A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 4-ARM STUDY TO INVESTIGATE SYMPTOMS, FUNCTION, HEALTH-RELATED QUALITY OF LIFE AND SAFETY WITH REPEATED SUBCUTANEOUS ADMINISTRATION OF PONSEGROMAB VERSUS PLACEBO IN ADULT PARTICIPANTS WITH HEART FAILURE
Phase: PHASE2
Conditions: Heart Failure
Sponsor: Pfizer

Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 1
Title Page
A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 4-ARM 
STUDY TO INVESTIGATE SYMPTOMS, FUNCTION, HEALTH-RELATED 
QUALITY OF LIFE AND SAFETY WITH REPEATED SUBCUTANEOUS 
ADMINISTRATION OF PONSEGROMAB VERSUS PLACEBO IN ADULT 
PARTICIPANTS WITH HEART FAILURE 
Study Intervention Number:
PF-06946860
Study Intervention Name:
Ponsegromab
US IND Number:
155929
EU CT Number:
2023-509747-27-00
ClinicalTrials.gov ID:  
NCT05492500
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C3651011
Phase:
2
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: A Phase 2 Study of the Effects of Ponsegromab on Health-Related Quality 
of Life and Safety in Patients With Heart Failure (GARDEN-TIMI 74)
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.
090177e1a1369fca\Approved\Approved On: 20-Jul-2024 06:57 (GMT)

Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 2
Document History
Document
Version Date
Amendment 2
18 July 2024
Amendment 1
06 June 2023
Original protocol
23 June 2022
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s).
Protocol Amendment Summary of Changes Table
Amendment 2 (18 July 2024)
Overall Rationale for the Amendment: The overall rationale for this amendment is to 
incorporate two optional study cohorts (Cohort C and Cohort D, respectively), add an 
adjudication committee and offer flexible language and clarifications.
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Inclusion of optional 
Cohort C and optional 
Cohort D, which includes 
the following unique items:

Study rationale

Study design

Study schema

Inclusion/Exclusion 
criteria

Study arms and 
duration

Objectives/endpoints
The addition of optional 
Cohort C allows for a 
more comprehensive 
evaluation of the safety 
and efficacy of the 
ponsegromab 100 mg dose 
level compared to placebo.
The addition of optional 
Cohort D is for a 
supportive assessment of 
efficacy and safety 
endpoints across the 
spectrum of GDF-15 
concentrations in 
participants with HF.
1 – Protocol Summary
2.3.1 – Risk Assessment
3 – Objectives, Endpoints, 
and Estimands
4 – Study Design
5 – Study Population
6 – Study Intervention(s) 
and Concomitant Therapy
7.1 – Discontinuation of 
Study Intervention
8 – Study Assessments and 
Procedures
9 – Statistical 
Considerations
Non-substantial Modification(s)
Added detailed language 
for adjudication committee.
Clinical outcomes of all 
deaths, HF hospitalization 
and urgent HF visits are 
tertiary endpoints of this 
1.1 – Synopsis
4.1 – Overall Design
8.2.5 – Clinical Outcomes
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 3
Description of Change
Brief Rationale
Section # and Name
protocol. Introduction of a 
formal adjudication of 
these events will support 
and strengthen exploratory 
analyses planned for these 
endpoints.
10.1.5 – Committees 
Structure
Removed “In the event of a 
Quality Assurance audit, 
the auditor(s) will be 
allowed access to 
unblinded study 
intervention records at the 
site(s) to verify that 
randomization/dispensing 
has been done accurately.”
Text is not applicable for 
this study and was 
inadvertently included in 
the protocol.
6.4.2 – Blinding of Site 
Personnel
Added “Deviation(s) from 
the protocol-specified 
dosage regimen should be 
recorded in the CRF. In 
exceptional circumstances 
and with agreement from 
the Sponsor, the study 
intervention may be 
administered outside of the 
window for a given dosing 
visit with appropriate 
consideration of timing of 
any subsequent dosing 
visit; in such 
circumstances, the rationale 
should be recorded in the 
CRF.”
Added text allows for 
flexibility for case-by-case 
evaluation to determine 
whether a missed dose of 
study intervention can be 
rescheduled with out-of-
window dosing and 
potential impact to timing 
of the subsequent dose(s) 
(eg, pushing to the outer 
limit of the study visit 
window).
6.5 – Study Intervention 
Compliance
Removed reference to the 
US and Canada regarding 
sites for the Open-label, PK 
cohort.
Offer more flexibility with 
any potential site/country 
selection.
1.1 – Synopsis
2.1 – Study Rationale
4.2 – Scientific Rationale 
for Study Design
5.4 – Screen Failures
8.1.1 – Screening 
Procedures
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 4
Description of Change
Brief Rationale
Section # and Name
Added urine sample for 
 
 (Cohorts C 
& D only)
Explore the effects of 
ponsegromab on 
 
 in a population 
with
 
 
1.3 – Schedule of Activities 
– Table 1 
8.7 – Biomarkers
10.2 Appendix 2 – Clinical 
Laboratory Tests
Modified contact details for 
a medically qualified 
individual.
Clarification: Protocol 
Administrative Change 
Letter dated 27 Feb 2024
10.1.11 – Sponsor’s 
Medically Qualified 
Individual
10.11 – Appendix 11: 
Abbreviations
Modified language to allow 
for flexibility to maximize 
the number of participants 
who complete follow-up 
visits.
Clarification: Protocol 
Administrative Change 
Letter dated 27 Feb 2024
7.1 – Discontinuation of 
Study Intervention
Added “…(if this rate is 
higher, or there is a high 
rate of non-compliance, 
more participants may be 
randomized to ensure the 
required number of 
evaluable participants).”
Clarification: Protocol 
Administrative Change 
Letter dated 27 Feb 2024
9.5 – Sample Size 
Determination – Open
Label, PK Cohort (Cohort 
B)
Added “If not previously 
administered, participants 
will received 2 SC 
injections of open-label, 
placebo (equivalent of 
highest possible does, 300 
mg) during the screening 
period to assess injection 
tolerability.”
Clarification: Protocol 
Administrative Change 
Letter dated 03 Oct 2023
1.1 – Synopsis
6 – Study Intervention(s) 
and Concomitant Therapy –
Study Interventions 
Administered – Study Arms 
for Open-label, PK Cohort
(Cohort B)
Modified language:
Section 8.1.1 – “Of note, a 
digital wrist device should
will be dispensed to 
participants at SV2.”
Section 8.2.4 – “An 
activity monitor should
will be placed on the 
Clarification: Protocol 
Administrative Change 
Letter dated 03 Oct 2023
8 – Study Assessments and 
Procedures
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CCI
CCI
CCI

Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 5
Description of Change
Brief Rationale
Section # and Name
participant’s non-dominant 
wrist from SV2 to Day 1 
and from Week 20 to Week 
22. The participant should
will be asked to wear the 
activity monitor 
continuously during these 
periods.”
Language added in section 
headings to maintain 
consistency with other 
section headings.
Clarification: Protocol 
Administrative Change 
Letter dated 03 Oct 2023
8.6 – Genetics
8.7 – Biomarkers
Updated EU CT Number
EU CT number replaces 
the EudraCT number 
(EudraCT Number 2022-
001809-50) as we are now 
using CTIS and run under 
CTR framework.
Opening page.
1.1 – Synopsis
Provided text clarification 
and corrections.
Minor clarifications and 
editorial/typographical 
changes have been made 
throughout, including 
those through new 
regulatory guidance.
Various sections of the 
protocol.
090177e1a1369fca\Approved\Approved On: 20-Jul-2024 06:57 (GMT)

Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 6
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
LIST OF FIGURES .................................................................................................................13
1. PROTOCOL SUMMARY...................................................................................................14
1.1. Synopsis ..................................................................................................................14
1.2. Study Schematic......................................................................................................22
1.3. Schedule of Activities .............................................................................................24
2. INTRODUCTION ...............................................................................................................31
2.1. Study Rationale .......................................................................................................31
2.2. Background .............................................................................................................31
2.2.1. Heart Failure ...............................................................................................31
2.2.1.1. GDF-15 and Heart Failure.........................................................31
2.2.2. Clinical Overview.......................................................................................32
2.2.2.1. Summary of Safety Data ...........................................................33
2.2.2.2. Summary of Pharmacokinetics..................................................34
2.2.2.3. Summary of GDF-15 Response ................................................34
2.2.2.4. Immunogenicity ........................................................................35
2.3. Benefit/Risk Assessment.........................................................................................35
2.3.1. Risk Assessment.........................................................................................36
2.3.2. Benefit Assessment.....................................................................................38
2.3.3. Overall Benefit/Risk Conclusion................................................................38
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................38
3.1. Main Cohort (Cohort A), Cohort C and Cohort D ..................................................38
3.2. Open-Label, PK Cohort (Cohort B) ........................................................................41
4. STUDY DESIGN.................................................................................................................42
4.1. Overall Design.........................................................................................................42
4.2. Scientific Rationale for Study Design.....................................................................43
4.2.1. KCCQ-23 Heart Failure Patient Reported Outcome Instrument................44
4.2.2. Patient Input Into Design............................................................................44
4.2.3. Diversity of Study Population ....................................................................45
4.2.4. Choice of Contraception/Barrier Requirements .........................................46
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 7
4.2.5. Collection of Retained Research Samples..................................................46
4.3. Justification for Dose ..............................................................................................46
4.4. End of Study Definition ..........................................................................................47
5. STUDY POPULATION......................................................................................................48
5.1. Inclusion Criteria.....................................................................................................48
5.2. Exclusion Criteria....................................................................................................49
5.3. Lifestyle Considerations..........................................................................................51
5.3.1. Contraception..............................................................................................51
5.4. Screen Failures ........................................................................................................51
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................52
6.1. Administration.........................................................................................................54
6.2. Preparation, Handling, Storage, and Accountability...............................................55
6.2.1. Preparation and Dispensing........................................................................56
6.3. Assignment to Study Intervention...........................................................................56
6.4. Blinding (Main Cohort [Cohort A]/Cohort C/Cohort D)........................................57
6.4.1. Blinding of Participants (Main Cohort [Cohort A]/Cohort C/Cohort 
D) .....................................................................................................................57
6.4.2. Blinding of Site Personnel (Main Cohort [Cohort A]/Cohort 
C/Cohort D) .....................................................................................................57
6.4.3. Blinding of the Sponsor (Main Cohort [Cohort A]/Cohort C/Cohort 
D) .....................................................................................................................57
6.4.4. Breaking the Blind (Main Cohort [Cohort A]/Cohort C/Cohort D)...........57
6.5. Study Intervention Compliance...............................................................................58
6.6. Dose Modification...................................................................................................58
6.7. Continued Access to Study Intervention After the End of the Study......................58
6.8. Treatment of Overdose............................................................................................58
6.9. Prior and Concomitant Therapy..............................................................................59
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................60
7.1. Discontinuation of Study Intervention ....................................................................60
7.1.1. COVID-19 ..................................................................................................61
7.2. Discontinuation From the Study .............................................................................61
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 8
7.2.1. Withdrawal of Consent...............................................................................62
7.3. Lost to Follow-Up ...................................................................................................62
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................63
8.1. Administrative Procedures ......................................................................................63
8.1.1. Screening Procedures..................................................................................64
8.1.2. Contracted Home Health Visits (Open-Label, PK Cohort [Cohort B] 
Only) ................................................................................................................65
8.2. Efficacy Assessments (Main Cohort [Cohort A]/Cohort C/Cohort D)...................65
8.2.1. Patient Reported Outcomes ........................................................................65
8.2.1.1. Kansas City Cardiomyopathy Questionnaire ............................65
8.2.1.2. PROMIS Fatigue (Version 7a)..................................................66
8.2.1.3. Patient’s Global Impression of Severity....................................66
8.2.1.4. Patient’s Global Impression of Change.....................................66
8.2.1.5. Qualitative Exit Interviews........................................................66
8.2.2. 6MWT.........................................................................................................67
8.2.3. Body Weight...............................................................................................67
8.2.4. Activity Monitoring (Main Cohort [Cohort A]/Cohort C/Cohort D).........67
8.2.5. Clinical Outcomes ......................................................................................67
8.3. Safety Assessments .................................................................................................68
8.3.1. Physical Examinations................................................................................69
8.3.2. Vital Signs ..................................................................................................69
8.3.2.1. Blood Pressure and Pulse Rate..................................................69
8.3.3. Electrocardiograms.....................................................................................69
8.3.4. Clinical Safety Laboratory Assessments ....................................................69
8.3.5. Pregnancy Testing ......................................................................................70
8.3.5.1. At-Home Pregnancy Testing.....................................................70
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................71
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......71
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................72
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................72
8.4.2. Method of Detecting AEs and SAEs ..........................................................72
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 9
8.4.3. Follow-Up of AEs and SAEs......................................................................72
8.4.4. Regulatory Reporting Requirements for SAEs...........................................73
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................73
8.4.5.1. Exposure During Pregnancy......................................................73
8.4.5.2. Exposure During Breastfeeding ................................................75
8.4.5.3. Occupational Exposure .............................................................76
8.4.6. Cardiovascular and Death Events...............................................................76
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................76
8.4.8. Adverse Events of Special Interest.............................................................76
8.4.8.1. Lack of Efficacy........................................................................76
8.4.9. Medical Device Deficiencies......................................................................76
8.4.10. Medication Errors.....................................................................................76
8.5. Pharmacokinetics ....................................................................................................77
8.6. Genetics...................................................................................................................78
8.6.1. Specified Genetics ......................................................................................78
8.6.2. Retained Research Samples for Genetics (Main Cohort [Cohort 
A]/Cohort C/Cohort D)....................................................................................78
8.6.3. Retained Research Samples for Future Genetic Research by TIMI 
(Main Cohort [Cohort A]/Cohort C/Cohort D)................................................78
8.7. Biomarkers ..............................................................................................................79
8.7.1. GDF-15.......................................................................................................79
8.7.2. Exploratory Biomarkers..............................................................................80
8.7.3. Specified Gene Expression (RNA) Research .............................................81
8.7.4. Specified Protein Research.........................................................................81
8.7.5. Specified Metabolomic Research ...............................................................81
8.7.6. Retained Research Samples for Biomarkers (Main Cohort [Cohort 
A]/Cohort C/Cohort D)....................................................................................81
8.7.7. Retained Research Samples for Future Biomarker Research by TIMI 
(Main Cohort [Cohort A]/Cohort C/Cohort D)................................................81
8.7.8. Samples for Exploratory Plasma Biomarker Research by Pfizer 
(Main Cohort [Cohort A]/Cohort C/Cohort D)................................................82
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 10
8.8. Immunogenicity Assessments.................................................................................82
8.9. Health Economics ...................................................................................................83
9. STATISTICAL CONSIDERATIONS ................................................................................83
9.1. Statistical Hypotheses .............................................................................................83
9.1.1. Estimands....................................................................................................83
9.1.1.1. Primary Estimands ....................................................................83
9.1.1.2. Secondary Estimands ................................................................84
9.1.1.3. Tertiary/Exploratory Estimands ................................................86
9.2. Analysis Sets ...........................................................................................................86
9.3. Statistical Analyses .................................................................................................87
9.3.1. General Considerations...............................................................................88
9.3.1.1. Analyses for Continuous Endpoints..........................................88
9.3.1.2. Analyses for Binary Endpoints .................................................88
9.3.2. Primary Endpoints Analysis .......................................................................88
9.3.3. Secondary Endpoints Analysis ...................................................................89
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis ................................................90
9.3.5. Other Safety Analyses ................................................................................90
9.3.6. Other Analyses............................................................................................90
9.4. Interim Analyses .....................................................................................................91
9.4.1. PK/PD Unblinding Plan..............................................................................92
9.5. Sample Size Determination.....................................................................................92
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................94
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............94
10.1.1. Regulatory and Ethical Considerations ....................................................94
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................94
10.1.2. Financial Disclosure .................................................................................95
10.1.3. Informed Consent Process ........................................................................95
10.1.4. Data Protection .........................................................................................96
10.1.5. Committees Structure ...............................................................................96
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 11
10.1.5.1. Steering Committee.................................................................96
10.1.5.2. Data Monitoring Committee ...................................................97
10.1.5.3. Internal Review Committee.....................................................97
10.1.5.4. Use of Adjudication Committee(s) .........................................97
10.1.6. Dissemination of Clinical Study Data ......................................................98
10.1.7. Data Quality Assurance ............................................................................99
10.1.8. Source Documents..................................................................................100
10.1.9. Study and Site Start and Closure ............................................................100
10.1.10. Publication Policy.................................................................................101
10.1.11. Sponsor’s Medically Qualified Individual............................................102
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................103
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...................................................................104
10.3.1. Definition of AE .....................................................................................104
10.3.2. Definition of an SAE ..............................................................................105
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period..........................................................................107
10.3.4. Reporting of SAEs..................................................................................110
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................112
10.4.1. Male Participant Reproductive Inclusion Criteria..................................112
10.4.2. Female Participant Reproductive Inclusion Criteria...............................112
10.4.3. Woman of Childbearing Potential ..........................................................112
10.4.4. Contraception Methods...........................................................................113
10.5. Appendix 5: Genetics..........................................................................................115
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .....116
10.7. Appendix 7: Kidney Safety Monitoring Guidelines ...........................................118
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury............................................................................118
10.7.2. Age-Specific Kidney Function Calculation Recommendations.............118
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .........................................................................................118
10.8. Appendix 8: ECG Findings of Potential Clinical Concern .................................119
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 12
10.9. Appendix 9: Prohibited Concomitant Medications.............................................121
10.10. Appendix 10: Protocol Amendment History.....................................................122
10.11. Appendix 11: Abbreviations .............................................................................130
11. REFERENCES ................................................................................................................134
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 13
LIST OF TABLES
Table 1.
Study Schedule of Assessment for the Main Cohort (Cohort A), 
Cohort C, and Cohort D............................................................................24
Table 2.
Study Schedule of Activities for Open-Label, PK Cohort (Cohort 
B) Only .....................................................................................................28
Table 3.
Summary of Predicted Steady State Total Ponsegromab Exposures 
and Associated Safety Margins and Exposure Multiples Following 
Q4W SC Doses.........................................................................................47
Table 4.
Summary of Predicted Steady State Unbound Ponsegromab 
Exposures and Associated Exposure Multiples Following Q4W SC 
Doses.........................................................................................................47
Table 5.
PRO Assessments.....................................................................................65
LIST OF FIGURES
Figure 1.
Schema......................................................................................................22
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 14
1. PROTOCOL SUMMARY
1.1. Synopsis 
Protocol Title: 
A Phase 2, Double-blind, Randomized, Placebo-controlled, 4-arm Study to Investigate 
Symptoms, Function, Health-Related Quality of Life, and Safety, With Repeated 
Subcutaneous Administration of Ponsegromab Versus Placebo in Adult Participants With 
Heart Failure.
Brief Title:
A Phase 2 Study of the Effects of Ponsegromab on Health-Related Quality of Life and Safety 
in Patients With Heart Failure (GARDEN-TIMI 74)
Regulatory Agency Identification Number(s):
US IND Number:
155929
EU CT Number:
2023-509747-27-00
ClinicalTrials.gov ID:  
NCT05492500
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C3651011
Phase:
2
Rationale:
The primary purpose of this study is to assess the effect of repeated SC administration of 
ponsegromab (PF-06946860) on frequency, severity, and burden of symptoms as well as 
physical limitations in participants with HF and elevated circulating GDF-15 concentrations. 
The study will also assess the safety, tolerability, PK, PD, and immunogenicity of 
ponsegromab. A separate, open-label, PK cohort, with more frequent PK and GDF-15 
collection after single and multiple SC administration of ponsegromab, will be enrolled at 
certain participating sites to facilitate a more comprehensive assessment of PK characteristics 
and PK/PD relationship for GDF-15 in participants with HF.
This study is also known as GDF-15 inhibition in heARt failure: quality of life DiffEreNces
(GARDEN-TIMI 74).
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Ponsegromab, PF-06946860
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Objectives, Endpoints, and Estimands:
Main Cohort (Cohort A), Cohort C and Cohort D
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To compare the effect of 
ponsegromab 300 mg 
versus placebo on HF 
disease-specific health 
status in participants with 
HF and serum GDF-15 
concentrations
pg/mL (Main Cohort 
[Cohort A] only).
Change from baseline in 
KCCQ-23 CSS at 
Week 22.
Estimand 1 (similar to “hypothetical”) is the 
difference between ponsegromab and placebo in mean 
change from baseline in KCCQ-23 CSS at Week 22, 
in participants with HF and serum GDF-15 
concentrations
pg/mL, under the scenario of no 
discontinuation of study intervention and without the 
potential confounding effect of prohibited procedures 
or participants’ non-compliance with dosing.
Secondary: 
Secondary:
Secondary: 
To compare the effect of 
ponsegromab versus 
placebo on HF 
disease-specific overall 
health status in participants 
with HF and serum GDF-
15 concentrations
pg/mL.
Change from baseline in 
KCCQ-23 CSS, OSS, 
TSS, and physical 
limitation at Week 22.
Estimand 2 (similar to “hypothetical”) is the 
difference between ponsegromab and placebo in mean 
change from baseline in each of KCCQ-23 CSS, OSS, 
TSS and physical limitation score at Week 22, in 
participants with HF and serum GDF-15 
concentrations
pg/mL, under the scenario of no 
discontinuation of study intervention and without the 
potential confounding effect of prohibited procedures 
or participants’ non-compliance with dosing.
To compare the effect of 
ponsegromab versus
placebo on HF 
disease-specific health 
status in participants with 
HF and serum GDF-15 
concentrations
pg/mL.
Responses as defined by a
≥5-point increase from 
baseline in KCCQ-23 
CSS, OSS, TSS, and 
physical limitation at 
Week 22.
Estimand 3 (similar to “hypothetical”) is the odds 
ratio between ponsegromab and placebo on the 
proportion of participants with ≥5-point increase from 
baseline in each of KCCQ-23 CSS, OSS, TSS, and 
physical limitation score at Week 22, in participants 
with HF and serum GDF-15 concentrations
pg/mL, under the scenario of no discontinuation of 
study intervention and without the potential 
confounding effect of prohibited procedures or 
participants’ non-compliance with dosing.
To compare the effect of 
ponsegromab versus
placebo on the physical 
function of participants 
with HF and serum GDF-
15 concentrations
pg/mL.
Change from baseline in 
6MWD at Week 22.
Estimand 4 (similar to “hypothetical”) is the 
difference between ponsegromab and placebo in mean 
change from baseline in 6MWD at Week 22, in 
participants with HF and serum GDF-15 
concentrations
pg/mL, under the scenario of no 
discontinuation of study intervention and without the 
potential confounding effect of prohibited procedures 
or participants’ non-compliance with dosing.
To compare the effect of 
ponsegromab versus 
placebo on fatigue reported 
by participants with HF and 
serum GDF-15 
concentrations
pg/mL.
Change from baseline in 
PROMIS Fatigue 7a at 
Week 22.
Estimand 5 (similar to “hypothetical”) is the 
difference between ponsegromab and placebo in mean 
change from baseline in PROMIS Fatigue 7a at Week 
22 in participants with HF and serum GDF-15 
concentrations
pg/mL, under the scenario of no 
discontinuation of study intervention and without the 
potential confounding effect of prohibited procedures 
or participants’ non-compliance with dosing.
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 16
Objectives
Endpoints
Estimands
To describe the safety and 
tolerability of ponsegromab 
in participants with HF.
Incidence of TEAEs, 
TESAEs, abnormal 
laboratory results, and 
vital signs.
There are no defined estimands for the incidence of 
TEAEs, TESAEs, abnormal laboratory results, and 
vital signs, and these endpoints will be analyzed using 
Pfizer data standards as applicable.
Open-Label, PK Cohort (Cohort B)
Objectives
Endpoints
Estimands
Secondary: 
Secondary:
Secondary: 
To evaluate the safety and 
tolerability of 
ponsegromab in 
participants with HF and 
elevated circulating GDF-
15 concentrations.
Incidence of TEAEs, 
TESAEs, abnormal 
laboratory results, and 
vital signs.
There are no defined estimands for the incidence of 
TEAEs, TESAEs, abnormal laboratory results, and 
vital signs, and these endpoints will be analyzed 
using Pfizer data standards as applicable.
Overall Design:
This is a Phase 2, parallel-group, randomized, double-blind, placebo-controlled study to 
evaluate the effect of ponsegromab on HRQL, physical activity, safety, and circulating 
biomarkers in adult participants with HF and elevated circulating GDF-15. 
For the Main Cohort (Cohort A), Cohort C, and Cohort D, following the 56-day screening 
period to confirm eligibility, the study will include a 22-week treatment period (from Day 1 
to Week 20, and Week 22 for primary endpoint collection), and a 10-week follow-up period 
for a total study duration of 32 weeks (not including the screening period).
Approximately 416 participants will be enrolled into the Main Cohort (Cohort A) and 
randomized to one of 3 doses of ponsegromab (100 mg [n=18], 200 mg [n=18], or 300 mg 
[n=190]) or to matched placebo (n=190). Participant randomization will be stratified based 
on
KCCQ-23 CSS: <45 or ≥45.
Approximately 195 additional participants may be enrolled into optional Cohort C and 
randomized in a 2:1 ratio to either 100 mg ponsegromab (n~130) or to matched placebo 
(n~65). The additional participants in optional Cohort C will allow for a more comprehensive 
evaluation of the safety and efficacy of the ponsegromab 100 mg dose level compared to 
placebo. For each of these cohorts, blinded study drug will be administered SC Q4W for a 
total of 6 doses during the 22-week treatment period.
The primary endpoint for the study is the change from baseline at Week 22 in 
KCCQ-23 CSS, an HRQL PRO instrument.
 
