GLOBAL PREVALENCE OF TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM) IN PARTICIPANTS WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)
Phase: NA
Conditions: Transthyretin Amyloid Cardiomyopathy, Heart Failure With Preserved Ejection Fraction
Sponsor: Pfizer

Protocol B3461087 
Amendment 2, 20 Aug 2020 
PFIZER CONFIDENTIAL 
Page 1 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be promptly 
notified. 
 
 
 
 
 
 
 
 
 
 
 
 
GLOBAL PREVALENCE OF TRANSTHYRETIN AMYLOID CARDIOMYOPATHY 
(ATTR-CM) IN PARTICIPANTS WITH HEART FAILURE WITH PRESERVED 
EJECTION FRACTION (HFpEF) 
 
 
Therapeutic Area: 
Rare Diseases 
Protocol Number: 
B3461087 
EudraCT Number: 
2020-002378-29 
NCT# 
04424914 
 
 
 
 
 
 
 

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Protocol Amendment Summary of Changes Table 
 
Document History 
Document 
Version Date 
Summary of Changes and Rationale 
Original protocol 
20 Dec 2019 
Not applicable (N/A) 
Amendment 1 
19 May 2020 
• Coversheet: 
Revision: 
Addition of EudraCT number. 
Rationale: 
Required for EU submissions. 
• Section 1.1 Synopsis; Section 3 
Objectives and Endpoints 
Current protocol CCI 
 
CCI 
; Appendix 2 
Abbreviations 
CCI 
Revision: 
CCI 
Rationale: 
Stress echo not being performed in 
study. 
• Section 1.1 Synopsis; Section 3 
Objectives and Endpoints CCI 
 
CCI 
 
Revision: Additional language 
CCI 
• Section 1.3 Schedule of Activities 
Revision: Editorial revisions for clarity 
in biospecimen collections. 
Rationale: Easier reading. 

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Document History 
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Version Date 
Summary of Changes and Rationale 
Section 1.3 Schedule of Activities, 
and Section 7.1.4 Follow Up Visit 1 
Current protocol: 
Visit day for Follow-Up Visit 1 is 7 
Days post last study visit (± 5 days) 
Revision: 
Visit day for Follow-Up Visit 1 is 14 
Days post last study visit (± 10 days) 
Rationale: 
The visit day and window for Follow- 
Up Visit 1 extended to permit required 
testing and analysis to be performed 
and reported. 
• Section 1.3 Schedule of Activities and 
Section 8.1.1 Screening 
Revision: Addition of Adverse event 
reporting at Screening 
Rationale: Inconsistency with Section 
11.1.2 
• Section 3 Objectives and Endpoints 
Revision: Additional language 
Electrocardiography - e.g.: PR, RR, 
QRS, QT, and corrected ECG QTc 
Interval using the Fridericia’s 
correction (QTcF interval), heart rate, 
and overall interpretation. 
Rationale: 
Addition of parameters to be analyzed 
for electrocardiography. 
• Section 4.4 End of Study Definition 
Section 10 Statistical Considerations 
Current protocol: 
A participant is considered to have 
completed the study if he/she has 
completed all phases of the study 
including the last visit or the last 
scheduled procedure shown in the 
schedule of activities. 

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The end of the study is defined as the 
date of the last visit of the last 
participant in the study or last 
scheduled procedure shown in the 
schedule of activities for the last 
participant in the trial globally. 
Revision: 
PCD has been moved to Section 10. 
Statistical Considerations 
The primary completion date (PCD) for 
the global prevalence estimate will be 
the date when all enrolled participants 
have either been diagnosed with 
ATTR-CM or found to be negative for 
ATTR-CM and have completed 
Follow-up Visit 1. Results will be 
reported at PCD and end of study. 
Rationale: 
All diagnostic assessments are obtained 
at Visit 1. Analyses of data can be 
performed after completion of these 
visits. Analyses of data from follow up 
visits will be performed at the end of 
the study. 
• Section 5.5 Screen Failures 
Minimal information includes 
demography, screen failure details, 
eligibility criteria, and any SAE. 
Revision: Additional language 
Minimal information includes screen 
failure details such as demography, 
eligibility criteria, and any SAE. 
Individuals who do not meet the 
criteria for participation in this study 
(screen failure) will be recorded as a 
screen failure but may be rescreened at 
a later date. Re-screened participants 
will be assigned a new screening 
number. Pfizer approval should be 
provided prior to re-screening a 
participant. 

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Document History 
Document 
Version Date 
Summary of Changes and Rationale 
Rationale: 
Rewording of language for ease of 
reading. Participants may not be able to 
complete required assessments for 
screening within the protocol specified 
timing. 
Section 6.2 Study Intervention 
Current protocol: 
Not applicable. 
Revision: 
No study treatment is administered. 
For the purposes of this protocol, study 
intervention refers to requirement for 
scintigraphy, possible endomyocardial 
biopsy and biological specimens. 
Rationale: 
Correct inconsistency. 
• Section 7.2 Participant 
Discontinuation/Withdrawal from 
the Study and Vital Status Follow-up 
Current protocol: 
A participant may withdraw from the 
study at any time at his/her own 
request. Reasons for discontinuation 
from the study include the following:… 
AND 
Due to assessment of vital status at 
Follow-Up 2, a Release of Medical 
Information Form will be required of 
all participants …. 
Revision: 
A participant may withdraw from the 
study at any time at his/her own 
request. Reasons for discontinuation 
from the study include but are not 
limited to the following: 
AND 
Due to assessment of vital status at 
Follow-Up Visit 2, a Release of 
Medical Information Form 

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Document History 
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Version Date 
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Rationale: 
Participants may discontinue for other 
reasons not included in the list such as 
Adverse Event. Vital status is obtained 
at Follow-up Visit 2. 
• Section 8.1.3 Visit 2; Section 8.2.4 
TTR Genotyping 
Current protocol: 
The following procedures will be 
completed at Visit 2. 
o Collect blood sample for TTR 
genotyping (if not done at Visit 
1). 
o Serum/Urine test for primary 
(light chain) amyloidosis (if not 
done at Visit 1). 
Revision: 
Blood sample for TTR genotyping and 
Serum/Urine test for primary (light 
chain) amyloidosis were deleted from 
Visit 2 to be consistent with Section 1.3 
Schedule of Activities (SoA). 
Rationale: 
Correct inconsistency in protocol. 
• Section 8.1.5 Follow Up Visit 2 
Current protocol: 
Participants should be followed for 
28 days after the last study visit to 
collect any AE/SAE information. This 
post-study follow-up can be conducted 
at the study site or by telephone. 
Revision: 
This visit is eliminated from the study. 
Rationale: 
Visit schedule streamlined to eliminate 
possible overlap of visits and duplicate 
data entry and payment. 

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Document History 
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Version Date 
Summary of Changes and Rationale 
• Section 8.2.6 
Current protocol: 
If a machine-read QTc value is 
prolonged, repeat measurements may 
not be necessary if a qualified 
physician’s interpretation determines 
that the QTc values are in the 
acceptable range. 
Revision: 
If a machine-read QTc value is 
prolonged, repeat measurements may 
not be necessary if a qualified 
physician’s interpretation determines 
that the QTc values using Fridericia’s 
formula are in the acceptable range. 
Rationale: 
Clarification that Fridericia’s formula 
should be used to evaluate QTc. 
• Section 8.2.15 Physical Examination 
and Height and Weight Measurement 
Revision: Additional language 
Units of inches for height and pounds 
for weight added. 
Rationale: 
To collect the value as determined by 
the clinical site without the need for a 
calculation. 
• Section 8.1.6 Follow Up Visit 3 
Current protocol: 
This visit will occur 6 months after 
diagnosis or at time of early 
discontinuation. 
Revision: 
This visit becomes Follow-Up Visit 2 
and will occur 6 months after Follow- 
up Visit 1 or at time of early 
discontinuation. 
Rationale: 
Correct inconsistency in protocol and 
accommodate the removal of a follow 

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Document History 
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Version Date 
Summary of Changes and Rationale 
up visit. 
• Section 8.2.6 Echocardiography 
Current protocol: 
Echocardiography (2D Doppler) will 
be performed for all participants at 
Screening. The assessment of end 
diastolic interventricular septal 
thickness for study entry will be based 
on the echocardiogram performed at 
the Screening visit as interpreted by the 
independent central laboratory. If the 
Screening echocardiographic recording 
is not clear enough to accurately 
determine the end diastolic 
interventricular septal wall thickness it 
must be repeated. 
Revision: 
Echocardiography (2D Doppler) will 
be performed for all participants at 
Screening. The assessment of end 
diastolic interventricular septal 
thickness and left ventricular ejection 
fraction for study entry will be based 
on the echocardiogram performed at 
the Screening visit as interpreted by the 
independent central laboratory. If the 
Screening echocardiographic recording 
is not clear enough to accurately 
determine the end diastolic 
interventricular septal wall thickness 
and left ventricular ejection fraction, it 
must be repeated. 
Rationale: 
Both assessments are required for 
eligibility. 
• Section 8.2.5 Testing for Light Chain 
Amyloid 
Current protocol: 
Specifications for testing samples are 
provided in the study laboratory 

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manual. Elderly participants with 
reduced renal function may experience 
elevations in levels of free kappa light 
chains and free lambda light chains 
with no change in the kappa/lambda 
ratio. Participants with elevated 
serum/urine levels of free kappa light 
chain, free lambda light chain and a 
serum free kappa/lambda ratio 
indicative of light chain amyloidosis 
(monoclonal gammopathy of unknown 
significance [MGUS]) will require 
confirmatory test using mass 
spectrometry or immunohistochemistry 
with electron microscopy or 
scintigraphy. Samples will be collected 
for all participants, but only analyzed 
for those with scintigraphy Grades 1-3. 
Revision: 
Specifications for testing samples are 
provided in the study laboratory 
manual. Blood specimen for measuring 
the ratio of kappa to lambda light 
chains with the serum free light chain 
assay and testing for immunofixation 
electrophoresis of serum and urine will 
be obtained from all participants, but 
only analyzed for those with 
scintigraphy Grades 1-3. Participants 
with serum or urine test result 
indicative of monoclonal gammopathy 
of undetermined significance (MGUS) 
will require a confirmatory biopsy 
performed locally. 
Rationale: 
Exclusion criteria for ruling out Light 
chain amyloid in clinical practice has 
been updated. Definition of MGUS has 
been corrected and edited for easier 
reading. 

