Clinical trial NCT00935012
Conditions: ATTR-CM TTR-CM
Keywords: TTR, ATTR, cardiomyopathy, amyloidosis, tafamidis
Sponsor: Pfizer
Start date: 2009-09-30; Completion date: 2019-11-20
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Open-label Safety and Efficacy Evaluation of Fx-1006a in Patients with V122i Or Wild-type Transthyretin (ttr) Amyloid Cardiomyopathy.

Patients who successfully complete Fx1B-201 will report to the clinical unit on Day 0 to sign the informed consent form and determine eligibility for Protocol Fx1B-303. In addition, on Day 0, patients will have their entrance criteria reviewed, and medical histories and demographic characteristics obtained.

The physical examination (including weight and vital signs) and the relevant end of study clinical laboratory tests (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, gamma glutamyl transferase, creatinine, total bilirubin, international normalized ratio, troponin I, troponin T, and amino-terminal B-type natriuretic peptide) from Protocol Fx1B-201 will be used for Protocol Fx1B-303. If more than 30 days has elapsed between the final study visit of Protocol Fx1B-201 and Day 0 of Protocol Fx1B-303, an abbreviated physical examination (including weight and vital signs) and clinical laboratory assessments must be performed on Day 0.

Eligible patients will begin once-daily dosing with 20 mg Fx-1006A at home on Day 1 (i.e., first dose) and will return to the clinical unit for study visits every 6 months.

Adverse events (AEs) and concomitant medication use will be collected at each 6-month visit to the clinical unit. Blood draws for clinical safety laboratory tests and abbreviated physical examinations (including weight and vital signs) will also be performed at each 6-month clinic visit. ECGs will be performed every 12 months on an annual basis. A telephone call will be made at 3-month intervals between clinic visits to assess safety and use of concomitant medications.

For the evaluation of efficacy, the Patient Global Assessment, NYHA classification, KCCQ, 6-minute walk test, and efficacy-related clinical laboratory tests (serum levels of troponin T, troponin I, and NT-pro-BNP) will be determined every 6 months. In addition, echocardiograms will be performed every 12 months on an annual basis.

An end of study visit including all safety and efficacy assessments will occur upon patient completion of the study, premature withdrawal (for any reason), or in the event of program discontinuation by the Sponsor.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: tafamidis
Intervention descriptions: intervention 1: Once daily 20 mg oral tafamidis (soft gelatin capsule)

Protocol documents:
Prot_000.pdf: 
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A wholly-owned subsidiary of Pfizer, Inc.
OPEN-LABEL SAFETY AND EFFICACY EVALUATION OF FX-1006A IN 
PATIENTS WITH V122I OR WILD-TYPE TRANSTHYRETIN (TTR) AMYLOID 
CARDIOMYOPATHY
Compound:
Fx-1006A/PF-06291826
Compound Name (if applicable):
tafamidis
US IND Number (if applicable):
Protocol Number:
Fx1B-303/B3461026
Phase:
3
The name, title, address and telephone number(s) of the sponsor's medical expert for the trial 
is documented in the study contact list located in the coordinator’s manual.
CCI


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Document History
Document
Version Date
Summary of Changes
Amendment 1
14 June 2012
1) Protocol - Update of sponsor name: FoldRx 
Pharmaceuticals, Inc is now a wholly-owned 
subsidiary of Pfizer, Inc.
2) Protocol – change in nomenclature for 
abbreviation from ATTR-CM and ATTR-PN to 
TTR-CM and TTR-FAP.
3) Protocol - extension of study duration to up to 
10 years or until subject has access to tafamidis 
for TTR-CM via prescription.  Upon regulatory 
approval for the treatment of TTR-CM in their 
respective country and access to prescription 
tafamidis, subjects may be withdrawn from the 
study.  The decision to withdraw subjects in a 
country will be done in consultation between the 
investigator and the sponsor.
4) Protocol – change of term “patient” to 
“subject”.
5) Protocol number – changed from Fx1B-303 to 
Fx1B-303/B3461026.
6) Protocol - Update of drug name: The 
compound “Fx-1006A” (research number) is 
“tafamidis meglumine” (20 mg soft gelatin 
capsule), thereafter referred to as simply, 
“tafamidis”.
7) Protocol - Change in chemical compound 
name: [N-methyl D-(2,3,4,5,6-pentahydroxy-
hexyl)-ammonium; 2-(3,5-dichloro-phenyl)-
benzoxazole-6-carboxylate].
Changed to: [d-glucitol, 1-deoxy-1-
(methylamino)-, 2-(3,5-dichlorophenyl)-6-
benzoxazolecarboxylate (1:1)].


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8) Renumbering of sections to align with standard 
Pfizer protocols:
Original 
section 
number
New section 
number
3.1
1.2
3.2
1.2.1
3.3
1.2.3
3.4
1.2.4
3.5
1.2.2
4
2.1
5.1
3 and 6
5.2
3.1
5.3
3.2
6.2
4.1
6.3
4.2
6.4
6.3
7.1
5.2.1
7.2
5.2.2
7.3
5.1
7.4
5.2.3
7.5
Removed
7.6
5.2.1
7.7
5.3
7.8
5.2.4
8, 8.1, 8.2, 
8.3
6.1
8.4
7.2
8.5
7.4
8.6
7.3
8.7
7.5
8.8
7.6
8.9
7.1
8.10
6.2.4
9
replaced
10 (10.1-
10.8)
9 (9.1-9.2.8)
11
Replaced 12
12
Replaced 15


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9) Schedule of activities – addition of allowable 
window for study visits. 
10) Section 1.1 Indication - Indication has been 
added.
11) Section 1 - Updated non-clinical and clinical 
summary information.
12) Section 1.2.3: Non-Clinical Experience 
- update of Clinical experience to reflect most 
current IB.
13) Section 1.2.4: Clinical Experience - update of 
Clinical experience to reflect most current IB.
14) Section 2.2: Endpoints - section added.
15) Section 3: Study design – abbreviated.
16) Section 4.1: Inclusion Criteria – Inclusion of 
evidence of a signed informed consent document 
added.
17) Section 4.2: Exclusion Criteria - Added 
exclusion: Pregnant females; breastfeeding 
females; females of childbearing potential.
18) Section 4.3.1: Contraception – added section 
to increase clarity.
19) Section 5.3 Drug Storage and Accountability 
- Updated storage conditions for investigational 
product.
20) Section 6: Study Procedures

Addition of possibility for alternative 
options for study visits added.

Sections 6.1, 6.2 added to increase clarity 
of required assessments and procedures to 
be performed at each telephone and clinic 
visit.


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This amendment incorporates all revisions to date, including amendments made at the 
request of country Health Authorities, IRB/ERB, etc.
21) Section 8: Adverse Event Reporting: Transfer 
of pharmacovigilance from ICON to Pfizer, Inc.  
Updated to include Pfizer requirements.
22) Section 9.6 Interim Analysis: Addition of 
interim analysis.
23) Sections 10, 11, 12, 13, 14, 15 – replace 
sections 11 and 12 from FoldRx protocol to 
reflect Pfizer requirements.
Original protocol
19 June 2009
N/A


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PROTOCOL SUMMARY
Indication:
Tafamidis is being developed for the treatment of transthyretin amyloidosis, specifically 
targeting TTR polyneuropathy and cardiomyopathy
Study Objectives:

To obtain additional, long-term, open-label safety and efficacy data for tafamidis in 
patients with transthyretin amyloid cardiomyopathy (TTR-CM).

To continue to provide the investigational product tafamidis to patients with TTR-CM 
who completed Protocol Fx1B-201.
Study Population:
Male and female patients with V122I or wild-type TTR-CM who have not undergone liver 
or heart transplantation and who completed Protocol Fx1B-201 (a Phase 2, open-label 
study to evaluate TTR stabilization, as well as the safety and tolerability of tafamidis). Up 
to 35 patients are anticipated.
Test Product, Dose, and Mode of Administration:
Tafamidis 20 mg soft gelatin capsule once daily (at the same time each day).
Duration of Treatment: Up to 10 years or until subject has access to tafamidis for TTR-
CM via prescription.  Upon regulatory approval for the treatment of TTR-CM in their 
respective country and access to prescription tafamidis, subjects may be withdrawn from 
the study.  Such subjects are considered study completers.  The decision to withdraw 
subjects to transition to commercial supply will be done in consultation between the 
investigator and the sponsor.
Clinical Endpoints:
Safety

Incidence of treatment-emergent adverse events;

Physical examinations;

Use of concomitant medications;

Electrocardiograms (ECGs);

Clinical safety laboratory tests;

Vital signs.
Efficacy

Patient Global Assessment;

New York Heart Association (NYHA) Classification;

6-Minute walk test;

Kansas City Cardiomyopathy Questionnaire (KCCQ);


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
Echocardiography;

Troponin I, troponin T, and amino-terminal B-type natriuretic peptide (NT-pro-BNP);

Mortality and hospitalization (all cause and cardiac-related).
Inclusion Criteria:

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.

Patient successfully completed Protocol Fx1B-201.

If female, patient is post-menopausal. If male, female partner is post-menopausal; or if 
female partner is of childbearing potential, then the patient is willing to use an 
acceptable method of birth control for the duration of the study and for at least three 
months after the last dose of study medication.

Patient is, in the opinion of the Investigator, willing and able to comply with the 
investigational product regimen and all other study requirements.
Exclusion Criteria:

Patient did not successfully complete Protocol Fx1B-201.

Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs 
(NSAIDs), defined as greater than 3 to 4 times/month. The following NSAIDs are 
allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethicin, ketoprofen, 
nabumetone, naproxen, nimesulide, piroxicam, and sulindac.

Patient has a clinically significant medical condition that, in the opinion of the 
Investigator, would place the patient at an increased risk to participate in the study.

Pregnant females; breastfeeding females; females of childbearing potential.

Patient has received a liver or heart transplant.
Study Design:
This is a Phase 3, open-label study designed to obtain additional long-term safety and 
efficacy data in patients who successfully completed Protocol Fx1B-201. These patients 
will be treated, with once daily 20 mg oral tafamidis (soft gelatin capsule) for up to 10 
years from the date of enrollment in Protocol Fx1B-303, or until subject has access to 
tafamidis for TTR-CM via prescription.  Upon regulatory approval for the treatment of 
TTR-CM in their respective country and access to prescription tafamidis, subjects may be 
withdrawn from the study.  The decision to withdraw subjects to transition to commercial 
supply will be done in consultation between the investigator and the sponsor.
Subjects who successfully complete Fx1B-201 will report to the clinical unit on Day 0 to 
sign the informed consent form and determine eligibility for Protocol Fx1B-303. In 
addition, on Day 0, subjects will have their entrance criteria reviewed, and medical 


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histories and demographic characteristics obtained.  The physical examination (including 
weight and vital signs) and the relevant end of study clinical laboratory tests (alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
gamma glutamyl transferase, creatinine, total bilirubin, international normalized ratio, 
troponin I, troponin T, and amino-terminal B-type natriuretic peptide) from Protocol Fx1B-
201 will be used for Protocol Fx1B-303. If more than 30 days has elapsed between the final 
study visit of Protocol Fx1B-201 and Day 0 of Protocol Fx1B-303, an abbreviated physical 
examination (including weight and vital signs) and clinical laboratory assessments must be
performed on Day 0.
Eligible subjects will begin once-daily dosing with 20 mg tafamidis at home on Day 1 (i.e., 
first dose) and will return to the clinical unit for study visits every 6 months.
Adverse events (AEs) and concomitant medication use will be collected at each 6-month 
visit to the clinical unit. Blood draws for clinical safety laboratory tests and abbreviated 
physical examinations (including weight and vital signs) will also be performed at each 6-
month clinic visit. ECGs will be performed every 12 months on an annual basis. A 
telephone call will be made at 3-month intervals between clinic visits to assess safety and 
use of concomitant medications.
For the evaluation of efficacy, the Patient Global Assessment, NYHA classification, 
KCCQ, 6-minute walk test, and efficacy-related clinical laboratory tests (serum levels of 
troponin T, troponin I, and NT-pro-BNP) will be determined every 6 months. In addition, 
echocardiograms will be performed every 12 months on an annual basis. 
An end of study visit including all safety and efficacy assessments will occur upon subject
completion of the study, premature withdrawal (for any reason), or in the event of program 
discontinuation by the Sponsor. 
Statistical Methods:
Safety and efficacy data will be summarized using descriptive statistics. For continuous 
variables, the means, standard deviations, medians, and ranges will be presented; for 
categorical variables, counts and percentages (with 95% confidence intervals) will be 
presented. Safety and efficacy data will also be shown in individual subject listings.
The cumulative efficacy data (starting from Protocol Fx1B-201) as measured by the Patient 
Global Assessment, NYHA classification, KCCQ, 6-minute walk test, echocardiograms, 
and serum levels of troponin I, troponin T, and NT-pro-BNP will be presented.
The endpoints of mortality and hospitalization (all cause and cardiac-related) will be 
analyzed individually and as composite measures. A Kaplan-Meier plot of time to event 
from the baseline of Protocol Fx1B-201 will be generated, and the event rate and 
associated 95% confidence intervals will be presented at 1, 2, 3, and 4 year intervals since 
the start of the investigational drug. The baseline data from protocol Fx1B-201 will be 
used as baseline for the analyses. Interim analyses will be performed during the course of 
the study to allow for the reporting of safety and efficacy data from the ongoing study.


