +1 or -1.  Comparisons of 
cardiovascular related hospitalization frequency for subjects who completed all 30 months 
study duration will be based on the earlier of the two actual study durations (days).
Subjects, who discontinue for transplantation (ie, heart transplantation and combined heart 
and liver transplantation) or for implantation of a cardiac mechanical assist device, will be 
handled in the primary analysis in the same manner as death.  More specifically, the time of 
the transplant or cardiac mechanical assist device implant will be used in the 
subject-to-subject comparison in the same manner as if the subject had died at that time 
(regardless of any additional vital status follow-up information).  Data from subjects who 
drop out for a liver-only transplantation will be handled in the same manner as the data from 
all other censored subjects.
To examine the potential effect of including heart transplantation or cardiac mechanical assist 
device as “deaths” in the primary analysis, a sensitivity analysis will be performed treating 
all transplantation or cardiac mechanical assist device in the same manner as any other 
censored observation.
As an additional sensitivity analysis, a multiple imputation analysis will be applied using the 
method developed by Rubin (Rubin 1987).  Combined results will be provided for the 
primary analysis (ie, using Finkelstein-Schoenfeld) as well as for the separate mortality and 
morbidity elements.  Details are provided in the SAP.
9.2.2. Analysis of Key Secondary Endpoints
The key secondary endpoints will be evaluated using a mixed model repeated measures
ANCOVA with an unstructured covariance matrix (or as appropriate); center and 
subject-within-center as random effects; treatment, visit, TTR genotype (variant and 
wild-type), and visit-by-treatment interaction, as fixed effects and Baseline score as 
covariate.
The key secondary variables are:
1. Change from Baseline to Month 30 in distance walked during the 6MWT
(Appendix 4).
2. Change from Baseline to Month 30 in KCCQ (Appendix 1.1) Overall Summary 
score.
To maintain the type 1 error rate at or below the specified level, a pre-specified hierarchical 
order for testing as indicated above will be used to maintain the overall alpha at 0.05 for 
these two key secondary endpoints.  The multiplicity procedure will be applied to the ITT 
analysis set only.


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Supplemental analyses of the two key secondary variables will be performed to support the 
robustness of the conclusions drawn. The pattern-mixture analysis will group the subjects on 
the basis of their dropout or missing-data patterns.  A grouping variable for this analysis is 
defined in the SAP.
Exploratory analyses of the key secondary endpoints will include results from the MMRM 
analysis at each individual time point other than Month 30.
Additional exploratory analyses of the key secondary endpoints will include results from the 
MMRM analysis at each individual time point by dose group (randomized dose group), TTR 
genotype (variant and wild-type), and NYHA Baseline classification. Descriptive statistics 
overall, by dose, by TTR genotype, and by NYHA Baseline classification will be provided 
for each time point.
Except for the analyses by dose, all analyses of the key secondary endpoints, including the 
proposed exploratory analyses of these endpoints, will compare the pooled tafamidis group 
with the placebo group.
9.3. Analysis of Secondary Endpoints
As a secondary analysis, the components of the primary endpoint (ie, all-cause mortality and 
frequency of cardiovascular-related hospitalizations) will be analyzed separately.  All-cause
mortality will be analyzed using SAS Proc Lifetest; p-values will be from the log-rank test.  
Kaplan-Meier survival curves for each treatment group along with median survival times (if 
applicable) will be presented.
All-cause mortality will also be analyzed using Cox proportional hazards model with 
treatment, TTR genotype (variant and wild-type), and NYHA Baseline classification (NYHA 
Classes I and II combined and NYHA Class III) as factors.  Frequency of
cardiovascular-related hospitalizations will be analyzed using a Poisson regression analysis 
with treatment, TTR genotype (variant and wild-type), NYHA Baseline classification
(NYHA Classes I and II combined and NYHA Class III), treatment-by-TTR genotype 
interaction, and treatment-by- NYHA Baseline classification interaction terms as factors 
adjusted for treatment duration.
Cardiovascular-related mortality will also be analyzed using the Kaplan-Meier and Cox 
proportional methods described above.
All the analyses on the secondary endpoints described above will additionally be presented 
by TTR genotype (variant versus wild-type), NYHA Baseline classification, as well as dose 
(randomized dose group), and will be considered exploratory.
The proportion of subjects who achieved TTR stabilization in each treatment group at Month 
1 will be compared using a Cochran-Mantel-Haenszel (CMH) test for proportions stratified 
by TTR genotype and Baseline severity (NYHA Classes I and II combined and NYHA Class
III). The analysis will be performed separately by TTR genotypes (variant and wild-type)
using a CMH test for proportions stratified by Baseline severity (NYHA Classes I and II 


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combined and NYHA Class III).  The analysis will also be performed separately by Baseline 
severity (NYHA Classes I and II combined and NYHA Class III) using a CMH test for 
proportions stratified by TTR genotypes (variant and wild-type).
Analyses of TTR stabilization at Month 1 by dose (low vs. placebo and high vs. placebo) will 
be compared using a Cochran-Mantel-Haenszel (CMH) test for proportions stratified by TTR 
genotype and Baseline severity (NYHA Classes I and II combined and NYHA Class III).
A similar test of proportion will be done on TTR stabilization at all other time points and 
considered exploratory. No subgroup analyses will be done at these other time points.
Except for the analyses by dose group, all analyses of the secondary endpoints, including the 
proposed exploratory analyses of these endpoints, will compare the pooled tafamidis group 
with the placebo group.
9.4. Analysis of Exploratory Endpoints
The primary analysis will be repeated by the dose group to which subjects were randomized 
(tafamidis 20 mg vs. placebo and tafamidis 80 mg vs. placebo) to explore the effect by dose 
group.
Subgroup analysis using the Finkelstein-Schoenfeld method comparing the pooled tafamidis 
group and the placebo group, similar to that of the primary analysis, will also be done by the 
TTR genotype (variant type and the wild-type) and Baseline severity (NYHA Classes I and II 
combined and NYHA Class III) status.
Frequency of all-cause hospitalization will be analyzed using a Poisson regression analysis 
with treatment, TTR genotype (variant and wild-type), NYHA Baseline classification, 
treatment-by-TTR genotype interaction, and treatment-by-NYHA Baseline classification 
interaction terms as factors adjusted for treatment duration.
Cardiovascular-related days hospitalized and all-cause days hospitalized will be analyzed 
using an analysis of variance (ANOVA) with treatment, TTR genotype (variant and 
wild-type), NYHA Baseline classification (NYHA Classes I and II combined and NYHA 
Class III), treatment-by-TTR genotype interaction, and treatment-by- NYHA Baseline 
classification interaction terms as factors.
An exploratory analysis based on the Finkelstein-Schoenfeld method similar to that of the 
primary analysis will be done for each of the combinations of variables listed below:
1. All-cause mortality and frequency of all-cause hospitalization.
2. All-cause mortality and cardiovascular-related days hospitalized.
3. Cardiovascular-related mortality and frequency of cardiovascular-related 
hospitalization.


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The exploratory endpoints listed below will be evaluated at each time point post-Baseline 
using a MMRM with an unstructured covariance matrix (or as appropriate) with center and 
subject-within-center as random effects and treatment, visit, TTR genotype (variant and 
wild-type), and visit-by-treatment interaction, as fixed effects and Baseline score as covariate
where applicable (for example, no Baseline will be used as a covariate for PGA):
1. Change from Baseline in Kansas City Cardiomyopathy Questionnaire: (KCCQ)
(Appendix 1.1) domain scores (Physical limitation, Symptom stability, Symptom
frequency, Symptom burden, Self-efficacy, Social limitation, and Quality of life) and 
domain summary scores (Functional summary and Clinical summary).
2. Change from Baseline in EuroQoL-5 Dimensions (EQ-5D-3L) (Appendix 2) Index 
Score and visual analog scale (VAS) scores.
3. Patient Global Assessment (Appendix 3).
4. Change from Baseline in modified Body Mass Index.
5. Change from Baseline in NT-proBNP concentration.
6. TTR concentration and oligomer concentration.
7. Change from Baseline in select echocardiographic parameters:
a.
End-diastolic interventricular septal wall thickness (mm);
b. Left ventricle posterior wall thickness (mm);
c.
Left ventricular ejection fraction (%);
d. Left ventricular stroke volume (mL).
e.
Global longitudinal strain;
f.
Circumferential strain mid global;
g. Radial strain mid global.
All other echocardiographic parameters listed in Section 7.6.5 will be analyzed descriptively.
An increase or decrease in NYHA classification relative to Baseline will be summarized 
using a shift table at each time point post-Baseline.


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9.4.1. Pharmacokinetic Data
Plasma concentrations of tafamidis will be summarized graphically and with descriptive 
statistics (n, arithmetic mean, standard deviation, coefficient of variation, geometric mean,
median, and minimum and maximum) by visit and nominal time.  Due to the sparse nature of 
the pharmacokinetic sampling scheme, a population approach will be used for 
pharmacokinetic data analysis.  Nonlinear mixed-effect modeling will be performed to 
characterize the pharmacokinetics of tafamidis.  These tafamidis concentration data may be 
pooled with data from previous clinical studies for analysis.  Results from any tafamidis 
concentration modeling conducted will be reportedly separately.  If appropriate, these 
pharmacokinetic data may be used for exposure-response analyses.
To confirm adequate exposures following administration of soft gel capsules in the 80 mg 
dose group, the Month 1 PK samples from the first 50 subjects enrolled in the study will be 
analyzed and summarized by treatment to evaluate approximately 20 subjects assigned to the 
80 mg dose. The PK sample collection time at the Month 1 visit targets the time of 
maximum tafamidis concentration at approximately 3 hours post-dose. The expected mean 
steady state tafamidis concentration is 8.0 ug/mL. If the geometric mean concentration from 
the 80 mg dose group is < 50% of the projected value, the 80 mg dose may be adjusted. The 
PK analyst reviewing de-identified tafamidis exposure data will be separate from study team 
members and will not have access to any unblinded safety or efficacy data. Details of the 
analysis procedure will be documented in a PK unblinding plan.
9.4.2. Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling
Pharmacokinetic/Pharmacodynamic (PK/PD) modeling of tafamidis treatment groups may be 
done using the primary and/or secondary efficacy endpoints compared to the corresponding 
endpoints in the placebo arm.  The basic PK/PD model will consist of structural variables for 
treatment arm and the time points out to 30 months.  Additional important covariates (such as 
demographics) may be added to the PK/PD model during the model building process.  The 
PK/PD model may contain a time course component that will help describe the onset of 
action as compared to the placebo arm.  Other efficacy, safety, and exploratory endpoints 
may also be modeled as needed to further understand tafamidis response variables. Results 
from any tafamidis PK/PD modeling conducted will be reportedly separately.
9.5. Safety Analysis
The safety assessments in the study are listed in Section 7.6. All randomized subjects who 
receive at least one dose of study treatment will be included in the safety analysis.  All 
adverse events that are observed from the time of first dosing with study medication (at 
randomization) until the end of study participation will be included in the safety analysis.  
Adverse events that occurred during treatment will be reported separately if the event 
occurred prior to randomization.
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by treatment group.  The incidence of 
treatment-emergent adverse events will be tabulated by treatment group and by system organ 
class.  The incidence of treatment-emergent adverse events will be displayed by severity and 


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attribution.  In addition, the incidence of serious adverse events and adverse events that cause 
withdrawal will be tabulated.  All adverse events will be listed.
The following 3-tier approach will be used to summarize AEs. Under this approach, AEs are 
classified into 1 of 3 tiers. Different analyses will be performed for different tiers and will be 
documented in the statistical analysis plan.
Tier-1 events: These are pre-specified events of clinical importance and are 
maintained in a list in the product’s Safety Review Plan. This list may be updated as 
more is understood about the drug.
Tier-2 events: These are events that are not Tier-1 but are “common”. A MedDRA 
Preferred Term (PT) is defined as a Tier-2 event if there are at least 4 in any treatment 
group.
Tier-3 events: These are events that are neither Tier-1 nor Tier-2 events.
All clinical laboratory data will be subjected to clinical review and summarized by frequency 
of events and mean changes from Baseline.
All vital sign measurements will be displayed in listings by subject for each sample 
collection date and time.  The measurement taken immediately prior to randomization will be 
used as the Baseline value for calculating changes in vital signs.
Centrally over-read ECG variables will be summarized by mean change from Baseline to 
each measurement time for heart rate, PR interval, QRS width, QT interval, and QTcB 
(Bazett’s correction) and QTcF (Fridericia’s correction) values.  Additionally, the incidence 
of categorical increases in QTc intervals will be provided.  Categories for QTcB and QTcF 
are ≥ 450 msec, ≥480 msec, and ≥ 500 msec.  Categories for QTcB and QTcF as change from 
Baseline are: ≥ 30 msec increase, ≥ 60 msec increase, and ≥ 75 msec increase.  QTcF is 
considered the primary QTc value as this correction is anticipated to be more appropriate.
All of the analysis on the safety endpoints will compare placebo with each tafamidis dose 
(20 mg and 80 mg) as well as the pooled group (combined tafamidis 20 mg and 80 mg).
The safety analyses will also be summarized by TTR genotype and NYHA Baseline 
classification.
9.6. Data Monitoring Committee 
This study will use an External Data Monitoring Committee (E-DMC) that is independent 
from Pfizer.  Information regarding the E-DMC can be found in the External Data 
Monitoring Committee Charter, including the membership of the committee.
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the E-DMC Charter through safety interim analyses of comparisons of safety 
information across treatment groups.  Any recommendations made by the E-DMC to alter the 


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conduct of the study based on safety findings will be forwarded to Pfizer for final decision.  
Pfizer will forward such decisions, which may include summaries of aggregate analyses of 
endpoint events and of safety data which are not endpoints, to regulatory authorities, as 
appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits to ensure that the protocol and 
Good Clinical Practices (GCPs) are being followed. The monitors may review source 
documents to confirm that the data recorded on CRFs are accurate.  The investigator and 
institution will allow Pfizer monitors/auditors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification.  This verification 
may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the Institutional Review Board (IRB)/ Ethics Committee (EC), and/or to quality 
assurance audits performed by Pfizer, or companies working with or on behalf of Pfizer, 
and/or to inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject’s medical records. The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.