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Document History 
Document 
Version Date 
Summary of Changes and Rationale 
CCI 

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Document History 
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Version Date 
Summary of Changes and Rationale 
CCI 
• Section 8.2.17. Body Mass 
Index/Modified Body Mass Index 
Revision: Additional language 
Height and weight collected at 
Screening will be used for this 
calculation. 
Rationale: 
Provide clarification that assessments 
collected for the study are to be used 
for calculation. 
• Section 9.2. Banked Specimens for 
Biomarkers 
Current protocol: 
Additional Banked Biospecimens 
collected at Visit 1 in this study are: 
10 mL whole blood Prep R1 optimized 
for RNA; Prep B1 optimized for 
plasma. 10-mL urine (Prep M2). 
Revision: 
• 
2.5mL whole blood (Prep R1 
optimized for RNA); 
• 
10-mL whole blood (Prep B1 
optimized for plasma); 
• 
10-mL urine (Prep M4). 
Rationale: 
• 
Blood volumes for the Prep R1 
specimen has been updated and 
Prep R1 and Prep B1 are separated 
for clarity. The total blood 
volume is ~104 mL as noted in 
Section 9.1. Sections 9.4 & 9.5 

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Document History 
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Version Date 
Summary of Changes and Rationale 
have been reworded for clarity. 
Substance of information has not 
changed. 

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Document History 
Document 
Version Date 
Summary of Changes and Rationale 
Amendment 2 
20 Aug 2020 
• Coversheet 
Revision: 
NCT number added. 
• General 
Editorial revisions. 
• Section 1.1 Synopsis 
Objectives and Endpoints 
Secondary endpoints: 
Current protocol: 
CCI 
 
Revision: 
CCI 
Rationale: 
Study simplified to improve feasibility. 
• Tertiary endpoints: 
Current protocol: 
• Electrocardiogram - e.g.: PR, RR, 
QRS, QT, and corrected ECG QTc 
Interval using the Fridericia’s 
correction (QTcF interval), heart rate, 
and overall interpretation. 
•TTR concentration. 
Revision: 
6-MWT added. ECG and TTR 
concentration were eliminated from 
protocol therefore will not be included 
in analysis. 
Rationale: 
Study simplified to improve feasibility 
• Number of Participants 
Current protocol: 
The empirical estimate for the 
prevalence of ATTR-CM in HFpEF 
participants is approximately 10%. 
The study will enroll approximately 
2500 HFpEF participants within whom 
it is expected to detect 250 ATTR CM 

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participants. Enrollment will be 
stopped if 250 ATTR CM participants 
are identified before 2500 HFpEF are 
enrolled. No formal sample size 
calculation was performed. A sample 
size of 2500 HFpEF participants would 
be adequately large to impact treatment 
guidelines and yield an estimate for the 
global prevalence of ATTR CM in 
HFpEF participants with a precision of 
±2.5%. 
Revision: 
The empirical estimate for the 
prevalence of ATTR-CM in HFpEF 
participants is approximately 10%. 
The study will enroll approximately 
2000 HFpEF participants within whom 
it is expected to detect 200 ATTR CM 
participants. Enrollment will be 
stopped if 200 ATTR CM participants 
are identified before 2000 HFpEF are 
enrolled. No formal sample size 
calculation was performed. A sample 
size of 2000 HFpEF participants would 
be sufficient to inform treatment 
guidelines and yield an estimate for the 
global prevalence of ATTR CM in 
HFpEF participants with a precision of 
±2.5%. 
Rationale: 
Sample size was decreased to 
2000 which is adequate to meet 
prevalence precision. 
• Statistical Analysis 
Revision: 
Visit 2 will be deleted from Safety 
Analysis. 
Rationale: 
Study simplified to improve feasibility. 

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Document History 
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• Section 1.4 Schedule of Activities 
Current protocol: 
Echo and NT-Pro-BNP performed at 
Screening; 
Biopsy performed at Visit 2; 
ECG, 6-MWT; blood collection 
for cardiac troponin I &T, 
creatinine, albumin, TTR 
concentration, blood and urine 
for banked biospecimens; mBMI, 
eGFR obtained at visit 1. 
Revision: 
Visit 2 was deleted; footnote a revised 
to: Echo performed if previous echo 
was > or = 6 months prior to screening 
visit. If echo was performed within 6 
months prior to screening and results 
are available, the echo can be used for 
study and does not need to be repeated. 
NT-Pro-BNP will be collected at Visit 
1. 
The following assessments were 
deleted: ECG, TTR concentration, 
banked biospecimens. Subsequent 
diagnosis testing was added to table. 
Rationale: 
Study simplified to improve feasibility. 
• Section 3 Objectives and Endpoints 
Secondary endpoints: 
CCI 
CCI 

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Document History 
Document 
Version Date 
Summary of Changes and Rationale 
CCI 
• Section 4.1 Overall Design 
Current protocol: 
The study will enroll approximately 
2500 participants. 
Revision: 
The study will enroll approximately 
2000 participants. 
Rationale: 
Sample size was decreased to 
2000 which is adequate to meet 
prevalence precision. 
• Section 5.1 Inclusion Criteria 
Current protocol: 
#5. Willing and able to undergo 
scintigraphy and biopsy (if Grade 1 
scintigraphy); #6. NT-ProBNP ≥600 
pg/ml. 
Revision: 
#5. Willing and able to undergo 
scintigraphy; #6 NT-Pro-BNP criterion 
eliminated 
Rationale: 
Endomyocardial biopsy requirement 
eliminated from protocol. Study 
simplified to improve feasibility; NT- 
Pro-BNP criterion eliminated for 
enrollment. 

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• Section 5.2 Exclusion Criteria 
Current protocol: 
#2. Presence or history of ischemic 
heart disease affecting at least 1 of the 
main coronary arteries. 
Revision: 
Prior clinical history of myocardial 
infarction, CABG or multi-vessel 
obstructive coronary disease (>50% 
stenosis of ≥2 epicardial coronary 
arteries). 
Rationale: 
To focus criterion on the medical to the 
aged HFpEF population and their 
associated comorbidities. 
• Section 6.2 Study Intervention 
Current protocol: 
For the purposes of this protocol, study 
intervention refers to requirement for 
scintigraphy, possible endomyocardial 
biopsy and biological specimens. 
Revision: 
For the purposes of this protocol, study 
intervention refers to requirement for 
scintigraphy and biological specimens. 
Rationale: 
Endomyocardial biopsy requirement 
eliminated from protocol. Study 
simplified to improve feasibility. 
• Section 8.1 Procedures 
Current protocol: 
The total blood sampling volume for 
individual participants in this study is 
approximately 104 mL. 
• Revision: 
The total blood sampling volume for 
individual participants in this study is 
approximately 63 mL. 
Additional language: 

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Protocol-specified safety laboratory 
tests may be performed at a local 
laboratory if the study participant is 
unable to visit the study site, where 
allowable by law or local guidance. 
Local laboratory reference ranges need 
to be documented. 
• Rationale: 
Some blood tests have been eliminated. 
Remote visits are permitted for 
consistency with local COVID-19 
guidance. 
• Section 8.1.1 Screening Visit 
Current protocol: 
Echocardiography; NT-ProBNP ≥600 
pg/ml. 
• Revision: 
Echocardiography (unless obtained ± 6 
months prior to Screening Visit and 
results are available); NT-ProBNP 
inclusion eliminated and assessment 
moved to Visit 1. 
Rationale: 
Study simplified to improve feasibility. 
• Section 8.1.2 Visit 1 
Current protocol: 
• Single 12-lead ECG- perform ECG 
prior to any blood collection or blood 
pressure measurements. 
Revision: 
NT-Pro-BNP has been moved from 
Screening to Visit 1. ECG, TTR 
concentration and banked biospecimens 
have been deleted. 
Rationale: 
Study simplified to improve feasibility. 
• Section 8.1.3 Visit 2 
Revision: 
Section deleted. 

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Rationale: 
Endomyocardial biopsy is no longer 
required therefore visit deleted. 
• Section 8.1.4 Follow-up 1 Visit 
Current protocol: 
Participants will be informed of their 
diagnosis and collect any AE/RRI 
information within 14 days of their last 
study visit. For participants with either 
a scintigraphy grade 0 OR grade 2 or 
higher, Follow-up Visit 1 will occur 14 
days after Visit 1. For participants who 
require a biopsy, Follow-up Visit 1 will 
occur 14 days after Visit 2. 
Revision: 
Participants will be informed of their 
diagnosis and collect any AE/RRI 
information within 14 days (+10 days) 
of study visit 1. 
Rationale: 
Endomyocardial Biopsy is no longer 
required so Visit 2 has been eliminated. 
• Section 8.1.5 Follow-up 2 Visit 
Current protocol: 
Participants diagnosed with ATTR-CM 
will be contacted to assess current 
medications and vital status 
(alive/dead). 
Revision: 
Participants with scintigraphy of grade 
1 or higher will be contacted to assess 
current medications and vital status . 
Participants with scintigraphy grade 1 
will be asked if they have undergone a 
biopsy or other testing as follow up to 
their scintigraphy since their last visit. 
Data will be collected on method of 
diagnosis and whether it confirmed the 
presence of ATTR-CM. This post study 
follow up can be conducted remotely. 