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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 (Section 6) and Assessments (Section 7) for detailed information 
on each procedure and assessment required for compliance with the protocol.   
Procedure/Evaluation 
End of study 
visit from 
Fx1B-201 
and/or Day 0
(baseline)
Open-label Investigational Product 
End of 
Study 
Visita
Day 1
Telephone 
(every 3 months 
between clinic 
visits)
Clinic Visit 
(every 6 
months)
±1 week
±1 week
±2 week
±2 week
Informed consent 
X
Inclusion/exclusion criteria 
X
Demographics 
X
Medical history
X
Complete physical examination 
X
Abbreviated physical 
examination
Xb
X
Blood/urine sample for 
laboratory testingg
Xh
X
X
Enrollment 
X
First dose of tafamidis 
Xd
Patient Global Assessment
X
X
NYHA Classification
X
X
KCCQ
X
X
6-Minute walk test 
X
X
Echocardiogram 
Annuallye
Xf
Electrocardiogram 
Annuallye
Xf
Adverse events 
X
X
X
X
Concomitant medication 
X
X
X
X
Tafamidis compliance and 
accountability  
X
Dispense tafamidisc
X
X
X
a
An end of study visit will occur upon subject completion of study, subject withdrawal (for any reason), or study
discontinuation by the Sponsor. 
b
The physical examination (including weight and vital signs) results from the end of study visit from Protocol Fx1B-201 
will be used for Day 0 of Protocol Fx1B-303. If more than 30 days has elapsed, then a brief physical examination must 
be performed on Day 0. 
c
Subjects will be given a 3-month supply of investigational product on Day 0. Subjects will return to the clinical unit 
every 6 months and will receive a 3-month supply of investigational product. At 3-month intervals between clinic 
visits, 3-month supplies of investigational product will be mailed directly to subjects from the clinical site. 
d
Subjects will self-administer study medication at home beginning on Day 1. 
e
Echocardiograms and ECGs will be performed on an annual basis (every 12 months). 
f
Echocardiograms and ECGs will be performed only if the previous assessments occurred more than six months prior to 
the end of study visit. 
g
Laboratory tests listed in Section 7.3.
h
Clinical laboratory test results from the end of study visit from Protocol Fx1B-201 will be used for Day 0 of Protocol 
Fx1B-303. If more than 30 days has elapsed, then clinical laboratory tests must be performed on Day 0.


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TABLE OF CONTENTS
LIST OF TABLES.........................................................................................................................13
1. INTRODUCTION .....................................................................................................................16
1.1. Indication.......................................................................................................................16
1.2. Background and Rationale ............................................................................................16
1.2.1. Tafamidis for the Treatment of TTR ................................................................18
1.2.2. Study Rationale.................................................................................................18
1.2.3. Non-Clinical Experience with Tafamidis.........................................................19
1.2.4. Tafamidis Clinical Experience .........................................................................21
2. STUDY OBJECTIVES AND ENDPOINTS.............................................................................26
2.1. Objectives......................................................................................................................26
2.2. Endpoints.......................................................................................................................26
3. STUDY DESIGN.......................................................................................................................27
3.1. Rationale for Study Design and Control Group............................................................27
3.2. Study Duration and Dates .............................................................................................27
4. SUBJECT SELECTION............................................................................................................27
4.1. Inclusion Criteria...........................................................................................................27
4.2. Exclusion Criteria..........................................................................................................28
4.3. Life Style Guidelines.....................................................................................................28
4.3.1. Contraception....................................................................................................28
5. STUDY TREATMENTS...........................................................................................................29
5.1. Allocation to Treatment ................................................................................................29
5.2. Drug Supplies................................................................................................................29
5.2.1. Formulation and Packaging..............................................................................29
5.2.2. Preparation and Dispensing..............................................................................29
5.2.3. Administration..................................................................................................30
5.2.4. Compliance.......................................................................................................30
5.3. Drug Storage and Drug Accountability.........................................................................30
5.4. Concomitant Medication(s)...........................................................................................31
6. STUDY PROCEDURES ...........................................................................................................31
6.1. Screening/Baseline Assessment ....................................................................................31


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6.2. Study Period ..................................................................................................................32
6.2.1. Months 3, 9, 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, 99, 
105, 111, 117................................................................................................32
6.2.2. Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 
102, 108, 114................................................................................................32
6.2.3. Months 12, 24, 36, 48, 60, 72, 84, 96, 108.......................................................33
6.2.4. End of Study Visit ............................................................................................33
6.3. Subject Withdrawal.......................................................................................................34
7. ASSESSMENTS........................................................................................................................35
7.1. Efficacy Assessments....................................................................................................35
7.2. Physical Examinations and Vital Signs.........................................................................36
7.3. Clinical Laboratory Tests..............................................................................................37
7.4. Electrocardiograms........................................................................................................38
7.5. Adverse Events..............................................................................................................38
7.6. Concomitant Medications .............................................................................................38
8. ADVERSE EVENT REPORTING............................................................................................38
8.1. Adverse Events..............................................................................................................38
8.2. Reporting Period ...........................................................................................................39
8.3. Definition of an Adverse Event.....................................................................................39
8.4. Abnormal Test Findings................................................................................................40
8.5. Serious Adverse Events.................................................................................................40
8.5.1. Potential Cases of Drug-Induced Liver Injury..................................................41
8.6. Hospitalization ..............................................................................................................42
8.7. Severity Assessment......................................................................................................43
8.8. Causality Assessment....................................................................................................43
8.9. Exposure During Pregnancy..........................................................................................44
8.10. Withdrawal Due to Adverse Events (See Also Section 6.3 Subject 
Withdrawal)................................................................................................................45
8.11. Eliciting Adverse Event Information ..........................................................................45
8.12. Reporting Requirements..............................................................................................45
8.12.1. Serious Adverse Event Reporting Requirements ...........................................45
8.12.2. Non-Serious Adverse Event Reporting Requirements ...................................46


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8.12.3. Sponsor Reporting Requirements to Regulatory Authorities .........................46
9. DATA ANALYSIS/STATISTICAL METHODS.....................................................................46
9.1. Sample Size Determination...........................................................................................46
9.2. Efficacy Analysis ..........................................................................................................46
9.2.1. Analysis of Primary Endpoint ..........................................................................46
9.2.2. Patient Global Assessment ...............................................................................47
9.2.3. New York Heart Association Classification.....................................................47
9.2.4. Kansas City Cardiomyopathy Questionnaire....................................................47
9.2.5. Six-minute Walk Test.......................................................................................47
9.2.6. Echocardiogram................................................................................................48
9.2.7. Troponin I, Troponin T, and NT-pro-BNP.......................................................48
9.2.8. Mortality and Hospitalization...........................................................................48
9.3. Analysis of Other Endpoints .........................................................................................49
9.3.1. Demographics and Baseline Characteristics.....................................................49
9.3.2. Physical Examination and Vital Signs..............................................................49
9.4. Concomitant Medication Usage....................................................................................49
9.5. Safety Analysis..............................................................................................................49
9.6. Interim Analysis ............................................................................................................49
9.7. Data Monitoring Committee .........................................................................................49
10. QUALITY CONTROL AND QUALITY ASSURANCE.......................................................49
11. DATA HANDLING AND RECORD KEEPING ...................................................................50
11.1. Case Report Forms/Electronic Data Record ...............................................................50
11.2. Record Retention.........................................................................................................50
12. ETHICS....................................................................................................................................51
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................51
12.2. Ethical Conduct of the Study ......................................................................................51
12.3. Subject Information and Consent................................................................................51
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP.............................................................................................................................52
13. DEFINITION OF END OF TRIAL.........................................................................................52
14. SPONSOR DISCONTINUATION CRITERIA ......................................................................52
15. PUBLICATION OF STUDY RESULTS................................................................................53


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15.1. Communication of Results by Pfizer ..........................................................................53
15.2. Publications by Investigators ......................................................................................53
16. REFERENCES ........................................................................................................................55
LIST OF TABLES
Table 1.
Summary of Most Common (≥5% in Tafamidis Treatment Group) 
Treatment-Emergent Adverse Events Sorted in Descending Incidence in 
the Overall Tafamidis Group – TTR-FAP Patients, Study Fx-005 (Safety 
Population)..................................................................................................................24
Table 2.
Summary of Adverse Drug Reactions ........................................................................25
APPENDICES
Appendix 1. Patient Global Assessment........................................................................................57
Appendix 2. New York Heart Association Classification .............................................................58
Appendix 3. Kansas City Cardiomyopathy Questionnaire............................................................59


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ABBREVIATIONS
Abbreviation
Definition
ADME
absorption, distribution, metabolism, excretion
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
Asp38Ala
aspartate replaced by alanine at position 38
AST
aspartate aminotransferase
ATTR
TTR amyloidosis
ATTR-CM
Transthyretin amyloid cardiomyopathy
ATTR-PN
Transthyretin amyloid polyneuropathy
AUC
area under the concentration-time curve
BUN
blood urea nitrogen
C
Celsius
cm
centimeter
Cmax
maximum plasma concentration
CRF
case report form
dL
deciliter
DMC
Data Monitoring Committee
EC
Ethics Committee
GCP
good clinical practice
GGT
gamma glutamyl transferase
Gly47Ala
glycine replaced by alanine at position 47
ICH
International Conference on Harmonisation
Ile107Val
isoleucine replaced by valine at position 107
IND
investigational new drug
INR
international normalized ratio
IRB
Institutional Review Board
KCCQ
Kansas City Cardiomyopathy Questionnaire
kg
kilogram
Leu58His
leucine replaced by histidine at position 58
mg
milligram
mL
milliliter
MRI
magnetic resonance imaging
NIS
Neuropathy Impairment Score
NIS-LL
Neuropathy Impairment Score – Lower Limb
nM
nanomolar
NOAEL
no observable adverse effect level
Norfolk QOL-DN
Norfolk Quality of Life-Diabetic Neuropathy 
NSAID
non-steroidal anti-inflammatory drug
NT-pro-BNP
Amino-terminal B-type natriuretic peptide
NYHA
New York Heart Association
PD
pharmacodynamic


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Abbreviation
Definition
Phe64Leu
phenylalanine replaced by leucine at position 64
PK
pharmacokinetic
SAE
serious adverse event
Ser77Phe
serine replaced by phenylalanine at position 77
Ser77Tyr
serine replaced by tyrosine at position 77
Thr60Ala
threonine replaced by alanine at position 60
TRACS
Transthyretin Amyloidosis Cardiac Study
TTR
transthyretin
TTR-CM
Transthyretin Cardiomyopathy
TTR-FAP
Transthyretin Familial Polyneuropathy
V122I
valine replaced by isoleucine at position 122
V30M
valine replaced by methionine at position 30
Val122Ile
valine replaced by isoleucine at position 122


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1. INTRODUCTION
1.1. Indication
Tafamidis is being developed for the treatment of transthyretin amyloidosis, specifically 
targeting ATTR polyneuropathy and cardiomyopathy.  This protocol will be specific for the 
ATTR cardiomyopathy (TTR-CM) indication.
1.2. Background and Rationale
Transthyretin amyloidosis (ATTR) is a disease induced by accumulation of insoluble fibrillar 
protein as amyloid in the tissues in amounts sufficient to impair normal function.  The major 
phenotypic presentations are a sensorimotor and autonomic neuropathy (ATTR with 
polyneuropathy, or TTR-FAP) and restrictive cardiomyopathy (ATTR with cardiomyopathy, 
or TTR-CM). Transthyretin, a 127-amino acid, 55 kDa protein, primarily synthesized in the 
liver, is a secreted protein present in the blood and cerebrospinal fluid and is a carrier of 
thyroxine and retinol-binding protein-retinol (vitamin A) complex [1, 2]. In its native state, 
TTR exists as a homotetramer with two C2 symmetric funnel-shaped thyroxine binding sites 
located at the central dimer-dimer interface [3, 4, 5].
Natural amino acid sequence (wild-type) TTR and mutated variants of TTR can be involved 
in amyloid disease. However, mutated TTR species are more prone to accelerated 
fibrillogenesis, the most important risk factor for TTR amyloidosis [1, 2]. There are more 
than 80 TTR point mutations that have been associated with TTR amyloidosis [6]. All 
disease-associated mutations characterized thus far destabilize the TTR tetramer and many 
influence the velocity of rate-limiting tetramer dissociation [7]. An amyloidogenic mutation 
or aging can lead to tetramer dissociation into an alternatively folded monomeric 
amyloidogenic intermediate. This intermediate self-assembles into profilaments, filaments, 
and, under certain conditions, amyloid fibrils [8, 9]. In fact, the rate determining step for 
TTR amyloid formation is tetramer dissociation [10].
Cardiac involvement in ATTR, also known as familial amyloid cardiomyopathy when 
associated with variant TTR, or senile systemic amyloidosis (SSA) when associated with 
wild-type TTR, is associated with amyloid fibril infiltration of the myocardium, leading to 
diastolic dysfunction progressing to restrictive cardiomyopathy and congestive heart failure 
[3]. ATTR-CM is a late-onset disease with symptoms typically occurring in patients over 
60 years of age. Although there are approximately 24 mutations associated with specific 
cardiac involvement, one common mutation, V122I (substitution of isoleucine for valine at 
position 122), has been reported with high frequency (prevalence of 3.4% to 3.9% [2]) in 
African-Americans. In an autopsy series, African Americans older than 60 years of age were 
found to be at greater risk of TTR amyloid cardiac deposits compared with Caucasians or 
Hispanics (1.6% vs. 0.4 and 0.13 respectively) [11]. In addition, 23% of the African 
American patients with TTR cardiac amyloidosis with evaluable DNA samples were 
heterozygous with the V122I mutation. Finally, all patients found to be V122I heterozygous 
had evidence of TTR cardiac amyloid on autopsy. These data confirm the association of the 
V122I TTR mutation with TTR amyloid cardiomyopathy and suggest a high clinical 
penetrance [11].