 
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
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Approximately 100 participants (maximum of approximately 150) who meet all eligibility 
criteria for Cohorts A and C, except the requirement for serum GDF-15 concentration 
pg/mL, may be enrolled into the optional Cohort D and randomized in a 1:1 ratio to either 
300 mg ponsegromab (n~50) or to matched placebo (n~50), administered SC Q4W for a total 
of 6 doses during the 22-week treatment period. Participant randomization in Cohort D will 
be stratified by KCCQ-23 CSS: <45 or ≥45. The purpose of this optional cohort is for a 
supportive assessment of efficacy and safety endpoints across the spectrum of GDF-15 
concentrations in participants with HF.
This study will use an unblinded E-DMC to monitor the safety of participants and an 
unblinded IRC to monitor the efficacy and safety of participants. A blinded Steering 
Committee will monitor the proportion of study participants with various NYHA classes, left 
ventricular ejection fractions, GDF-15 concentrations, KCCQ-23 CSS scores, and the relative 
proportions qualifying under the cachexia, fatigue, and functional impairment criteria and 
may cap 1 or more to ensure a broad population.
This study will also use a separate blinded adjudication committee consisting of independent 
external experts who will be responsible for adjudication of all deaths and investigator-
reported HF hospitalizations and urgent HF visits.
Open-label, PK Cohort (Cohort B): At certain sites, where permitted, participants who fail 
to qualify for the Main Cohort may be eligible for participation in a separate open-label, PK 
cohort. Approximately 20 participants, after confirmation of eligibility, will be randomized to 
one of 3 dose levels of open-label ponsegromab (100 mg [n=4], 200 mg [n=8], or 300 mg 
[n=8]) administered SC Q4W for a total of 4 doses, with last dose at Week 12 and follow-up 
to Week 22.
Number of Participants
Up to approximately 781 participants will be randomized in the study (approximately 416 
participants in the Main Cohort [Cohort A], approximately 20 participants in the open-label, 
PK cohort [Cohort B], approximately 195 participants in Cohort C, and approximately 100 
participants [maximum of approximately 150] in Cohort D).
Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process and randomization. A participant will be 
considered enrolled if the informed consent is not withdrawn prior to participating in any 
study activity after screening. Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.
Study Population: Key inclusion and exclusion criteria are listed below.
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Ponsegromab, PF-06946860
Protocol C3651011
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PFIZER CONFIDENTIAL
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Inclusion Criteria
Age and Sex:
1. Participants aged 18 years or older (or the minimum age of consent in accordance 
with local regulations) at screening.