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This will occur 6 months after the 
Follow-up 1 Visit (+/- 30 days) or at 
early study discontinuation. 
Rationale: 
Endomyocardial biopsy is no longer 
required in the protocol. Collection of 
available diagnosis information on 
participants with scintigraphy grade 1. 
• Section 8.2.1.1 Endomyocardial 
biopsy 
Revision: 
Section deleted. 
Rationale: 
Study simplified to improve feasibility. 
• Section 8.2.2 Echocardiogram 
Current protocol: 
Echocardiography (2D Doppler) will 
be performed for all participants at 
Screening. Each echocardiogram will 
be sent to an independent central 
laboratory that will conduct a 
centralized review of the results for 
determination of eligibility. The 
central reading of the Screening 
echocardiogram must be completed 
prior to participant enrollment. The 
assessment of end diastolic 
interventricular septal thickness and 
left ventricular ejection fraction for 
study entry will be based on the 
echocardiogram performed at the 
Screening visit as interpreted by the 
independent central laboratory. 
Revision: 
Echocardiography (2D Doppler) will 
be performed for all participants at 
Screening unless one has been obtained 
within 6 months prior to Screening 
Visit and results are available. The 
assessment of end diastolic 

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interventricular septal thickness and 
left ventricular ejection fraction for 
study entry will be based on the 
echocardiogram performed at the 
Screening visit as interpreted locally by 
the site. Additional parameters to be 
measured: End diastolic 
interventricular septal wall thickness 
(mm), End-diastolic left ventricular 
posterior wall thickness (mm), Left 
ventricular ejection fraction (%), Left 
atrial diameter, anterior posterior 
(mm), Left atrial diameter, medio 
lateral (mm), Left atrial diameter, 
superior inferior (mm), Left ventricular 
end systolic diameter (mm), Left 
ventricular end systolic volume (mL), 
Left ventricular end diastolic diameter 
(mm), Left ventricular end diastolic 
volume (mL), E/A Ratio, E/E’ Ratio. 
Rationale: 
Study simplified to improve feasibility. 
Central readings will no longer be 
performed. Collection of aortic valve 
parameters to monitor presence of 
aortic stenosis. 
• Section 8.2.3 Cardiac Biomarkers: N 
Terminal Pro-Hormone Brain 
Natriuretic Peptide (NT-proBNP) 
and CCI 
Curr 
A 2.5 mL blood sample for NT- 
proBNP will be collected at Screening. 
CCI 
Revision: 
A 2.5 mL blood sample for NT 
proBNP will be collected at Visit 1 and 
analyzed locally by the investigator 
site. CCI 

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CCI 
Rationale: 
Study simplified to improve feasibility. 
• Section 8.2.5 TTR Genotyping 
Current protocol: 
Samples will be collected for all 
participants, but only analyzed for 
those that are diagnosed with ATTR 
CM. The sample will be sent to a 
reference laboratory for complete 
genomic sequencing. 
Revision: 
Samples will be collected for all 
participants, but only analyzed for 
those with scintigraphy grades 1, 2, & 
3. The sample will be sent to a 
reference laboratory for complete 
genomic sequencing of TTR gene. 
Rationale: 
Participants with scintigraphy grade 1 
may not have biopsy confirmation of 
ATTR-CM therefore, clarification 
added to perform genotyping on 
participants with scintigraphy grades 1- 
3. Also, clarity provided for 
sequencing. 
• Section 8.2.6 Electrocardiogram 
Revision: 
Assessment eliminated from protocol. 
Rationale: 
Study simplified to improve feasibility. 
CCI 

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CCI 
• Section 8.2.11 TTR Concentration 
Revision: 
Section deleted. 
Rationale: 
Study simplified to improve feasibility. 
CCI 
• Section 8.2.16. Body Mass 

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Index/Modified Body Mass Index 
Current protocol: 
A modified Body Mass Index (mBMI) 
will be calculated at Visit 1 as weight 
(kg)/[height (meters)]2. The mBMI is 
calculated by multiplying BMI by 
serum albumin concentration (g/L). A 
blood sample (2.5 mL) will be 
collected at Visit 1 to measure serum 
albumin. Height and weight collected 
at Screening will be used for this 
calculation. 
Revision: 
Serum albumin test is not required in 
the protocol, however, if a serum 
albumin has been obtained within 6 
months of Screening visit, data will be 
collected. 
Rationale: 
Study simplified to improve feasibility. 
• Section 8.2.17 Vital Status 
Current protocol: 
Participants, or their delegate, will be 
contacted at Follow-up 3 to determine 
vital status (alive or dead). 
Revision: 
Participants, or their delegate, will be 
contacted at Follow-up 2 to determine 
vital status. For participants who had 
scintigraphy grade 1 at Visit 1, 
subsequent testing information will be 
collected. 
Rationale: 
Diagnosis data collection. 
• Section 8.3.1 Adverse Events 
Current protocol 
Any AE that occurs from the time the 
participant signs the informed consent 
through and including 28 days 
following the participant’s last visit 

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(Follow-up Visit 1) must be recorded. 
Revision: 
Any AE that occurs from the time the 
participant signs the informed consent 
through and including 14 days 
following the participant’s last visit 
(Follow-up Visit 1) must be recorded. 
Rationale: 
Correct inconsistency with SoA. 
• Section 9.1 Banked Biospecimens for 
Genetics 
Revision: 
Section has been deleted 
Rationale: 
Study simplified to improve feasibility. 
• Section 9.2 Banked Biospecimens for 
Biomarkers 
Revision: 
Section has been deleted. 
Rationale: 
Study simplified to improve feasibility. 
• Section 9.3 ATTR Biomarker 
Identification and Validation 
Revision: 
Section moved to Section 8.2.4. 
Rationale: 
Improvement in protocol flow. 
• Section 9 Statistical Considerations 
Current protocol: 
The empirical estimate for the 
prevalence of ATTR-CM in HFpEF 
participants is approximately 10%. 
The study will enroll approximately 
2500 HFpEF participants within whom 
it is expected to detect 250 ATTR CM 
participants. Enrollment will be 
stopped if 250 ATTR CM participants 
are identified before 2500 HFpEF are 

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Document History 
Document 
Version Date 
Summary of Changes and Rationale 
enrolled. No formal sample size 
calculation was performed. A sample 
size of 2500 HFpEF participants would 
be adequately large to impact treatment 
guidelines and yield an estimate for the 
global prevalence of ATTR CM in 
HFpEF participants with a precision of 
±2.5%. 
Revision: 
The empirical estimate for the 
prevalence of ATTR-CM in HFpEF 
participants is approximately 10%. 
The study will enroll approximately 
2000 HFpEF participants within whom 
it is expected to detect 200 ATTR CM 
participants. Enrollment will be 
stopped if 200 ATTR CM participants 
are identified before 2000 HFpEF are 
enrolled. No formal sample size 
calculation was performed. A sample 
size of 2000 HFpEF participants would 
be sufficient to inform treatment 
guidelines and yield an estimate for the 
global prevalence of ATTR CM in 
HFpEF participants with a precision of 
±2.5%. 
Rationale: 
Sample size was decreased to 
2000 which is adequate to maintain the 
precision. 
• Section 9 Statistical Analysis – 
Analysis by Scintigraphy, Analysis 
by Disease Status, Safety Analysis 
Revision: 
Visit 2 will be deleted from Safety 
Analysis. 
Rationale: 
Study simplified to improve feasibility. 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs. 

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TABLE OF CONTENTS 
1. PROTOCOL SUMMARY ................................................................................................... 30 
1.1. Synopsis ................................................................................................................... 30 
1.2. Rationale .................................................................................................................. 34 
1.3. Schema .................................................................................................................... 34 
1.4. Schedule of Activities (SoA) ................................................................................... 35 
2. STUDY INTRODUCTION ................................................................................................. 37 
2.1. Rationale .................................................................................................................. 37 
2.2. Background .............................................................................................................. 37 
2.3. Benefit/Risk Assessment ......................................................................................... 38 
3. OBJECTIVES AND ENDPOINTS ..................................................................................... 39 
4. STUDY DESIGN ................................................................................................................. 40 
4.1. Overall Design ......................................................................................................... 40 
4.2. Scientific Rationale for Study Design ..................................................................... 40 
4.3. Justification for Dose ............................................................................................... 41 
4.4. End of Study Definition ........................................................................................... 41 
5. STUDY POPULATION ...................................................................................................... 41 
5.1. Inclusion Criteria ..................................................................................................... 41 
5.2. Exclusion Criteria .................................................................................................... 42 
5.3. Schema .................................................................................................................... 42 
5.4. Lifestyle Requirements ............................................................................................ 42 
5.5. Screen Failures ......................................................................................................... 42 
6. STUDY INTERVENTION .................................................................................................. 43 
6.1. Participant Compliance ............................................................................................ 43 
6.2. Study Intervention.................................................................................................... 43 
6.3. Study Intervention Storage ...................................................................................... 43 
6.4. Measures to Minimize Bias: Randomization and Blinding ..................................... 43 
6.5. Study Intervention Accountability ........................................................................... 43 
6.6. Concomitant Treatment(s) ....................................................................................... 43 
7. PARTICIPANT DISCONTINUATION/WITHDRAWAL ................................................. 43 
7.1. Discontinuation of Study Intervention ..................................................................... 43 