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The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, (eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, (eg,
recruitment advertisements, if applicable, from the IRB/IEC).  All correspondence with the
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.


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The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008).24,12
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or in other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The investigator
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH, GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject (or a legal representative), is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator 
will retain the original of each subject's signed consent document.


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH/GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all other Participating Countries
End of Trial in all other participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of tafamidis at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 30 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of this study on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical 
Trials Database (EudraCT) and/or www.pfizer.com, and other public registries in accordance 
with applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product, regardless 
of the geographical location in which the study is conducted.  US Basic Results are 
submitted for posting within 1 year of the primary completion date for studies in adult 
populations
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
EudraCT
Pfizer posts clinical trial results on EudraCT for all Pfizer-sponsored interventional studies 
that are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 
year of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.


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If the Study is part of a multi-center study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
Almeida MR, Macedo B, Cardoso I, et al. Selective binding to transthyretin and 
tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy 
by an iodinated diflunisal derivative. Biochem. J. 2004;381: 351-356
2.
Ando Y, Coelho T, Berk J, et. al.  Guidelines for transthyretin-related hereditary 
amyloidosis for clinicians.  Orphanet Journal of Rare Disease 2013; 8: 31
3.
Blake CC, Geisow MJ, Oatley SJ, et al.  Structure of prealbumin: secondary, tertiary, 
and quaternary interactions determined by Fourier refinement at 1.8 A. J Mol Biol. 
1978;121:339-356.
4.
Bokhari S, Castaño A, Pozniakoff T, et al.  (99m)Tc-pyrophosphate scintigraphy for 
differentiating light-chain cardiac amyloidosis from the transthyretin-related familial 
and senile cardiac amyloidoses. Circ Cardiovasc Imaging. 2013 Mar 1;6(2):195-201.
5.
Bokhari S, Shahzad R, Castaño A, et al.  Nuclear imaging modalities for cardiac 
amyloidosis. J Nucl Cardiol. 2014 Feb;21(1):175-84. doi:10.1007/s12350-013-9803-2. 
PubMed PMID: 24162886.
6.
Buxbaum J, Jacobson D, Tagoe C, et al.  ransthyretin V122I in african americans with 
congestive heart failure. J Am Coll Cardiol, 2006; 47:1724-1725.
7.
Coelho T, Maia L, Martins de Silva A, et al.  Tafamidis for transthyretin familial 
amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012;79:785–792.
8.
Connors LH, Prokaeva T, Lim A, et.al. Cardiac amyloidosis in African Americans: 
comparison of clinical and laboratory features of transthyretin V122I amyloidosis and 
immunoglobulin light chain amyloidosis. Am Heart J. 2009 Oct;158(4):607-614.
9.
Connors LH, Doros G, Sam F, et al.  Clinical features and survival in senile systemic 
amyloidosis: comparison to familial transthyretin cardiomyopathy. Amyloid 2011;18 
Suppl 1:152-154.
10.
Cornwell GG, Murdoch WL, Kyle RA, et al. Frequency and distribution of senile 
cardiovascular amyloid. Am J Med 1983;75:618-623.
11.
DeVit M, Wang L, Weigel C, et al. In vitro profile of Fx-1006A, a novel, potent and 
selective transthyretin (TTR) stabilizer. Proceedings of the 11th International 
Symposium on Amyloidosis; 5-9 Nov 2006; Woods Hole, MA, USA (Abstract).
12.
Declaration of Helsinki (World Medical Association 1996 & 2008).
13.
Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN. Cardiac transthyretin amyloidosis. 
Heart 2012,98:1546-1554.


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14.
EuroQol Group. EuroQol: A new facility for the measurement of health-related quality
of life. Health Policy 1990;16:199-208.
15.
Falk RH. Cardiac Amyloidosis: a treatable disease, often overlooked. Circulation 
2011;124:1079-1085.
16.
Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in 
clinical trials. Statist Med 1999;18:1341-1354.
17.
Gertz MA, Skinner M, Connors LH, et al.  Selective binding of nifedipine to amyloid 
fibrils. Am J Cardiol. 1985 Jun 1;55 (13 Pt 1):1646.
18.
Glaudemans AW, van Rheenen RW, van den Berg MP, et al.  Bone scintigraphy with 
(99m)technetium-hydroxymethylene diphosphonate allows early diagnosis of cardiac 
involvement in patients with transthyretin-derived systemic amyloidosis. Amyloid. 
2014 Jan 23. [Epub ahead of print] PubMed PMID: 24455993.
19.
Green CP, Porter CB, Bresnahan DR, et al.  Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J 
Am Coll Cardiology 2000;35:1245-1255.
20.
Guidance for Industry:  Pharmacokinetics in patients with impaired renal function –
study design, data analysis, and impact on dosing and labeling (March 2010).
21.
Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: 
US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug 
Abuse, and Mental Health Administration; 1976.
22.
National Kidney Disease Education Program (NKDEP). 2014. Estimating Glomerular 
Filtration Rate (GFR). [ONLINE] Available at: 
http://nkdep.nih.gov/lab-evaluation/gfr/estimating.shtml. [Accessed 16 Apr 14].
23.
U.S. Department of Health and Human Services Food and Drug Administration Center 
for Drug Evaluation and Research (CDER). 2010. Guidance for Industry 
Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data 
Analysis, and Impact on Dosing and Labeling. [ONLINE] Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM204959.pdf. [Accessed 16 Apr 14].
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Guidelines for GCP (ICH 1996).
25.
Hammarström P, Jiang X, Hurshman AR, et al.  Sequence-dependent denaturation 
energetics: a major determinant in amyloid disease diversity. Proc Natl Acad Sci USA 
2002 December 10;99 Suppl 4:16427-16432.


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26.
Herlenius G, Wilczek HE, Larsson M, et al. Ten years of international experience with 
liver transplantation for familial amyloidotic polyneuropathy:  results from the Familial 
Amyloidotic Polyneuropathy World Transplant Registry.  Transplantation 
2004;7:1:64-71.
27.
Holmgren G, Ericzon B-G, Groth C-G, et al.  Clinical improvement and amyloid 
regression after liver transplantation in hereditary transthyretin amyloidosis.  Lancet 
1993;341:1113-1116.
28.
International Ethical Guidelines for Biomedical Research Involving Human Subjects 
(Council for International Organizations of Medical Sciences 2002).
29.
Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin 
(isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med
1997; 336:466–473.
30.
Jacobson D, Tagoe C, Schwartzbard A, et al.  Relation of clinical, echocardiographic 
and electrocardiographic features of cardiac amyloidosis to the presence of the 
transthyretin V122I allele in older African-American men. Am J Cardiol 2011 Aug 
1;108(3):440-444.
31.
Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile 
amyloidosis with cardiac involvement. Am J Med 1996 Oct;101(4):395-400.
32.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern. Med 2009;150 (9):604-612
33.
Lewis WD, Skinner M, Simms RW, et al.  Orthotopic liver transplantation for familiar 
amyloidotic polyneuropathy. Clinical Transplantation 1994;8:107-110.
34.
Monaco HL, Rizzi M, Coda A. Structure of a complex of two plasma proteins: 
transthyretin and retinol-binding protein. Science 1995;268:1039-1041.
35.
National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney 
disease: Evaluation, Classification and Stratification. Kidney Disease Outcomes 
Quality Initiative. Am J Kidney Dis 2002;39 (Suppl 1):S1-266
36.
Nilsson SF, Rask L, Peterson PA. Studies on thyroid hormone-binding proteins. J Biol 
Chem 1975; 250(21):8554-8563.
37.
Pages RA, Robbins J, Edelhoch H. Binding of thyroxine and thyroxine analogs to 
human serum prealbumin. Biochemistry 1973 Jul 3;12(14):2773-2779.
38.
Quintas A, Vaz DC, Cardoso I, et al. Tetramer dissociation and monomer partial 
unfolding precedes protofibril formation in amyloidogenic transthyretin variants. J Biol 
Chem 2001 July 20;276(29):27207-27213.


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39.
Rapezzi C, et al. Transthyretin-related amyloidoses and the heart: a clinical overview.  
Nat Rev Cardiol 2010; 7:398-408.
40.
Razavi H, et al. Benzoxazoles as transthyretin amyloid fibril inhibitors. Angewandte 
Chemie International Edition 2003; 42(24): 2758-2761.
41.
Ruberg, FG and BerkJL.  Transthyretin (TTR) Cardiac Amyloidosis.  Circulation 
2012;126: 1286-1300.
42.
Ruberg FL, Maurer MS, Judge DP, et al.  Prospective evaluation of the morbidity and 
mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy:  the 
Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J 2012;164:222-228.
43.
Rubin D, Multiple imputation for nonresponse in surveys, New York: John Wiley & 
Sons Inc; 1987.
44.
Rubinow A, Skinner M, and Cohen AS.  Digoxin Sensitivity in Amyloid 
Cardiomyopathy.  Circulation 1981; 63 (6): 1285-1288.
45.
Saraiva MJ. Transthyretin mutations in hyperthyroxinemia and amyloid diseases. Hum 
Mutat 2001;17:493-503.
46.
Sekijima Y et al. Familial Transthyretin Amyloidosis, 2009 
www.ncbi/nlm.gov/books/NBK1194 PMID2030173.
47.
Smith TJ, Kyle RA, Lie JT. Clinical significance of histopathologic patterns of cardiac 
amyloidosis. Mayo Clin Proc 1984 Aug;59(8):547-555.
48.
Thygesen K, Alpert J, Jaffe A, et al.  Third Universal Definition of Myocardial 
Infarction.  Circulation 2012; 126:2020-2035.


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Appendix 1. Patient Reported Outcomes
Appendix 1.1. KCCQ
THE KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE: (KCCQ)
The following questions refer to your heart failure and how it may affect your life.  Please read and complete 
the following questions.  There are no right or wrong answers. Please mark the answer that best applies to you.
1. Heart Failure affects different people in different ways.  Some feel shortness of breath while others feel fatigue.  
Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in your ability to do the 
following activities over the past 2 weeks.
Place an X in one box on each line
Activity
    Extremely
Quite a bit     Moderately
  Slightly          Not at all
       Limited for other 
reasons
     limited
limited           limited
   limited              limited
                     or did not 
do the 
activity
Dressing yourself          
    
      
                                               
Showering/Bathing             
    
     
                                                
Walking 1 block on level ground
        
                                                                                                   
Doing yardwork, housework or carrying groceries           
           
                           
                                               
Climbing a flight of stairs without stopping
           
                                                    
                                                
Hurrying or jogging (as if to catch a bus)       
                                                                                                  
2.  Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, fatigue or ankle swelling)
changed?  My symptoms of heart failure have become…
     Much worse
Slightly worse
Not changed
Slightly better
  Much better           I’ve had no symptoms
  over the last 2 weeks
                                                           
3.  Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when you woke up in the 
morning?
     Every          3 or more times 
     1-2 times a           Less than once         Never over the


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    morning        a week, but not            week                     a week                      past 2 weeks
                                
every day
         
      
       
                                                            
4.  Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you?
     In has been…
   Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no swelling
     bothersome
bothersome
bothersome
bothersome          bothersome
         
       
                                                                        
5.  Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you want?
All of the time    Several times       At least once a       3 or more times   1-2 times per
Less than once a
Never over
                                  per day                    day               per week but not         week                      week                 the past 2     
                                                                                                every day   
     weeks
                           
                                           
                           
6.  Over the past 2 weeks, how much has your fatigue bothered you?
     It has been…
     Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no fatigue
    bothersome
bothersome
bothersome
bothersome
bothersome
           
       
                                                                            
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your ability to do what you wanted?
All of the time    Several times       At least once a       3 or more times          2 times per
Less than once a
Never over
                              per day                      day                  per week but not            week                    week                 the past 2
                                                                                               every day  
     weeks
                         
                                               
                             
8.  Over the past 2 weeks, how much has your shortness of breath bothered you?
Extremely
Quite a bit
Moderately
Slightly
Not at all               I’ve had no shortness
bothersome
bothersome
bothersome
bothersome          bothersome                     of breath
    
       
                                                 
                       


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9.  Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a chair or with at 
least 3  pillows to prop you up because of shortness of breath?
     Every night
3 or more times
1-2 times a
Less than once
Never over the 
                               a week, but not
    week
     a week
  past 2 weeks
every day
          
       
                                                    
10. Heart Failure symptoms can worsen for a number of reasons.  How sure are you that you know what to do, or 
whom to call, if your heart failure gets worse?
      Not at all 
Not very sure
Somewhat sure
Mostly sure
Completely sure
          sure
          
       
                                                       
11.  How well do you understand what things you are able to do to keep your heart failure symptoms from getting 
worse? (for example, weighing  yourself, eating a low salt diet, etc.)
        Do not
   Do not
Somewhat
   Mostly
Completely
      understand
understand            understand
understand
understand
         at all
  very well
         
       
                                                      
12.  Over the past 2 weeks, how much has your heart failure limited your enjoyment of life?
It has extremely
It has limited
    It has
It has slightly
It has not limited my
    limited my
my enjoyment
moderately
  limited my
enjoyment of life
  enjoyment of
  of life quite
limited my
enjoyment of
        at all
       life                      a bit
enjoyment of life         life
       
       
                                                      
13. If you had to spend the rest of your life with your heart failure the way it is right now, how would you feel about 
this?
     Not at all
    Mostly
Somewhat          Mostly satisfied
Completely
      satisfied
dissatisfied
  satisfied
  
   satisfied       
         
       
                                                      
14. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of your heart failure?