A female participant is eligible to participate if she is not pregnant or 
breastfeeding.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
Disease Characteristics:
2. Clinical evidence of HF with each of the following criteria: 
a.
LVEF <50% on most recent measurement, within 12 months of screening.
Note: An assessment of LVEF in the prior 12 months is not required in situations 
where LVEF has been persistently <50% on prior assessments obtained at least 3 
months apart (including the most recent measurement).
b. NYHA class II-IV at screening.
c.
NT-proBNP ≥400 pg/mL at screening (Note: Does not apply to open-label, PK 
cohort [Cohort B]).
3. Serum GDF-15 concentration
pg/mL at screening.

Cohort D only: Serum GDF-15 concentration
pg/mL at screening
4. KCCQ-23 CSS <75 at screening (Note: Does not apply to open-label, PK cohort
[Cohort B]).
5. Evidence of cachexia or fatigue or functional impairment, as demonstrated by at least 
1 of the following at screening (Note: Does not apply to open-label, PK cohort
[Cohort B]):
a.
Non-edematous unintentional weight loss ≥5% in the last 6 months or current 
BMI <20 kg/m2, associated with subjective fatigue or anorexia; or
b. Fatigue at least 3 times per week AND at least moderately bothersome fatigue in 
the past 2 weeks based on the KCCQ-23 administered at screening; or
c.
A score of <60 on the Physical Limitations Domain of the KCCQ-23 
administered at screening.
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Ponsegromab, PF-06946860
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PFIZER CONFIDENTIAL
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6. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures (including 
but not limited to subcutaneous injection of study intervention).
Exclusion Criteria
1. Acute decompensated HF within 1 month prior to SV1 or during the screening period.
2. Implantation of a cardiac resynchronization therapy device or valve repair or 
replacement within 3 months prior to randomization or intent to do so during the trial.

For the open-label, PK cohort only (Cohort B): implantation of a cardiac 
resynchronization therapy device more than 1 month prior to randomization is 
permitted.
3. History of heart transplantation, currently listed for heart transplant, current/planned 
mechanical circulatory support, or current/planned use of intravenous inotropes (eg, 
dobutamine, milrinone).
4. Acute coronary syndrome within 1 month prior to randomization.
5. Coronary revascularization (percutaneous coronary intervention or coronary artery 
bypass grafting) within 3 months prior to randomization or intent to undergo coronary 
revascularization during the trial.

For the open-label, PK cohort only (Cohort B): coronary revascularization 
more than 1 month prior to randomization is permitted.
6. Untreated indication for an implantable cardiac defibrillator or pacemaker to treat a 
cardiac rhythm abnormality (ie, tachyarrhythmia or bradyarrhythmia).
7. History of allergic or anaphylactic reaction to any therapeutic or diagnostic 
monoclonal antibody (IgG protein) or molecules made of components of monoclonal 
antibody.
8. Other medical (eg, severe, uncorrected aortic stenosis; active malignancy) 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, may limit life expectancy to less than 
1 year and/or make the participant inappropriate for the study.
9. Current use of any prohibited concomitant medication(s). Refer to Section 6.9. 
10. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention 
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Ponsegromab, PF-06946860
Protocol C3651011
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PFIZER CONFIDENTIAL
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TMF Doc ID: 164.01
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used in this study (whichever is longer). Treatment with an investigational 
biotherapeutic agent within 6 months or 5 half-lives (whichever is longer) of Day 1.
11. Previous exposure to ponsegromab in a prior clinical study.
12. Renal disease requiring ongoing dialysis.
13. Cirrhosis with evidence of portal hypertension not due to HF, or the following LFT 
abnormalities at the time of screening, confirmed by a repeat test if deemed 
necessary: AST or ALT level ≥3 x ULN, or total bilirubin level ≥2 x ULN (unless 
history of Gilbert’s syndrome).
14. 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.
Study Arms and Duration:
Intervention Name
Ponsegromab
Placebo
Arm Name
(group of participants receiving a specific 
treatment or no treatment)
Ponsegromab 
double-blind treatment
Placebo double-blind treatment 
Unit Dose Strength(s)
100 mg/mL
Placebo
Dosage Level(s)
100, 200 or 300 mg Q4W
Placebo Q4W
Route of Administration
SC
SC
Use
Experimental
Placebo
IMP or NIMP/AxMP
IMP
IMP
Study Arms for Main Cohort (Cohort A) a
Arm Title
Ponsegromab or 
Placebob 100 mg
Ponsegromab or Placebob
200 mg
Ponsegromab or Placebob
300 mg
Arm Type
Experimental
n=18
Placebo
n=6
Experimental
n=18
Placebo
n=6
Experimental
n=190
Placebo
n=178
Arm 
Description
Participants 
will receive 
100 mg 
Q4W SC
Participants 
will receive
placebo 
Q4W SC
Participants 
will receive 
200 mg 
Q4W SC
Participants 
will receive 
placebo
Q4W SC
Participants 
will receive 
300 mg 
Q4W SC
Participants will 
receive placebo
Q4W SC
Associated 
Intervention 
Labels
Ponsegroma
b 100 mg
Placebo
Ponsegromab 
200 mg
Placebo
Ponsegromab 
300 mg
Placebo
a.
A total of 6 doses will be administered from Day 1 to Week 20.
b.
As different volumes are required for the different dose levels of ponsegromab, each study arm will have a 
volume-matched placebo to maintain blinding within each study arm. Each dose will be administered as 2 SC 
injections of equal volume. In addition, during SV2 all participants will receive 2 SC injections of open-label placebo 
(equivalent to high dose, 300 mg) to assess injection tolerability.
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
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Study Arms for Open-label, PK Cohort (Cohort B) a,b
Arm Title
Ponsegromab 100 mg
Ponsegromab 200 mg
Ponsegromab 300 mg
Arm Type
Experimental 
n=4
Experimental 
n=8
Experimental 
n=8
Arm Description
Participants will receive 
100 mg Q4W SC
Participants will receive 
200 mg Q4W SC
Participants will receive 300 
mg Q4W SC
Associated 
Intervention 
Labels
Ponsegromab 100 mg
Ponsegromab 200 mg
Ponsegromab 300 mg
a.
A total of 4 doses will be administered from Day 1 to Week 12.
b.
If not previously administered, participants will receive 2 SC injections of open-label placebo (equivalent of highest 
possible dose, 300 mg) during the screening period to assess injection tolerability.
Study Arms for Cohort C a
Arm Title
Ponsegromab or Placebob 100 mg
Arm Type
Experimental
n~130
Placebo
n~65
Arm Description
Participants will receive 100 mg Q4W SC
Participants will receive placebo Q4W SC
Associated 
Intervention 
Labels
Ponsegromab 100 mg
Placebo
a.
A total of 6 doses may be administered from Day 1 to Week 20.
b.
Each dose will be administered as 2 SC injections of equal volume. In addition, during SV2, all 
participants will receive 2 SC injections of open-label placebo (equivalent of highest possible dose, 
300 mg) to assess injection tolerability.
Study Arms for Cohort D a
Arm Title
Ponsegromab or Placebob 300 mg
Arm Type
Experimental
n~50
Placebo
n~50
Arm Description
Participants will receive 300 mg Q4W SC
Participants will receive placebo Q4W SC
Associated 
Intervention 
Labels
Ponsegromab 300 mg
Placebo
a.
A total of 6 doses may be administered from Day 1 to Week 20.
b.
Each dose will be administered as 2 SC injections of equal volume. In addition, during SV2, all 
participants will receive 2 SC injections of open-label placebo (equivalent of highest possible dose, 
300 mg) to assess injection tolerability.
Ethical Considerations:
The results of previous studies of ponsegromab support the investigation of its use for 
improving symptoms of heart failure, and there is a favorable benefit-risk profile to support 
the rationale for this study. Taking into account the measures to minimize risk to participants, 
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Ponsegromab, PF-06946860
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Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
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the potential risks associated with ponsegromab are justified by the anticipated benefits that 
may be afforded to participants with heart failure.