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7.2. Participant Discontinuation/Withdrawal from the Study and Vital Status 
Follow-up ...................................................................................................................43 
7.3. Withdrawal of Consent: ...........................................................................................44 
7.4. Lost to Follow-up ....................................................................................................44 
8. STUDY ASSESSMENTS AND PROCEDURES ...............................................................45 
8.1. Procedures ...............................................................................................................45 
8.1.1. Screening Visit ............................................................................................46 
8.1.2. Visit 1 ..........................................................................................................46 
8.1.3. Follow-up 1 Visit ........................................................................................47 
8.1.4. Follow-up 2 Visit ........................................................................................47 
8.2. Assessments .............................................................................................................47 
8.2.1. Scintigraphy ................................................................................................47 
8.2.1.1. Management of Incidental Findings from Scintigraphy ............48 
8.2.2. Echocardiogram ..........................................................................................48 
8.2.3. Cardiac Biomarkers: N-Terminal Pro-Hormone Brain Natriuretic 
Peptide (NT-proBNP) CCI ....................................................................................... 49 
8.2.4. Biospecimens for ATTR-CM Biomarker Identification and 
Validation .........................................................................................................49 
8.2.5. TTR Genotyping .........................................................................................49 
8.2.6. Testing for Light Chain Amyloid................................................................50 
8.2.7. Medical History ..........................................................................................50 
8.2.8. Vital Signs ...................................................................................................50 
8.2.9. Medications .................................................................................................51 
8.2.11. NYHA Classification ................................................................................51 
8.2.14. Physical Examination and Height and Weight Measurement ...................52 
8.2.17. Vital Status ................................................................................................53 
8.2.18. Subsequent Diagnosis of ATTR-CM ........................................................53 
8.3. Safety .......................................................................................................................53 
CCI 
CCI 
CCI 

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8.3.1. Adverse Events ........................................................................................... 53 
8.3.2. Research Related Injury .............................................................................. 53 
9. STATISTICAL CONSIDERATIONS ................................................................................. 54 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................... 56 
10.1. Regulatory, Ethical, and Study Oversight Considerations ..................................... 56 
10.1.1. Regulatory and Ethical Considerations ..................................................... 56 
10.1.2. Informed Consent Process ........................................................................ 57 
10.1.3. Data Protection .......................................................................................... 58 
10.1.4. Data Quality Assurance............................................................................. 58 
10.1.5. Source Documents .................................................................................... 59 
10.1.6. Study and Site Closure .............................................................................. 60 
10.1.7. Publication Policy ..................................................................................... 60 
10.1.8. Sponsor’s Qualified Medical Personnel .................................................... 61 
CCI 
 
APPENDIX 2. ABBREVIATIONS ......................................................................................... 63 
11. REFERENCES ................................................................................................................... 65 

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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Rationale 
Transthyretin Amyloid Cardiomyopathy (ATTR-CM) occurs when transthyretin amyloid 
fibrils infiltrate the myocardium, leading to deposits of extracellular amyloid. Deposition of 
transthyretin fibrils occurs between the myocardial cells and produces a thickening and 
stiffening of the myocardial tissue. This infiltration of the myocardium results in diastolic 
dysfunction progressing to restrictive cardiomyopathy, congestive heart failure, and 
ultimately death. 
 
The most frequent form of heart failure (HF) in patients with ATTR-CM is HF with 
preserved ejection fraction (HFpEF). HFpEF is also the most common form of heart failure 
in elderly patients and accounts for up to 50% of HF-related hospital admissions. It has 
recently been described that ATTR-CM is significantly underdiagnosed and may be more 
common than current prevalence estimates. The purpose of this study is to assess the 
prevalence of ATTR-CM in the HFpEF population. 
 
Objectives and Endpoints 
 
Primary Objective(s): 
Primary Endpoint(s): 
To assess the prevalence of 
ATTR-CM among patients with 
HFpEF within a clinically at-risk 
population. 
Estimate of global prevalence of ATTR-CM in 
HFpEF patients. Diagnosis of ATTR-CM is 
defined by: 
• Cardiac Scintigraphy Grade 1, with 
confirmation of ATTR by cardiac biopsy, or: 
• Cardiac Scintigraphy Grade 2 or above. 
Secondary Objective(s): 
Secondary Endpoint(s): 
To assess variations in prevalence of 
ATTR-CM (wild-type [WT] and 
hereditary) among patients with 
HFpEF at a country, regional, and 
global level. 
• Estimate of prevalence of ATTR-CM in 
patients with HFpEF based on: 
• Geographical or regional distribution; 
• Age categories; 
• Gender. 
• Proportion of patients with WT and hereditary 
forms among patients diagnosed with 
ATTR-CM. 
• Baseline characteristics of HFpEF patients 

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with and without ATTR-CM: 
• New York Heart Association (NYHA) 
classification; 
• NT-proBNP. 
CCI 

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Overall Design 
 
This study is a global, multi-center epidemiology study designed to estimate the global 
prevalence of ATTR-CM in participants with HFpEF within a clinically at-risk population. 
 
Number of Participants 
 
The empirical estimate for the prevalence of ATTR-CM in HFpEF participants is 
approximately 10%. The study will enroll approximately 2000 HFpEF participants within 
whom it is expected to detect 200 ATTR-CM participants. Enrollment will be stopped if 
200 ATTR-CM participants are identified before 2000 HFpEF are enrolled. No formal 
sample size calculation was performed. A sample size of 2000 HFpEF participants would be 
sufficient to inform treatment guidelines and yield an estimate for the global prevalence of 
ATTR-CM in HFpEF participants with a precision of ±2.5%. 
 
Statistical Methods 
 
The primary endpoint is an estimate of the global prevalence of ATTR-CM in HFpEF 
participants. Diagnosis of ATTR-CM is defined as: 
 
• Cardiac Scintigraphy Grade 1, with confirmation of ATTR by cardiac biopsy; or 
• Cardiac Scintigraphy Grade 2 or above. 
This global prevalence estimate will be obtained by dividing the number of participants 
who are diagnosed with ATTR-CM in the study by the total number of HFpEF 
participants evaluated. A 95% confidence interval on the estimate will also be calculated. 
 
As secondary analysis, prevalence will be estimated for: 
 
• Regions and countries; 
• Age categories (60-64, 65-69, 70-74, 75-79, 80-85, >85); 
CCI 

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CCI 
• Gender (male, female). 
Prevalence estimates along with 95% confidence interval (CI) will be generated for 
regions and countries with at least 50 participants. For regions and countries that enroll 
fewer than 50 participants, prevalence will not be estimated. Regions will be defined in 
the statistical analysis plan. The proportion of HFpEF participants who were diagnosed 
with wild-type and variant ATTR-CM will be descriptively summarized. 
 
As a general rule, the secondary endpoints other than the prevalence estimates and all 
CCI 
 reported as numerical values will be analyzed descriptively using 
mean, standard deviation, median, minimum, and maximum. Endpoints that are categorical 
will be summarized using frequency tables. 
 
Analysis by Scintigraphy: 
 
Participants who are diagnosed with ATTR-CM will be analyzed by scintigraphy grades 
(Grade 1, 2, or 3) using the 6-MWT, NT-proBNP, medical history, demographics (including 
age, TTR Genotype, gender and race), NYHA classification (Class I, II, III, or IV), and all 
Analysis by Disease Status: 
 
Participants who are diagnosed with ATTR-CM will be analyzed by NYHA Classification 
(Class I, II, III, or IV) using the 6-MWT, NT-proBNP, medical history, demographics 
(including age, TTR Genotype, gender, and race)CCI 
CCI 
 
 
Participants who are diagnosed with ATTR-CM will also be analyzed by 6-MWT quartile 
groups using NYHA classification (Class I, II, III, or IV), NT-proBNP, medical history, 
demographics (including age, TTR Genotype, gender, and race)CCI 
  
CCI 
 
 
Analysis Comparing ATTR-CM participants with HFpEF patients without ATTR-CM: 
 
HFpEF participants diagnosed with ATTR-CM will be compared with HFpEF participants 
not diagnosed with ATTR-CM descriptively using medical history, demographics (including 
age, TTR Genotype, gender, and race)CCI 
Medical history data will be used to generate descriptive statistics for time from symptom 
onset to HFpEF diagnosis and time from symptom onset to ATTR-CM diagnosis. 
 
Endpoints measuring proportion of participants (NYHA Classification and symptoms of 
interest from medical history) will be compared between HFpEF participants diagnosed with 
ATTR-CM and those that are not diagnosed with ATTR-CM. The Chi-square test will be 
used to compare the proportions between these 2 groups of HFpEF participants. Fisher’s 
exact test will be used instead of the chi-square test if any one of the cells has ≤5 participants. 
Secondary CCI 
 numerical endpoints that are normally distributed will be 

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compared between 2 groups of HFpEF participants using a t-test. Endpoints that are not 
normally distributed will be compared using the Wilcoxon rank sum test. 
 
Safety Analysis: 
 
Adverse events (AEs) and research related injuries (RRI) collected at Visit 1 or during 
follow-up, will be summarized overall and separately for HFpEF participants diagnosed with 
ATTR-CM and HFpEF participants not diagnosed with ATTR-CM. 
 
1.2. Rationale 
Transthyretin Amyloid Cardiomyopathy (ATTR-CM) occurs when transthyretin amyloid 
fibrils infiltrate the myocardium, leading to deposits of extracellular amyloid. Deposition of 
transthyretin fibrils occurs between the myocardial cells and produces a thickening and 
stiffening of the myocardial tissue. This infiltration of the myocardium results in diastolic 
dysfunction progressing to restrictive cardiomyopathy, congestive heart failure, and 
ultimately death. 
 
The most frequent form of HF in patients with ATTR-CM is HF with preserved left 
ventricular ejection fraction (HFpEF).1 HFpEF is also the most common form of HF in 
elderly patients and accounts for up to 50% of HF-related hospital admissions.2,3 It has 
recently been described that ATTR-CM is significantly underdiagnosed and may be more 
common than current prevalence estimates. The purpose of this study is to assess the 
prevalence of ATTR-CM in the HFpEF population. 
 
1.3. Schema 
Not Applicable. 

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C 
CCI 
CCI 
nal 
1.4. Schedule of Activities (SoA) 
The SoA table provides an overview of the protocol visits and procedures. Refer to the 
Section 8 of the protocol for detailed information on each procedure and assessment required 
for compliance with the protocol. 
 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA 
table, in order to conduct evaluations or assessments required to protect the well-being of the 
participant. 
 