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A mutation in TTR is not a pre-requisite for developing ATTR-CM. In the elderly, wild-type 
(normal) TTR may become structurally unstable resulting in deposition of amyloid fibrils 
primarily in heart tissue and leading to diastolic dysfunction, restrictive cardiomyopathy, and 
congestive heart failure [4, 5, 6, 7]. The frequency of TTR amyloid deposition in cardiac 
ventricles reported from autopsy studies in patients >80 years of age range from 1.8% [12] to 
16.5% [13], with a rate of clinical cardiac disease pre-mortem of 34% [13].
For both wild-type and variant ATTR-CM, TTR amyloid fibrils are deposited in the 
myocardial interstitium, causing an increase in ventricular wall thickness, inducing 
myocardial damage and affecting myocardial function. Clinical symptoms include dyspnea 
on exertion, shortness of breath, orthostatic hypotension, syncope, and atrial fibrillation. 
Electrocardiogram findings demonstrate low voltage [14], particularly in light of the 
markedly thickened ventricular walls (median wall thickness of 17 mm [14]) demonstrated 
by echocardiogram. Amino-terminal B-type natriuretic peptide (NT-Pro-BNP), a serum 
marker of cardiac wall stress, is elevated in this population [15].
Current treatment is symptomatic, with careful fluid management and management of 
arrhythmias the mainstay. Median survival is approximately 60 months [14, 15], with 
42% of patients dying from a cardiac cause [16]. Combined heart and liver transplantation is 
a current treatment option, however limited organ availability and significant patient co-
morbidity limit transplant as a treatment option.
The natural history of TTR-CM was studied in the Transthyretin Amyloidosis Cardiac Study 
(TRACS), in a cohort of patients followed longitudinally for 24 months. Using a variety of 
cardiovascular monitoring examinations (e.g., electrocardiograms [ECG], echocardiography, 
cardiac magnetic resonance imaging [MRI], exercise tolerance testing), the study evaluated 
how the disease affects patients over time. This information will be utilized in two ways: 
(1) to better define the natural course of the disease; and (2) more importantly, to better 
understand how to measure the effectiveness of future treatments by identifying endpoints 
that are well-correlated with disease progression/regression and to support the selection of 
endpoints to be used in clinical trials.
Data on 29 patients (mean age 74 years) have been analyzed (18 wild-type and 11 V122I). 
Most patients are male (92%) and are New York Heart Association (NYHA) 
Classification I or II with significant cardiac symptoms reported at baseline. After an 
average follow-up time of 16 months, 11 patients died and one patient underwent cardiac 
transplant, giving the proportion of death/cardiac death of 41%, and a death rate per patient 
month exposure of 0.03. In addition, 41% of the patients experienced a cardiac 
hospitalization at least once, and 55% of the patients died or had a cardiac hospitalization. 
Preliminary analysis of cardiac assessments demonstrate significantly elevated NT-Pro-BNP 
and troponin levels, abnormal functional status as assessed by the 6-minute walk test, and 
significant diastolic dysfunction and thickened ventricles as assessed by echocardiography 
and cardiac MRI.


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1.2.1. Tafamidis for the Treatment of TTR
Pfizer Inc is currently investigating tafamidis for the treatment of TTR-CM. Tafamidis
meglumine [d-glucitol, 1-deoxy-1-(methylamino)-, 2-(3,5-dichlorophenyl)-6-
benzoxazolecarboxylate (1:1)] is the meglumine salt form of 
2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid and is a novel, small molecule 
stabilizer of transthyretin. Specifically, tafamidis exhibits negative cooperative binding (i.e., 
dissociation constants of 2 nM [Kd1] and 154 nM [Kd2], respectively) to the two thyroxine 
binding sites on the native tetrameric form of TTR and thereby prevents its dissociation into 
monomers. At low pH, fibril formation of wild-type TTR and the most prevalent 
amyloidogenic variants, V30M and V122I, is potently inhibited by tafamidis. No fibril 
formation is observed for wild-type, V30M, and V122I variants at a 2:1 tafamidis:TTR 
stoichiometry. Under urea denaturating conditions, only 33% of TTR tetramer dissociates 
after incubation for 72 hours with equimolar quantity of tafamidis, when negligible tetramer 
dissociation is observed at a 2:1 tafamidis:TTR stoichiometry. Based on these data, it 
appears that a 1:1 tafamidis:TTR stoichiometry should be sufficient to stabilize TTR. The 
normal range of TTR level is between 18 and 38 mg/dL, corresponding to 3.2 to 6.8 M of 
TTR. Therefore, plasma levels of 3.6 to 7.2 M (~1-2 g/mL) of tafamidis should stabilize 
TTR levels at least to the upper limit of the normal range.
In vitro addition of tafamidis to human plasma stabilizes wild-type, V30M, and V122I 
tetrameric TTR under strong urea denaturing conditions for at least four days. Under these 
same conditions most of the TTR is denatured in two days in the absence of stabilizer. 
Stabilization is observed at tafamidis concentrations between 3.6 and 7.2 M for TTR plasma 
levels ranging from low (15.5 mg/dL [2.8 M]) to high (28 mg/dL [5 M]), confirming the 
effective therapeutic plasma level range between 3.6 and 7.2 M (corresponding to 
~1-2 g/mL concentration of tafamidis in plasma). Ex-vivo results with plasma samples 
from initial Phase 1 clinical testing confirm this hypothesis and indicate that drug plasma 
levels between 0.7 to 1.7 g/mL stabilize plasma TTR (when TTR plasma levels are between 
16 and 36 mg/dL) after once a day dosing with tafamidis. Based on Phase 1 results, this drug 
level range would be achieved at steady-state after once-daily 20 mg (soft gelatin capsule), 
the tafamidis dose chosen for clinical evaluation.
1.2.2. Study Rationale
The initial development activities for tafamidis were undertaken in patients with TTR-FAP.
Safety data in this population, and the results from the TRACS study, led to the initiation of 
Protocol Fx1B-201, a 12-month trial of tafamidis in patients with TTR-CM. The results of 
the Fx1B-201 study will be used in the design of a Phase 3 program that will evaluate the 
efficacy and safety of tafamidis in TTR-CM.
TTR-CM is a slowly progressing disease with a median survival of approximately 60 months 
[14, 15].  It is currently not known whether tafamidis will be effective in slowing or halting 
the progression of TTR amyloid cardiomyopathy, or when such an impact would become 
evident. Therefore, the purpose of the current study is to assess the long-term safety and 


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efficacy of tafamidis in patients with ATTR-CM. Eligible patients who successfully 
completed Protocol Fx1B-201, having received open-label tafamidis for 12 months, may 
enroll in Protocol Fx1B-303 and continue to receive open-label tafamidis for up to an 
additional 10 years.
1.2.3. Non-Clinical Experience with Tafamidis
Nonclinical pharmacology, pharmacokinetic (absorption, distribution, metabolism, and 
excretion; ADME), and toxicology studies conducted both in vitro and in vivo in the mouse, 
rat, rabbit, and dog have been completed.  In vitro nonclinical studies have confirmed that the 
pharmacological activity of tafamidis is consistent with its high affinity binding to the two 
thyroxine binding sites of TTR in a non-cooperative manner and the resulting stabilization of 
TTR (wild type and amyloidogenic variants) by preventing dissociation of tetramers into 
monomers.
The general safety pharmacology profile of tafamidis demonstrated minimal nonselective 
binding to enzymes or ion channels, with no potential for anti-inflammatory activity.  
Tafamidis had minimal effects on either the central nervous system or cardiopulmonary
physiology parameters in dogs. Tafamidis did not demonstrate the potential for QT 
prolongation. QTc shortening, observed at doses of 100 and 300 mg/kg, was associated with 
total plasma concentrations that exceeded 90 µg/mL. However, mean human steady-state 
maximum concentration (Cmax) values following the daily therapeutic dose of 20 mg in 
elderly and nonelderly subjects were 2.8 and 2.3 µg/mL respectively. Given the 30 to 
40-fold difference in exposures, it is felt that the nonclinical observations have little 
relevance to the clinical profile of tafamidis.
Predictable pharmacokinetic behavior of tafamidis was demonstrated following oral 
administration in the nonclinical species. Tafamidis was absorbed following oral 
administration with an absolute bioavailability >90% and exhibited dose proportional 
increases in Cmax and AUC at dose up to 30 mg/kg, but further increases in the administered 
dose provided less than proportional increases in systemic exposure, indicating saturation in 
the drug absorption. Terminal plasma half life is about 40 hours following a single 
administration. Drug accumulation has been confirmed in repeated dose studies.
Tafamidis is readily absorbed through the intestinal wall upon administration and is bound to 
a high extent to plasma proteins (>97%), essentially TTR and albumin. Tafamidis distributes 
widely in tissues (maternal and fetal), crosses the placental barrier to an extent of less than 
5% of the initial dose, and ~ 30% of the dam’s dose transferred into the milk.
Tafamidis demonstrated a high degree of metabolic stability and its limited biotransformation 
resulted in the formation of a monoglucuronide (acylglucuronide) as the primary metabolite 
in most of the nonclinical species and humans, while a monooxidative product was only 
detected in the mouse and rabbit.  In rats, tafamidis is cleared primarily via biliary excretion 
and fecal elimination with some enterohepatic circulation, with a smaller contribution by the 
urine.  A human ADME study suggests similar pathways are operative in humans.


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Tafamidis meglumine has been evaluated in vitro to assess protein binding, induction and 
inhibition of cytochrome P450 enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5), and 
inhibition of transporter protein P glycoprotein (P gp), with results suggesting very low 
likelihood for clinical drug-drug interactions.  No significant CYP 450 inhibition was 
observed.  A series of nonclinical toxicity studies were conducted in mice, rats, and dogs to 
assess the safety of tafamidis. The absence of acute toxicity following a single dose of 
tafamidis up to 600 mg/kg in dogs is indicative of a low risk for overdose.  Tafamidis was 
well tolerated following repeated daily oral administration up to 26 weeks in rats and 
39 weeks in dogs. The NOAEL was determined to be 30 mg/kg/day in the rat and 
45 mg/kg/day in dog. When doses were increased above the NOAELs, rodents had a drug 
accumulation in their stomachs while dogs vomited. Other signs of toxicity accompanied 
these obvious signs, including decreased food intake, modified feces, stress related signs, 
increase in liver weight and in liver enzyme levels, lymphoid depletion, and kidney lesions in 
rodents. 
Tafamidis was nongenotoxic in a battery of in vitro studies, although a slight increase in 
frequency of polyploid cells was observed at 100 and 200 µg/mL in the presence of 
S9 activation but not without metabolic activation in the in vitro chromosome aberration 
assay using human peripheral lymphocytes. Polyploidy is not considered to be a reliable 
surrogate marker for aneugenicity.  The lack of risk for aneuploidy induction with tafamidis 
was further evidenced by the lack of micronucleus induction in the bone marrow of 
Sprague-Dawley rats at the doses producing Cmax and AUC values significantly exceeding 
the predicted clinical exposures (~ 72X over the Cmax and ~ 67X over the steady state 
AUC(0-24) observed in humans, based on exposure in a 4-week rat study). The evaluation of 
the carcinogenic potential in hemizygous Tg.rasH2 mice did not demonstrate an increase in 
the incidence of neoplasia.
Tafamidis did not demonstrate any effects on fertility, general reproductive performance and 
early embryo-fetal development in the rat and the maternal and paternal NOEL for 
reproductive toxicity was determined to be greater than 30 mg/kg/day. Developmental 
toxicity was evident in the rat by reduced fetal weights in the 30 and 45 mg/kg/day maternal 
dosage groups (developmental NOAEL = 15 mg/kg). Developmental toxicity in the rabbit 
was demonstrated by increased post-implantation loss, reduced fetal body weight and 
associated skeletal variations, and malformation at 8 mg/kg and skeletal variations at 
2 mg/kg/day. The NOEL for developmental toxicity in rabbits was 0.5 mg/kg/day.
Tafamidis-related toxicity in the developmental and perinatal/postnatal reproduction toxicity 
study in rats resulted in a NOAEL for reproductive toxicity and for viability and growth of 
the F1 generation of 5 mg/kg/day. Women of child-bearing potential should take measures 
to prevent pregnancy while being treated with tafamidis.
Non-clinical data indicate that there is a large safety margin above the anticipated human 
efficacious plasma concentration and those concentrations associated with toxicity in rats or 
dogs. Emesis was the most common form of clinical intolerance in the dog. Owing to the 
dosing strategy, the immediate emetic activity led to apparent aspiration of gastric contents 
and/or drug, leading to moribundity and subsequent euthanasia. The gastric impaction and 


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subsequent delayed gastric emptying, presumably followed by circulatory distress, shock and 
multiorgan failure, in rats was caused by a supraclinical dosing regimen and is not a relevant 
risk to human subjects. While the exact mechanism(s) for the toxicities observed following 
the oral administration of tafamidis has not been elucidated, there is an ample therapeutic 
margin to permit safe exposure to humans and there was no toxicity identified that would 
preclude human use, such as undetectable lesions or irreversible damage.
No target organs of tafamidis-related toxicity were identified in the repeated dose toxicity 
studies conducted in rats or dogs (26 weeks and 39 weeks, respectively). However, in the 
CByB6F1 hybrid mouse and the tg.rasH2 mouse, the liver and/or kidney have been identified 
as target organs as non-neoplastic lesions were noted following treatment for 28 days 
(CByB6F1 hybrid mouse) or 26 weeks (tg.rasH2 mouse). Nephrosis was the primary lesion 
noted in the kidneys, only in male mice and in a dose-dependent manner. In the liver, 
centrilobular hypertrophy and scattered single cell necrosis were present in male mice more 
than in the female mice in terms of the incidence of both lesions and the severity of the 
centrilobular hypertrophy. The incidence of both liver lesions was dose dependent.
However, the mouse (CByB6F1) did not demonstrate a unique monooxide metabolite that 
was not present in the rat or dog, nor has it been detected in the plasma of humans 
administered tafamidis.  However, a causal relationship between the monoxide metabolite 
and the liver and/or kidney lesions has not been established.
Generally, there were no significant toxicities observed in the repeated dose toxicology 
studies in the rat and dog. Therefore, tafamidis was considered to be well tolerated in the rat 
at dose levels up to 30 mg/kg/day for 26 weeks, providing an exposure ratio of 45- to 63-fold 
based on the human AUC at steady state, and in the dog at dose levels up to 45 mg/kg/day for 
39 weeks providing an exposure ratio of 29- to 36-fold based on the human AUC at steady 
state.  Additionally, there was no evidence for an increased risk of neoplasia at exposures at 
least 31-fold the human AUC nor was there evidence of any tafamidis-related genotoxicity.
With the exception of the reproductive developmental toxicity findings, tafamidis has an 
excellent nonclinical safety profile.
Refer to the Tafamidis Investigator Brochure for further details.
1.2.4. Tafamidis Clinical Experience
The clinical development program for tafamidis has included 13 controlled and uncontrolled 
clinical trials and two non-interventional, observational studies completed primarily in 
patients with TTR-FAP.  As of 13 May 2011, patients with TTR-FAP (n=127) received 
20 mg of tafamidis administered daily for an average of 538 days (range of 15 to 994 days) 
or approximately 187 patient-years. The mean duration of exposure was 17.7 months: 
87 were treated for at least 1 year, 43 were treated for at least 2 years, and 31 were treated for 
at least 30-<36 months.  
The tafamidis 20 mg soft gelatin capsule (as used in the clinical studies) demonstrated a 
half-life average of 59 hours and Cavg(SS) average of 2.07 μg/mL (SD=0.20). The tafamidis 
20-mg soft gelatin capsule daily dose resulted in an average fluctuation (peak to trough) of 