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Final Protocol Amendment 3, 24 May 2016
Page 109
     I felt that way I felt that way
I occasionally
I rarely felt that
I never felt that 
     all of  the
most of the
felt that way
         way
        way  
         time
    time
       
          
       
                                                      
15.  How much does your heart failure affect your lifestyle?  Please indicate how your heart failure may have limited 
your participation in the following activities over the past 2 weeks?
Please place an X in one box on each line
Activity
    Severely
Limited         Moderately
  Slightly               Did not
             Does not apply 
or did
     limited             quite a bit         limited
   limited              limit at all            not do for other 
reasons
Hobbies, 
recreational activities     
    
                
                                               
Working or doing 
household chores                                                  
                                                 
Visiting family or friends
out of your home            
                        
                                                  
Intimate relationships
with loved ones              
                                     
                                                  
Developed by John Spertus et al.,  Mid America Heart Institute, Saint Luke’s Hospital, Kansas City, MO.


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Appendix 2. EQ-5D-3L


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Appendix 3. PGA
PGA Item for Baseline Visit:
Taking your cardiomyopathy into account, would you say the state of your health is:

Normal, not at all ill;

Borderline ill;

Mildly ill;

Moderately ill;

Markedly ill;

Severely ill;

Among the most extremely ill.
PGA Item for Follow-Up Visits:
Place an X in the box you feel most closely describes any change which you have 
experienced since beginning the study medication.
Take into account all change, whether or not you believe it is entirely due to drug treatment.
Choose only ONE response.
Since starting the study medication, my cardiomyopathy (HEART FAILURE) is:
(1) Very Much Improved
(2) Much Improved
(3) Minimally Improved
(4) No Change
(5) Minimally Worse
(6) Much Worse
(7) Very Much Worse


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Page 113
Appendix 4. 6-Minute Walk Test
The walking test should be performed indoors, along a long, flat, straight enclosed corridor 
with a hard surface that is seldom traveled.  The walking course should be 30 meters in 
length.  A 100 foot hallway is, therefore, required.  The length of the hallway should be 
marked every 3 meters.  The starting line should be clearly marked with bright colored tape.  
A treadmill is NOT recommended.
Study Coordinator/Observers:  Should be trained using the standard protocol and then 
supervised before performing the test alone.  They should have completed cardiopulmonary 
resuscitation training.
Required Equipment:
1. Countdown timer/Stopwatch.
2. Mechanical lap counter.
3. Two small cones to mark the turnaround points.
4. A chair that can be easily moved along the walking course.
5. Worksheets on a clipboard.
6. A source of oxygen.
7. Sphygmomanometer.
8. Telephone.
9. Automated electronic defibrillator.
Subject Preparation:
1. Comfortable clothing should be worn.
2. Appropriate shoes for walking should be worn.
3. Subjects should use their usual walking aids for the test (cane, walker, etc).
4. The subject’s usual medical regimen should be continued.
5. A light meal is acceptable before early morning or early afternoon tests.
6. Subject should not have exercised vigorously within 2 hours of beginning the test.


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Measurements:
1. Where possible, repeat testing should be performed about the same time of day to 
minimize variability.
2. A “warm-up” period before the test should NOT be performed.
3. The subject should sit at rest for about 10 minutes before the test starts.  Complete the 
first part of the work sheet.
4. Pulse oximetry is optional.
5. Have the subject stand and rate their Baseline dyspnea and overall fatigue using the 
Borg scale.
The Borg Scale:
0 – Nothing at all
0.5 – Very, very slight (just noticeable)
1 – Very slight
2 – Slight (light)
3 – Moderate
4 – Somewhat severe
5 – Severe
6
7 – Very severe
8
9
10 – Very, very severe (maximal)
Ask the subject what their level of shortness of breath is and then ask what their level of 
fatigue is.
1. Set the lap counter to zero and the timer to 6 minutes.  Assemble all necessary 
equipment, and move to starting point.
2. Instructions to the subject: 


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a.
“The object of this test is to walk as far as possible for 6 minutes.  You will walk 
back and forth in this hallway.  Six minutes is a long time to walk, so you will be 
exerting yourself.  You will probably get out of breath or become exhausted.  You 
are permitted to slow down, to stop and to rest as necessary.  You may lean 
against the wall while resting, but resume walking as soon as possible as you are 
able;
b. You will be walking back and forth around the cones.  You should pivot briskly 
around the cones and continue back the other way without hesitation.  “Now I’m 
going to show you.  Please watch the way I turn without hesitation”;
c.
Demonstrate by walking one lap yourself.  Walk and pivot around a cone briskly;
d. “Are you ready to do that? I am going to use this counter to keep track of the 
number of laps you complete.  I will click it each time you turn around at this 
starting line.  Remember that the object is to walk AS FAR AS POSSIBLE in 
6 minutes, but don’t run or jog;
e.
Do you have any questions?
f.
Start now or whenever you are ready.”
3. Position the subject at the starting line.  You should also stand near the starting line 
during the test.  Do not walk with the subject.  As soon as the subject starts to walk, 
start the timer.
4. Do not talk to anyone during the walk.  Use an even tone of voice when using the 
standard phrases of encouragement.  Watch the subject.  Do not get distracted and 
lose count of the laps.  Each time the participant returns to the starting line, click the 
lap counter once (or mark the lap on the worksheet).  Let the participant see you do it.  
Exaggerate the click using body language, like using a stop-watch at a race.
a. After the first minute, tell the subject the following (in an even tone) “You are 
doing well.  You have 5 minutes to go.”
b. When the timer shows 4 minutes remaining, tell the subject the following: “You 
have 4 minutes to go.”
c.
When the timer shows 3 minutes remaining, tell the subject the following:  “You 
are doing well.  You are half way done.”
d. When the timer shows 2 minutes remaining, tell the subject the following:  “Keep 
up the good work.  You have only 2 minutes left.”
e.
When the timer shows only 1 minute remaining, tell the subject:  “You are doing 
well.  You have only 1 minute to go.”


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f.
Do not use other words of encouragement (or body language to speed up).
g. If the subject stops walking during the test and needs a rest, say this:  “You can 
lean against the wall if you would like; then continue walking whenever you 
feel able.”  Do not stop the timer.  If the subject stops before the 6 minutes are up 
and refuses to continue (or decides that they should not continue), wheel the chair 
over for the subject to sit on, discontinue the walk, and note on the worksheet the 
distance, the time stopped and the reason for stopping prematurely.
5. Post-test: Record the post walk Borg dyspnea and fatigue levels and ask this: “What, 
if anything, kept you from walking farther?”
6. If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and then 
remove the sensor.
7. Record the number of laps from the counter (or tick marks from the worksheet).
8. Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides.  Calculate the total distance walked, 
rounding to the nearest meter, and recording it on the worksheet.
9. Congratulate the subject on a good effort and offer a drink of water.

SAP_001.pdf: 
Protocol B3461028 Statistical Analysis Plan
Page 1
Protocol B3461028
A MULTICENTER, INTERNATIONAL, PHASE 3, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF DAILY ORAL DOSING OF 
TAFAMIDIS MEGLUMINE (PF-06291826) 20 MG OR 80 MG IN COMPARISON TO 
PLACEBO IN SUBJECTS DIAGNOSED WITH TRANSTHYRETIN 
CARDIOMYOPATHY (TTR-CM)
Statistical Analysis Plan 
(SAP)
Version:
5
Author:
 
Date:
30-Jan-2018
PPD
PPD


Protocol B3461028 Statistical Analysis Plan
Page 2
Table 1.
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Version 1.0
October 8, 2013
Original SAP
Version 2.0
May 19 , 2014
Amended to reflect the protocol amendment 1 
and agreements with regulatory authorities.
Version 3.0
March 26, 2015
Amended to reflect the protocol amendment 2 
and removed specification of a table. 
Version 4.0
June 15, 2016
Amended to reflect the protocol amendment 3
Version 5.0
Jan 30, 2017
 
Amendment to make minor corrections to the 
SAP
PPD
PPD
PPD
PPD
PPD
PPD


Protocol B3461028 Statistical Analysis Plan
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................8
2.1. Study Design .............................................................................................................9
2.2. Study Objectives .....................................................................................................10
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................10
4. HYPOTHESES AND DECISION RULES.........................................................................10
4.1. Statistical Hypotheses .............................................................................................10
4.2. Statistical Decision Rules........................................................................................10
5. ANALYSIS SETS ...............................................................................................................10
5.1. Intent-to-Treat Analysis Set ....................................................................................11
5.2. ‘Per Protocol’ Analysis Set .....................................................................................11
5.3. Safety Analysis Set..................................................................................................11
5.4. Other Analysis Sets .................................................................................................11
5.5. Treatment Misallocations........................................................................................11
5.6. Protocol Deviations.................................................................................................11
5.6.1. Deviations Assessed Prior to Randomization.............................................11
5.6.2. Deviations Assessed Post-Randomization..................................................11
6. ENDPOINTS AND COVARIATES ...................................................................................12
6.1. Efficacy Endpoint(s) ...............................................................................................12
6.1.1. Primary Efficacy Endpoint(s).....................................................................12
6.1.2. Key Secondary Efficacy Endpoint(s) .........................................................12
6.1.3. Secondary Endpoints ..................................................................................12
6.1.4. Exploratory Endpoints................................................................................12
6.2. Safety Endpoints .....................................................................................................15
6.3. Other Endpoints.......................................................................................................15
6.4. Covariates................................................................................................................15
7. HANDLING OF MISSING VALUES ................................................................................15
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................15
8.1. Statistical Methods ..................................................................................................15
8.1.1. Finkelstein-Schoenfeld Analyses................................................................15


Protocol B3461028 Statistical Analysis Plan
Page 4
8.1.2. Survival Analyses .......................................................................................17
8.1.3. Mixed Model Repeated Measures (MMRM) Analyses..............................18
8.1.4. ANOVA......................................................................................................18
8.1.5. Poisson Regression for Frequencies...........................................................18
8.1.6. Cochran-Mantel-Haenszel Test for Proportions.........................................19
8.2. Statistical Analyses .................................................................................................19
8.2.1. Primary Analysis ........................................................................................19
8.2.2. Key-Secondary Analyses............................................................................19
8.2.3. Secondary Analyses....................................................................................21
8.2.4. Exploratory Analyses..................................................................................21
8.2.5. Safety Analyses ..........................................................................................23
9. REFERENCES ....................................................................................................................27
10. APPENDICES ...................................................................................................................28
LIST OF TABLES
Table 1.
Revision History.....................................................................................................2
Table 2.
Summary of Proposed Efficacy and Safety Analyses ..........................................25
APPENDICES
Appendix 1. Statistical Methodology Details..........................................................................28
Appendix 1.1. Finkelstein-Schoenfeld Example Scoring Algorithm ......................................28
Appendix 1.2. Definition and Use of Visit Windows in Reporting.........................................29
Appendix 1.3. Sample SAS Code for Analyses Described in Sections 8.1.2 – 8.2.6..............30
Appendix 1.4. Details of Multiple Imputation Method to be Used in Sensitivity 
Analysis ................................................................................................................32


Protocol B3461028 Statistical Analysis Plan
Page 5
1. AMENDMENTS FROM PREVIOUS VERSION(S) 

Status of study when amendment made:
Study is ongoing and remains blinded.