Visit Identifier 
Screeningb 
Visit 1b 
Follow-up 1bc 
Follow-up 2b,f 
Visit Day 
Day 1 
14 Days Post 
Last Study Visit 
6 Months Post 
Last Study Visit 
Visit Window 
Days -28 to -3 
+10 Days 
±30 Days 
Informed consent 
X 
Review entrance criteria 
X 
Echocardiographya 
X 
Medical History 
X 
Record current medications 
X 
X 
Demography 
X 
NYHA classification 
X 
Physical Examination including height and body 
weight 
X 
Vital Signs 
X 
CCI 
Scintigraphy 
X 
TTR genotypinge 
X 
CCI 
Laboratory samples 
Cardiac Biomarkers (NT-proBNP) 
X 
Serum/Urine tests for primary (light chain) 
amyloidosise 
X 
Blood and Urine specimens for ATTR-CM 
biomarkers 
X 
CCI 
Inform participant of diagnosis 
X 
Adverse Event reporting 
X 
X 
X 
Vital Status 
X 
Subsequent diagnosis testing 
X 
Abbreviations: NYHA = New York Heart Association; CCI 
CI 
TTR – transthyretin; 
 
 
a. 
Echo performed if previous echo was ≥6 months prior to screening visit. If echo was performed within 6 
months prior to screening and results are available, the echo can be used for study and does not need to be 
repeated. 
b. May be performed by remote participant visit. 
c. 
Participants should be followed for 14 days after the last study visit day to collect any AE/RRI information. 
d. Or at early discontinuation. 

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e. 
Sample collected from all participants, only those samples from participants that are scintigraphy 
Grade 1, 2, or 3 will be analyzed. 
f. 
For participants with scintigraphy grade 1, 2 or 3. 

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2. STUDY INTRODUCTION 
2.1. Rationale 
Transthyretin Amyloid Cardiomyopathy (ATTR-CM) occurs when transthyretin amyloid 
fibrils infiltrate the myocardium, leading to deposits of extracellular amyloid. Deposition of 
transthyretin fibrils occurs between the myocardial cells and produces a thickening and 
stiffening of the myocardial tissue. This infiltration of the myocardium results in diastolic 
dysfunction progressing to restrictive cardiomyopathy, congestive heart failure, and 
ultimately death. 
 
The most frequent form of HF in patients with ATTR-CM is HF with preserved left 
ventricular ejection fraction (HFpEF).4 HFpEF is also the most common form of HF in 
elderly patients and accounts for up to 50% of HF-related hospital admissions.5,6 It has 
recently been described that ATTR-CM is significantly underdiagnosed and may be more 
common than current prevalence estimates. The purpose of this study is to assess the 
prevalence of ATTR-CM in the HFpEF population. 
 
2.2. Background 
Transthyretin (TTR) amyloidosis is a rare protein misfolding disease with a broad spectrum 
of manifestations. The condition is caused by the destabilization and dissociation of the 
native TTR tetramer which can result in misfolding and the formation of amyloid fibrils and 
progressive amyloid deposition in tissues.7,8,9,10 This can occur in amounts sufficient to 
impair normal functioning. The 2 major phenotypes which form the spectrum of ATTR 
amyloidosis are transthyretin amyloid polyneuropathy (ATTR-PN), which primarily affects 
the peripheral and autonomic nerves, and ATTR-CM which primarily affects the 
myocardium. These clinical manifestations may occur in isolation or together. Both result in 
progressively impaired function, and ultimately in death. 
 
ATTR-CM is a fatal disorder, characterized by the deposition of misfolded transthyretin 
amyloid fibrils in the ventricular walls (extra-myocardial), causing progressive disruption in 
the ability of the heart to effectively pump blood through the circulatory system. In 
ATTR-CM, the myocardium is the key site of ATTR deposition, and accumulation can lead 
to diastolic dysfunction progressing to restrictive cardiomyopathy and heart failure. 
 
ATTR-CM can be inherited as an autosomal dominant trait caused by mutation in the TTR 
gene, or by deposition of wild-type transthyretin protein, previously called senile systemic or 
senile cardiac amyloidosis.10,11 The median age of patients with wild-type ATTR-CM has 
been reported as 75 years of age at diagnosis.12 In the Tafamidis for ATTR-CM Trial 
(ATTR-ACT) the average age of patients was 74.5 ±7.2 (standard deviation).13 The 
hereditary (genetic variants) form of disease can affect multiple generations in a family and 
have a substantial emotional impact on patients and their families.14 ATTR-CM is associated 
with genetic variants of TTR such as Val122Ile and Leu111Met (also known as familial 
amyloid cardiomyopathy) but may also occur in the absence of a specific mutation (i.e., 
wild-type TTR).10,11 The Val122Ile mutation allele occurs in 3.3% to 4.0% of the US 
African-American population,15,16 and is exceedingly rare in White patients. Median survival 
from diagnosis for patients with ATTR-CM has been reported as 41 months for patients with 

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a Val122Ile mutation and 46 months for patients with ATTR-CM due to wild-type TTR,17 
with most patients dying from cardiac causes, including sudden death, CHF, and myocardial 
infarction.18,19 Untreated ATTR-CM is currently associated with mean progression to death 
within 24 to 36 months (median survival 25.6 months) of diagnosis for variants and up to 60 
months (median survival 43.0 months) for wild type.20 
The prevalence of ATTR-CM is defined as rare, but no prevalence estimates have been 
published. There are more than 120 mutations in the TTR gene which cause a variable 
phenotype determined by the relative extent of amyloid deposition in the myocardium and 
peripheral nerves.21 Though prevalence of wild-type TTR is uncertain, studies using a 
non-biopsy approach to diagnosis22,23 report a prevalence of 13% in HF patients with 
preserved ejection fraction,24 16% in patients undergoing transcatheter aortic valve 
replacement for severe aortic stenosis,25 and 5% of patients with presumed hypertrophic 
cardiomyopathy.26 
ATTR-CM (due to wild-type or variant TTR) uniformly presents with the typical symptoms 
of HF (restrictive cardiac disease) including shortness of breath, dyspnea on exertion, 
orthostatic hypotension, syncope, and dysrhythmias including atrial fibrillation. Signs of 
ATTR-CM are evaluated via testing performed as part of routine HF assessment including 
electrocardiography, echocardiography, and cardiac biomarkers (e.g., N-terminal 
prohormone B type natriuretic peptide [NT-proBNP]). As the symptoms are very 
non-specific, a diagnosis of ATTR-CM may often be delayed for years.27,28 An 
electrocardiogram (ECG) and echocardiogram aid in the diagnosis. Definitive confirmation 
of ATTR-CM has been typically achieved through a cardiac biopsy,29 although cardiac 
magnetic resonance imaging (MRI) and scintigraphy are increasingly used to confirm 
evidence of disease. A non-biopsy approach using technetium-labeled bone scintigraphy 
tracers has been validated as a method for identification of patients with ATTR-CM. This 
approach is highly sensitive and specific for diagnosing ATTR-CM due to both hereditary 
and wild-type disease,18,19,28 and can detect ATTR prior to an increase in left ventricular wall 
thickness or the development of the clinical syndrome of heart failure and a rise in cardiac 
biomarkers30,31 and even predict prognosis.21,30 Early identification and treatment is now 
more likely with the availability of effective diagnostic tools and therapy. 
 
The most frequent form of HF in patients with ATTR-CM is HF with preserved left 
ventricular ejection fraction (HFpEF). HFpEF is also the most common form of HF in 
elderly patients and accounts for 50% of HF-related hospital admissions. It has recently been 
described that ATTR amyloidosis is significantly underdiagnosed, taking into consideration 
that both the clinical presentation and the symptoms are non-specific. The aim of this 
epidemiology study is to assess the prevalence of ATTR-CM in a clinically at risk HFpEF 
population. 
 
2.3. Benefit/Risk Assessment 
Participants in this study will already be diagnosed with HFpEF. Through participation in 
this study a further diagnosis of ATTR-CM will be assessed which will allow the health care 
provider to consider further treatment options for the participant. Potential risk includes 
those inherent from the procedures described. 

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3. OBJECTIVES AND ENDPOINTS 
 
Primary Objective(s): 
Primary Endpoint(s): 
To assess the prevalence of 
ATTR-CM among patients with 
HFpEF within a clinically at-risk 
population. 
Estimate of global prevalence of ATTR-CM in 
HFpEF patients. Diagnosis of ATTR-CM is 
defined as: 
• Cardiac Scintigraphy Grade 1, with 
confirmation of ATTR by cardiac biopsy, or: 
• Cardiac Scintigraphy Grade 2 or above. 
Secondary Objective(s): 
Secondary Endpoint(s): 
To assess variations in prevalence of 
ATTR-CM (wild-type [WT] and 
hereditary) among patients with 
HFpEF at a country, regional, and 
global level. 
• Estimate of prevalence of ATTR-CM in 
patients with HFpEF based on: 
• Geographical or regional distribution; 
• Age categories; 
• Gender. 
• Proportion of patients with WT and hereditary 
forms among patients diagnosed with 
ATTR-CM. 
• Baseline characteristics of HFpEF patients 
with and without ATTR-CM: 
• New York Heart Association (NYHA) 
classification; 
• NT-proBNP. 
CCI 

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4. STUDY DESIGN 
4.1. Overall Design 
This study is a global, multi-center epidemiology study designed to estimate the global 
prevalence of ATTR-CM in participants with HFpEF within a clinically at-risk population. 
The study will enroll approximately 2000 patients. 
 
4.2. Scientific Rationale for Study Design 
It has recently been described that ATTR amyloidosis is significantly underdiagnosed, taking 
into consideration that both the clinical presentation and the symptoms are non-specific. The 
most frequent form of HF in patients with ATTR-CM is HF with preserved left ventricular 
ejection fraction (HFpEF). The aim of this epidemiology study is to assess the prevalence of 
ATTR-CM in a clinically at risk HFpEF population. Inclusion of an age criteria of ≥60 years 
enables only at-risk HFpEF participants to be enrolled. 
 