Participants may benefit, clinically, from more intense monitoring and more frequent 
assessments compared to usual standard of care. Participants may benefit from 
contributing to research in heart failure and improving our understanding of the 
condition.

Based on the experience with ponsegromab, the potential risks for its use in heart 
failure include discomfort from subcutaneous injections and/or injection site 
reactions.

Participants will be expected to commit time and may experience some discomfort 
while undergoing study assessments. In addition, participants of childbearing 
potential must agree to use appropriate contraception methods.
1.2. Study Schematic
Figure 1.
Schema
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
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Final Protocol Amendment 2, 18 July 2024
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
All study assessments and procedures conducted on scheduled dosing visits should be completed prior to study intervention 
administration, unless otherwise specified. 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.
Table 1.
Study Schedule of Assessment for the Main Cohort (Cohort A), Cohort C, and Cohort D
Visit Identifier
See abbreviations in 
Appendix 11.
SV1
SV2
Week 
0
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
22
EoT
Week  
24
F/U1
Week 
32
F/U2
Flex 
PK/PD 
visit*
Early 
Term
Notes
Study day 
No 
earlier 
than 
-56 
No later 
than
-15, 
when
feasible
1
29
57
85
113
141
155
169
225
SV2 may commence following confirmation of eligibility from 
SV1 assessments.
SV2 should commence at a minimum of 15 days prior to first 
dose, when feasible.
Study day relative to start of dosing (Day 1).
F/U1 and F/U2 and/or the Flexible PK/PD visit may be 
conducted by qualified personnel at the participant’s home or 
current residence.
Visit Window (days)
N/A
N/A
N/A
±3
±3
±3
±3
±3
±2
±3
±7
Informed consent
X
See Section 10.1.3.
Screen for eligibility 
X
X
See Section 5.1 and Section 5.2.
Screening will be conducted in at least 2 visits (SV1 and SV2). 
See Section 8.1.1.
Investigator reported
assessment of eligibility 
for Inclusion Criteria #5a
X
See Section 8.1.1. Performed after participant completion of 
KCCQ-23 at SV1.
Demographics
X
Randomization
X
See Section 6.3.
Medical history
X
X
Physical examination
X
X
X
See Section 8.3.1. Brief physical examinations to be completed 
before administration of study intervention.
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Table 1.
Study Schedule of Assessment for the Main Cohort (Cohort A), Cohort C, and Cohort D
Visit Identifier
See abbreviations in 
Appendix 11.
SV1
SV2
Week 
0
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
22
EoT
Week  
24
F/U1
Week 
32
F/U2
Flex 
PK/PD 
visit*
Early 
Term
Notes
Study day 
No 
earlier 
than 
-56 
No later 
than
-15, 
when
feasible
1
29
57
85
113
141
155
169
225
SV2 may commence following confirmation of eligibility from 
SV1 assessments.
SV2 should commence at a minimum of 15 days prior to first 
dose, when feasible.
Study day relative to start of dosing (Day 1).
F/U1 and F/U2 and/or the Flexible PK/PD visit may be 
conducted by qualified personnel at the participant’s home or 
current residence.
Visit Window (days)
N/A
N/A
N/A
±3
±3
±3
±3
±3
±2
±3
±7
Height and Weight
X
X
X
X
X
X
X
X
See Section 8.3.1. Height will be collected at SV1 only.
Vital Signs 
X
X
X
X
X
X
X
X
X
X
See Section 8.3.2.
12-Lead ECG 
X
X
See Section 8.3.3.
Contraception check
X
X
X
X
X
X
X
X
X
X
X
X
X
Refer to Appendix 4. Contraception through Week 28 will be 
confirmed at the Week 32 visit.
AE/SAE monitoring
X









X
X
X
See Section 8.4 and Section 8.4.3.
Study Intervention and 
Other Treatments
See Section 6 for additional information.
Study intervention 
administration
X
X
X
X
X
X
X
At SV2 only, open-label SC placebo will be administered to 
assess tolerability (see Section 8.1.1). Also, see Section 6.1.
Prior/concomitant 
treatment(s)
X









X
X
X
See Section 6.9.
Clinical Outcomes
See Section 8 .
KCCQ-23
X
X
X
X
X
X
X
X
X
SV1 KCCQ-23 CSS required to confirm eligibility. Refer to 
Section 8.2.1.1.
PROMIS Fatigue 7a
X
X
X
X
Refer to Section 8.2.1.2. 
PGI-S
X
X
X
X
X
X
X
X
Refer to Section 8.2.1.3. 
PGI-C
X
X
X
Refer to Section 8.2.1.4. 
6-Minute Walk Test
X
X
X
X
See Section 8.2.2.
Qualitative Exit 
Interviews
X
X
Refer to Section 8.2.1.5. Phone interview occurs within 10 BDs
of Week 22/early termination visit.
Activity monitoring
X
X
X 
X
Digital activity wrist monitor placed on participant from SV2 to
Day 1 and from Week 20 to Week 22. Refer to Section 8.2.4.
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PFIZER CONFIDENTIAL
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TMF Doc ID: 164.01
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Table 1.
Study Schedule of Assessment for the Main Cohort (Cohort A), Cohort C, and Cohort D
Visit Identifier
See abbreviations in 
Appendix 11.
SV1
SV2
Week 
0
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
22
EoT
Week  
24
F/U1
Week 
32
F/U2
Flex 
PK/PD 
visit*
Early 
Term
Notes
Study day 
No 
earlier 
than 
-56 
No later 
than
-15, 
when
feasible
1
29
57
85
113
141
155
169
225
SV2 may commence following confirmation of eligibility from 
SV1 assessments.
SV2 should commence at a minimum of 15 days prior to first 
dose, when feasible.
Study day relative to start of dosing (Day 1).
F/U1 and F/U2 and/or the Flexible PK/PD visit may be 
conducted by qualified personnel at the participant’s home or 
current residence.
Visit Window (days)
N/A
N/A
N/A
±3
±3
±3
±3
±3
±2
±3
±7
Laboratory
Assessments
Refer to lab manual for collection volumes.
Hematology & chemistry
X
X
X
X
X
See Appendix 2. Samples on dosing days must be collected 
prior to dosing.
Lipid panel
X
X
X
Pregnancy test
X
X
X
X
X
X
X
X
X
X
X
Refer to Section 8.3.5. Serum pregnancy only at SV1. Urine or 
serum pregnancy tests collected and analyzed locally at all other 
timepoints. 
Ponsegromab PK
X
X
X
X
X
X
X
X
X
X*
X
Refer to Section 8.5. PK samples collected on dosing days must 
be collected prior to dosing. 
*One flexible PK collection visit to occur 1 week (±2 days) 
after any IP dosing visit (eg, at W1, or W5, or W9, or W13, or 
W17, or W21) with the corresponding flexible PD sample.
Immunogenicity 
(ADA/NAb)
X
X
X
X
X
X
X
X
Refer to Section 8.7.8. Samples collected on dosing visits must
be collected prior to dosing.
Biomarker 
Assessments
See laboratory manual.
GDF-15 
X
Required for eligibility. Refer to Section 8.7.1.
NT-proBNP in plasma
X
X
X
X
X
Day 1 samples collected prior to dosing. Refer to Section 8.7.2.
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TMF Doc ID: 164.01
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Table 1.
Study Schedule of Assessment for the Main Cohort (Cohort A), Cohort C, and Cohort D
Visit Identifier
See abbreviations in 
Appendix 11.
SV1
SV2
Week 
0
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
22
EoT
Week  
24
F/U1
Week 
32
F/U2
Flex 
PK/PD 
visit*
Early 
Term
Notes
Study day 
No 
earlier 
than 
-56 
No later 
than
-15, 
when
feasible
1
29
57
85
113
141
155
169
225
SV2 may commence following confirmation of eligibility from 
SV1 assessments.
SV2 should commence at a minimum of 15 days prior to first 
dose, when feasible.
Study day relative to start of dosing (Day 1).
F/U1 and F/U2 and/or the Flexible PK/PD visit may be 
conducted by qualified personnel at the participant’s home or 
current residence.
Visit Window (days)
N/A
N/A
N/A
±3
±3
±3
±3
±3
±2
±3
±7
hsCRP, albumin, 
pre-albumin in serum
X
X
X
 