Details of Changes and Rationale:
Amendment 1 (SAP Version 2) 
Section of the SAP
Summary of change
Rationale
Various sections
Typographical corrections and 
clarifications 
For example: Changed “patients” 
to “subjects” for consistency.
Corrected minor typographical errors 
and inconsistent terminology.
2.1 Study Design

Clarified specification of 
sample size as 400 subjects.

Specified the duration of 
30 months to be equal to 
910 days.
Inserted new text from protocol 
amendment 1.
5.6.2. Deviations Assessed 
Post Randomization
Added use of 3 prohibited 
medications, ie, diflunisal, 
tauroursodeoxycholate, and 
doxycycline as criteria for 
exclusion from Per-Protocol 
Analysis Set.
Use of prohibited medication as 
described in protocol amendment 1 
Section 5.8.1. Contraindicated 
Therapies. 
6.1.4. Exploratory Endpoints
Added echo strain and other 
parameters.
Inserted new text from protocol 
amendment 1.
8.1.1. Finkelstein Schoenfeld 
Analyses

Clarified text around 
algorithm involving 
“censored” subjects.

Removed sentence related to 
analysis of “indeterminate” 
events.

Modified text to improve clarity.

Removed sentence regarding 
analysis of events adjudicated as 
“indeterminate” as it was 
inconsistent with the last sentence 
of the first paragraph of 
Section 8.1.1. 
8.2.2. Key Secondary 
Analyses
Added specification of pattern 
mixture analysis as a 
supplemental analysis of the 
key-secondary analyses.
Inserted new text per agreement with 
FDA.
8.2.3. Secondary Analyses
Added a statement describing the 
handling of deaths adjudicated as 
“indeterminate” similar to the 
handling of “hospitalizations”.
Added missing detail for handing 
“indeterminate” deaths in the analysis. 
8.2.4. Exploratory Analyses

Added analysis of placebo vs 
80 mg randomized subjects 
who were not downtitrated as 
requested by PMDA.

Added analysis by region as 
requested by FDA.

Added additional exploratory 
endpoints.

Added analysis requested by 
PMDA and FDA.

Added exploratory endpoints to 
be consistent with protocol
amendment 1.


Protocol B3461028 Statistical Analysis Plan
Page 6
Table 2 Summary of Proposed 
Efficacy and Safety Analyses
Updated to reflect the changes to 
SAP.
Table updated to be consistent with 
the body of SAP and protocol 
amendment 1.
Appendix 1.2. Sample SAS 
Code for Analyses

Added code for 
pattern-mixture. 

Made a minor correction to 
the SAS code for analyses 
described in Section 8.1.3, 
ie, added RANDOM 
statement.

Added SAS code for new 
pattern-mixture analysis 
consistent with May 2014 
agreement with FDA. 

Made minor correction to 
previous SAS code.
Amendment 2 (SAP Version 3) 
Section of the SAP
Summary of change
Rationale
Sections 2.1, 8.1.1, 8.1.2, 8.2.4
Cardiac mechanical assist device 
was added as a reason for 
discontinuation and treated 
similar to heart transplant in the 
analysis.
Cardiac mechanical assist device is 
indicative of end stage disease similar 
to a heart transplant. 
Section 8.2.5
Removed specification of an 
unnecessary table.
Listing of adverse events occurring 
during the trial will include those that 
start prior to randomization.
Amendment 3 (SAP Version 4) 
Section of the SAP
Summary of change
Rationale
Sections 6.4, 8.1.1, 8.1.2, 
8.1.3, 8.1.4, 8.1.5, 8.1.6, 8.2.4
NYHA baseline classification 
categories were change from 
“NYHA class I and NYHA 
classes II and  III combined ” to 
“NYHA classes I and II combined 
and NYHA class III”.
Redefined the baseline groupings for 
New York Heart Association (NYHA) 
Functional Classification that will be 
used for efficacy analyses, grouping 
subjects with NYHA Class I and II 
together to be compared against 
NYHA Class III.
Given the very low number of 
enrolled subjects with NYHA Class I, 
the NYHA baseline groupings were 
redefined for efficacy analyses.  This 
permits a more appropriate baseline 
adjustment in the primary analysis as 
well as other secondary and 
exploratory analyses.  
Section 2.1
Study number of the extension 
study included and other edits.
Edits to reflect the changes to the 
protocol.
Section 6.1.4, Section 8.2.4, 
Table 2
KCCQ subjects symptoms 
subscales clarified.
Better delineated the analysis planned 
for Kansas City Cardiomyopathy 
Questionnaire (KCCQ) scores related 
to subject symptoms.
Section 6.2
Text updated to be consistent with 
protocol.
The italicized text was update to be 
consistent with protocol.


Protocol B3461028 Statistical Analysis Plan
Page 7
Section 8.1.1, Section 6.4
Clarification of how subjects 
incorrectly classified during 
randomization will be handled in 
the primary analysis.
Subjects who were incorrectly 
classified during randomization will 
be analyzed using the correct value of 
the stratification factors (TTR 
Genotype or NYHA baseline 
classification) in the primary analysis.
Section 8.2
Frequency of TTR mutation
analysis added.
Frequency of various TTR mutations
enrolled in the study will be 
summarized.
Section 8.2.1, Section 8.2.4
Clarified the term “down-
titration” to “dose reduction”.
Wording modified per protocol to 
more accurately represent the change 
in dose that may occur when a subject 
is unable to tolerate the randomized 
dose.
Section 8.2.4
Cross-tabulation summary added 
for Patient Global Assessment.
Additional descriptive summary for 
Patient Global Assessment added.
Section 8.2.5
A lag of 28 days will be used in 
determining
treatment-emergence.
Clarifying and documenting a 
program wide standard procedure with 
respect to lag.
Appendix 1.2
Visit window algorithm details 
added.
An algorithm was added to detail how 
early termination visits will be 
assigned to nominal study visits.
Amendment 4 (SAP Version 5)
Section of the SAP
Summary of change
Rationale
6.1.4. Exploratory Endpoints
Updated KCCQ related domain 
and summary scores.
Updated to be consistent with the 
developers’ names for the KCCQ 
domain and summary scores.
8.1.1. Finkelstein Schoenfeld 
Analyses
Corrected an error in the notation
(replace subscript “i” with “j”)
describing the calculation of Ui.
Update to correct a minor error in the 
equation describing calculation of Ui
(
)
8.2.2. Key Secondary 
Analyses
Updated reference for sample 
SAS code for pattern mixture 
analysis from Appendix 1.2 to 
Appendix 1.3.
Updated to correct the referenced
Appendix number.
8.2.4. Exploratory Analyses
Removed exploratory analysis 
comparing subjects reduced to 
40 mg vs placebo.
The analysis is not meaningful given 
the very low number of total blinded 
dose reductions in the study.
8.2.4. Exploratory Analyses
Added tables summarizing 
plasma concentrations of 
tafamidis and a listing of plasma 
concentration of diflunisal.
Added plasma based summary tables 
for tafamidis and listing for diflunisal.
8.2.5. Safety Analyses
Added by-gender summary 
tables for treatment-emergent 
adverse events and serious 
adverse events.
Added analyses evaluating gender 
based differences in adverse events 
between the study treatments.
Table 2
Updated KCCQ related domain 
and summary scores.
Updated to be consistent with the 
developers version of KCCQ.
Appendix 1.2
Updated windowing for 
Echocardiogram endpoints.
Added details of the windowing 
algorithm for Echocardiogram 
endpoints based on the study visits 
when they were collected.


Protocol B3461028 Statistical Analysis Plan
Page 8
Appendix 1.3
Updated sample SAS code for 
pattern mixture code.
Update code to fix an error in the 
ESTIMATE statement in the sample 
SAS code.
Appendix 1.3
Updated sample SAS code to use 
PROC GLM replacing PROC 
ANOVA.
Replaced PROC ANOVA with, 
PROC GLM which is a more 
appropriate procedure for un-balanced 
data.
Appendix 1.4. Details of 
Multiple Imputation Method 
to be Used in Sensitivity 
Analysis
Details to text and SAS code
added.
Added details to text and SAS code to 
improve clarity.
2. INTRODUCTION
Amyloidosis is a severely debilitating condition induced by the accumulation of various 
insoluble fibrillar proteins, or amyloid, within the tissues in amounts sufficient to impair 
normal function.  Different precursor proteins have been associated with amyloid 
cardiomyopathy, including immunoglobulin light chains (associated with primary or AL 
amyloidosis), serum amyloid A (associated with secondary or AA amyloidosis) and 
transthyretin (TTR) representing the most common inherited amyloidosis.  Transthyretin 
(also referred to as pre-albumin), a 127-amino acid, 55 kDa protein that is primarily 
synthesized in the liver, is a transport protein of thyroxine and retinol-binding protein-retinol 
(vitamin A) complex (Blake 1978, Monaco 1995).  A mutation in TTR accelerates the process 
of fibrillogenesis whereby the tetrameric structure of the TTR protein dissociates leading to 
amyloid deposition (Nilsson 1975, Saraiva 2001).  Dissociation of the TTR tetramer into 
monomers is the initial and rate-limiting step in amyloidogenesis (Nilsson 1975, 
Saraiva 2001).
Transthyretin amyloidosis can present as either a hereditary or an age-related disease.  The 
major phenotypic presentations of TTR amyloidosis include transthyretin familial amyloid 
polyneuropathy (TTR-FAP), which can present with sensorimotor and autonomic 
polyneuropathy and transthyretin cardiomyopathy (TTR-CM), which can present in either a 
genetic variant or a wild-type form (the latter is also known as senile systemic amyloidosis or 
SSA).
Median survival from diagnosis for patients with TTR-CM was 41 months in a study of the 
V122I mutation and median survival was reported as 46 months for wild-type (Connors 
2011).  Death in most patients with cardiac amyloidosis is from cardiac causes, including 
sudden death, heart failure, and myocardial infarction (Kyle 1996, Smith 1984).
Tafamidis is an oral small molecule, under development by Pfizer, as a disease modifying 
therapy for TTR amyloid diseases.  It binds to the thyroxine binding sites on the TTR 
tetramer, thereby preventing destabilization into the monomeric form.  In study Fx1B-201, 
tafamidis effectively stabilized TTR in 34 of 35 (97.1%) subjects, representing both wildtype 
and V122I, at Week 6, with approximately 88% stabilized throughout the 12 months of the 
study.  Of note, tafamidis has also been studied in TTR-FAP and effectively stabilized TTR in 
98% of subjects as well as demonstrating effects relative to placebo on clinical measures 
(Coelho 2012).


Protocol B3461028 Statistical Analysis Plan
Page 9
TTR-CM is a rare disease with very little available published information.  Based on this, the 
natural history and disease progression of TTR-CM were prospectively evaluated in a 
noninterventional study involving 29 subjects (Transthyretin Amyloidosis Cardiac Study 
[TRACS]; Study Fx-001; Ruberg 2012).  In addition, subsequent to the TRACS study, an 
open-label, Phase 2 Study Fx1B-201 was initiated.  This study involved 35 subjects with 
TTR-CM who received open-label tafamidis 20 mg QD for 12 months along with routine
standard of care.  The proportion of patients with the variant genotype was substantially 
lower in Fx1B-201 compared with TRACS.
2.1. Study Design
This is a Phase 3, multicenter, international, three-arm, parallel design, placebo-controlled,
randomized study with a 30-month double-blind treatment phase, to determine efficacy, 
safety and tolerability of tafamidis on clinical outcomes in subjects with either transthyretin 
genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy (TTR-CM).
There will be approximately 400 subjects enrolled in the study in a 2:1:2 ratio 
(placebo:20 mg:80 mg).  The subjects will be allocated to the 3 arms of the study in the 
following manner: n=160 in the placebo arm, n=80 in the 20 mg arm, and n=160 in the 
80 mg arm.  Subjects who experience adverse events that may be associated with poor 
tolerability to treatment with tafamidis that may impact dosing adherence have the option of 
blinded treatment re-assignment and potential dose-reduction (see Section 5.5 of protocol).  
Subjects will be stratified during enrollment by TTR genotype (variant and wild-type) and 
structured such that greater than 30% of randomized subjects have a TTR mutation and
greater than 30% of subjects have a diagnosis of wild-type TTR cardiomyopathy, with the 
intent to enroll comparable numbers between the variant and wild-type groups.
Enrollment may be closed for either wild-type or variant stratum in order to enroll at least 
30% of subjects with each TTR genotype (wild-type and variant).
Additionally, stratification to treatment assignment will be done for Baseline severity of 
disease based on NYHA classification (NYHA Class I and NYHA Classes II and III
combined).  Stratification will be implemented in order to maintain a balance of both TTR 
genotype and disease severity across the treatment assignments.  The site will ensure a 
Month 30 follow-up contact to determine the subject’s vital status and whether the subject 
has had a heart and / or liver transplant or implantation of cardiac mechanical assist device.  
Upon completion of the study at the Month 30 visit, subjects may be eligible for treatment 
with tafamidis in a separate study (B3461045), which will permit the collection of additional 
safety and efficacy data, and may include the assessment of hospitalizations, mortality, and 
other outcomes relating to disease progression.  For the purpose of this study, 30 months is 
defined as 910 days.  Eligibility for the extension study (B3461045) requires subject 
participation in this study at least through Day 896 (Month 30 minus 2 weeks).