Definitive diagnosis of ATTR-CM may include invasive tissue biopsy. Extracardiac biopsy 
has a low diagnosis yield in ATTR amyloidosis, particularly in wild-type ATTR (ATTRwt). 
Therefore, in the setting of high clinical suspicion and a negative extracardiac biopsy, 
endomyocardial biopsy would be required. This invasive diagnostic approach carries 
CCI 

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associated complications and delays in diagnosis.22 Alternatively, noninvasive cardiac 
scintigraphy has marked a crucial change in the diagnostic workup of the disease. Data show 
that a Grade 2 or 3 uptake, in the absence of monoclonal proteins on serum and urine 
immunofixation electrophoresis and serum free light chain assay, is associated with 100% 
sensitivity and 100% specificity for cardiac ATTR amyloidosis.22 In the case of Grade 1 
uptake, histological confirmation through endomyocardial biopsy with typing of amyloid is 
required. 
 
4.3. Justification for Dose 
Not applicable. 
 
4.4. End of Study Definition 
The end of study is when all participants have completed all applicable study visits 
(including Follow-up Visit 2,) as shown in the SoA. 
 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
 
5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
1. Male and female participants ≥60 years of age at time of screening. 
 
2. Medical history of heart failure (HF) with: 
 
a. At least 1 episode with clinical evidence of HF (without hospitalization) by signs 
or symptoms of volume overload or elevated intracardiac pressures that 
required/requires treatment with a diuretic for improvement; OR 
 
b. 1 prior hospitalization for HF. 
 
3. Left ventricular ejection fraction (LVEF) >40%. 
 
4. End-diastolic interventricular septal wall thickness (IVST) ≥12 mm. 
 
5. Willing and able to undergo scintigraphy. 

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6. Capable of giving signed informed consent as described in Section 10.1.2 which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol. 
 
7. Participants who are willing and able to comply with all scheduled visits, laboratory 
tests, and other study procedures. 
 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
 
1. Diagnosis of heart failure with reduced ejection fraction (HFrEF) (EF ≤40%). 
 
2. Prior clinical history of myocardial infarction, CABG or multi-vessel obstructive 
coronary disease (>50% stenosis of ≥2 epicardial coronary arteries). 
 
3. Presence or history of any severe valvular heart disease (obstructive or regurgitant). 
 
4. A confirmed diagnosis of a non-amyloid infiltrative cardiomyopathy (i.e., cardiac 
sarcoidosis, hemochromatosis), muscular dystrophies, cardiomyopathy with 
reversible causes, hypertrophic obstructive cardiomyopathy with known genetic 
etiology, or known pericardial constriction. 
 
5. Any type of diagnosed amyloidosis (e.g., amyloid A amyloidosis, primary [light 
chain] amyloidosis) or prior diagnosis of ATTR-CM. 
 
6. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members. 
 
7. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
 
5.3. Schema 
Not Applicable. 
 
5.4. Lifestyle Requirements 
Not applicable. 
 
5.5. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 

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respond to queries from regulatory authorities. Minimal information includes screen 
failure details such as demography, eligibility criteria, and any SAE. Individuals who do 
not meet the criteria for participation in this study (screen failure) will be recorded as a 
screen failure but may be rescreened at a later date. Rescreened participants will be 
assigned a new screening number. Pfizer approval must be provided prior to re-screening a 
participant. 
6. STUDY INTERVENTION 
Not applicable. 
 
6.1. Participant Compliance 
Not applicable. 
 
6.2. Study Intervention 
No study treatment is administered. For the purposes of this protocol, study intervention 
refers to requirement for scintigraphy and biological specimens. 
 
6.3. Study Intervention Storage 
Not applicable. 
 
6.4. Measures to Minimize Bias: Randomization and Blinding 
Not applicable. 
 
6.5. Study Intervention Accountability 
Not applicable. 
 
6.6. Concomitant Treatment(s) 
Not applicable. 
 
7. PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
Not applicable. 
 
7.2. Participant Discontinuation/Withdrawal from the Study and Vital Status 
Follow-up 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include but are not limited to the following: 
 
• Refused further follow-up; 
• Lost to follow-up; 
• Death; 

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• Study terminated by sponsor. 
Due to assessment of vital status at the Follow-Up 2 Visit, a Release of Medical Information 
Form will be required of all participants for the purpose of access to medical records as well 
as for obtaining vital status follow-up with the participant’s primary physician or with death 
registries. The signing of this Release of Medical Information Form is in addition to the 
Informed Consent Document. In some cases, sites may combine these 2 forms into a single 
form, as is their standard practice. 
 
Participants should be questioned regarding their reason for withdrawal. A Follow-Up 2 
Visit should be performed for those participants with ATTR-CM if consent has been 
obtained. The participant will be permanently discontinued from the study at that time. 
 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. If the participant withdraws from the 
study and also withdraws consent (see below) 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. 
 
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved. 
 
7.3. Withdrawal of Consent: 
Participants who request to discontinue study participation must continue to be followed for 
protocol-specified follow-up procedures. The only exception to this is when a participant 
specifically withdraws consent for any further contact with him or her or persons previously 
authorized by the participant to provide this information. Participants should notify the 
investigator in writing of the decision to withdraw consent from future follow-up, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by 
the investigator, as to whether the withdrawal is only from study procedures and/or study 
follow-up and entered on the appropriate case report form (CRF) page. In the event that vital 
status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
 
7.4. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
 
The following actions must be taken if a participant fails to return for a required study visit: 
 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 

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• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
Discontinuation of specific sites or of the study as a whole is handled as part of Section 
10.1.6 . 
 
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1. Procedures 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
 
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant in the study should continue. 
 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
 
The total blood sampling volume for individual participants in this study is approximately 
63 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days. 
 
Protocol-specified safety laboratory tests may be performed at a local laboratory if the study 
participant is unable to visit the study site, where allowable by law or local guidance. Local 
laboratory reference ranges need to be documented. 

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8.1.1. Screening Visit 
The following procedures will be conducted during the Screening visit. Details of the 
assessments are located in Section 8.2: 
 
• Informed consent. 
• All inclusion and exclusion criteria will be reviewed to ensure eligibility for 
participation in this study. 
 
• Echocardiography (unless obtained within 6 months prior to Screening Visit and 
results are available). 
 
• Complete medical history. 
• Measure vital signs (systolic and diastolic blood pressure supine and standing and 
pulse rate supine and standing). 
 
• Demography (date of birth, age, gender, race and ethnicity). 
• Full physical examination including weight and height measurements will be 
performed. 
 
• Adverse event reporting. 
8.1.2. Visit 1 
The following procedure will be completed at Visit 1. Details of the assessments are located 
in Section 8.2: 
 
• Record current medications. 
• Record NYHA classification. 
 
• Perform scintigraphy. 
• Collect blood, and urine samples for the following clinical laboratories: 
• NT-Pro-BNP 
• Serum/urine test for primary (light chain) amyloidosis; 
• ATTR-CM biomarker samples; 

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• TTR genotyping. 
 
• Adverse event reporting. 
8.1.3. Follow-up 1 Visit 
Participants will be informed of their diagnosis and collect any AE/RRI information within 
14 days (+10 days) of study visit 1. This follow-up can be conducted remotely. 
 
8.1.4. Follow-up 2 Visit 
• Participants with scintigraphy of grade 1 or higher will be contacted to assess current 
medications and vital status. Participants with scintigraphy grade 1 will be asked if 
they have undergone a biopsy or other testing as follow up to scintigraphy since their 
last visit. Data will be collected on method of diagnosis and whether it confirmed the 
presence of ATTR-CM. 
 
This post-study follow-up can be conducted remotely. This will occur 6 months after the 
Follow-up 1 Visit (+/- 30 days) or at early study discontinuation. 
 
8.2. Assessments 
8.2.1. Scintigraphy 
All participants will undergo radionuclide cardiac scintigraphy at Visit 1 with a 
bisphosphonate radiotracer: 99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP. Cardiac retention of 
all 99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP will be determined by the central reader 
according to the grading: 
 
Grade 0=absent cardiac uptake. 
Grade 1=mild uptake less than bone. 
Grade 2=moderate uptake equal to bone. 
Grade 3=high uptake greater than bone. 
Details of scintigraphy will be provided in a separate laboratory manual (Scintigraphy 
manual). 
 
To confirm a diagnosis of ATTR-CM a participant with Grade 1 scintigraphy should undergo 
an endomyocardial biopsy.20,32 If biopsy or other confirmatory testing is performed, data will 
be collected. 

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8.2.1.1. Management of Incidental Findings from Scintigraphy 
An incidental finding is one unknown to the participant that has potential health or 
reproductive importance, which is discovered unexpectedly in the course of a research study 
but is unrelated to the purpose and beyond the aims of the study. 
 
Scintigraphy images will be reviewed by a central review facility. The purpose of this 
review is to evaluate images for diagnosis of ATTR-CM. Central image review is not a 
complete medical review of the participant. If, during the central review process, an 
unexpected observation is identified and this finding could, in the opinion of the central 
reviewer, have a significant health or reproductive consequence, this finding may be shared 
with the study sponsor for disclosure to the principal investigator (PI). All follow-up testing 
and final diagnosis will be left to the discretion of the medical professionals at the site or 
those with an existing physician-participant relationship. The PI will be responsible for 
reporting any adverse events (AEs) identified from incidental findings as described in the AE 
reporting section. Identification of such incidental findings during the central review process 
should not be expected, and the site maintains responsibility for performing a general safety 
review of all images as per site protocols. 
 