(Cohorts C and D only)
X
X
X
Sample collected on Day 1 should be collected prior to dosing. 
Otherwise, timing of sample collection is random. Refer to 
Section 8.7.2.
Exploratory Plasma 
Biomarker
X
X
Refer to Section 8.7.2. Day 1 sample collected prior to dosing. 
Also, refer to Section 8.7.8.
Retained research 
samples 
Pfizer Retained Research 
Samples (Prep D1 
K2EDTA whole blood, 
Prep B1 plasma, Prep B2 
serum, Prep R1 
PAXgene whole blood)
X
X
See Section 8.6.2 Prep D1 collected at Day 1 visit only, predose. 
If not collected on Day 1, collect at the next available time 
point when biospecimens are being collected. Also, refer to 
Section 8.7.6.
TIMI retained research 
samples (K2EDTA 
whole blood, plasma, 
serum)
X
X
Section 8.6.3 K2EDTA whole blood sample should be collected 
at Day 1 visit only, predose. Also, refer to Section 8.7.7.
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Table 2.
Study Schedule of Activities for Open-Label, PK Cohort (Cohort B) Only
Visit Identifier 
See abbreviations in 
Appendix 11.
SV
Week 
0
Week 
1
Week 
2
Week 
3
Week 
4
Week 
8
Week 
12
EoT
Week 
13
Week 
14
Week 
15
Week 
16
F/U1
Week 
18
Week 
22
F/U2
Early 
Term
Notes
Study day 
No earlier 
than 
-56 
1
8
15
22
29
57
85
92
99
106
113
127
155
Study day relative to start of study 
intervention (Day 1).
Visit Window 
(days)
N/A
N/A
±2
±2
±2
±2
±3
±2
±1
±2
±2
±3
±3
±3
N/A
Visit Location
On-site
On-site or at home
On-site
On-site or at home
On-
site
On-site or at 
home
On-
site
me” refers to participant’s home or 
current residence
Informed consent
X
See Section 10.1.3.
Screen for eligibility 
X
See Section 5.1 and Section 5.2.
Screening will be conducted at SV. See 
Section 8.1.1.
Demographics
X
Randomization
X
Randomization occurs following 
confirmation of eligibility. See 
Section 6.3.
Medical history
X
Physical examination
X
X
X
See Section 8.3.1. Brief physical 
examinations to be completed before 
administration of study intervention.
Height and Weight
X
X
X
X
X
X
See Section 8.3.1. Height will only be 
collected at SV.
Vital Signs 
X
X
X
X
X
X
See Section 8.3.2.
12-Lead ECG 
X
X
See Section 8.3.3.
Contraception check
X
X
X
X
X
X
X
X
Refer Appendix 4. Contraception 
through Week 20 will be confirmed at 
the Week 22 visit.
AE/SAE monitoring
X












X
X
See Section 8.4 and Section 8.4.3.
Study Intervention 
and Other 
Treatments
See Section 6.
Open-Label placebo 
injection
X
At SV only, open-label SC placebo will 
be administered to assess tolerability 
(see Section 8.1.1).
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TMF Doc ID: 164.01
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Table 2.
Study Schedule of Activities for Open-Label, PK Cohort (Cohort B) Only
Visit Identifier 
See abbreviations in 
Appendix 11.
SV
Week 
0
Week 
1
Week 
2
Week 
3
Week 
4
Week 
8
Week 
12
EoT
Week 
13
Week 
14
Week 
15
Week 
16
F/U1
Week 
18
Week 
22
F/U2
Early 
Term
Notes
Study day 
No earlier 
than 
-56 
1
8
15
22
29
57
85
92
99
106
113
127
155
Study day relative to start of study 
intervention (Day 1).
Visit Window 
(days)
N/A
N/A
±2
±2
±2
±2
±3
±2
±1
±2
±2
±3
±3
±3
N/A
Visit Location
On-site
On-site or at home
On-site
On-site or at home
On-
site
On-site or at 
home
On-
site
me” refers to participant’s home or 
current residence
Open-Label, Study 
intervention 
administration
X
X
X
X
See Section 6.1.
Prior/concomitant 
treatment(s)
X