Protocol B3461028 Statistical Analysis Plan
Page 10
2.2. Study Objectives
The primary objective of this study is to assess the efficacy of an oral dose of 20 mg or 80 mg 
tafamidis meglumine soft-gel capsules based on all-cause mortality and on frequency of 
cardiovascular-related hospitalizations as well as to assess safety and tolerability in 
comparison to placebo.  Tafamidis or placebo will be administered once daily, in addition to 
standard of care, for 30 months in subjects diagnosed with variant or wild-type TTR 
cardiomyopathy (TTR-CM).
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal efficacy interim analysis is planned. 
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the E-DMC Charter through safety interim analyses consisting of comparisons 
of safety information across treatment groups. Un-blinded descriptive summaries of 
mortality, hospitalization, adverse events, laboratory data, and other safety monitoring data 
as requested by the E-DMC will be provided for their review.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The null hypothesis for the primary analysis is that neither all-cause mortality nor frequency 
of cardiovascular-related hospitalizations is different between the tafamidis and placebo 
treatment groups.  The corresponding alternative hypothesis is that at least one and possibly 
both all-cause mortality and frequency of cardiovascular-related hospitalizations are 
different between the tafamidis and placebo treatment groups.
4.2. Statistical Decision Rules
All hypothesis testing will be conducted using two-sided tests with alpha = 0.05 level of
significance.  The list of key-secondary endpoints and the methodology for controlling the 
study-level Type I error at 0.05 due to multiple analyses are detailed in Section 8.2.2.
5. ANALYSIS SETS
The following sets are defined for use in the analyses:

Intent-To-Treat (ITT) Analysis Set;

Per-Protocol (PP) Analysis Set;

Safety Analysis Set.
Both the ITT and PP analysis sets will be used for the primary analysis and for the analyses 
of the key-secondary endpoints, with the ITT being primary.  The secondary endpoints and
the exploratory endpoints will only be analyzed using the ITT analysis set.  The Safety 
Analysis Set will be used in the analyses of the safety data.


Protocol B3461028 Statistical Analysis Plan
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5.1. Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all subjects in the safety population who 
had at least 1 post Baseline efficacy evaluation (ie, post Baseline hospitalization, study visit, 
or date of death).  This may also be referred to as a modified intent-to-treat group but for 
simplicity will be referred to throughout the protocol and SAP as ITT.
5.2. ‘Per Protocol’ Analysis Set 
The per protocol (PP) analysis set will include all subjects in the ITT set who did not violate 
inclusion/exclusion criteria and who did not have protocol violations considered to impact 
the interpretation of the primary efficacy analysis.
5.3. Safety Analysis Set
The safety analysis set will include all subjects who are enrolled (randomized) and received 
at least 1 dose of double-blind medication.
5.4. Other Analysis Sets
No other analysis sets are defined for this study.
5.5. Treatment Misallocations
For subjects, who were not treated, not randomized, or received incorrect treatment, the
following rules will be used:

Randomized but not treated, then they will be excluded from the ITT and PP analysis 
sets for efficacy evaluations and excluded from the safety analyses as actual treatment 
is missing.

Treated but not randomized, then by definition they will be excluded from the 
efficacy analyses since randomized treatment is missing, but will be reported under 
the treatment they actually received for all safety analyses.

Randomized but took incorrect treatment, then they will be reported under their 
randomized treatment group for all efficacy analyses, but will reported under the 
treatment they actually received for all safety analyses.
5.6. Protocol Deviations
Below are the protocol deviations that relate to the “Per-Protocol Analysis Set” (Section 5.2).
5.6.1. Deviations Assessed Prior to Randomization
A protocol deviator is a subject who was wrongly enrolled into the study, when inclusion or 
exclusion criteria were not appropriately satisfied. See Protocol, Section 4.
5.6.2. Deviations Assessed Post-Randomization
Protocol deviations include but are not limited to the following:

Violations on concomitant medications (see protocol Section 5.5);


Protocol B3461028 Statistical Analysis Plan
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
Lack of dosing adherence (level to be defined case by case);

Dosing errors (eg, treatment misallocation, see Section 5.5 in this SAP);

Use of diflunisal, tauroursodeoxycholate, and doxycycline during the study.
A full list of protocol deviations will be compiled for the study report prior to database 
closure. All deviations will be reviewed and a determination of which data to include in the 
Per-Protocol Analysis Set will be made prior to unblinding the study database.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
6.1.1. Primary Efficacy Endpoint(s)
The primary analysis uses a hierarchical combination applying the method of 
Finkelstein-Schoenfeld (Finkelstein 1999) to:

All-cause mortality, and

Frequency of cardiovascular-related hospitalizations over the duration of the trial, 
which is defined as the number of times a subject is hospitalized (ie, admitted to a 
hospital) for cardiovascular-related morbidity.
6.1.2. Key Secondary Efficacy Endpoint(s)
1. Change from Baseline to Month 30 in the distance walked during 6-Minute Walk Test 
(6MWT),
2. Change from Baseline to Month 30 in the Kansas City Cardiomyopathy 
Questionnaire Overall Score (KCCQ-OS).
6.1.3. Secondary Endpoints
1. Cardiovascular-related mortality,
2. Frequency of cardiovascular-related hospitalization,
3. All-cause mortality,
4. TTR stabilization at Month 1.
6.1.4. Exploratory Endpoints

Frequency of all-cause hospitalization,

Cardiovascular-related days hospitalized,

All-cause days hospitalized,


Protocol B3461028 Statistical Analysis Plan
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
All-cause mortality and the frequency of all-cause hospitalization using the 
Finkelstein-Schoenfeld analysis,

All-cause mortality and cardiovascular-related days hospitalized using the 
Finkelstein-Schoenfeld analysis,

Cardiovascular-related mortality and frequency of cardiovascular-related 
hospitalization using the Finkelstein-Schoenfeld analysis,

TTR stabilization at each time points other than Month 1,

TTR concentration at each time point, Change from baseline at time points other than 
Month 30 in the 6-Minute Walk Test (6MWT),

Change from baseline at time points other than Month 30 in the Kansas City 
Cardiomyopathy Questionnaire Overall Score (KCCQ-OS),

Change from baseline at each time point in Kansas City Cardiomyopathy 
Questionnaire: (KCCQ) domain scores (Physical limitation, Symptom stability, 
Symptom frequency, Symptom burden, Total symptom, Self-efficacy, Social limitation, 
and Quality of life) and Clinical summary score,

Change from Baseline at each time point in EuroQoL-5 Dimensions (EQ-5D-3L) 
Index Score and visual analog scale (VAS) scores,

Patient Global Assessment at each time point,

New York Heart Association Classification (NYHA) at each time point,

Change from Baseline at each time point in modified Body Mass Index,

Change from Baseline at each time point in NT-proBNP concentration,

TTR oligomer concentration at each time point,

Change from Baseline at each time point in select echocardiographic parameters, 
including: 

End-diastolic interventricular septal wall thickness (mm),

Left ventricle posterior wall thickness (mm),

Left ventricular ejection fraction (%),

Left ventricular stroke volume (mL).

Global Longitudinal Strain,


Protocol B3461028 Statistical Analysis Plan
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
Basal Septal,

Mid Septal,

Apical Septal,

Basal Lateral,

Mid Lateral,

Apical Lateral,

Circumferential strain basal global,

Circumferential strain mid global,

Circumferential strain apical global,

Radial strain basal global,

Radial strain mid global,
Radial strain apical global.  Additionally, the following echocardiographic 
parameters will also be measured:

Fractional shortening (%),

Left atrial diameter, anterior-posterior (mm),

Left atrial diameter, medio-lateral (mm),

Left atrial diameter, superior-inferior (mm),

Left ventricular end systolic diameter (mm),

Left ventricular end systolic volume (mL),

Left ventricular end-diastolic diameter (mm),

Left ventricular end-diastolic volume (mL),

Left ventricular mass (g),

E/A Ratio,

E/E’ Ratio.


Protocol B3461028 Statistical Analysis Plan
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6.2. Safety Endpoints
Safety and tolerability will be assessed with adverse event reporting as well as the conduct of 
ECGs, clinical laboratory testing, vital signs, and physical examinations.
6.3. Other Endpoints
Not Applicable.
6.4. Covariates
Baseline values will be included as a covariate in the analysis using the mixed model 
repeated measures (MMRM) model detailed in Section 8.1.3.  Where baseline scores are not 
available (or applicable) for the endpoints (eg, frequency of cardiovascular-related 
hospitalization), the NYHA baseline classification (NYHA Classes I and II combined and 
NYHA Class III ) will be included in the appropriate models to address baseline severity 
levels.
All subjects who were incorrectly classified during randomization (wrong TTR Genotype or 
NYHA baseline classification) will be analyzed using the correct TTR Genotype or NYHA 
baseline classification values.
7. HANDLING OF MISSING VALUES
No imputation will be done for missing cases for the primary analysis based on the 
Finkelstein-Schoenfeld method.  A sensitivity analysis (of the primary) using multiple 
imputation as described in Appendix 1.4 will be performed.  Supplemental analyses of the 
two key secondary variables will group the subjects on the basis of their dropout or 
missing-data patterns using a pattern mixture model described in Section 8.2.2.  For all 
analyses using mixed model repeated measures, no imputation of missing values will be 
done.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
8.1.1. Finkelstein-Schoenfeld Analyses
The test is based on the principle that each subject in the clinical study is compared to every 
other subject within each stratum in a pair-wise manner.  The method recognizes the higher 
importance of all-cause mortality.  The pair-wise comparison proceeds in hierarchical 
fashion using all-cause mortality first, assigning a +1 to the “better” subject and a -1 to the 
“worse” subject (Appendix 1.1).  A score,
, represents the pair wise comparison and 
indicates whether patient i has the more favorable outcome than patient j.  The 
“cardiovascular- related hospitalization” in all analyses, unless otherwise specified, will 
combine hospitalizations adjudicated as cardiovascular-related with hospitalizations 
adjudicated as indeterminate.

If both subjects are dead, then the subject with a longer survival time is assigned +1.


Protocol B3461028 Statistical Analysis Plan 
 
 
 
 
Page 16 
 If one subject is alive and the other is not, the live subject receives a +1 and the 
deceased one a -1.  
 If both subjects are alive, the comparison uses cardiovascular-related hospitalization 
to assign scores.  The subject with the fewer cardiovascular related hospitalization 
(frequency) receives a +1 while the other receives -1. 
The test statistic is based on the sum of these scores and will be stratified by TTR genotype 
(variant and wild-type) and NYHA baseline classification (NYHA Classes I and II combined 
and NYHA Class III ) resulting in a total of 4 strata (2 x 2).  
The term “censored” refers to a subject who discontinues from the trial for reasons other 
than death.  For such subjects, there will be additional follow-up to obtain vital status (and 
transplant status / cardiac mechanical assist device status) at Month 30 and that information 
will be used in the analysis.  In the case where one subject is censored before a second 
subject has died, and where the vital status of the first patient at Month 30 is missing, then 
the frequency of cardiovascular-related hospitalizations at the shorter of their follow-up 
times (the shorter of the 2 subjects’ study participation) will be used in assigning a +1 or -1.  
In the simpler case where one subject drops out but both are known to be alive at Month 30, 
the frequency of cardiovascular-related hospitalizations, at the shorter of their follow-up 
times (the shorter of the 2 subjects study participation), will be used in assigning a +1 or -1.  
Comparisons of cardiovascular related hospitalization frequency for subjects who completed 
all 30 months study duration will be based on the earlier of the two actual study durations 
(days). 
Subjects, who discontinue for transplantation (ie, heart transplantation and combined heart 
and liver transplantation) or for implantation of a cardiac mechanical assist device, will be 
handled in the primary analysis in the same manner as death.  More specifically, the time of 
the transplant or cardiac mechanical assist device implant will be used in the 
subject-to-subject comparison in the same manner as if the subject had died at that time 
(regardless of any additional vital status follow-up information).  Data from subjects who 
drop out for a liver-only transplantation will be handled in the same manner as the data from 
all other censored subjects.  
The proposed test is a score test based on the sum of the scores for the treated group.  A 
value of 
 =1 for subjects in tafamidis and 
 =0 for subjects in the placebo group.  Using 
the 
 for every pair of subjects defined above, we assign a score to each subject. 
The subjects are divided into 4 strata k =1; 2; 3, 4.  If 
is the set of indices of the 
 
subjects in the kth strata and that 
 is calculated within strata (for 
;  
), 
then the test statistic is based on 
 