8.2.2. Echocardiogram 
Echocardiography (2D Doppler) will be performed and data collected for all participants at 
Screening unless one has been obtained within 6 months prior to Screening Visit and results 
are available. The assessment of end-diastolic interventricular septal thickness and left 
ventricular ejection fraction for study entry will be based on the echocardiogram performed 
at (or within 6 months prior to) the Screening visit as interpreted locally by the qualified 
reader (physician trained in echocardiography) at the site. If the Screening 
echocardiographic recording is not clear enough to accurately determine the end-diastolic 
interventricular septal wall thickness and left ventricular ejection fraction, it must be 
repeated. Each echocardiogram will be recorded and reviewed locally by the qualified reader 
at the clinical site, and the clinical significance of echocardiogram findings will be assessed 
by the investigator. 
 
The following echocardiographic parameters should be collected if available: 
 
1. End-diastolic interventricular septal wall thickness (mm). 
 
2. End-diastolic left ventricular posterior wall thickness (mm). 
 
3. Left ventricular ejection fraction (%). 
 
4. Left atrial diameter, anterior-posterior (mm). 
 
5. Left atrial diameter, medio-lateral (mm). 
 
6. Left atrial diameter, superior-inferior (mm). 
 
7. Left ventricular end systolic diameter (mm). 

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8. Left ventricular end systolic volume (mL). 
 
9. Left ventricular end-diastolic diameter (mm). 
 
10. Left ventricular end-diastolic volume (mL).. 
 
11. E/A Ratio. 
 
12. E/E’ Ratio. 
 
8.2.3. Cardiac Biomarkers: N-Terminal Pro-Hormone Brain Natriuretic Peptide 
(NT-proBNP) 
A 2.5 mL blood sample for NT-proBNP will be collected at Visit 1 and analyzed locally by 
the investigator site. 
 
Specifications for sample collection can be found in the study laboratory manual. 
 
8.2.4. Biospecimens for ATTR-CM Biomarker Identification and Validation 
The following biospecimens for ATTR-CM biomarker research are required and will be 
collected from all participants in this study at Visit 1 as specified in the SoA (as allowed by 
local law): 
 
• Collection of 56 mL blood including: 
o 
2 K2EDTA plasma samples (10mL each), 
o 2 lithium heparin plasma samples (8mL each), and 
o 
2 serum sample tubes (10mL each). 
• Collection of 10 mL of urine. 
Details on processes for collection and shipment of these samples can be found in the study 
laboratory manual. 
 
8.2.5. TTR Genotyping 
Participants will require collection of a 4 mL blood sample for potential TTR genotype 
testing, subject to local laws and regulations, at Visit 1. If the participant is diagnosed with 
scintigraphy grades 1, 2, or 3 then the sample will be sent to a reference laboratory for 
analysis and complete genomic sequencing of the TTR gene. 
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8.2.6. Testing for Light Chain Amyloid 
Specifications for testing samples are provided in the study laboratory manual. Blood and 
urine specimens for serum free light chains assay and the serum and urine electrophoresis 
with immunofixation will be obtained from all participants, but only analyzed for those with 
scintigraphy Grades 1, 2, or 3. As standard of care, participants with serum or urine test 
result indicative of monoclonal gammopathy of undetermined significance (MGUS) will 
require a confirmatory biopsy performed locally. 
 
8.2.7. Medical History 
A complete medical history is to be documented for all participants at the Screening visit. 
This medical history will document the specific symptoms the participant reports associated 
with ATTR-CM, as well as any additional co-morbid conditions or symptoms including but 
not limited to: 
 
• Sprains/strains. 
• Transthyretin amyloid polyneuropathy (ATTR-PN). 
• Arthroplasty. 
• Pacemaker or implantable cardioverter defibrillator (ICD). 
• Carpal tunnel syndrome. 
• Biceps tendon rupture. 
• Lumbar spinal stenosis. 
• Achilles tendon rupture (nontraumatic). 
• Rotator cuff injury (nontraumatic). 
• Atrial fibrillation/Atrial flutter. 
• Heart block. 
• Intracardiac thrombus. 
• Embolic stroke. 
8.2.8. Vital Signs 
Vital signs (including systolic and diastolic blood pressure, and pulse rate) will be assessed 
and recorded at the Screening visit. Orthostatic blood pressure changes will be measured 
with the participant’s arm supported at the level of the heart and recorded to the nearest 
mm Hg. Rounding up to the nearest 5 or 10 mmHg is not permitted. The participant should 
be supine for at least 3 minutes before the supine blood pressure is obtained. Standing blood 

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pressure should then be measured approximately 2 minutes after the participant assumes the 
standing position. 
 
The use of automated devices for measuring BP and pulse rate is acceptable, although when 
performed manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. 
 
When the timing of these measurements coincides with a blood collection, blood pressure 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
 
8.2.9. Medications 
A list of current medications will be collected at Visit 1 for all participants; and Follow-up 
2 Visit for participants with scintigraphy grade 1, 2 or 3. 
 
8.2.11. NYHA Classification 
The extent of participants’ heart failure will be evaluated at Visit 1 using the New York Heart 
Association (NYHA) classification. 
 
Class I: Participants 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: Participants with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or angina pain. 
 
Class III: Participants 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: Participants with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is increased. 
 

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8.2.14. Physical Examination and Height and Weight Measurement 
All participants will undergo a full physical examination at the Screening visit, including 
assessment of the following body systems: 
 
General appearance 
Neurological 
Head and neck 
Cardiovascular 
Eyes 
Abdomen 
Ears 
Skin 
Nose 
Musculoskeletal 
Throat 
Lungs 
Genitourinary 
Measurement of height in centimeters (cm) or inches (in) and weight in kilograms (kg) or 
pounds (lbs.) will be performed at the Screening visit. 
 

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8.2.17. Vital Status 
Participants, or their delegate, will be contacted at the Follow-up 2 Visit to determine vital 
status. 
 
8.2.18. Subsequent Diagnosis of ATTR-CM 
For participants who had scintigraphy grade 1 at Visit 1, information on subsequent diagnosis 
testing for cardiac amyloidosis and method thereof will be collected. 
 
8.3. Safety 
8.3.1. Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related to 
the study intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention. 
 
Any AE that occurs from the time the participant provides informed consent through and 
including up to 14 days following the participant’s last visit must be recorded. The 
investigator is required to assess whether the AE may be related to the participant’s 
participation in the study. All AEs (i.e., serious and non-serious, including those attributed to 
qualifying procedure identified as research-related injury) are collected in the clinical study 
database. 
 
The investigator must pursue and obtain information adequate to determine the outcome of 
the AE and to assess whether it meets the criteria for classification as a research related 
injury requiring immediate notification to Pfizer as described below. 
 
8.3.2. Research Related Injury 
Should a participant, in the investigator’s opinion, suffer a medically important research 
related injury caused by their participation in the study, the designated Pfizer clinician or 
medical monitor must be notified immediately. 
 
A medically important research related injury is any untoward medical occurrence that: 
 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 

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• 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 injury 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 participant or may require intervention to prevent one of the other 
outcomes listed in the definition above, the important medical event should be reported as a 
research related injury. 
 
An investigator may be requested by the designated Pfizer clinician or medical monitor to 
obtain specific additional follow-up information in an expedited fashion. In general, this will 
include a description of the injury in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality. Information on 
other possible causes of the event, such as concomitant treatments, vaccines, and/or illnesses 
must be provided. In the case of a participant death, a summary of available autopsy findings 
must be submitted as soon as possible to Pfizer or its designated representative. 
 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented and will be maintained by the sponsor. 
 
The primary completion date (PCD) for the global prevalence estimate will be the date when 
all enrolled participants have either been diagnosed with ATTR-CM (scintigraphy grades 2 
or 3), have scintigraphy grade 1 or found to be negative for ATTR-CM (scintigraphy grade 0) 
and have completed Follow-up Visit 1. Results will be reported after PCD and at the end of 
study (LPLV for participants with scintigraphy grade 1, 2 or 3). 
 
The empirical estimate for the prevalence of ATTR-CM in HFpEF participants is 
approximately 10%. The study will enroll approximately 2000 HFpEF participants within 
whom it is expected to detect 200 ATTR-CM participants. Enrollment will be stopped if 
200 ATTR-CM participants are identified before 2000 HFpEF are enrolled. No formal 
sample size calculation was performed. A sample size of 2000 HFpEF participants would be 
sufficient to inform treatment guidelines and yield an estimate for the global prevalence of 
ATTR-CM in HFpEF participants with a precision of ±2.5%. 
 
The primary endpoint is an estimate of the global prevalence of ATTR-CM in HFpEF 
participants. Diagnosis of ATTR-CM is defined as: 
 
• Cardiac Scintigraphy Grade 1, with confirmation of ATTR by cardiac biopsy; or 
• Cardiac Scintigraphy Grade 2 or above. 

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This global prevalence estimate will be obtained by dividing the number of participants who 
are diagnosed with ATTR-CM in the study by the total number of HFpEF participants 
evaluated. A 95% confidence interval on the estimate will also be calculated. 
 
As secondary analysis, prevalence will be estimated for: 
 
• Regions and countries. 
• Age categories (60-64, 65-69, 70-74, 75-79, 80-85, >85). 
• Gender (male, female). 
Prevalence estimates along with 95% CI will be generated for regions and countries with at 
least 50 participants. For regions and countries that enroll fewer than 50 participants, 
prevalence will not be estimated. Regions will be defined in the statistical analysis plan. The 
proportion of HFpEF participants who were diagnosed with wild-type and variant ATTR-CM 
will be descriptively summarized. 
 
As a general rule, the secondary endpoints other than the prevalence estimates and all 
reported as numerical values will be analyzed descriptively using 
mean, standard deviation, median, minimum and maximum. Endpoints that are categorical 
will be summarized using frequency tables. 
 