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51.8%, with an average minimum concentration (Cmin) of 1.61 μg/mL and an average Cmax of 
2.66 μg/mL. The average range was consistent with the 1 to 2 µg/mL required to stabilize 
TTR levels beyond the upper limit of the normal range; steady state was attained within 
12 days, and exposure was consistent across subjects, with low variability across subjects for 
key PK parameters.  Note that steady-state exposure was similar between males and females.  
Therefore, the 20 mg daily dose has been used in the development program.  Further, based 
on a population PK analysis, no dose adjustment is necessary for the elderly or patients with 
hepatic or renal impairment. 
The primary purpose of a therapy such as tafamidis is to stabilize the TTR tetramer, thus 
inhibiting the amyloid cascade and ultimately halting or slowing TTR-FAP disease 
progression over a sustained period of time.  During the 18-month period of intervention in 
Study Fx-005, tafamidis slowed the course of neurological impairment and maintained 
quality of life in treated patients. Together, with the extension Study Fx-006 data, tafamidis 
demonstrated a sustained effect over 30 months, a period of time representing approximately 
25% of the average TTR-FAPPN disease duration of 10 years. Further, Study Fx1A-201 was 
a small Phase 2II open label, single-treatment arm study designed primarily to determine the 
efficacy of tafamidis in stabilizing TTR variants other than the V30M (valine replaced by 
methionine at position 30) mutation. The results from this study of non-V30M TTR-FAP
patients, which represented an older, more severely affected patient population, strongly 
supported the observed efficacy of tafamidis in V30M patients.  As in Study Fx-005, the 
consistency of response across endpoints measuring different aspects of this multi-faceted 
disease was again observed following 12 months treatment with tafamidis.  The results 
indicated the disease-modifying utility of tafamidis in treating all patients with TTR-FAPPN, 
regardless of mutation. 
Study Fx1B-201 was a small Phase 2 study in TTR-CM in which a total of 35 patients were 
enrolled and analyzed, 31 patients with wild-type genotype and 4 with V122I genotype.  As 
expected, the patients were elderly (mean age approximately 76 years), with significant 
disease duration (approximately 8 years) and signs and symptoms of mild to moderate 
cardiac dysfunction (84% with NYHA Class I or II) at the time of enrollment.
Tafamidis effectively stabilized TTR in 34 of 35 (97.1%) patients, representing both 
wild-type and V122I, at Week 6, with approximately 88% stabilized throughout the 
12 months.
Following 12 months treatment with tafamidis, along with routine standard of care, 
2/35 (5.7%) patients died, 9/35 (25.7%) experienced at least one cardiovascular 
hospitalization, and 9/35 (25.7%) experienced the composite endpoint of death or 
cardiovascular hospitalization.  Results were similar between the TTR genotype groups.  
These data were numerically better than that reported in the TRACS historical control cohort, 
during which the 12-month rate of death, cardiovascular hospitalizations and 
death/cardiovascular hospitalizations were 6/29 (20.7%), 10/29 (34.5%) and 13/29 (44.8%), 
respectively.


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Cardiac biomarkers (NT-proBNP, troponin I and T) at baseline were elevated, which was not 
unexpected given the patients’ underlying cardiac involvement.  The change in NT-proBNP 
over 12 months was relatively small, and numerically lower than that observed in TRACS.  
Troponin I and T, more specific markers of cardiac necrosis, remained stable, 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 6MWT.  At 
12 months, 75% of the patients had improved or preserved NYHA classification, with the 
overall population demonstrating minimal change in distance walked (-11 meters).  This 
maintained functional walking capacity is in contrast to the deterioration observed in TRACS 
at 12 months (-44 meters).
Non-invasive cardiac assessments demonstrated significant cardiac involvement at baseline, 
with substantial ventricular wall thickening (echocardiography and cardiac MRI) and 
elevated intra-cardiac filling pressures (echocardiography).  There were no consistent 
clinically relevant changes in these parameters over time (echocardiography).  For the 
wild-type patients (the majority of patients in the study), the deterioration in ejection fraction 
(-3.9) and stroke volume (-8.0) observed in the current study was less than that observed in 
TRACS (-10.5 and -15.4, respectively) at 12 months.  Similar findings were observed in a 
subset of patients that underwent cardiac MRI.  An additional finding in cardiac MRI was a 
decrease in percent of left ventricle (LV) mass with amyloid observed at 12 months in the 
small subgroup of patients undergoing this assessment, 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 as demonstrated by improved 
heart rate variability indices.
Over the 12 months of tafamidis treatment, the patients’ quality of life was maintained as was 
their functional status, as assessed by the SF-36, and KCCQ and PGA, respectively. The 
majority of these results were also better when compared with TRACS. 
Seven patients participated in both TRACS (median follow up 12.5 months, with range of 
6-26 months) and in Study Fx1B-201. All seven patients completed 12 months of treatment 
with tafamidis. However, given the small number of patients, 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 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. 
Overall, tafamidis was effective in achieving and maintaining TTR stabilization in both 
wild-type and V122I patients and showed an apparent stabilization of the progression of 
cardiac disease.


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The safety data described reflect exposure of 127 TTR-FAP patients to 20 mg of tafamidis 
administered daily for an average of 538 days (ranging from 15 to 994 days).  The population 
was composed of adult patients diagnosed with symptomatic TTR-FAP, with a mean age of 
approximately 44 years; approximately half of the patients were female, and approximately 
90% of the patients were Caucasian. Note that primary evidence of safety and efficacy was 
obtained from a placebo-controlled 18-month study in patients with TTR-FAP.  
Table 1 provides a summary of the most common treatment emergent adverse events 
(TEAEs) (≥5% in tafamidis treatment group) during study Study Fx-005. 
Table 1.
Summary of Most Common (≥5% in Tafamidis Treatment Group) 
Treatment-Emergent Adverse Events Sorted in Descending Incidence in the 
Overall Tafamidis Group – TTR-FAP Patients, Study Fx-005 (Safety 
Population)
Number (%) of Subjects 
MedDRA Preferred Term 
Tafamidis 20 mg N=65 
Placebo N=63 
Number of patients with at least 1 AE 
60 (92.3) 
61 (96.8) 
Diarrhea 
17 (26.2) 
11 (17.5) 
Urinary tract infection 
15 (23.1) 
8 (12.7) 
Pain in extremity 
11 (16.9) 
6 (9.5) 
Headache 
10 (15.4) 
12 (19.0) 
Influenza 
10 (15.4) 
9 (14.3) 
Nasopharyngitis 
9 (13.8) 
8 (12.7) 
Upper abdominal pain 
8 (12.3) 
2 (3.2) 
Nausea 
8 (12.3) 
8 (12.7) 
Vomiting
7 (10.8) 
8 (12.7) 
Lacrimation decreased 
6 (9.2) 
7 (11.1) 
Back pain 
5 (7.7) 
4 (6.3) 
Myalgia 
5 (7.7) 
2 (3.2) 
Punctate keratits 
5 (7.7) 
3 (4.8) 
Anxiety 
4 (6.2) 
3 (4.8) 
Constipation 
4 (6.2) 
7 (11.1) 
Depression 
4 (6.2) 
3 (4.8) 
Erectile dysfunction 
4 (6.2) 
4 (6.3) 
Peripheral edema 
4 (6.2) 
8 (12.7) 
Pharyngitis 
4 (6.2) 
5 (7.9) 
Thermal burn 
4 (6.2) 
5 (7.9) 
Upper respiratory tract infection 
4 (6.2) 
3 (4.8) 
Vaginal infection 
4 (6.2) 
1 (1.6) 
Adverse drug reactions (ADRs) were determined by including review of all treatment 
emergent adverse events, both serious and non-serious, regardless of investigator relatedness 
assessment, and review of vital sign data, laboratory data (including electrocardiogram data) 


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and discontinuations due to adverse events.  In addition, other factors taken into 
consideration for the determination of ADRs included but were not limited to the mechanism 
of action of tafamidis, the known symptoms of the underlying TTR amyloidosis, the 
temporality of the adverse event to the administration of tafamidis, and the relative rates of 
comparative adverse events in the placebo groups in the controlled trials.  Based on the 
review of the totality of the available safety data, it was determined that there are four 
adverse events for which there is basis to believe there is a causal relationship between their 
occurrence and the use of tafamidis; as such these adverse events were identified as ADRs, 
with the incidence observed in the placebo-controlled 18 month Phase 2/3 Study 
Fx-005 presented in Table 2.
Table 2.
Summary of Adverse Drug Reactions
System Organ Class Preferred Term 
Tafamidis N=65 n 
(%) 
Placebo N=63 n (%) 
Gastrointestinal disorders 
Diarrhea 
17(26) 
11(18) 
Upper abdominal pain 
8(12) 
2(3) 
Infections and infestations 
Urinary tract infection 
15(23) 
8(13) 
Vaginal infection* 
4(12) 
1(3) 
There were no meaningful changes in vital signs, clinical laboratory parameters, ECG 
parameters (including QTc interval), or other safety parameters measured.  No meaningful 
changes in echocardiogram and ECG were observed for patients with a medical history of 
cardiomyopathy.  Tafamidis has been well tolerated by both healthy subjects during the 
Phase 1 clinical studies as well as in patients during the Phase 2 and 3 clinical studies.
Tafamidis was also studied in patients with TTR cardiomyopathy in Study Fx1B-201.  These 
patients were elderly (mean age 76 years) with signs and symptoms of mild to moderate 
cardiac dysfunction.  While there was no placebo control group, the adverse event profile of 
tafamidis reported during this study reflects the patients’ underlying disease, co-morbid 
conditions, and elderly status.  The most frequent adverse events overall were related to the 
symptoms and episodes of heart failure (dyspnea, cardiac failure and edema).  Eighteen 
(51.4%) patients reported at least one TEAE that was considered at least possibly related to 
study medication as assessed by the Investigator.  The most common (>5%) treatment-related 
TEAEs included balance disorder (14.3%), ageusia (8.6%), constipation, diarrhea, edema 
peripheral, fall, weight increased, and decreased appetite and dyspnea (5.7% each). The 
majority (≥85%) of patients experienced TEAEs considered mild or moderate in severity.  
One event 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.


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Complete information for this compound may be found in the Single Reference Safety 
Document, which for this study is the Investigators Brochure.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives

To obtain additional, long-term, open-label safety and efficacy data for tafamidis in 
subjects with TTR-CM.

To continue to provide the investigational product tafamidis to subjects with TTR-CM 
who have completed Protocol Fx1B-201.
2.2. Endpoints
The efficacy endpoints for this study are:

Patient Global Assessment;

New York Heart Association (NYHA) Classification;

6-Minute walk test;

Kansas City Cardiomyopathy Questionnaire (KCCQ);

Echocardiography;

Troponin I, troponin T, and amino-terminal B-type natriuretic peptide (NT-pro-BNP);

Mortality and hospitalization (all cause and cardiac-related).
The safety endpoints for this study are:

Incidence of treatment-emergent adverse events;

Physical examinations;

Use of concomitant medications;

Electrocardiograms (ECGs);

Clinical safety laboratory tests;

Vital signs.


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3. STUDY DESIGN
This is a Phase 3, open-label study designed to obtain additional, long-term, open-label safety 
and efficacy data for tafamidis, and to continue to provide subjects who have completed 
Protocol Fx1B-201 (a Phase 2, open-label study to evaluate TTR stabilization, as well as the 
safety and tolerability of tafamidis) with 20 mg oral tafamidis (soft gelatin capsule) for up to 
10 years or until subject has access to tafamadis for TTR-CM via prescription.  Upon 
regulatory approval for the treatment of TTR-CM in their respective country and access to 
prescription tafamadis, subjects may be withdrawn from the study.  Such subjects will be 
considered study completers.  The decision to withdraw subjects to transition to commercial 
tafamidis will be done in consultation between the investigator and the sponsor (see 
section 6.3).
Subjects who successfully complete Protocol Fx1B-201 will be eligible to enter study
Fx1B-303. 
3.1. Rationale for Study Design and Control Group
This is an open-label study designed to obtain additional safety and efficacy data and to 
continue to provide tafamidis to subjects with TTR-CM who have not had a liver or heart 
transplant and who have completed Protocol Fx1B-201. A control group will not be included 
in this open-label study design.
3.2. Study Duration and Dates
Enrolled subjects will receive 20 mg tafamidis (soft gelatin capsules) for up to 10 years or 
until subject has access to tafamadis for TTR-CM via prescription.  Upon regulatory approval 
for the treatment of TTR-CM in their respective country and access to prescription tafamadis, 
subjects may be withdrawn from the study.  The decision to withdraw subjects to transition to 
commercial tafamidis will be done in consultation between the investigator and the sponsor 
(see section 6.3).
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.


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Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:

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.

Male or female subjects with TTR-CM who have not undergone liver or heart 
transplantation and who have successfully completed Protocol Fx1B-201.

Subject has successfully completed Protocol Fx1B-201.

If female, subject is post-menopausal. If male, female partner is post-menopausal; or 
if female partner is of childbearing potential, then the subject is willing to use an 
acceptable method of birth control for the duration of the study and for at least three 
months after the last dose of study medication.
Note: The definition of acceptable method of birth control will be based on the 
judgement of the Investigator or designated associate.
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Subject has not successfully completed Protocol Fx1B-201.
2. Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs 
(NSAIDs), defined as greater than 3 to 4 times/month. The following NSAIDs are 
allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethicin, ketoprofen, 
nabumetone, naproxen, nimesulide, piroxicam, and sulindac.
3. Subject has a clinically significant medical condition that, in the opinion of the 
Investigator, would place the subject at an increased risk to participate in the study.
4. Pregnant females; breastfeeding females; females of childbearing potential.
5. Subject has received a liver or heart transplant.
4.3. Life Style Guidelines 
4.3.1. Contraception
All female subjects must be postmenopausal.
All male subjects with partners of childbearing potential must agree to use a highly effective 
method of contraception consistently and correctly for the duration of the active treatment 
period and for at least 3 months after the last dose of investigational product.  The 


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investigator, in consultation with the subject, will select the most appropriate method of 
contraception for the individual subject.  The investigator, at each study visit, will confirm 
and document consistent and correct use.  In addition, the investigator will instruct the 
subject to call immediately if the selected birth control method is discontinued or if 
pregnancy is known or suspected.  
5. STUDY TREATMENTS
5.1. Allocation to Treatment
This is an open-label, single-treatment study. All enrolled subjects will be assigned to 
receive a single oral daily dose of 20 mg tafamidis.
5.2. Drug Supplies
5.2.1. Formulation and Packaging
Tafamidis [d-glucitol, 1-deoxy-1-(methylamino)-, 2-(3,5-dichlorophenyl)-6-
benzoxazolecarboxylate (1:1)] is the meglumine salt of 2-(3,5-dichloro-phenyl)-benzoxazole-
6-carboxylic acid. Tafamidis will be supplied by the Sponsor as opaque 12 oblong soft 
gelatin capsules filled with a suspension containing 20 mg of tafamidis.
Investigational product will be supplied in 10-count child resistant blisterpacks. 
Study medication labels will contain: the kit number, tafamidis, dosage and strength, quantity 
of dosage units, route of administration, directions for use, protocol number, study sponsor, 
storage conditions, emergency contact information, and a caution statement regarding the 
investigational status of the compound.
5.2.2. Preparation and Dispensing
Investigational product will be dispensed to subjects according to the following schedule:

On Day 0, an initial 3-month supply of investigational product will be dispensed to 
subjects at the clinical unit. Subjects will take their first dose of investigational product 
at home beginning on Day 1 (i.e., first dose).