Let 
be the total number of subjects in the 
 stratum who are in the tafamidis group.  
Then in
 strata  


Protocol B3461028 Statistical Analysis Plan 
 
 
 
 
Page 17 
 and 
 
where 
 is the Kronecker delta (valued as 1 if i =j and 0 otherwise).  
Since 
 this implies that the mean of  is zero and its variance is  
. 
The hypothesis of interest is tested by comparing 
 to the normal distribution. 
In the event there is insufficient information for the adjudication process to classify either a 
mortality or hospitalization as cardiovascular related or not cardiovascular related, then the 
event will be classified as “indeterminate”.  In the adjudication process, cases with at least 
some information indicating a contributory cardiovascular cause, including ambiguous 
cases, will be adjudicated to the cardiovascular-related category.  The test statistic for the 
“by TTR Genotypes” subgroup analysis will be stratified by NYHA baseline classification 
(NYHA Classes I and II combined and NYHA Class III).  The test statistic for the “by 
NYHA classifications” subgroup analysis will be stratified by TTR Genotype (variant and 
wild-type).  Subjects who were incorrectly classified during randomization (wrong TTR 
Genotype or NYHA baseline classification) will be analyzed using the correct TTR Genotype 
or NYHA baseline classification values. 
8.1.2. Survival Analyses 
Time to event endpoints including all-cause mortality, and cardiovascular-related mortality 
will be analyzed using SAS Proc Lifetest; p-values will be from the log-rank test.  For 
cardiovascular-related mortality, subjects who died for reasons other than cardiovascular 
(including “inderterminate”) will be designated as censored at the time of death.  Subjects 
who discontinue for transplantation (ie, heart transplantation and combined heart and liver 
transplantation) or cardiac mechanical assist device will be handled in the same manner as 
death (as done in the primary analysis).  
Kaplan-Meier survival curves for each treatment group along with median survival times (if 
applicable) will be presented.  Kaplan-Meier product limit estimators will be generated.  The 
number of subjects at risk, number of events and number of censored observations through 
6, 12, 18, 24, 30 months will be summarized using the “Method=Life” option in PROC 
LIFETEST. 
Time to event endpoints will also be analyzed using Cox proportional hazards model using 
Proc PHREG with treatment, TTR genotype (variant and wild-type), and NYHA baseline 
classification (NYHA Classes I and II combined and NYHA Class III ) as factors.  


Protocol B3461028 Statistical Analysis Plan
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For the analyses by NYHA baseline classification, the Cox proportional hazard model will 
include treatment and TTR genotype.  For the analyses by TTR genotype, the model will 
include treatment and NYHA baseline classification.  The Kaplan-Meier survival curves will 
also be generated for the analyses by NYHA baseline classification and TTR genotype.
8.1.3. Mixed Model Repeated Measures (MMRM) Analyses 
The endpoints evaluated at multiple time points will be analyzed using a mixed model 
repeated measures ANCOVA (MMRM) with an unstructured covariance matrix (or as 
appropriate); center and subject-within-center as random effects; treatment, visit, TTR 
genotype (variant and wildtype), and visit-by-treatment interaction, as fixed effects and 
Baseline score as covariate.  While the NYHA baseline classification may serve as an 
indicator of baseline severity, the endpoints that are evaluated at baseline (and at multiple 
points post-baseline) will use their respective baseline scores as the appropriate covariate for 
the MMRM analysis described above.
For the analyses by TTR genotype, the same model specified above will be used, with the 
addition of terms for TTR genotype-by-treatment interaction and TTR 
genotype-by-treatment-by-visit 3–way interaction.  Similarly for dose, the same model 
specified above will be used with replacement of “dose” for “treatment”.  Appropriate 
CONTRAST statements will be used to generate the LSMEANS from the MMRM model 
(eg, for dose, 20 mg vs placebo and 80 mg vs placebo) at each post-baseline study visit.  The 
subgroup analysis by NYHA baseline classification (NYHA Classes I and II combined and 
NYHA Class III ) will be done using ANCOVA (MMRM) with an unstructured covariance 
matrix (or as appropriate); center and subject-within-center as random effects; treatment, 
visit, TTR genotype (variant and wildtype), NYHA baseline classification, visit-by-treatment 
interaction, NYHA baseline classification-by-treatment interaction, NYHA baseline 
classification-by-treatment-by-visit 3–way interaction as fixed effects and baseline score as 
covariate.  All the subgroup analyses will be considered exploratory.
8.1.4. ANOVA
Cardiovascular-related days hospitalized and all-cause days hospitalized will be analyzed 
using an analysis of variance (ANOVA) with treatment, TTR genotype (variant and 
wild-type), NYHA Baseline classification (NYHA Classes I and II combined and NYHA 
Class III), treatment-by-TTR genotype interaction, and treatment-by-NYHA Baseline 
classification interaction terms as factors.
8.1.5. Poisson Regression for Frequencies
Frequency of cardiovascular-related hospitalization and frequency of all-cause 
hospitalization will be analyzed using Poisson regression analysis with treatment, TTR 
genotype (variant and wild-type), NYHA Baseline classification (NYHA Classes I and II 
combined and NYHA Class III ), treatment-by-TTR genotype interaction, and 
treatment-by-NYHA Baseline classification interaction terms as factors adjusted for 
treatment duration.


Protocol B3461028 Statistical Analysis Plan
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For the subgroup analyses by NYHA classification (NYHA Classes I and II combined and 
NYHA Class III), the Poisson regression analysis will have treatment, TTR genotype (variant 
and wild-type), and treatment-by-TTR genotype interaction terms as factors adjusted for 
treatment duration.
For the subgroup analyses by TTR genotype, the Poisson regression analysis will have 
treatment, NYHA baseline classification, and treatment-by- NYHA baseline classification
(NYHA Classes I and II combined and NYHA Class III ) as factors adjusted for treatment 
duration.
8.1.6. Cochran-Mantel-Haenszel Test for Proportions
A Cochran-Mantel-Haenszel (CMH) will be used as a test of proportions.  For the overall, 
and analyses by dose( placebo vs 20 mg and placebo vs 80 mg), a Cochran-Mantel-Haenszel 
test for proportions stratified by TTR genotype and NYHA baseline severity (NYHA 
Classes I and II combined and NYHA Class III ) will be used.  For subgroup analysis by 
TTR genotype, a CMH test for proportions stratified by NYHA baseline severity will be 
used.  The analysis will also be performed separately by Baseline severity using a CMH test 
for proportions stratified by TTR genotypes (variant and wild-type).
8.2. Statistical Analyses 
The number of subjects screened, randomized to the double-blind treatment phase, and 
completing the study will be summarized.  The reason for all discontinuations will be 
summarized by treatment group.  Baseline demographic and other characteristics, including 
the frequency of specific genotypes will be tabulated for the ITT population.  Quantitative 
variables will be described by standard descriptive statistics (mean, standard deviation, 
minimum, and maximum), and qualitative variables will be summarized by frequency tables.
Concomitant medications including their preferred term and therapeutic subgroup will be 
summarized by treatment groups.
The primary analysis and key-secondary endpoints will be analyzed using both ITT and PP 
Analysis Sets.  All other efficacy analyses will be performed on ITT Analysis Set only.
8.2.1. Primary Analysis
The primary analysis uses a hierarchical combination of all-cause mortality and frequency of 
cardiovascular-related hospitalizations (which is defined as the number of times a subject is 
hospitalized [ie, admitted to a hospital] for cardiovascular-related morbidity) over the 
duration of the trial as described in Section 8.1.1.  The primary analysis will combine the 
subjects in the tafamidis 20 mg and tafamidis 80 mg groups (including subjects in 80 mg 
group that may have had a dose reduction to 40 mg) into one pooled group.  This pooled 
group (tafamidis) will be compared with the placebo group using the Finkelstein-Schoenfeld 
method (Finkelstein 1999).
8.2.2. Key-Secondary Analyses
The key secondary endpoints listed below will be evaluated using a mixed model repeated 
measures ANCOVA detailed in Section 8.1.3. 


Protocol B3461028 Statistical Analysis Plan
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1. Change from Baseline to Month 30 in distance walked during the 6MWT;
2. Change from Baseline to Month 30 in KCCQ Overall score.
To maintain the type 1 error rate at or below the specified level, a pre-specified hierarchical
order for testing as indicated above will be used to maintain the overall alpha at 0.05 for
these two key secondary endpoints.  The multiplicity procedure will be applied to the ITT 
analysis set only.
Statistical significance of the key-secondary analyses is dependent on first achieving 
statistically significant results in the primary analysis.  In this hierarchical approach of 
key-secondary endpoints, the change from Baseline to Month 30 in distance walked during 
the 6MWT is first tested at the 0.05 level.  If the p-value for the test of 6MWT is 0.05, the 
2nd variable in the list, the change from Baseline to Month 30 in KCCQ Overall Summary 
score will be tested at the 0.05 level.  If the p–value of the test for 6MWT is >0.05, then 
statistical significance cannot be achieved for the subsequent test on KCCQ.
Supplemental analyses of the two key secondary variables will be performed to support the 
robustness of the conclusions drawn.  The pattern-mixture analysis will group the subjects on 
the basis of their dropout or missing-data patterns. ‘Patterns’ will be defined under the 
following two cases:
Case 1:
Pattern 1A - all subjects who have provided the key-secondary endpoint (each done 
separately) data for month 30.
Pattern 1B - all subjects who have not provided the key-secondary endpoint data for 
month 30.
Case 2:
Pattern 2A - all subjects who have the key-secondary endpoint data (each done separately)
for month 15 or beyond.
Pattern 2B - all subjects who do not have key-secondary endpoint data beyond month 15.
The pattern mixture analysis will use a mixed model repeated measures ANCOVA (MMRM) 
with an unstructured covariance matrix (or as appropriate); center and subject within center 
as random effects; treatment, visit, TTR genotype (variant and wild-type), pattern, visit by 
treatment interaction, and treatment by pattern interaction as fixed effects and baseline score 
as covariate.  Sample SAS code is provided in Appendix 1.3.
Exploratory analyses of the key secondary endpoints will include results from the MMRM 
analysis at each individual time point other than month 30. 


Protocol B3461028 Statistical Analysis Plan
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Additional exploratory analyses of the key secondary endpoints will include results from the 
MMRM analysis at each individual time point by dose group (randomized dose group), TTR 
genotype (variant and wild-type), and NYHA baseline classification.  Descriptive statistics 
overall, by dose, by TTR genotype, and by NYHA baseline classification will be provided for 
each time point. 
Except for the analyses by dose, all analyses of the key-secondary endpoints, including the 
proposed exploratory analyses of these endpoints will compare the pooled tafamidis group 
with the placebo group.
8.2.3. Secondary Analyses
The "cardiovascular -related mortality" in all analyses, unless otherwise specified, will 
combine deaths adjudicated as cardiovascular-related with deaths adjudicated as 
indeterminate.
The cardiovascular-related mortality and all-cause mortality will be analyzed using survival 
analysis methods detailed in Section 8.1.2.
Frequency of cardiovascular-related hospitalizations will be analyzed using the Poisson 
regression analyses detailed in Section 8.1.5.
All the analyses on the secondary endpoints described above will additionally be presented 
by TTR genotype (variant and wild-type), NYHA baseline classification as well as dose 
(randomized dose group) and will be considered exploratory.
The proportion of subjects who achieved TTR stabilization in each treatment group at 
Month 1 will be compared using a Cochran-Mantel-Haenszel test detailed in Section 8.1.6.
A similar test of proportion will be done on TTR stabilization at all other time points and 
considered exploratory.  No subgroup analyses will be done at these other time points.
Except for the analyses by dose group, all analyses of the secondary endpoints, including the 
proposed exploratory analyses of these endpoints will compare the pooled tafamidis group 
with the placebo group.
8.2.4. Exploratory Analyses
A supplemental analysis, repeating the methodology of the primary analysis, will only 
include hospitalizations adjudicated as cardiovascular related and exclude hospitalizations 
adjudicated as “indeterminate”.  To examine the potential effect of including heart 
transplantation or cardiac mechanical assist device as “deaths” in the primary analysis, a 
sensitivity analysis will be performed treating all transplantation or cardiac mechanical 
assist device in the same manner as any other censored observation.  As an additional 
sensitivity analysis, a multiple imputation analysis will be applied using the method 
developed by Rubin (Rubin 1987).  Combined results will be provided for the primary 
analysis (ie, using Finkelstein-Schoenfeld) as well as for the separate mortality and
morbidity elements.  Details are provided in Appendix 1.4.