X
X
See Section 6.9.
Laboratory 
Assessments
Refer to lab manual for collection 
volumes.
Hematology and 
blood chemistry
X
X
X
X
X
See Appendix 2. Samples on dosing 
days must be collected prior to dosing.
Lipid panel
X
X
X
Pregnancy test 
X
X
X
X
X
X
X
X
Refer to Section 8.3.5. Serum 
pregnancy only at SV. Urine or serum 
pregnancy tests collected and analyzed 
locally at all other timepoints.  
Ponsegromab PK
X
X
X
X
X
X
X
X
X
X
X
X
X
Refer to Section 8.5. PK samples 
collected on dosing days must be 
collected prior to dosing.
Immunogenicity 
(ADA/NAb)
X
X
X
X
X
X
X
Refer to Section 8.7.8. Samples 
collected on dosing visits must be 
collected prior to dosing.
Biomarker 
Assessments
See laboratory manual.
GDF-15 
X
Required for eligibility. Refer to
Section 8.7.1.
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TMF Doc ID: 164.01
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Table 2.
Study Schedule of Activities for Open-Label, PK Cohort (Cohort B) Only
Visit Identifier 
See abbreviations in 
Appendix 11.
SV
Week 
0
Week 
1
Week 
2
Week 
3
Week 
4
Week 
8
Week 
12
EoT
Week 
13
Week 
14
Week 
15
Week 
16
F/U1
Week 
18
Week 
22
F/U2
Early 
Term
Notes
Study day 
No earlier 
than 
-56 
1
8
15
22
29
57
85
92
99
106
113
127
155
Study day relative to start of study 
intervention (Day 1).
Visit Window 
(days)
N/A
N/A
±2
±2
±2
±2
±3
±2
±1
±2
±2
±3
±3
±3
N/A
Visit Location
On-site
On-site or at home
On-site
On-site or at home
On-
site
On-site or at 
home
On-
site
me” refers to participant’s home or 
current residence
NT-proBNP in 
plasma
X
X
X
X
X
Day 1 sample collected prior to dosing.
Refer to Section 8.7.2.
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2. INTRODUCTION
Ponsegromab (PF-06946860) is a humanized mAb which binds to circulating GDF-15. 
GDF-15 concentrations are elevated in patients with HF. This study investigates the effects 
of ponsegromab on heart failure symptoms, HRQL, and circulating biomarkers in study 
participants with HF and elevated concentrations of GDF-15.
2.1. Study Rationale 
The primary purpose of this study is to assess the effect of repeated SC administration of 
ponsegromab on frequency, severity, and burden of symptoms as well as physical limitations 
in participants with HF and elevated circulating GDF-15 concentrations. The study will also 
assess the safety, tolerability, PK, PD, and immunogenicity of ponsegromab. A separate, 
open-label, PK cohort, with more frequent PK and GDF-15 collection after single and 
multiple SC administration of ponsegromab, will be enrolled at certain participating sites to 
facilitate a more comprehensive assessment of PK characteristics and PK/PD relationship for 
GDF-15 in participants with HF.
This study is also known as GDF-15 inhibition in heARt failure: quality of life DiffEreNces 
(GARDEN-TIMI 74).
2.2. Background 
A summary of relevant, currently available data is provided in this protocol. Additional 
details, and further information for this compound, may be found in the IB. 
2.2.1. Heart Failure
HF is a clinical syndrome in which impaired myocardial contractile function leads to dyspnea 
or exertional limitations that impair a patient’s ability to perform activities of daily life.1
Based on data collected from the National Health and Nutrition Examination Survey from 
2013 to 2016, an estimated 6.2 million American adults have HF and its prevalence is 
expected to increase to more than 8 million adults by 2030.2 It is generally a chronic 
progressive condition, which can be stabilized with medications and/or therapeutic devices, 
or treated in suitable candidates with heart transplantation. The primary goals of HF care are 
the prevention of disease progression, the amelioration of symptoms, and the prevention of 
cardiovascular mortality. 
2.2.1.1. GDF-15 and Heart Failure 
GDF-15, also known as MIC-1, is a member of the TGF-superfamily. In healthy 
individuals, GDF-15 is expressed and secreted at low concentrations by a range of cell types. 
In response to acute and cellular stressors, such as inflammation, oxidative stress, and 
cellular senescence, GDF-15 expression increases.3,4,5,6 As such, circulating GDF-15 
concentrations are markedly elevated in several chronic conditions such as cancer, HF, 
COPD, and CKD, compared to concentrations in healthy individuals.7,8,9,10,11
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In patients with HF, GDF-15 is a well-established prognostic biomarker of cardiovascular 
morbidity and mortality.12 Circulating GDF-15 concentrations are highly associated with HF 
symptom severity, functional status, and exercise capacity. Moreover, elevated GDF-15 
concentrations predict an increased risk of death and adverse HF events in patients with HF.13
It is hypothesized that ponsegromab may neutralize effects of GDF-15 and thereby improve
symptoms in HF patients.
2.2.2. Clinical Overview
To date, the safety of ponsegromab has been assessed in 2 completed Phase 1 clinical studies 
in healthy adult volunteers (C3651001 and C3651002) and in 2 completed Phase 1b studies 
in patients with elevated serum GDF-15 levels and cancer cachexia (C3651009) and cancer 
anorexia (C3651010). A total of 80 participants were exposed to at least one dose of 
ponsegromab across these studies. A summary of the completed studies is presented in the 
table below.
Completed Clinical Studies with Ponsegromab
Study 
Identifier
Study Design 
and Type of 
Control
Dosing Regimen, 
Formulation, Dose
Number of 
Participants 
Randomized
Population
Treatment 
Duration 
C3651001
Phase 1, 
double-blind, 
randomized, 
sponsor-open, 
placebo 
controlled, 
single 
ascending 
dose study.
Ponsegromab or 
placebo. 
Subcutaneously 
administered 
solution
Dose: 
0.1, 0.3, 1, 3, 10, 
30, 100 and 300 mg
Total: 63
47 ponsegromaba, 
16 placebo
Eight sequential 
cohorts of 
healthy adult 
participants. 
Single dose 
C3651002
Phase 1, 
double-blind,
randomized, 
sponsor-open, 
placebo 
controlled, 
single dose 
study.
Ponsegromab or 
placebo. 
Subcutaneously 
administered 
solution
Dose: 100 mg
Total: 8
6 ponsegromab, 
2 placebo
One cohort of 
healthy adult 
Japanese 
participants. 
Single dose 
C3651009
Phase 1b, 
open-label 
multiple dose 
study
Ponsegromab
Subcutaneously 
administered 
solution
Dose: 200 mg Q3W
Total: 11
10 ponsegromabb
Participants 
with cancer, 
cachexia, and 
serum GDF-15 
levels ≥ 1500 
pg/ml.
12 weeks
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Completed Clinical Studies with Ponsegromab
Study 
Identifier
Study Design 
and Type of 
Control
Dosing Regimen, 
Formulation, Dose
Number of 
Participants 
Randomized
Population
Treatment 
Duration 
C3651010
Phase 1b, 
double-blind, 
randomized, 
placebo 
controlled 
followed by 
open-label 
extension
Ponsegromab or 
placebo
Subcutaneously 
administered 
solution
Dose: 200 mg Q3W
Total: 18
Double-blind 
period
12 ponsegromab
6 placebo
Open-label period
14 ponsegromabc
Participants 
with cancer, 
anorexia, and 
serum GDF-15 
levels ≥ 1500 
pg/ml.
6 weeks 
followed by 
18 week 
open-label 
extension.
a: n=6 per dose except for the 300 mg dose group where n=5.
b: 1 participant randomized and not dosed.
c: Of these 14, 5 received placebo and 9 received ponsegromab during the preceding double-blind period.
More detailed information for the completed studies may be found in the ponsegromab IB, 
which is the SRSD for this study.
Of note, the safety and efficacy of ponsegromab is being evaluated in patients with cancer, 
cachexia, and elevated GDF-15 in an ongoing Phase 2, randomized, double-blind, placebo-
controlled, 4-arm, parallel group, multicenter study (C3651003).
2.2.2.1. Summary of Safety Data
Ponsegromab has been administered to a total of 53 healthy participants in the Phase 1 
studies. Single doses of ponsegromab were well-tolerated by study participants when 
administered subcutaneously at 0.1 to 300 mg in these studies. All AEs reported across both
studies were mild, and a majority (99 of 103) of events were assessed as not related to study 
treatment; there were no deaths, and no severe or serious TEAEs. None of the TEAEs 
reported were associated with discontinuation from the study. No adverse, clinically 
significant trends were observed in safety parameters including laboratory data, vital signs 
and ECG parameters. There was no apparent dose-dependent increase in frequency of 
abnormalities in any the safety parameters assessed.
In the single arm, open-label Phase 1b C3651009 study of patients with cancer, cachexia, and 
elevated GDF-15 levels, there were 92 TEAEs reported for 10 participants dosed with
ponsegromab 200 mg Q3W SC. None of these TEAEs were attributed to study intervention
by investigator or sponsor. Of these non-treatment related TEAEs, most were mild or 
moderate; 5 were serious, of which one was fatal due to neoplasm progression during the 
follow-up period (131 days after randomization). No deaths occurred during the treatment 
period. 
In the Phase 1b C3651010 study in patients with cancer, anorexia, and elevated GDF-15 
levels, there were 58 TEAEs (including 8 SAEs) across 18 participants. Only 1 TEAE 
(myalgia) was considered treatment-related by the investigator. The incidence and severity of 
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TEAEs were similar between the two treatment arms. In the double-blind treatment phase 
there were 3 deaths: one in a participant receiving placebo, due to a cardiac arrest, and 2 in 
the ponsegromab 200 mg Q3W treatment arm, one due to respiratory failure and one due to 
acute myocardial infarction. During the open-label extension there were 3 deaths attributed to 
disease progression. None of these deaths were considered treatment related. Refer to SRSD 
or IB.
2.2.2.2. Summary of Pharmacokinetics
Following single dose administration of ponsegromab to healthy non-Japanese participants, 
SC absorption of unbound ponsegromab for the 3 to 300 mg dose groups occurred with 
median Tmax ranging from 2.25 to 7.00 days. In general, over the 10 to 300 mg dose range, 
increases in geometric mean unbound Cmax in serum were approximately dose-proportional 
and increases in unbound AUClast and AUCinf in serum appeared to be greater than dose-
proportional. The geometric mean CL/F appeared to decrease with increasing dose, and mean 
terminal t½ increased with increasing dose, ranging from 3.52 to 11.1 days across the 10 to 
300 mg dose groups.
Following single doses of SC ponsegromab in healthy participants, absorption of total 
ponsegromab occurred with median Tmax ranging from 6.00 to 14.0 days across the 1 to 300 
mg dose groups. In general, increases in geometric mean total Cmax, AUClast, and AUCinf in 
serum appeared to be less than dose-proportional over the 10 to 100 mg dose range, while 
increases in exposure from 100 to 300 mg doses were largely dose proportional. The mean 
terminal t½ values increased from 20.1 days for the 10 mg group to 30.9 days for the 300 mg 
group. The long terminal t½of total ponsegromab in serum is driven primarily by the half-life 
of bound ponsegromab (ponsegromab-GDF-15 complex), as the terminal t½ of unbound 
ponsegromab observed over the same dose range was much shorter. Unbound ponsegromab 
(not total ponsegromab) is the active moiety that accounts for pharmacological activity of the 
drug.
 