At 3-month intervals between clinic visits, 3-month supplies of investigational product 
may be mailed from the clinical site directly to subject’s home.

Every six months subjects will return to the clinical unit and will be instructed to bring all 
investigational product and packaging with them to determine investigational product 
compliance and accountability. At these clinic visits, 3-month supplies of investigational 
product will be dispensed directly to subjects for self-administration at home.


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5.2.3. Administration
All enrolled subjects will self-administer a once-daily oral dose of 20 mg tafamidis at home 
as instructed by the clinical staff. All investigational product is to be taken by mouth, with 
water. Subjects will be instructed to take investigational product at the same time each day 
throughout the treatment period.
Medication errors may result, in this study, from the administration or consumption of the 
drug by the subject at the wrong time, or at the wrong dose strength. Such medication errors 
occurring to a study participant are to be captured on the adverse event (AE) page of the 
CRFs 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 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 and, if applicable, any associated adverse event(s) is 
captured on an adverse event (AE) CRF page (refer to Adverse Event Reporting section for 
further details).
5.2.4. Compliance
All investigational product will be self-administered by subjects at home. Subjects should be 
instructed to bring all investigational product and packaging to each follow-up visit to the 
clinical unit every six months. Compliance to investigational product will be determined 
through capsule counting procedures at subject visits to clinic. Compliance will be 
monitored and recorded in each subject’s case report form (CRF). Additionally, 
investigational product accountability audits will be performed by the study monitor during 
routine monitoring visits.
5.3. Drug Storage and Drug Accountability 
All investigational product (tafamidis) should be stored at controlled room temperature 
15-25°C (59-77°F). Investigational product should be stored in its original package and 
should be protected from light.
Storage conditions stated in the Investigator Brochure (IB) may be superseded by the label 
storage.


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Temperature of storage conditions should be monitored using validated devices that record 
maximum and minimum temperatures, are regularly calibrated, and data are regularly 
recorded.  Should the product experience temperature excursion, relative to label instruction, 
during storage, then the impact to product quality and use should be addressed with relavant 
subject matter experts and documented accordingly.
Occasional short-term excursions from the intended storage conditions may occur. If the 
duration is short and the deviation in temperature is small, an investigation into the quality of 
the product is generally not required.
Subjects should be reminded of the storage conditions when drug is dispensed.  
5.4. Concomitant Medication(s)
On Day 0, in conjunction with the review of their medical history, all subjects will be asked 
what medications they are taking.  Thereafter, subjects will be asked what medications they 
have been taking at 3-month intervals (i.e., during clinic visits every 6 months and via 
telephone contact at 3-month intervals between clinic visits).  All concomitant medications 
will be recorded on the CRF.

Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs 
(NSAIDs), defined as greater than 3 to 4 times/month is not permitted.

The following NSAIDs are allowed: acetylsalicylic acid, etodolac, ibuprofen, 
indomethicin, ketoprofen, nabumetone, naproxen, nimesulide, piroxicam, and 
sulindac.
6. STUDY PROCEDURES 
Every effort should be made to ensure that scheduled visits are made and protocol required
tests and procedures are completed as described.  From time to time there may be 
circumstances, outside of the control of the investigator, which may not make a clinic visit 
possible.  In these cases, with prior discussion and approval from the sponsor, alternative 
options may be considered.  Approved alternate options will not be considered protocol 
deviations.
Study procedures are outlined in the Schedule of Activities.
6.1. Screening/Baseline Assessment
The end of study physical examination (including weight and vital signs) and the relevant 
clinical laboratory assessments from Protocol Fx1B-201 will be used as the 
Day 0 assessments for Protocol Fx1B-303. If more than 30 days has elapsed between the 
final study visit of Protocol Fx1B-201 and Day 0 of Fx1B-303, an abbreviated physical 
examination (including weight and vital signs) and clinical laboratory assessments must be 
performed on Day 0.


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Subjects will be required to sign an informed consent form before beginning participation in 
Protocol Fx1B-303. The following procedures will be performed on Day 0:

All inclusion and exclusion criteria will be reviewed to ensure eligibility for 
participation in this study.

Demographics (date of birth, age, gender, and race) for all subjects will be collected.

A complete medical history will be obtained.

Abbreviated physical exam including weight and vital signs (if not conducted within 
30 days of Day 0).

Collect blood/urine samples for clinical laboratory assessments (Section 7.3) (if not 
collected within 30 days of Day 0).

Ask subjects non-leading questions such as “How do you feel?” and record adverse 
events.

Record concomitant medications.

Dispense 3 month supply of investigational product with instructions that subject is to 
administer the first dose at home on the following day as instructed (Section 5.2.3).
6.2. Study Period
6.2.1. Months 3, 9, 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, 99, 105, 111, 117
Subjects will be contacted by telephone, contact is to be made ± 1 week of scheduled time:

Ask subjects non-leading questions such as “How do you feel?” and document 
adverse events.

Record concomitant medications.

Mail 3 month supplies of investigational product following telephone contact.

These phone visits can be conducted in person at the clinic at the discretion of the 
sites.
6.2.2. Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114
Subjects will return to the clinic for the following assessments.  Visits are to occur ± 2 weeks 
of the scheduled time:

Conduct abbreviated physical examination, including weight and vital signs.


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
Collect blood/urine samples for clinical laboratory assessments (section 7.3).

Perform Patient Global Assessment.

Determine NYHA Classification.

Administer Kansas City Cardiomyopathy Questionnaire.

Conduct 6-minute walk test.

Ask subjects non-leading questions such as “How do you feel?” and record adverse 
events.

Record concomitant medications.

Determine drug compliance and accountability.

Dispense 3 month supply of investigational product.
6.2.3. Months 12, 24, 36, 48, 60, 72, 84, 96, 108
In addition to the above assessments, collect ECG and echocardiogram every 12 months.
6.2.4. End of Study Visit
The end of study visit will occur upon subject withdrawal from the study or upon subject 
completion (up to 10 years or until subject has access to tafamadis for TTR-CM via 
prescription).  Upon regulatory approval for the treatment of TTR-CM in their respective 
country and access to prescription tafamadis, subjects may be withdrawn from the study.  
Such subjects will be considered study completers. The decision to withdraw subjects in a 
country will be done in consultation between the investigator and the sponsor (see Section
6.3), subject withdrawal (for any reason), or program discontinuation by the Sponsor.  The 
following activities will be completed:

Complete physical examination, weight and vital signs.

Collect blood samples for clinical laboratory assessments (section 7.3).

Perform Patient Global Assessment.

Determine NYHA Classification.

Administer Kansas City Cardiomyopathy Questionnaire.

Conduct 6-minute walk test.


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
Echocardiogram (unless performed within 6 months prior).

Electrocardiogram (unless performed within 6 months prior).

Ask subjects non-leading questions such as “How do you feel?” and record adverse 
events.

Record concomitant medications.

Determine drug compliance and accountability.
In the event a subject is unable to return to the study site for the end of study visit, telephone 
contact with the subject approximately 30 days after the last dose of medication to assess 
adverse events and concomitant medications and treatments is expected. If laboratory 
assessments are needed to follow-up unresolved adverse events, retrieval of assessments 
performed at an institution local to the subject is acceptable.
The outcome of adverse events with a date of onset during the study period should be 
reevaluated, and any new adverse events should be recorded. All serious adverse events, and 
those non-serious adverse events assessed by the investigator as possibly related to study 
drug should continue to be followed even after subject withdrawal from study. These 
adverse events should be followed until they resolve or until the investigator assesses them to 
be “chronic” or “stable”. Additional information on Adverse Event Reporting can be found 
in Section 8.
6.3. Subject Withdrawal
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. In addition, the Sponsor may choose to discontinue 
this study, at which time all subjects will be withdrawn.
A subject may be withdrawn from the study for any of the following reasons:

Withdrawal of consent;

Adverse event;

Protocol noncompliance;

Subject lost to follow-up;

Subject death.


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Subjects who are prematurely withdrawn from the study will not be replaced.  Subjects who 
discontinue from the study at any time following enrollment will have a final end of study 
visit performed, including all safety and efficacy assessments, at the time of discontinuation.
Upon regulatory approval of tafamadis for the treatment of TTR-CM in their respective 
country, and access to prescription tafamidis, subjects may be withdrawn from the study.
The decision to withdraw subjects in a country will be done in consultation between the 
investigator and the sponsor. Subjects will have all end of study procedures completed prior 
to study withdrawal. These subjects are considered completers.  
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request the subject 
to return all unused investigational product(s), request the subject to return for a final visit, if 
applicable, 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.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
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 the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the subject. When a protocol required test 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.
7.1. Efficacy Assessments
All efficacy evaluations will be performed at each 6-month clinic visit, except for 
echocardiograms, which will be performed every 12 months on an annual basis.
Each echocardiogram will be recorded and reviewed locally by the clinical site, and the 
clinical significance of the findings will be assessed by the Investigator. Each 
echocardiogram will also be sent to an independent imaging laboratory for centralized review 
of the results. Detailed instructions for performing echocardiography will be provided in a 
separate manual.
The 6-minute walk test will be conducted in accordance with guidelines established by the 
American Thoracic Society. Detailed instructions for conducting the 6-minute walk test will 
be provided in a separate manual.


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Refer to Appendices 1, 2 and 3, respectively, for the Patient Global Assessments, NYHA 
classification, and KCCQ efficacy evaluation forms.
Classification of mortality and hospitalization (all cause and cardiac-related) will be 
determined by the Primary Investigator and the Sponsor.
7.2. Physical Examinations and Vital Signs
A complete physical examination, weight and vital signs, will be performed at the end of 
study visit, including assessment of the following body systems:
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Skin
Nose
Musculoskeletal
Throat
Neurological
Respiratory
Immunologic/Allergies
Genitourinary
Hematologic/Lymphatic
During the trial, abbreviated physical examinations, including weight and vital signs, will 
assess general appearance, cardiovascular, respiratory, and gastrointestinal systems at each 
6-month clinic visit.
Vital signs to be measured include lying and standing systolic and diastolic blood pressure 
(mmHg), lying and standing pulse (beats per minute), oral temperature (ºC), and respiration 
rate (breaths/minute).


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7.3. Clinical Laboratory Tests
Blood samples will be collected at every 6-month visit to the clinical unit. The following 
clinical laboratory tests will be assessed:
Serum chemistry
Sodium
Globulin
Potassium
Alkaline phosphatase
Chloride
Alanine aminotransferase (AST)
Bicarbonate
Aspartate aminotransferase (ALT)
Blood urea nitrogen
Gamma glutamyl transferase
Creatinine
Cholesterol 
Calcium
Uric acid 
Inorganic Phosphorous
Thyroid-stimulating hormone
Glucose 
Total thyroxine (T4)
Total bilirubin
Free T4
Total protein
Prealbumin (transthyretin)
Albumin
Retinol-binding protein
NT-pro-BNP
Troponin I and T
Coagulation
Prothrombin time (PT)
International normalized ratio (INR)
Note: laboratory assessment for PT and INR will not be sent to a central laboratory but will 
be processed by the local laboratory at each site.
Hematology
Hemoglobin
Platelets
Hematocrit
White blood cell count
Red blood cell count
Neutrophils 
Packed cell volume
Lymphocytes 
Mean corpuscular volume
Monocytes 
Mean corpuscular hemoglobin
Eosinophils 
Mean corpuscular hemoglobin concentration
Basophils
Urinalysis
pH
Blood (free Hb)
Protein
Nitrite
Glucose
Urobilinogen
Ketones
Specific gravity 
Bilirubin


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7.4. Electrocardiograms
During the trial, ECGs will be performed annually every 12 months.
The site will perform ECGs in accordance with standard site practice. Ten-second rhythm 
strips will accompany each ECG. The ECGs will be recorded and reviewed locally by the 
clinical site, and the clinical significance of the findings will be assessed by the Investigator.
7.5. Adverse Events
Starting from the date the informed consent form is signed, adverse events (AEs) will be 
recorded in the CRF and monitored throughout the study. All adverse events should be 
monitored until they are resolved or are clearly determined to be due to a subject’s stable or 
chronic condition or intercurrent illness(es). All AEs will be recorded on the CRF. 
Definitions, documentation, and reporting of AEs are described in Section 9.
7.6. Concomitant Medications
On Day 0, in conjunction with the review of their medical history, all subjects will be asked 
about the medications they are taking. Thereafter, subjects will be asked about the 
medications they have been taking at 3-month intervals (i.e., during clinic visits every six 
months and via telephone contact at 3-month intervals between clinic visits). All 
concomitant medications will be recorded on the CRF.
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.  


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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.  Should an investigator be made aware of any 
SAE occurring any time after the active reporting period, it must be promptly reported. 

AEs (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of study treatment through last subject 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;

Exposure via breastfeeding;

Medication error.


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8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

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.
8.5. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

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.


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8.5.1. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin 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:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 3 times the upper limit of normal (X 
ULN) concurrent with a total bilirubin 2 X ULN with no evidence of hemolysis and 
an alkaline phosphatase 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 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 by one time the upper limit of normal or ≥3 times the 
upper limit of normal (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 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/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 subject, 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 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.