Protocol B3461028 Statistical Analysis Plan
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An exploratory analysis, using the methodology of the primary analysis, will be repeated by 
the dose group to which subjects were randomized (tafamidis 20 mg vs placebo and tafamidis 
80 mg vs placebo) to explore the effect by dose group. 
Exploratory analysis of the secondary endpoint, all-cause mortality will be done by treating 
all heart transplantation or cardiac mechanical assist device in the same manner as any other 
censored observation.  Exploratory subgroup analysis using the Finkelstein-Schoenfeld 
method comparing the pooled tafamidis group and the placebo group, similar to that of the 
primary analysis, will also be done by the TTR genotype (variant type and the wild-type) and 
Baseline severity (NYHA Classes I and II combined and NYHA Class III) status.
To examine the potential effect of region, the primary analysis will be repeated with the 
inclusion of a factor for region.  More specifically, the test statistic will be stratified by TTR 
genotype (variant and wild-type), baseline severity category (NYHA Classes I and II 
combined and NYHA Class III ), and region (US and Ex-US).
Frequency of All-cause hospitalization will be analyzed using the Poisson regression 
analyses detailed in Section 8.1.5.
Cardiovascular-related days hospitalized, and all-cause days hospitalized will be analyzed 
using an analysis of variance (ANOVA) detailed in Section 8.1.4.
An exploratory analysis based on the Finkelstein-Schoenfeld method similar to that of the 
primary analysis detailed in Section 8.1.1 will be done for combination of variables listed 
below:

All-cause mortality and frequency of all-cause hospitalizations,

All-cause mortality and cardiovascular-related days hospitalized using the 
Finkelstein-Schoenfeld analysis,

Cardiovascular-related mortality and frequency of cardiovascular-related 
hospitalization using the Finkelstein-Schoenfeld analysis.
The exploratory endpoints listed below will be evaluated at each time point post-baseline 
using a mixed model repeated measures ANCOVA (MMRM) as detailed in Section 8.1.3.

Change from Baseline in Kansas City Cardiomyopathy Questionnaire: (KCCQ) 
domain scores (Physical limitation, Symptom stability, Symptom frequency, 
Symptom burden, Total symptom, Self-efficacy, Social limitation, and Quality of life) 
and clinical summary score,

Change from Baseline in EuroQoL-5 Dimensions (EQ-5D-3L) Index Score and visual 
analog scale (VAS) scores,

Patient Global Assessment,

Change from Baseline in Modified Body Mass Index,


Protocol B3461028 Statistical Analysis Plan
Page 23

Change from Baseline in NT-proBNP concentration,

TTR oligomer concentration at each time point,

TTR concentration at each time point, 

Change from Baseline in echocardiographic parameters: 

End-diastolic interventricular septal wall thickness (mm),

Left ventricle posterior wall thickness (mm),

Left ventricular ejection fraction (%),

Left ventricular stroke volume (mL),

Global longitudinal strain,

Circumferential strain mid global,

Radial strain mid global.
All other echocardiographic parameters listed as endpoints in Section 6.1.4 will be 
analyzed descriptively.
The TTR oligomer concentration and TTR concentration will additionally be analyzed by 
dose.  Descriptive statistics are presented by visit for the NYHA Classification (Class I, II, 
III, and IV).  The number and percent of subjects with an improvement (decrease by at least 
one classification), those who worsened (increase by at least one classification), and those 
with no change (same classification) from baseline are presented at each visit using a shift 
table.  A cross-tabulation of baseline severity level and post baseline change level will be 
presented at each visit for Patient Global Assessment scale.
Plasma concentrations of tafamidis will be summarized with descriptive statistics (n, 
arithmetic mean, standard deviation, coefficient of variation, geometric mean, median, and 
minimum and maximum) by dose, visit, and nominal time.
Plasma concentrations of diflunisal will be provided as listings by visit.
8.2.5. Safety Analyses
The safety assessments in the study are listed in Section 6.2.  All randomized subjects who 
receive at least one dose of study treatment will be included in the safety analysis.  All 
adverse events that are observed from the time of first dosing with study medication (at 
randomization) until the end of study participation will be included in the safety analysis.
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by treatment group.  The incidence of 
treatment-emergent adverse events will be tabulated by treatment group and by system organ 


Protocol B3461028 Statistical Analysis Plan
Page 24
class.  The incidence of treatment-emergent adverse events will be displayed by severity and 
attribution.  In addition, the incidence of serious adverse events and adverse events that 
cause withdrawal will be tabulated.  All adverse events will be listed.
The effective duration of treatment is determined by the lag time.  Any event occurring 
within the lag time, whether this occurs during a break in treatment or at the end of treatment, 
is attributed to the corresponding treatment period.  A lag of 28 days will be used for this 
study.
The following 3-tier approach will be used to summarize AEs.  Under this approach, AEs are 
classified into 1 of 3 tiers. While the AEs will be additionally analyzed by subgroups, the
3-tier approach will only be applied to the overall AE analyses.
Tier-1 events: These are pre-specified events of clinical importance and are 
maintained in a list in the product’s Safety Review Plan.  This list may be updated as 
more is understood about the drug. 
Tier-2 events: These are events that are not tier-1 but are “common”.  A MedDRA 
Preferred Term (PT) is defined as a tier-2 event if there are at least 4 in any 
treatment group.
Tier-3 events: These are events that are neither tier-1 nor tier-2 events.
The analyses of adverse events under the 3-tier approach is considered exploratory. There 
will be no adjustment for multiple comparisons or stratification factors in the analyses. For 
tier-1 and tier-2 events, the proportion of AEs observed in each treatment groups will be 
presented along with the point estimates and associated 95% confidence intervals of the risk 
difference for the pooled tafamidis group compared with placebo. 
For Tier-1 events p-values will be included in the presentations.  AEs will be arranged in the 
output sorted in descending point estimate of the risk difference within system organ class.
Footnotes in the outputs will include the methods used to derive any p-values and confidence 
intervals as per Pfizer standards. The Tier 1 AEs will be analyzed using the approach of 
Chan and Zhang (1999) who inverted two one-sided tests at half the significance level each 
for calculating P-values and confidence intervals.
For Tier 2 AEs, both proportion and 95% CIs will be generated using an asymptotic approach 
(Proc Binomial).  A MedDRA PT is defined as a Tier-2 event if there are at least 4 in any 
treatment group.  A cross-industry expert team on safety planning, evaluation and reporting 
(Crowe et al, 2009) suggests to use the “Rule of 4” to define tier-2 events.  The “Rule of 4” 
says that if a trial has 400 or fewer subjects per group and there are 4 or more subjects with a 
given MedDRA PT in any treatment group, then that PT will be categorized as a tier-2 event.
For Tier 3 events, simple proportions will be presented.
All clinical laboratory data will be subjected to clinical review, summarized by frequency of
events and mean changes from baseline.


Protocol B3461028 Statistical Analysis Plan
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All vital sign measurements will be displayed in listings by subject for each sample collection 
date and time.  The measurement taken immediately prior to randomization will be used as 
the baseline for calculating changes in vital signs.
Centrally over-read ECG variables will be summarized by mean change from baseline to 
each measurement time for heart rate, PR interval, QRS width, QT interval and QTcB 
(Bazett’s correction) and QTcF (Fridericia correction) values.  Additionally, the incidence of 
categorical increases in QTc intervals will be provided.  Categories for QTcF and QTcB are 
450 msec, 480 msec, and 500 msec.  Categories for QTcF and QTcB as change from 
baseline are 30 msec increase, 60 msec increase and 75 msec increase.  QTcF is 
considered the primary QTc value as this correction is more appropriate.
All of the analysis on the safety endpoints will compare placebo with each tafamidis dose 
(20 mg and 80 mg) as well as the pooled group (combined tafamidis 20 mg and 80 mg).
The safety analyses will also be summarized by TTR genotype and NYHA baseline 
classification.  Treatment-emergent adverse events and serious adverse events will be 
summarized by gender as well.
Summary of Efficacy Analyses 
Table 2.
Summary of Proposed Efficacy and Safety Analyses
End Point or Assessment
Overall
By 
dose
Wild-type 
vs 
Variant
NYHA 
Baseline 
Classification
Primary Analysis
Primary – FS Method (All-cause mortality and CV 
Hospitalization)*
x#
x
x
x
Key-Secondary Analyses
Change from Baseline to Month 30 on the distance 
walked during 6-Minute Walk Test (6MWT)*
X##
x
x
x
Change from Baseline to Month 30 on the Kansas 
City Cardiomyopathy Questionnaire Overall Score 
(KCCQ-OS)*
X##
x
x
x
Secondary Analyses
Cardiovascular-related mortality 
x
x
x
x
Frequency of cardiovascular-related hospitalization 
x
x
x
x
All-cause mortality 
x
x
x
x
TTR stabilization at Month 1
x
x
x
-
Exploratory Analyses
TTR stabilization at each time point other than 
month 1
x
-
-
-
Frequency of all-cause hospitalization
x
-
-
-
Cardiovascular-related Days Hospitalized
x
-
-
-
All-cause Days Hospitalized
x
-
-
-
FS-method – All-cause mortality and frequency of 
all-cause hospitalization 
x
-
-
-
FS-method – all cause mortality + CV-related hosp 
days
x
-
-
-
FS-method – CV-related mortality + frequency of 
CV-related hosp 
x
-
-
-


Protocol B3461028 Statistical Analysis Plan
Page 26
End Point or Assessment
Overall
By 
dose
Wild-type 
vs 
Variant
NYHA 
Baseline 
Classification
Change from Baseline at each time point on 
EuroQoL-5Dimensions (EQ-5D-3L) Index Score and 
visual analog scale (VAS) scores
x
-
-
-
TTR oligomer concentration at each time point
x
x
TTR concentration at each time point
x
x
Patient Global Assessment at each time point
x
-
-
-
NYHA classification change from baseline (shift 
table)
x
-
-
-
Change from Baseline at each time point on Kansas 
City Cardiomyopathy Questionnaire:  (KCCQ) 
domain scores (Physical limitation, Symptom 
stability, Symptom frequency, Symptom burden, 
Total symptom, Self-efficacy, Social limitation, and 
Quality of life) and clinical summary scores 
x
-
-
-
Change from Baseline at each time point on Modified 
BMI Mass Index
x
-
-
-
Change from Baseline at each time point in 
Echocardiography (septal and ventricular wall 
thickness, ejection fraction, and stroke volume, Global 
longitudinal strain, Circumferential strain mid global, 
Radial strain mid global)
x
-
-
-
Change from Baseline at each time point on 
NT-proBNP concentration
x
-
-
-
Change from Baseline at time points other than 
month 30 on the distance walked during 6-Minute 
Walk Test (6MWT)
x
-
-
-
Change from Baseline at time points other than month
30 on the Kansas City Cardiomyopathy Questionnaire 
Overall Score (KCCQ-OS)
x
-
-
-
Additional echocardiographic parameters (listed in 
Section 6.1.4)
x
Safety
AEs labs, Vitals
X
X
X
X
*Analysis will be performed using both ITT and PP Analysis Sets.  All other efficacy analysis will be 
performed on ITT Analysis Set only.
#Sensitivity analysis of the primary analysis will be done as described in Section 8.2.4.
## Supplemental analysis of the key-secondary endpoints will be done as described in Section 8.2.2.


Protocol B3461028 Statistical Analysis Plan
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9. REFERENCES
1.
Blake CC, Geisow MJ, Oatley SJ, et al. Structure of prealbumin:  secondary, tertiary, 
and quaternary interactions determined by Fourier refinement at 1.8 A.  J Mol Biol. 
1978;121:339-356.
2.
Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics, 55:1201–1209.
3.
Coelho T, Maia L, Martins de Silva A, et al. Tafamidis for transthyretin familial 
amyloid polyneuropathy:  a randomized, controlled trial.  Neurology 2012;79:785–792.
4.
Connors LH, Doros G, Sam F, et al. Clinical features and survival in senile systemic 
amyloidosis:  comparison to familial transthyretin cardiomyopathy.  Amyloid 2011;18 
Suppl 1:152-4.
5.
Crowe B, Xia HA, Berlin JA, et al. (2009). Recommendations for safety planning, data 
collection, evaluation and reporting during drug, biologic and vaccine development: a 
report of the safety planning, evaluation and reporting team. Clinical Trials, 6:430-440.
6.
Finkelstein DM, Schoenfeld DA. Combining Mortality and Longitudinal Measures in 
Clinical Trials. Statist. Med. 1999; 18; 1341-1354
7.
Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile 
amyloidosis with cardiac involvement.  Am J Med 1996 Oct;101(4):395-400.
8.
McCullagh, P., and Nelder, J. (1989).  Generalized Linear Models, Second Edition, 
Chapman Hall/CRC: Boca Raton, FL.
9.
Monaco HL, Rizzi M, Coda A. Structure of a complex of two plasma proteins:  
transthyretin and retinol-binding protein.  Science 1995;268:1039-1041.
10.
Nilsson SF, Rask L, Peterson PA. Studies on thyroid hormone-binding proteins.  J Biol 
Chem 1975; 250(21):8554-63.
11.
Ruberg FL, Maurer MS, Judge DP, et al. Prospective evaluation of the morbidity and 
mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy:  the 
Transthyretin Amyloidosis Cardiac Study (TRACS).  Am Heart J 2012;164:222-8.
12.
Rubin, D. (1987).  Multiple Imputation for Non-response in Surveys, Wiley: New York.
13.
Saraiva MJ. Transthyretin mutations in hyperthyroxinemia and amyloid diseases. Hum 
Mutat 2001;17:493-503.
14.
Smith TJ, Kyle RA, Lie JT. Clinical significance of histopathologic patterns of cardiac 
amyloidosis.  Mayo Clin Proc 1984 Aug;59(8):547-55.