Analysis by Scintigraphy: 
 
Participants who are diagnosed with ATTR-CM will be analyzed by scintigraphy grades 
(Grade 1, 2, or 3) using the 6-MWT, NT-proBNP, medical history, demographics (including 
age, TTR Genotype, gender and race), NYHA classification (Class I, II, III, or IV), and all 
 
Analysis by Disease Status: 
 
Participants who are diagnosed with ATTR-CM will be analyzed by NYHA Classification 
(Class I, II, III, or IV) using the 6-MWT, NT-proBNP, medical history, demographics 
(including age, TTR Genotype, gender, and race)CCI 
 
CCI 
 
 
Participants who are diagnosed with ATTR-CM will also be analyzed by 6-MWT quartile 
groups using NYHA baseline classification (Class I, II, III, or IV), NT-proBNP, medical 
history, demographics (including age, TTR Genotype, gender, and race)CCI 
 
CCI 
 
 
Analysis Comparing ATTR-CM participants with HFpEF patients without ATTR-CM: 
 
HFpEF participants diagnosed with ATTR-CM will be compared with HFpEF participants 
not diagnosed with ATTR-CM descriptively using medical history, demographics (including 
age, TTR Genotype, gender, and race)CCI 
 
CCI 

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Medical history data will be used to generate descriptive statistics for time from symptom 
onset to HFpEF diagnosis and time from symptom onset to ATTR-CM diagnosis. 
 
Endpoints measuring proportion of participants (NYHA Classification and symptoms of 
interest from medical history) will be compared between HFpEF participants diagnosed with 
ATTR-CM and those that are not diagnosed with ATTR-CM. The Chi-square test will be 
used to compare the proportions between these 2 groups of HFpEF participants. Fisher’s 
exact test will be used instead of the chi-square test if any one of the cells has ≤5 participants. 
Secondary CCI 
endpoints that are normally distributed will be 
compared between 2 groups of HFpEF participants using a t-test. Endpoints that are not 
normally distributed will be compared using the Wilcoxon rank sum test. 
 
Safety Analysis: 
 
Adverse events (AEs) and research related injuries (RRI) collected at Visit 1 or during 
Follow-up visits, will be summarized overall and separately for HFpEF participants 
diagnosed with ATTR-CM and HFpEF participants not diagnosed with ATTR-CM. 
 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines; 
 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines; 
 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(e.g., advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated. 
 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
 
The investigator will be responsible for the following: 
 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC. 

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• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures. 
 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
 
10.1.2. Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. The participant should be given 
sufficient time and opportunity to ask questions and to decide whether or not to participate in 
the trial. 
 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/EC or study center. 
 
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
 
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data. 
 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICD. 
 
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study. 
 
A copy of the ICD(s) must be provided to the participant. 
 
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 

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additional research does not require the collection of any further samples. The investigator 
or authorized designee will explain to each participant the objectives of the additional 
research. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a participant's agreement to allow specimens to be 
used for additional research. Participants who decline to participate in this optional 
additional research will not provide this separate signature. 
 
10.1.3. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law. 
 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code. 
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred. All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code. The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity and medical record 
identification. In case of data transfer, the sponsor will protect the confidentiality of 
participants’ personal data consistent with the clinical study agreement and applicable 
privacy laws. 
 
10.1.4. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties. 
 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 

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verification may also occur after study completion. 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. 
 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan. 
 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
 
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained. 
 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
 
10.1.5. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
 
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 

Protocol B3461087 
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explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 
Definition of what constitutes source data can be found in the monitoring plan. 
 
Description of the use of computerized system is documented in the Data Management Plan. 
 
10.1.6. Study and Site Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
 
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants. 
 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines. 
 
• Inadequate recruitment of participants by the investigator. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant follow-up. 
 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
 
10.1.7. Publication Policy 
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first. 

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The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results. 
 
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors. 
 
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
 
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply. 
 
10.1.8. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent. The contact card contains, at a minimum, protocol identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study. The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site. 

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CCI 

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APPENDIX 2. ABBREVIATIONS 
 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
6-MWT 
6-minute walk test 
AE 
adverse event 
ATTR 
transthyretin amyloid 
ATTR amyloidosis 
transthyretin amyloidosis 
ATTR-ACT 
Tafamidis for ATTR-CM Trial 
ATTR-CM 
transthyretin amyloid cardiomyopathy 
ATTR-PN 
transthyretin amyloid polyneuropathy 
ATTRwt 
wild-type ATTR 
BP 
blood pressure 
CABG 
Coronary artery bypass grafting 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 
CRF 
case report form 
CRO 
contract research organization 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EF 
Ejection fraction 
eGFR 
estimated glomerular filtration rate 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
Database 
GCP 
Good Clinical Practice 
HCRU 
Healthcare Resource Utilization 
HF 
heart failure 
HIPAA 
Health Insurance Portability and Accountability Act 
HFpEF 
heart failure with preserved ejection fraction 
HFrEF 
heart failure with reduced ejection fraction 
ICD 
informed consent document 
ICH 
International Council on Harmonisation 
IRB 
institutional review board 
IVST 
interventricular septal wall thickness 
K2EDTA 
potassium ethylenediaminetetraacetic acid 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
Leu111Met 
leucine replaced by methionine at position 111 
LVEF 
Left ventricular ejection fraction 

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Abbreviation 
Term 
mBMI 
modified body mass index 
MGUS 
monoclonal gammopathy of unknown significance 
MDRD 
Modification of Diet in Renal Disease 
MRI 
magnetic resonance imaging 
N/A 
not applicable 
NCT 
National clinical trial number 
NT-proBNP 
N-terminal prohormone B-type natriuretic peptide 
NYHA 
New York Heart Association 
PCD 
primary completion date 
PI 
principal investigator 
QTc 
corrected QT interval 
QTcF 
corrected QT interval by Fredericia formula 
RRI 
research related injury 
SAE 
Serious adverse event 
Scr 
Serum creatinine 
SoA 
schedule of activities 
TTR 
transthyretin 
US 
United States 
Val122Ile 
valine replaced by isoleucine at position 122 
WT 
wild-type 

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11. REFERENCES 
 
 
1 
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2 
Paulus WJ, Tschope C, Sanderson JE, et al. How to diagnose diastolic heart failure: a 
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3 
Komajda M, Lam CS. Heart failure with preserved ejection fraction: a clinical dilemma. 
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4 
Connelly S, Choi S, Johnson SM, et al. Structure based design of kinetic stabilizers that 
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5 
Klabunde T, Petrassi HM, Oza VB, et al. Rational design of potent human transthyretin 
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6 
Johnson SM, Wiseman RL, Sekijima Y, et al. Native state kinetic stabilization as a 
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7 
Sekijima Y, Kelly JW, Ikeda S. Pathogenesis and therapeutic strategies to ameliorate the 
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8 
Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant sequence transthyretin 
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9 
Saraiva MJ. Transthyretin mutations in health and disease. Hum Mutat 1995;5(3):191 6. 
10 
Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac 
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11 
Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with 
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12 
“Voice of the Patient Report – Amyloidosis” (June 2016), Amyloidosis Research 
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13 
Buxbaum J, Jacobson D, Tagoe C, et al. Transthyretin V122I in African Americans 
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14 
Quarta CC, Buxbaum JN, Shah AM, et al. The amyloidogenic V122I transthyretin 
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15 
Connors LH, Doros G, Sam F, et al. Clinical features and survival in senile systemic 
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16 
Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile 
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17 
Smith TJ, Kyle RA, Lie JT. Clinical significance of histopathologic patterns of cardiac 
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18 
Ruberg FL, Maurer MS, Judge DP, et al. Prospective evaluation of the morbidity and 
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Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J 2012;164:222 228. 
 
19 
Rosenblum H, Castano A, Alvarez J, Goldsmith J, Helmke S, Maurer MS. TTR 
(Transthyretin) Stabilizers Are Associated With Improved Survival in Patients With 
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20 
Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin 
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21 
Castano A, Haq M, Narotsky DL, et al. Multicenter Study of Planar Technetium 99m 
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22 
Gonzalez Lopez E, Gallego Delgado M, Guzzo Merello G, et al. Wild type transthyretin 
amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 
2015;36:2585 94. 
 
23 
Castano A, Narotsky DL, Hamid N, et al. Unveiling transthyretin cardiac amyloidosis 
and its predictors among elderly patients with severe aortic stenosis undergoing 
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24 
Damy T, Costes B, Hagege AA, et al. Prevalence and clinical phenotype of hereditary 
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25 
Ando Y et al. Guideline of transthyretin related hereditary amyloidosis from clinicians. 
Orphanet Journal of Rare Diseases. 2013;8:31. 
 
26 
Picken MM. Modern approaches to the treatment of amyloidosis: the critical importance 
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27 
Rapezzi C, Quarta CC, Riva L, et al. Transthyretin related amyloidoses and the heart: a 
clinical overview. Nat Rev Cardiol 2010;7:398–408. 
 
28 
Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc 
pyrophosphate scintigraphy for differentiating light chain cardiac amyloidosis from the 
transthyretin related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 
2013;6:195 201. 
 
29  Haq M, Pawar S, Berk JL, Miller EJ, Ruberg FL. Can (99m)Tc Pyrophosphate Aid in 
Early Detection of Cardiac Involvement in Asymptomatic Variant TTR Amyloidosis? 
JACC Cardiovasc Imaging 2017;10:713 4. 
 
30  Galat A, Rosso J, Guellich A, et al. Usefulness of (99m)Tc HMDP scintigraphy for the 
etiologic diagnosis and prognosis of cardiac amyloidosis. Amyloid 2015;22:210 20. 
 
31 
Green CP, Porter CB, Bresnahan DR, et al. Development and evaluation of the Kansas 
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32 Hafeez AS. Bavry AA. Diagnosis of Transthyretin Amyloid Cardiomyopathy. Cardiol 
Ther. 2020; 9(1):85–95. 

 
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Document Approval Record 
 
B3461087 Protocol Amendment 2, 20 Aug 2020 
 
B3461087 Protocol Amendment 2, 20 Aug 2020 
 
 
PPD 
 
PPD 
  
22- Aug-2020 01:26:04 
Final Approval 
 
23- Aug-2020 23:21:14 
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