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8.6. Hospitalization
AEs reported from studies associated with hospitalization or prolongations of hospitalization 
are considered serious.  Any initial admission (even if less than 24 hours) to a healthcare 
facility meets these criteria.  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, neurological floor to a tuberculosis unit).
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Routine emergency room admissions;

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 exam);

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 should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.


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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.
8.7. 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.
8.8. 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 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.


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8.9. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy (also 
referred to as exposure in-utero (EIU) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or being
exposed (eg, due to treatment or environmental exposure) or after discontinuing or 
having been directly exposed to the investigational product;
2. A male has been exposed (eg, due to treatment or environmental exposure) to the 
investigational product prior to or around the time of conception 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 Pfizer on an EIU Form (this is a specific version of the Serious Adverse Event 
Form).  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 pregnancy outcome information 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: 

Spontaneous abortion includes miscarriage and missed abortion;

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 
serious adverse events when the investigator assesses the neonatal death as related or 
possibly related to exposure to investigational product.


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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 EIU Pregnant Partner 
Release of Information Form to deliver to his partner. The Investigator must document on 
the EIU Form that the subject was given this letter to provide to his partner.
8.10. Withdrawal Due to Adverse Events (See Also Section 6.3 Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to insufficient response, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a subject withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements defined below.
8.11. 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.
8.12. 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.
8.12.1. 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 and exposure via 
breastfeeding 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.
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 


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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 and 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. 
8.12.2. 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.
8.12.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected serious unexpected 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, 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
There is no formal sample size calculation for this protocol. Subjects who completed 
Protocol Fx1B-201 are eligible; up to 35 subjects are expected to enroll in Protocol 
Fx1B-303.
9.2. Efficacy Analysis
9.2.1. Analysis of Primary Endpoint 
For subjects who enroll into this protocol, the cumulative efficacy data (starting from 
Protocol Fx1B-201) as measured by the Patient Global Assessment, NYHA classification, 
KCCQ, 6-minute walk test, echocardiograms, and serum levels of troponin I, troponin T, and 
NT-proBNP will be presented. 
Baseline data from protocol Fx1B-201 will be used as baseline for these analyses.
Subjects who enroll into the study and receive any amount of investigational product will be 
included in the safety population.  Subjects who receive any amount of investigational 
product and have at least one post-baseline efficacy assessment will be included in the 
efficacy population.


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9.2.2. Patient Global Assessment
Each subject’s overall quality of life, as measured by the Patient Global Assessment 
(Appendix 1), will be summarized using descriptive statistics. In addition, the percentage of 
subjects with unchanged, worsened, or improved global assessments (and 95% confidence 
intervals) will be presented at each scheduled assessment.
9.2.3. New York Heart Association Classification
Subjects will be evaluated using the New York Heart Association (NYHA) classification 
(Appendix 2). Descriptive statistics will be presented by visit for each classification: 
Class I, Class II, Class III, and Class IV (see Appendix 2 for definitions). The number and 
percentage of subjects who improved, worsened, or with no change from baseline will also 
be presented at each visit. 
9.2.4. Kansas City Cardiomyopathy Questionnaire
The Kansas City Cardiomyopathy Questionnaire (KCCQ, Appendix 3) will be summarized 
by the following summary scores calculated using the guidelines established in the KCCQ 
Scoring Instruction Manual:
Physical limitations
Self-efficacy
Symptom stability
Quality of life
Symptom frequency
Social limitation
Symptom burden
Overall summary score
Total symptom score
Clinical summary score
Change from baseline for each summary score of the KCCQ will be analyzed using a mixed 
model analysis (with baseline value as covariate, subjects as random effect, and time as fixed 
effect). Data will also be summarized by each scheduled assessment and a graphical 
presentation of these data will be presented.
9.2.5. Six-minute Walk Test
Descriptive statistics will be presented by visit for the distance walked (in meters), the 
change from baseline in distance walked, the categories of distance walked (<300 meters, 
300-374.9 meters, 375-449.9 meters, and ≥450 meters), and the classification of improved, 
no change, or worsened. Pre- and post-baseline dyspnea and fatigue values (using the Borg 
Scale) will be summarized by visit, as well as post-test change from baseline in dyspnea and 
fatigue.


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9.2.6. Echocardiogram
Echocardiogram parameters will include, but are not limited to:
Interventricular septal thickness
Valvular abnormalities (thickening, 
regurgitation)
Posterior left ventricular wall thickness
Pericardial effusion (yes/no)
Left atrial diameter
Lateral s’, e’, a’
Left ventricular end diastolic diameter
Septal s’, e’, a’
Left ventricular mass
Tissue Doppler
Ejection fraction
Mitral deceleration time
Right ventricular wall thickness
e:e’ ratio
Doppler data
E/A ratio
Each echocardiogram parameter will be compared to baseline. In addition, select 
echocardiogram parameters will be categorized as normal or abnormal. These classifications 
will be compared to baseline and assessed over time.
9.2.7. Troponin I, Troponin T, and NT-pro-BNP
Serum levels of troponin I and T, and NT-pro-BNP will be assessed at baseline and at each 
clinic visit. Descriptive statistics for each analyte will be presented for the actual values and 
the change from baseline at each clinic visit. 
9.2.8. Mortality and Hospitalization
The endpoints of mortality and hospitalization (all cause and cardiac-related) will be 
analyzed individually and as composite measures.
A Kaplan-Meier plot of time to event from the start of Protocol Fx1B-201 will be generated, 
and the event rate and associated 95% confidence intervals will be presented at 1, 2, 3, and 
4 years since the start of the investigational drug.


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9.3. Analysis of Other Endpoints
9.3.1. Demographics and Baseline Characteristics
Demographics and baseline data (medical history, age, gender, race, weight, and height) will 
be summarized using descriptive statistics.
9.3.2. Physical Examination and Vital Signs
Physical examinations and vital signs (lying and standing blood pressure and pulse, 
respiratory rate, and temperature) will be summarized using descriptive statistics. 
9.4. Concomitant Medication Usage
All data on concomitant medication usage collected on the CRF will be presented in 
summary tables and in data listings.
9.5. Safety Analysis
All AE data collected on the CRF will be presented in summary tables and data listings.
9.6. Interim Analysis
Given the lack of long-term data in TTR-CM, interim analyses will be performed during the 
course of the study to allow for the reporting of safety and efficacy data.
9.7. Data Monitoring Committee
This study will use a Data Monitoring Committee.
The DMC will be responsible for ongoing monitoring of the efficacy and safety of subjects in 
the study according to the Charter.  The recommendations made by the DMC to alter the 
conduct of the study 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.  In this instance, 
such disease-related efficacy endpoints are not reported individually as SAEs. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, 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 is accurate.  The 
investigator and institution will allow Pfizer monitors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification.


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The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), 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.
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.
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 


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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.
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 2008). 
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 
on any sponsor forms, reports, publications, or in any other disclosures, except where
required by laws.


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Subject names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
subject. In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of subject personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document used in this study, and any changes made during the course 
of the study, must be prospectively approved by both the IRB/IEC and Pfizer before use.
The investigator must ensure that each study subject, or his/her 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 or the subject's legal representative before any study-specific 
activity is performed. The investigator will retain the original of each subject's signed 
consent document.
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
End of Trial in all 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 28 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.


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15. PUBLICATION OF STUDY RESULTS
Publication of study results is discussed in the CSA.
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).  Pfizer posts the results of 
all studies that it has registered on ClinicalTrials.gov regardless of the reason for registration.
The results are posted in a tabular format called Basic Results. 
For studies involving a Pfizer product, the timing of the posting depends on whether the 
Pfizer product is approved for marketing in any country at the time the study is completed:

For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, FDA-approved products, 
Pfizer posts results within one year of the primary outcome completion date (PCD). 
For studies involving products approved in any country, but not FDA approved, 
Pfizer posts results one year from last subject, last visit (LSLV). 

For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days of US regulatory approval, or 
one year after the first ex-US regulatory approval of the product (if only submitted for 
approval ex-US);

For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year of discontinuation of the program (if 
there are no plans for outlicensing or within two years if outlicensing plans have not 
completed).
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 trial concluded according to the pre-specified protocol or was 
terminated.
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.


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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.
If the Study is part of a multi-centre 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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Colon W, Kelly JW. Partial denaturation of transthyretin is sufficient for amyloid fibril 
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Adams D, Samuel D, Goulon-Goeau C, et al. The course and prognostic factors of 
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Sousa A, Coelho T, Barros J, et al. Genetic epidemiology of familial amyloidotic 
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Jacobson DR, Buxbaum JN. Genetic aspects of amyloidosis. Adv Hum Genet. 1991;20: 
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Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin 
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13.
Cornwell GG, Murdoch WL, Kyle RA, Westermark P, Pitkanen P. Frequency and 
distribution of senile cardiovascular amyloid: a clinicopathologic correlation.  Am J 
Med. 1983;75: 618-623.
14.
Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile 
amyloidosis with cardiac involvement. Am J Med. 1996;101(4):395-400.
15.
Lachman HJ, Goodman HJB, Gilbertson JA, et al. Natural history and outcome in 
systemic aa amyloidosis. N Engl J Med. 2007;356:2361-2371.
16.
Smith TJ, Kyle RA, Lie JT. Clinical significance of histopathologic patterns of cardiac 
amyloidosis. Mayo Clin Proc. 1984;59 547-555.


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Appendix 1. Patient Global Assessment
Patient Global Assessment:
At Baseline, the Patient Global Assessment will be:
“In general, how do you feel today?”

Excellent

Very good

Good

Fair

Poor
At each follow-up visit, the Patient Global Assessment will be:
“How do you feel today as compared to when we last talked with you for a study visit?”

Markedly improved

Moderately improved

Mildly improved

Unchanged

Mildly worsened

Moderately worsened

Markedly worsened


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Appendix 2. New York Heart Association Classification 
New York Heart Association (NYHA) Classification:
Class I
Patients 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
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Class III
Patients 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
Patients 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.
Adopted from: Dolgin M, editor.  Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great 
Vessels.  The Criteria Committee of the New York Heart Association. 9th ed.  Boston: Little Brown & Co, 
1994:253–256.


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Appendix 3. Kansas City Cardiomyopathy Questionnaire
CCI


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P
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CCI

SAP_001.pdf: 
Protocol FoldRx1B-303 
Statistical Analysis Plan 
 
 
 
 
Protocol Fx1B-303 (B3461026) 
 
 
Open-Label Safety and Efficacy Evaluation of Fx-1006A 
in Subjects with V122I or Wild-Type  
Transthyretin (TTR) Amyloid Cardiomyopathy 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
Version 
Date 
Author 
Original 
29May2014 
, 
SCBU Statistics 
Amendment 1 
04Nov2015 
, Manager, GIPB 
RDRO Group 
 
 
 
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TABLE OF CONTENTS  
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................4 
2. INTRODUCTION .......................................................................................................................7 
2.1. Study Design ...................................................................................................................7 
2.2. Study Objectives .............................................................................................................7 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ........................................7 
3.1. Data Safety Monitoring Board (DSMB) .........................................................................7 
3.2. Additional Interim Analyses ...........................................................................................8 
4. HYPOTHESES AND DECISION RULES .................................................................................8 
4.1. Statistical Hypotheses .....................................................................................................8 
4.2. Statistical Decision Rules ................................................................................................8 
5. ANALYSIS SETS .......................................................................................................................8 
5.1. Safety Analysis Population .............................................................................................8 
5.2. Intention to Treat (ITT) Population .................................................................................8 
6. ENDPOINTS AND COVARIATES ...........................................................................................8 
6.1. Efficacy Endpoints ..........................................................................................................8 
6.2. Safety Endpoints .............................................................................................................9 
6.3. Physical exam and Medical history ...............................................................................12 
6.4. Adverse Events ..............................................................................................................12 
6.5. Discontinuations ............................................................................................................12 
6.6. Covariates ......................................................................................................................12 
6.7. Baseline .........................................................................................................................12 
7. HANDLING OF MISSING VALUES ......................................................................................13 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................13 
8.1. Statistical Methods ........................................................................................................13 
8.1.1. Analyses for Continuous Data ..........................................................................13 
8.1.2. Analyses for Categorical Data ..........................................................................13 
8.1.3. Analyses for Time to Event Endpoints .............................................................13 
8.2. Efficacy Analyses ..........................................................................................................14 
8.3. Safety Analyses .............................................................................................................14 
APPENDICES ...............................................................................................................................18 
Appendix 1. Data Derivation details ..............................................................................................18 
Appendix 1.1. KCCQ (See protocol for a copy of the questionnaire) ...........................................18 
 
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Appendix 1.2. 6 Minute Walk Test Categorization .......................................................................22 
Appendix 1.3. Calculation of QTc Interval Corrections ................................................................23 
Appendix 2. Definition and Use of Visit Windows in Reporting ..................................................23 
Appendix 3. Algorithm for imputing missing last dosing date of study drug ...............................24 
Appendix 4. Example SAS code for Delayed Entry Model in Survival Analysis .........................25 
 
 
 
 
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Statistical Analysis Plan 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
Amendment 1, 31Oct2015:  The Statistical Analysis Plan has been amended to include the 
following: 
 
 
Change 
Date 
 
Section(s) 
Affected 
Corresponds 
to a 
Protocol 
Amendment 
 
 
Statistician  
1. Changed the word 
patient to subject in 
order to agree with the 
amended protocol. 
May 29, 2014 
 
 
 
Throughout 
 
 
 
Yes (# 1) 
 
 
 
2. Additional information 
on the use of interim 
analyses. 
May 29, 2014 
 
 
3.2 
 
 
Yes (# 1) 
 
 
 
3. Additional clarification 
of visit windowing 
May 29, 2014 
 
Appendix 2 
 
No 
 
 
4. Additional clarification 
of missing data rules is 
included. 
May 29, 2014 
 
 
Appendix 3 
 
 
No 
 
 
 
5. Clarification of the 
categorical outcome 
variable analyses has 
been included, as well 
as the addition of shift 
tables for the analysis of 
these variables. 
May 29, 2014 
 
 
 
 
 
 
8.1.2 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
6. The list of the 
laboratory measures to 
be summarized was 
shortened to those 
laboratory measures 
which are potentially 
related to disease.  All 
values will be listed in 
the subject listings. 
Additionally, duplicated 
laboratory measures 
were removed. 
 