Protocol B3461028 Statistical Analysis Plan
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10. APPENDICES 
Appendix 1. Statistical Methodology Details
Appendix 1.1. Finkelstein-Schoenfeld Example Scoring Algorithm
Scenario
i/j
All-cause
Mortality
Survival 
Time (from 
baseline)
Cardiovascular-related 
hospitalization
Score
1
i
Dead
-
-
-1
j
Alive
-
-
2
i
Dead
Low
-
-1
j
Dead
High
-
3
i
Dead
Tied
High
-1
j
Dead
Tied
Low
4
i
Dead
Tied
Tied
0
j
Dead
Tied
Tied
5
i
Alive
-
High
-1
j
Alive
-
Low
6
i
Alive
-
Tied
0
j
Alive
-
Tied
Subjects that are tied on “all-cause mortality” will be compared by frequency of 
cardiovascular-related hospitalization. If the 2 subjects have different follow-up times, the 
smaller of the 2 follow-up times will be used in comparing the frequency of 
cardiovascular-related hospitalization.
If i and j are reversed in severity than the value assigned to i is +1.


Protocol B3461028 Statistical Analysis Plan
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Appendix 1.2. Definition and Use of Visit Windows in Reporting 
The following describes the clinical visits windows allowed within the protocol after month 1 
visit:
Clinic Visits (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30) 2 weeks
End of Study Visit (Month 30) 2 weeks or Early Study Discontinuation
However, in order to maximize the use of all available data, the visit windows for each visit 
are expanded as follows:
For endpoints collected every 3 months:
Clinic Visits (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30) 6 weeks
All nominal visits (months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30) will use the data as collected 
from that visit.  Early termination visits will never replace an existing visit.  If the visit 
covered by the windowing rules above is already populated with an existing nominal visit, 
then the early termination visit should be mapped forward to the next 3 month visit.
For endpoints collected every 6 months:
Clinic Visits (Months 6, 12, 18, 24, 30) 3 months
All nominal visits (months 6, 12, 18, 24, 30) will use the data as collected from that visit.  
Early termination visits will never replace an existing visit.  If the visit covered by the 
windowing rules above is already populated with an existing nominal visit, then the early 
termination visit should be mapped forward to the next 6 month visit.
For Echocardiogram collected at months 6, 18, and 30:
Clinic Visits (Months 6, 18, 30) 6 months
All nominal visits (months 6, 18, 30) will use the data as collected from that visit.  Early 
termination visits will never replace an existing visit.  If the visit covered by the windowing 
rules above is already populated with an existing nominal visit, then the early termination 
visit should be mapped forward to the next nominal visit.


Protocol B3461028 Statistical Analysis Plan
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Appendix 1.3. Sample SAS Code for Analyses Described in Sections 8.1.2 – 8.2.6
Sample SAS code to fit the mixed model repeated measures specified in Section 8.1.3 is 
given below.  The response variable Y is the change from baseline at the study visits. 
PROC MIXED DATA=xxx METHOD=REML EMPIRICAL;
CLASS pid center trt visit genotype;
MODEL y= ybase trt visit genotype trt *visit;
RANDOM int/SUBJECT=center; 
REPEATED visit /SUBJECT= pid (center) r type=UN;
RUN;
Sample SAS code for the survival analysis specified in Section 8.1.2 is given below. 
PROC LIFETEST DATA=xxx PLOTS=(s) graphics;
TIME dur *status(0);
STRATA trt;
RUN;
PROC PHREG DATA=xxx;
MODEL dur*status(0)=trt genotype NYHAbase/ ties=EXACT;
RUN
Sample SAS code for the ANOVA specified in Section 8.1.4 is given below. 
PROC GLM DATA=xxx;
CLASS trt genotype NYHAbase;
MODEL y= trt genotype NYHAbase trt*genotype trt*NYHAbase;
RUN;
Sample SAS code for the Poisson regression specified in Section 8.1.5 is given below. 
PROC DATA=xxx;
ln_styyr=log(styyr);* log transformation to normalize duration of participation ;
RUN;
PROC GENMOD DATA=xxx;
CLASS trt genotype NYHAbase;
MODEL y= trt genotype NYHAbase trt*genotype 
trt*NYHAbase/ type 3 dist=poisson link=log offset=ln_styyr;
RUN;


Protocol B3461028 Statistical Analysis Plan
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Sample SAS code for the CMH test specified in Section 8.1.6 is given below.  In the code 
below, the variable NYHA_GENOTYPE is obtained from combining NYHA baseline 
classification and TTR genotype into one variable (with 4 levels).
PROC FREQ DATA=xx;
TABLES NYHA_GENOTYPE*TRT*STABILIZED / CMH
RUN;
Sample SAS code for the pattern mixture analysis specified in Section 8.1.5 is given below. 
PROC MIXED DATA=xxx empirical; 
CLASS pid visit center trt pattern genotype; 
MODEL y= ybase visit trt genotype pattern visit*trt 
trt*pattern / solution; 
random int/subject=center; 
repeated visit /subject= pid (center) r type=UN; 
ESTIMATE 'Tafamidis vs placebo Month 30' 
trt 1 -1 visit*trt 0 0 0 0 0 0 0 0 1 -1 
trt*pattern 0.5 0.5 -0.5 -0.5 /cl e; * Placebo adjusted LSMEANS of Tafamidis 
averaged over the pattern (equal weight=0.5); 
run;


Protocol B3461028 Statistical Analysis Plan
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Appendix 1.4. Details of Multiple Imputation Method to be Used in Sensitivity Analysis
For purposes of the missing data sensitivity analyses, the study duration of 30 months will be 
partitioned into 3 intervals of 10 months each.  These will be referred to as period 1, period 2, 
and period 3, representing months 1-10, 10-20, and 20-30 respectively. Imputation models 
will be estimated and applied separately for each treatment group.  Hospitalizations are not 
imputed for subjects after their death.  The imputation procedure consists of two distinct 
phases: 1) models for cardiovascular-related hospitalization rates are estimated for each time 
interval, and 2) these models are then used to impute the number of cardiovascular 
hospitalizations following censoring (dropout) amongst subjects who dropout in an interval.  
Dropouts are the only source of missing hospitalization data, so there will be a monotone 
missing data pattern.  The two-stage multiple imputation process developed here follows the 
procedure for monotone missing data in Rubin (1987). 
Within each short time interval (10 months), a Poisson regression model with a constant rate 
will be assumed for hospitalization counts.  No imputation is required for a patient who dies 
during the interval.  Because the model applies only to subjects who survive the interval, and 
subjects who die during the interval are likely to have differing hospitalization rates, subjects
who die in an interval will be excluded from the imputation model estimation.  All other 
subjects still in the study at the beginning of the interval are included in the model 
estimation.  The reduced exposure of dropouts during the intervals is represented by an 
exposure multiplier (between 0-10) of the monthly hospitalization rate (McCullagh and 
Nelder, 1989).  The monthly hospitalization rate during the first period is a function of the 
baseline covariates NHYA baseline classification and TTR genotype.  The monthly 
hospitalization rate during the second period is a function of the baseline covariates and the 
hospitalization counts during the first period.  The monthly hospitalization rate during the 
third period is a function of the baseline covariates, and the hospitalization counts during the 
first and second periods.
PROC GENMOD will be used to compute maximum likelihood estimates (MLE) of the 
parameters of the Poisson regression model.  It will also be used to compute the 
variance-covariance matrix for the estimates from each time period.  A total of 1000 imputed 
data sets will be generated.  To account for estimation error when forming the imputed data 
sets, 1000 independent sets of the Poisson model parameters will be generated for each time 
period from a multivariate normal distribution with mean equal to the MLE, and with the 
variance-covariance matrix equal to the MLE variance-covariance matrix.  The ith set of 
Poisson model parameters from each time period are paired together, yielding 1000 sets of 
parameters for generating the 1000 imputed data sets.  For each iteration, the individual 
patient Poisson rate (lambda) will be generated using the Poisson regression coefficient 
estimates for that iteration.
The imputation process described here is applied with each set of Poisson model parameters.  
Subjects without complete data are comprised of two types: those with no participation 
during the period, and those with partial participation during the period.  For those with no 
participation, the prediction equation will be used to impute a hospitalization count for the 
entire period.  For those with partial participation, the prediction model will be applied to 
impute a hospitalization count appropriate for the remainder of the period after the patient 


Protocol B3461028 Statistical Analysis Plan
Page 33
dropped out.  The imputed value will be added to the actual observed value for that patient 
from the part of the period prior to their dropping out.  For example, consider a patient who 
drops out at month 5.  The patient’s Period 1 imputed value will be the sum of their actual 
hospitalization count from month 1 to month 5 added to the predicted value from month 5 to 
month 10.
Any missing data are imputed sequentially beginning with the first time period, then the 
second and third periods.  The imputation model during the first period depends only on fully 
observed baseline covariates.  The imputation model during the second period also depends 
on the hospitalization count during the first period.  For any patient who dropped out during 
the first period, their imputed count in the first period is used in the model to produce the 
imputed value for that subject in period 2.  Note that this differs from the process when 
estimating the imputation model (Rubin, 1987).  A similar procedure is applied for 
imputation of missing values during period 3.  Finally, the hospitalizations for each patient 
are summed to generate a complete 30-month (imputed) CV hospitalization frequency.
The null hypothesis will be tested based on the 1000 imputed data sets by computing the 
components of the complete-data Finkelstein-Schoenfeld statistic to yield 1000 numerator 
values, and 1000 denominator values (square root of the numerator variance).  Following 
Rubin (1987), the numerators will then be averaged.  The variance of this average will be the
average within-imputation variance computed from the 1000 complete-data variances of the 
numerators combined with the between imputation variability in the numerators to yield a 
normal Z-statistic.  The 1000 imputed hospitalization data sets will also be used to 
summarize hospitalization rates in the treatment groups. 
Sample SAS Code
Poisson model specified below will be used to fit cardiovascular hospitalization data and will 
then be used to impute the missing data. The model will be fit separately for each of the 
3 periods and will be done separately for both treatment groups (placebo and pooled 
tafamidis). Only the subjects that entered a given period (not completely missing during the 
period) will be used in determining the model. The “OFFSET” in the linear model 
implemented by PROC GENMOD is the adjustment for the exposure time in the interval
(those who entered the period but did not complete the 10 months). The variable 
“months_exposure”, used in the “OFFSET”, is a log transformation of the months of 
exposure in a given period.
proc genmod data = nonmissingperiod1; ;* Only includes subjects with non-missing count 
data for period 1;
class NYHAnum MUTATIONnum;
model count = NYHAnum MUTATIONnum /dist=p link=log offset=months_exposure 
;*model terms for period1;
output out=predpoi p=p;
run;


Protocol B3461028 Statistical Analysis Plan
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proc genmod data = nonmissingperiod2; ;* Only includes subjects with non-missing count 
data for period 2;
class NYHAnum MUTATIONnum;
model count = countbase1 NYHAnum MUTATIONnum /dist=p link=log 
offset=months_exposure;*model terms for period 2 where countbase1 is CV hospitalization 
count from period 1;
output out=predpoi p=p;
run;
proc genmod data = nonmissingperiod3;* Only includes subjects with non-missing count 
data for period 3;
class NYHAnum MUTATIONnum;
model count = countbase1 countbase2 NYHAnum MUTATIONnum /dist=p link=log 
offset=months_exposure;* model terms for period 3 where countbase1 and countbase2 are 
CV hospitalization counts from period 1 and 2 respectively;
output out=predpoi p=p;run;
The macro below can be used to perform the multiple imputation. The variable “seedval”
will be the starting seed and the variable “numimp” will specify the number of multiple 
imputations to be performed. The dataset “withmissing” will contain all the subjects that will 
be imputed.
%macro impute (output, seedval, numimp);
data &output;
set withmissing;
seed=&seedval;
do MInum = 1 to &numimp;
lambda= exp(± x.xx ± x.xxx countbase(varies depending on the period) ± x.xx *NYHAnum 
±  x.xx*MUTATIONnum);
count = ranpoi(seed, lambda); * coefficients will be randomly generated from a normal 
distribution based on the estimates and standard error output from PROC GENMOD;
output;
end;
run;
%mend impute;
The macro input statement will use a seed value of 999 and perform 1000 multiple 
imputations.
%impute (impute2, 999, 1000);