 
 
 
 
 
 
 
 
 
 
May 29, 2014 
 
 
 
 
 
 
 
 
 
 
 
6.2 item 7 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
7. The report of physical 
examinations has been 
changed from a 
summary to a listing 
and a listing of medical 
history has been added 
May 29, 2014 
 
 
 
 
 
6.3 
 
 
 
 
 
No 
 
 
 
 
 
 
 
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8. The LOCF analysis has 
been removed, due to 
the nature of the 
discontinuation criteria 
from this study LOCF 
is not an appropriate 
analysis. 
 
 
 
 
 
 
May 29, 2014 
 
 
 
 
 
 
7 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
9. The specification and 
summary of the use of 
pacemakers and/or 
defibrillators were 
added. 
May 29, 2014,  
Nov 3, 2015 
 
 
 
8.3 
 
 
 
No 
 
 
 
 
 
10. The cox regression 
models for time to 
event were removed 
due to the single arm 
study design. 
May 29, 2014 
 
 
8.1.3 
 
 
No 
 
 
 
11. Time to event analysis 
has been modified to 
specify time from 
randomization and time 
from onset of disease. 
May 29, 2014 
 
 
 
 
8.1.3 
 
 
 
 
No 
 
 
 
 
 
12. Added specifications 
for a table of clinically 
significant ECGs. 
May 29, 2014 
 
 
8.3 
 
 
No 
 
 
 
13. Added formulae for 
calculating QTc 
correction factors (QTcB 
and QTcF). 
May 29, 2014 
 
 
Appendix 1.3 
 
 
 
No 
 
 
 
 
14. Replaced the scoring 
for the KCCQ with a 
clearer version of the 
manual to agree with 
the programming used 
in Fx1B-201. 
May 29, 2014 
 
 
 
 
Appendix 1.1 
 
 
 
 
 
No 
 
 
 
 
 
 
15. Clarified Section 6.1 
and 8.2 for efficacy 
endpoints and analyses 
to be consistent with the 
protocol.  
May 29, 2014 
 
6.1 and 8.2 
 
No 
 
 
16. Clarification of the data 
points for the 6 minute 
walk test Borg scale 
values. 
 
 
 
May 29, 2014 
 
 
 
6.1, item, 4c 
 
 
 
No 
 
 
 
 
17. Eliminated an overlap 
in ECG change 
May 29, 2014 
 
6.2, item 6k 
 
No 
 
 
 
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categories. 
18. Corrected typographic 
error.  Changed PRS to 
QRS. 
May 29, 2014 
 
 
6.2, item 6c 
 
 
No 
 
 
 
19. Added specifications 
for clinical significant 
changes in vital signs 
and definition of 
orthostatic hypotension. 
May 29, 2014 
 
 
 
 
8.3 
 
 
 
 
No 
 
 
 
 
 
20. Added analyses of 
mortality and 
hospitalization. 
Sep 19, 2014 
 
 
8.3 
 
 
No 
 
 
 
21. Added delayed entry 
model for time to 
mortality analysis from 
symptom onset. 
June 12, 2015 
 
 
8.1.3 and 
Appendix 5 
 
 
 
No 
 
 
 
 
22. Added the definitions of 
cardiac-related death 
and cardiac-related 
hospitalizations. 
June 12, 2015 
 
 
 
6.2 
 
 
 
No 
 
 
 
 
 
 
 
 
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2. INTRODUCTION 
This is a Phase 3, open-label study designed to obtain additional, long-term, open-label safety 
and efficacy data for Tafamidis, and to continue to provide subjects who have completed 
Protocol Fx1B-201 (a Phase 2, open-label study to evaluate TTR stabilization, as well as the 
safety and tolerability of Tafamidis) with 20 mg oral Tafamidis (soft gelatin capsule) for ten 
years or until tafamidis is commercially available for the subjects in this study. 
Eligible subjects will continue once-daily dosing with 20 mg Tafamidis at home on Day 1 
(i.e., first dose) and will return to the clinical unit for study visits every 6 months, with 
telephone visits every 3 months between the clinic visits. 
2.1. Study Design 
This is a Phase 3, open-label study designed to obtain additional, long-term, open-label 
safety and efficacy data for tafamidis, and to continue to provide subjects who have 
completed Protocol Fx1B-201 (a Phase 2, open-label study to evaluate TTR stabilization, as 
well as the safety and tolerability of tafamidis) with 20 mg oral tafamidis (soft gelatin 
capsule) for up to 10 years or until subject has access to tafamidis for TTR-CM via 
prescription.  Upon regulatory approval for the treatment of TTR-CM in their respective 
country and access to prescription tafamidis, subjects may be withdrawn from the study.  
Such subjects will be considered study completers.  The decision to withdraw subjects to 
transition to commercial tafamidis will be done in consultation between the investigator and 
the sponsor). 
Subjects who successfully complete Protocol Fx1B-201 will be eligible to enter study 
Fx1B-303.  
2.2. Study Objectives 
1 
To obtain additional, long-term, open-label safety and efficacy data for 
tafamidis in subjects with TTR-CM. 
2 
To continue to provide the investigational product tafamidis to subjects with 
TTR-CM who have completed Protocol Fx1B-201. 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
3.1. Data Safety Monitoring Board (DSMB) 
The study will be reviewed by an independent DSMB to assess the safety of subjects 
participating in the protocol on an ongoing basis.  The DSMB consists of an independent 
medical monitor (who also serves as chairperson), two external cardiology experts, and an 
independent statistician.  The DSMB will review cumulative safety data on a periodic 
timetable. Handling of this data is described in detail in the DSMB Charter.  The DSMB can 
recommend that the study team modify or discontinue the trial due to safety concerns. 
 
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3.2. Additional Interim Analyses 
Given the lack of long-term data in TTR-CM, interim analyses will be performed during the 
course of the study to allow for the reporting of safety and efficacy data to the scientific 
community through presentation at scientific and professional meetings or for regulatory 
purposes. Analyses can also be performed for publication of safety and efficacy data 
provided there is Pfizer cross functional line review and agreement. 
This is an open-label study as such the data will not need to be unblinded.  
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
This study is descriptive in nature, and as such, there are no formal hypotheses to be tested.  
4.2. Statistical Decision Rules 
The data will be summarized using descriptive measures with 95% confidence intervals. 
5. ANALYSIS SETS 
5.1. Safety Analysis Population 
The safety analysis population consists of all subjects who are enrolled in this study and who 
have taken at least one dose of study medication. 
5.2. Intention to Treat (ITT) Population 
The intent to treat (ITT) population consists of all subjects who are enrolled in this study, 
who have taken at least one dose of study medication, and who have baseline and at least one 
post-baseline cardiac measure. This population will be used for efficacy analysis. 
6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoints 
1. 
Patient Global Assessment: Severity at each visit and change from baseline  
2. 
Patient Global Assessment: Improvement at each visit  
3. 
New York Heart Association (NYHA) Classification:  by category and improvement:  
at each visit 
4. 
6-Minute walk test:  at each visit and change from baseline 
a. 
Distance walked (in meters) 
b. 
Categories of distance walked (<300 meters, 300-374.9 meters, 375-449.9 
meters, and ≥450  meters)  
c. 
Pre- and post-baseline dyspnea and fatigue values (using the Borg Scale).  This 
will yield four values for analysis per post-baseline visit.  The pre walk test 
 
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values, the post walk test values, the within difference value and the change 
from baseline difference value [that is the difference between the baseline 
difference value and the visit difference value]. 
d. 
Based on the categories defined in b, subjects will be classified as improved, no 
change or worsened.  
5. 
Kansas City Cardiomyopathy Questionnaire (KCCQ):  at each visit and change from 
baseline 
a. 
Physical limitations 
b. 
Self-efficacy 
c. 
Symptom stability 
d. 
Quality of life 
e. 
Symptom frequency 
f. 
Social limitation 
g. 
Symptom burden 
h. 
Overall summary score 
i. 
Total symptom score 
j. 
Clinical summary score 
6.2. Safety Endpoints 
1. 
Echocardiography:  at each visit and change from baseline 
a. Interventricular septal thickness (mm)  
b. Posterior left ventricular wall thickness (mm)  
c. Left atrial diameter (mm)  
d. Left atrial volume (cc)  
e. Left ventricular end diastolic diameter (mm)  
f. Left ventricular mass (g)  
g. Ejection fraction (%)  
h. Right ventricular wall thickness (mm)  
2. 
Doppler data  
a. E/A ratio  
b. Mitral Deceleration time (msec)  
3. 
Tissue Doppler   
a. Septal s’, e’, a’ (cm/sec)  
b. Lateral s’, e’, a’ (cm/sec)  
c. Pericardial effusion (yes/no)  
d. Valvular abnormalities (thickening, regurgitation)    
4. 
Calculated Echo variables will include, but are not limited to:  
a. Relative LV wall thickness (Post wall thickness X 2 divided by LVED)  
b. LA Volume index (LA size/body surface area)  
c. LV mass/voltage ratio (LV mass divided by largest voltage on ECG)  
d. e:e’ ratio  
5. 
Select echocardiogram parameters will be categorized as indicated below: 
a. Left ventricular posterior wall thickness ≥ 13 mm  
b. Left ventricular septal thickness ≥ 13 mm  
 
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c. Right ventricular thickness ≥ 7 mm  
d. E/A ratio ≥ 2  
e. E/Eprime Lateral > 15  
f. E/Eprime Septal > 15  
g. Ejection fraction < 50%  
h. E deceleration time ≤ 150 msec  
i. Isovolumic relaxation time (IVRT) ≤ 70 msec  
j. Any valve thickening  
k. Abnormal respiratory variation of inferior vena cava  
l. Pericardial effusion  
6. 
ECG values:  at each visit and change from baseline 
a. 
PR interval (msec) 
b. 
RR interval (msec) 
c. 
QRS interval (msec) 
d. 
QT and QTc interval (msec) 
e. 
heart rate (bpm) 
f. 
overall interpretation, normal/ abnormal findings and clinical significance 
g. 
Corrected QTc will be calculated using Bazett’s and Fridericia’s correction 
formulas.   
h. 
QTc > 450 msec 
i. 
QTc > 480 msec 
j. 
QTc > 500 msec 
k. 
Change in QTc between 30 msec (inclusive) and < 60 msec 
l. 
Change in QTc ≥ 60 msec  
m. 
Change in QTc ≥ 90 msec  
7. 
Clinical laboratory tests:  at each visit and change from baseline 
The following list of clinical laboratory endpoints was collected during the course of 
the study.  However, the summary tables will be restricted to the measures indicated 
with an asterisk (*).  All measures will be included in the subject listings. 
Hematology and Biochemistry 
a. Alkaline phosphatase (ALP)* 
b. Alanine aminotransferase (ALT)* 
c. Aspartate aminotransferase (AST)* 
d. amino-terminal B-type natriuretic peptide (NT-pro-BNP)* 
e. Blood urea nitrogen (BUN) 
f. Gamma glutamyl transferase (GGT)* 
g. Creatinine 
h. Total bilirubin* 
i. International normalized ratio (INR)* 
j. Troponin I* 
k. Troponin T* 
l. Prothrombin time*   
m. Sodium  
n. Globulin  
 
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o. Potassium   
p. Chloride   
q. Bicarbonate   
r. Cholesterol   
s. Calcium  
t. Uric acid  
u. Inorganic Phosphorous   
v. Thyroid-stimulating hormone   
w. Glucose  
x. Total thyroxine (T4)  
y. Free T4  
z. Total proteins   
aa. Prealbumin (transthyretin)   
bb. Hemoglobin   
 
cc. Platelets  
dd. Hematocrit   
 
ee. White blood cell count   
ff. Red blood cell count   
 
gg. Neutrophils  
hh. Lymphocytes   
ii. Mean corpuscular volume  
 
jj. Monocytes   
kk. Mean corpuscular hemoglobin   
 
ll. Eosinophils  
mm. Mean corpuscular hemoglobin concentration 
nn. Basophils   
oo. Retinol-binding protein 
 
Urinalysis  
 
a. Bilirubin 
b. pH   
c. Blood (free Hb)   
d. Protein  
 
e. Nitrite  
f. Glucose  
 
g. Urobilinogen  
h. Ketones  
 
i. Specific gravity   
 
8. 
Mortality and hospitalization (all-cause and cardiac-related) 
All-cause of mortality is defined as any death occurring during the study. Cardiac-
related mortality will be any mortality meeting the following MedDRA criterion:1) AE 
body system (AEBODSYS) = “CARDIAC DISORDERS”, or 2) AE preferred  term 
(AEDECOD ) in (CHEST DISCOMFORT, CHEST PAIN, DEATH, 
CEREBROVASCULAR ACCIDENT,  EMBOLIC STROKE, DISEASE 
 
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PROGRESSION).  Description on the time to mortality analysis can be found in 
Section 8.1.3. 
 
All cause of hospitalization is defined as any adverse event for which SAE type 
“3=Hospitalization” in the Adverse Event (AE) CRF. The cardiac-related 
hospitalization will be any hospitalization meeting the following MedDRA criterion:1) 
AE body system (AEBODSYS) = “CARDIAC DISORDERS”, or 2) AE preferred  
term (AEDECOD ) in (CHEST DISCOMFORT, CHEST PAIN, DEATH, 
CEREBROVASCULAR ACCIDENT,  EMBOLIC STROKE, DISEASE 
PROGRESSION). 
 
6.3. Physical exam and Medical history 
Physical exam will be listed by subject and visit in the listings.  Medical history will be listed 
by subject. 
 
6.4. Adverse Events 
Treatment emergent adverse events will be summarized by all causes and treatment 
relatedness groupings.  Treatment emergent is defined as either a new adverse event or a 
worsening of an ongoing adverse event during the course of Study Fx1B-303 (B3461026). In 
addition, severity of the adverse events will be summarized by all causes and treatment 
relatedness. 
6.5. Discontinuations  
All reasons for discontinuation will be summarized including: discontinuations due to 
adverse events, discontinuations due to laboratory abnormalities, discontinuations due to 
death, discontinuations due to liver and/or heart transplant and all cause discontinuation.   
 
6.6. Covariates  
Due to the small number of subjects, lack of comparator group and the descriptive nature of 
this study, baseline will be used as a covariate in the change from baseline models and where 
appropriate, duration of disease will be used as a covariate.   
6.7. Baseline 
Baseline will be defined for Fx1B-201 and B3461026, respectively. The baseline for Fx1B-
201 will be defined as the last measurement prior to the first dose of study drug in Study 
Fx1B-201. The baseline for B3461026 will be defined as the measurement from the end of 
study visit of Study Fx1B-201, or from the Day 0 visit of Study B3461026, whichever comes 
later.  Baseline for Fx1B-201 and for B3461026 will be summarized.   
 
 
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7. HANDLING OF MISSING VALUES 
Data which are based on entire scales which are missing will be analyzed as follows: 
If the data are time until event data and there is no observed event (at any point during the 
trial) the observation will be censored at the last observation.  If there was an observed event, 
the data associated with the first observation of that event will be used; all other observations 
will not be needed. 
For all other data types, the data will be analyzed as follows:  for analyses at each visit, the 
missing observations will not be used. Any visit after the subject was discontinued will 
remain as missing data. 
For any subject  missing a 12-month visit observation from Study Fx1B-201, if the Day 0 
visit observation from theFx1B-303 study is reported, the  Day 0 visit observation from the 
Fx1B-303 will be imputed for the12-month visit observation for Study Fx1B-201. 
For specific scoring details, see Appendix 1. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
8.1.1. Analyses for Continuous Data 
All continuous data will be summarized with descriptive statistics, including mean, standard 
deviation, median, IQR, range and 95% confidence intervals.   In addition, change from 
baseline statistics will be presented as appropriate, to include the appropriate descriptive 
statistics. For analysis of change from baseline, baseline data from protocol Fx1B-201 will be 
used as baseline for these analyses. For the change from baseline statistics, the estimate will 
be adjusted for baseline and the LSMean and standard error will be presented with the 95% 
confidence interval based on an MMRM model with a random effect for subject and 
covariate of baseline. 
8.1.2. Analyses for Categorical Data  
All categorical data will be summarized as n, percentage and 95% confidence intervals. The 
95% CI intervals will be estimated using exact methods due to the decreasing sample size. In 
addition, a shift table will be provided for such variables as the 6 minute walk test, PGA, and 
NYHA class. 
8.1.3. Analyses for Time to Event Endpoints 
Kaplan-Meier estimates will be computed for all time to event endpoints, including median 
and interquartile ranges, where appropriate. 95% confidence intervals will be presented at 
yearly intervals from the start of the investigational drug (baseline of Fx1B-201).  Time to 
event will use randomization and onset of disease as starting points for the calculation of 
time to event.    
 
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Subjects are required to survive to enroll in the parent study (Fx1B-201). Such conditions 
yield a left-truncated death time distribution from symptom onset. To account for the 
potential immortal time bias, the time to death from onset of symptom will be analyzed using 
the delayed entry (left truncation) technique. Survival probabilities will be calculated 
conditional on subjects having survived until study entry of the parent study (Fx1B-201). 
SAS codes for the delayed entry (left truncation) technique are provided in Appendix 5. 
8.2. Efficacy Analyses 
Efficacy analyses will be performed for cumulative efficacy data as measured by Patient 
Global Assessment (PGA), New York Heart Association (NYHA) classification, Kansas City 
Cardiomyopathy Questionnaire (KCCQ), 6-minute walk test (6MWT), echocardiograms, and 
serum levels of troponin I, troponin T, and NT-proBNP. 
The analyses will use the methods described above for these continuous outcomes in Section 
8.1.1: 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 6-minute walk test (6MWT) 
• Echocardiograms 
• Serum levels of troponin I, troponin T, and NT-proBNP. 
The analyses will use the methods described above for these categorical outcomes in Section 
8.1.2: 
• Patient Global Assessment (PGA) 
• New York Heart Association (NYHA) classification  
• 6-minute walk test (6MWT) (categorized by level as described below) 
Shift tables will be provided for the following variables: 
• Patient Global Assessment (PGA) 
• New York Heart Association (NYHA) classification  
• 6-minute walk test (6MWT) (categorized as stable, improved, worsened) 
8.3. Safety Analyses 
Safety data will be summarized for the safety analysis population. 
Treatment and Disposition of Subjects: Subject evaluation groups will show end of study 
subject disposition and will show which subjects were analyzed for efficacy, as well as for 
 
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safety (adverse events and laboratory data).  Frequency counts will be supplied for subject 
discontinuation(s) by treatment. 
A listing of treatment duration for each subject will be reported in accordance with the 
sponsor reporting standards. 
Demographic and Baseline Characteristics.  A break-down of demographic data will be 
provided for age, race, weight, body mass index, and height.  Each will be summarized by 
sex at birth and ‘All Subjects’ in accordance with the sponsor reporting standards.  All 
baseline and disease characteristics will also be summarized for Fx1B-201 and B3461026, 
respectively.   
Discontinuations. Subject discontinuations or temporary discontinuations due to adverse 
events will be detailed and summarized.  
Adverse events (AEs): Adverse events will be summarized by causality and severity. 
Mortality and Hospitalization (all-cause and cardiac-related): Time to all-cause mortality 
and time to cardiac-related mortality will be calculated from the first dose of the randomized 
treatment in Study Fx1B-201, and from onset of symptom, respectively. For cardiac-related 
mortality, subjects who died for reasons other than cardiovascular will be designated as 
censored at the time of death. Subjects alive at the end of the study will be censored at the 
last visit date.  Death after discontinuation will be censored at time of discontinuation. For 
subjects who have received a liver and/or heart transplant, time will be censored at the time 
of transplant. The analyses will use the methods described for time to event endpoints in 
Section 8.1.3. The analyses will be performed on the safety analysis population (defined in 
Section 5.1).  
The number and percentage of subjects hospitalized (all-cause and cardiac-related) during the 
study will be summarized descriptively. 
Hematology, Biochemistry and Urinalysis:  Descriptive statistics will be provided for each 
test result and for change from baseline by visit.  
Baseline is defined as the last evaluation prior to the first dose of study drug in Study Fx1B-
201. 
Cardiac Measures: Changes from baseline (defined as the last evaluation prior to the first 
dose of study drug) will be summarized for each of the cardiac parameters listed above by 
visit.  Clinically significant changes in ECG measures (as indicated by the items in Section 
6.2, #6, item h through m) at any point during the study will be summarized.   
Pacemaker and defibrillator insertion procedures will be identified through a programmatic 
search of potentially related terms in the clinical database coupled with a manual review by 
Pfizer Clinical.   
 
The following MedDRA Lower Level Terms (codes) will be applied to the Medical History, 
Adverse Events, and Investigator Comments to identify potential procedures in the clinical 
 
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database: CARDIOVERTER PLACEMENT (10053015), INSERTION OF IMPLANTABLE 
CARDIOVERTER DEVICE (10052044), CARDIAC PACEMAKER INSERTION 
(10007598), PACEMAKER INSERTION (CARDIAC) (10033352), 
DEFIBRILLATOR/PACEMAKER INSERTION (10069072), IMPLANTABLE 
DEFIBRILLATOR INSERTION (10049442).  
 
The following terms will also be searched to identify potential associated procedures 
collected in the Investigator Comments CRF: pacemaker, implantable cardiac device, ICD, 
AICD, cardioversion, cardioverter,  defibrillator, ventricular fibrillation, ventricular 
tachycardia.   
 
Final search criteria and categorization of pacemaker and defibrillator will be based on the 
results of the clinical review and will be described in the programming plan prior to database 
finalization.   
 
The number and percentage of subjects with pacemaker or defibrillator insertion procedures 
(defined above) will be summarized by category and for overall at baseline of Fx1B-201, the 
number and percentage of subjects who have such devices implanted during the course of 
Fx1B-201 and during the course of B3461026 (Fx1B-303), respectively.   
 
Vital signs: Will be summarized using descriptive statistics, to include:  values at each visit, 
change from baseline to each visit and a categorization of clinically significant changes. 
Significant changes from baseline are defined as follows: 
• Systolic Blood Pressure (mmHg) Decrease (Change < -20, or Value < 90) 
• Systolic Blood Pressure (mmHg) Increase (Change > 20, or Value > 180)  
• Diastolic Blood Pressure (mmHg) Decrease (Change < -15, or Value < 50)  
• Diastolic Blood Pressure (mmHg) Increase (Change > 15, or Value > 105)  
• Heart Rate (bpm) Decrease (Change < -15, or Value < 50)  
• Heart Rate (bpm) Increase (Change > 15, or Value > 120)  
• Weight (kg) Decrease (Change < -7%)  
• Weight (kg) Increase (Change > 7%) 
 
Orthostatic hypotension is present under any of the following conditions: 
 
• (Lying Systolic Blood Pressure - Standing Systolic Blood Pressure) >= 20 mmHg, or 
• (Lying Diastolic Blood Pressure - Standing Diastolic Blood Pressure) >= 10 mmHg, 
or 
• (Standing Pulse - Lying Pulse) > 20 bpm along with (Standing Pulse or Lying Pulse > 
100bpm)  
 
If pulse is missing at any visit, then evaluate orthostatic hypotension using only blood 
pressure measures. 
 
 
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Concomitant medications: will be summarized. 
Physical Examination and Medical History: Results will be summarized and listed.   
 
 
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APPENDICES  
Appendix 1. Data Derivation details 
Appendix 1.1. KCCQ (See protocol for a copy of the questionnaire) 
 
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Appendix 1.2. 6 Minute Walk Test Categorization 
 
 
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a. Level 1: < 300 m  
b. Level 2: 300-374.9 m  
c. Level 3: 375-449.9 m  
d. Level 4: ≥ 450 m  
The categories above represent increasing levels of ability. 
 
To determine if a subject has improved, you would create a new variable/flag which would 
be based on the subtraction of [category at time 1] – [category at time 2]. 
 
e.g.:  baseline category – visit 1 category 
 
If this is negative, for example baseline = 2 and visit 1 = 3, thus 2-3 = -1, then the subject 
would be indicated as improved. 
 
If the subtraction is 0 then the subject is unchanged.  And finally, if the subtraction is positive 
then the subject worsened. 
 
Appendix 1.3. Calculation of QTc Interval Corrections 
Fridericia’s heart rate correction formula: QTcF = QT / (RR)1/3 where RR = 60/HR; 
Bazett’s heart rate correction formula: QTcB = QT / (RR)1/2 where RR = 60/HR; 
 
Appendix 2. Definition and Use of Visit Windows in Reporting 
For the purpose of this study, Day 1 is defined as the first dose day under this protocol. 
Day 1 + 1 week 
Every other 3 month telephone visits between clinic visits + 1 week 
Clinic visits every 6 months + 2 weeks 
End of study visit + 2 weeks 
 
However, in order to maximize the use of all available data, the visit windows for each visit 
are expanded as follows:  
 
Day 0:  End of study visit from Fx1B-201  
Day 1 + 1.5 months 
Telephone contact (every 3 months between clinic visits) + 1.5 months  
Clinic visits (every 6 months) + 3 months 
End of study visit (see details below) 
 
In the event that there is a break between the last visit of the parent study (Fx1B-201,) and 
the first day of dosing in the current study Fx1B-303 (B3461026); then the visit associated 
with the first day of enrollment in the current study Fx1B-303 (B3461026) will be the 
baseline visit of this study. 
 
 
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For an early termination visit within study B3461026 (Fx1B-303):  The existing windowing 
rules will be used and as such, the data in the early termination visit should never replace an 
existing visit.  If the visit covered by the windowing rules above is already populated with an 
existing visit, then the EOS visit should be mapped forward to the next clinic visit. 
 
      As an example, the EOS visit occurs at month 68. 
              If there is no month 66 visit, then the EOS visit becomes the month 66 visit. 
              If there is a month 66 visit, then the EOS visit becomes the month 78 visit. 
 
For an unscheduled visit: 
 
If possible, the existing windowing rules will be used, but the data should never 
replace an existing visit.  If the visit is already populated, then the unscheduled visit should 
be mapped forward to the next appropriate visit for that measure if that visit is available. 
            As an example, the unscheduled visit occurs at month 68 and the data are collected 
annually. 
               If there is no month 66 visit, then the unscheduled visit becomes the month 66 visit. 
               If there is a month 66 visit, but no month 78 visit then the unscheduled 
visit becomes the month 78 visit. 
               If there are both month 66 and month 78 visits, then the unscheduled visit is not 
included in the summary analyses but is included in the listing as unscheduled. 
   
 
Appendix 3. Algorithm for imputing missing last dosing date of study drug  
If the last dosing date is missing and the subject has discontinued from the study, the 
following method will be used to impute the missing last dosing date. 
 
If the subject discontinues prior to the next expected visit date (last visit plus 90 days) 
regardless of reason for discontinuation then the last dosing date is the date of 
discontinuation or death whichever is first . 
 
If the subject discontinues after the next expected visit date (last visit plus 90 days) then the 
following will be examined. Note that the use of July 1, 2013 in the algorithm reflects 
the change in capsules dispensed. 
 
If the last visit was a telephone contact and the last visit is prior to or equal to July 1, 
2013 then last dosing day = (last visit + 5 months [151 days]) or date of death or 
date of discontinuation whichever is first. 
 
If the last visit was a telephone contact and the last visit is after to July 1, 2013 then 
last dosing day = (last visit + 4.5 months [136 days]) or date of death or date of 
discontinuation whichever is first. 
 
If the last visit was a clinic visit and the last dosing date is prior to or equal to July 1, 
2013 then last dosing day = (last visit + 4 months [121 days]) or date of death or 
date of discontinuation whichever is first. 
 
 
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If the last visit was a clinic visit and the last dosing date is after to July 1, 2013 then 
last dosing day = (last visit + 3.5 months [106 days]) or date of death or date of 
discontinuation whichever is first. 
 
If there is a partial date of last dose which is just the year of last dose then use the 
previous rule.  If the partial date is a month and year then the last dosing date = 
maximum of last date of the partial date month or the result of the rule whichever 
is first. 
 
Appendix 4. Example SAS code for Delayed Entry Model in Survival Analysis 
Delayed entry model in survival analysis: 
 
The total survival time is the length of time specified by the time variable. Entry into Study 
Fx1B-201 is after the amount of time specified by the los variable, which is defined from 
symptom onset to the start of Fx1B-201. The amount of time that the subjects were at risk in 
this model is time - los. 
 
proc phreg data=data; /* add the METHOD=PL option in the baseline 
statement only when using SAS version 9.2 or higher */ 
    model time*deathflag(0)= /entry=los; 
  baseline out=table survival=S stderr=stderr atrisk=atrisk /method=pl ;   
 
 
 
 
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