 
2.2.2.3. Summary of GDF-15 Response
In study C3651001, following single SC administration of 1 to 300 mg doses of 
ponsegromab to healthy non-Japanese adults, 
 
 
 
 
 
Following a single 
SC administration of ponsegromab 100 mg in healthy Japanese adult participants in study 
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C3651002, serum unbound GDF-15 concentrations were suppressed to below the LLOQ 
starting 
, with the median duration of suppression 
In study C3651009, following SC administration of ponsegromab at 200 mg Q3W through 
Week 12 (Day 85) in participants with cancer, cachexia and elevated serum GDF-15 
concentrations, median unbound GDF-15 concentrations were suppressed from the baseline 
concentration of 2269 pg/mL to below the LLOQ at all visits between Day 1 and Week 15 
(Day 106).
2.2.2.4. Immunogenicity
Based on the available ADA/Nab data from the Phase 1 C3651001 and C3651002 studies 
conducted in healthy participants (n=53), none of the 53 participants had pre-existing ADA at 
baseline and
 
. Overall, there was no apparent effect 
of ADA observed on the PK, PD and safety profile of ponsegromab.
In C3651009 and C3651010 studies, following SC administration of ponsegromab at 200 mg 
Q3W through 12 and 24 weeks, respectively, in participants with cancer, cachexia or 
anorexia, and elevated serum GDF-15 concentrations, the incidence of treatment-induced 
ADA was very low with overall incidence of treatment-induced ADA of 0 and 9.1% (1/11), 
respectively, and no incidence of NAb was observed in either study.
2.3. Benefit/Risk Assessment
The available clinical data described in the IB show that no safety concerns have been 
identified in the four clinical trials completed to date.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ponsegromab may be found in the IB, which is the SRSD for this study. 
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) ponsegromab
SC injection site reactions and hypersensitivity 
reactions.
Although there were no injection site reactions or 
delayed hypersensitivity reactions observed in the 
completed clinical studies, as with all injectable 
mAbs, there is the potential for injection site 
reactions or delayed hypersensitivity reactions.
The following exclusion criterion is added: History 
of allergic or anaphylactic reaction to any 
therapeutic or diagnostic monoclonal antibody 
(IgG protein) or molecules made of components of 
monoclonal antibody. Additionally, injection site 
reactions will be monitored, and injection sites 
rotated.
Use of a placebo arm.
Use of a placebo arm represents a risk of lack of 
benefit for those not receiving active therapy. As 
there are no data on efficacy yet, this risk cannot 
be assessed.
Participants will continue to receive standard of 
care throughout the study for their heart failure.
Study Procedures
Biologic samples required for this study require 
invasive procedures (eg, needle insertion), which 
may lead to bruising or discomfort at insertion site.
HF patients may be sensitive to needle insertions. 
Experienced health care providers will deliver a 
subcutaneous injection during the screening visit 
so that potential study participants have an 
opportunity to decline participation if they do not 
tolerate the procedure.
Challenges in collecting the requisite amount of 
blood required.
Participants may be anemic or have a concomitant 
condition that makes it difficult to collect requisite 
volume of bio-samples. 
Effort to streamline bio sample collection in the 
SoA and reduce volume collected where feasible.
Other 
The COVID-19 pandemic may pose risks to study 
participation.
Historical precedent. 
Main Cohort (Cohort A), Cohort C, and Cohort 
D: Follow-up visits (F/U1 and/or F/U2) and/or the 
Flexible PK/PD visit may be conducted by 
qualified personnel at the participant’s home or 
current residence, in order to reduce the risk of 
exposure at the site.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Open-label, PK Cohort (Cohort B): Scheduled
visits, where permitted per SoA, may be conducted 
by a contracted home health service at the 
participant’s home or current residence, in order to 
reduce the risk of exposure at the site.
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2.3.2. Benefit Assessment
Ponsegromab has not been administered to patients with HF prior to this study. Based upon 
nonclinical data, it is hypothesized that dosing with ponsegromab will lessen participants’ 
frequency and/or burden of symptoms associated with HF. Participants may benefit, 
clinically, from more intense monitoring and more frequent assessments compared to usual 
standard of care. Participants may benefit from contributing to research in heart failure and 
improving our understanding of the condition.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account all available nonclinical and clinical data regarding the safety and 
tolerability of ponsegromab to date, and measures to monitor and minimize risk to study 
participants, the overall benefit/risk profile supports further clinical development of 
ponsegromab in participants with HF.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
3.1. Main Cohort (Cohort A), Cohort C and Cohort D
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To compare the effect of 
ponsegromab 300 mg versus 
placebo, on HF disease-specific 
health status in participants with HF
and serum GDF-15 concentrations 
pg/mL (Main Cohort [Cohort 
A]) only.
Change from baseline in 
KCCQ-23 CSS at Week 22.
Estimand 1 (similar to 
“hypothetical”) is the difference 
between ponsegromab and placebo 
in mean change from baseline in 
KCCQ-23 CSS at Week 22, in 
study participants with HF and 
serum GDF-15 concentrations 
pg/mL, under the scenario 
of no discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures or 
participants’ non-compliance with 
dosing.
Secondary: 
Secondary:
Secondary: 
To compare the effect of 
ponsegromab versus placebo on HF 
disease-specific overall health status 
in participants with HF and serum 
GDF-15 concentrations 
pg/mL.
Change from baseline in 
KCCQ-23 CSS, OSS, TSS, and 
physical limitation at Week 22.
Estimand 2 (similar to 
“hypothetical”) is the difference 
between ponsegromab and placebo 
in mean change from baseline in 
each of KCCQ-23 CSS, OSS, TSS 
and physical limitation score at 
Week 22, in participants with HF
and serum GDF-15 concentrations 
pg/mL, under the scenario 
of no discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures or 
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 39
Objectives
Endpoints
Estimands
participants’ non-compliance with 
dosing.
To compare the effect of
ponsegromab versus placebo on HF
disease-specific health status in 
participants with HF and serum 
GDF-15 concentrations
pg/mL.
Responses as defined by a ≥5-point 
increase from baseline in 
KCCQ-23 CSS, OSS, TSS, and 
physical limitation at Week 22.
Estimand 3 (similar to 
“hypothetical”) is the odds ratio 
between ponsegromab and placebo 
on the proportion of participants 
with ≥5-point increases from 
baseline in each of 
KCCQ-23 CSS, OSS, TSS, and 
physical limitation score at 
Week 22, in participants with HF
and serum GDF-15 concentrations 
pg/mL, under the scenario 
of no discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures or 
participants’ non-compliance with 
dosing.
To compare the effect of 
ponsegromab versus placebo on the 
physical function of participants 
with HF and serum GDF-15 
concentrations
pg/mL.
Change from baseline in 6MWD at 
Week 22.
Estimand 4 (similar to 
“hypothetical”) is the difference 
between ponsegromab and placebo 
in mean change from baseline in 
6MWD at Week 22, in 
participants with HF and serum 
GDF-15 concentrations
 
pg/mL, under the scenario of no 
discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures or 
participants’ non-compliance with 
dosing.
To compare the effect of 
ponsegromab versus placebo on 
fatigue reported by participants with 
HF and serum GDF-15 
concentrations
pg/mL.
Change from baseline in PROMIS 
Fatigue 7a at Week 22.
Estimand 5 (similar to 
“hypothetical”) is the difference 
between ponsegromab and placebo 
in mean change from baseline in  
PROMIS Fatigue 7a at Week 22 in 
participants with HF and serum 
GDF-15 concentrations
pg/mL, under the scenario of no 
discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures or 
participants’ non-compliance with 
dosing.
To describe the safety and 
tolerability of ponsegromab in 
participants with HF.
Incidence of TEAEs, TESAEs, 
abnormal laboratory results, and 
vital signs.
There are no defined estimands for 
the incidence of TEAEs, TESAEs, 
abnormal laboratory results, and 
vital signs, and these endpoints 
will be analyzed using Pfizer data 
standards as applicable.
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Protocol C3651011
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TMF Doc ID: 164.01
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Objectives
Endpoints
Estimands
Tertiary/Exploratory: 
Tertiary/Exploratory:
Tertiary/Exploratory: 
To compare the effect of 
ponsegromab 300 mg versus 
placebo, on HF disease-specific 
health status in participants with HF
and any serum GDF-15 
concentration.
Change from baseline in 
KCCQ-23 CSS, OSS, TSS, and 
physical limitation at Week 22.
Responses as defined by a ≥5-point 
increase from baseline in 
KCCQ-23 CSS, OSS, TSS, and 
physical limitation at Week 22.
Not applicable.
To compare the effect of 
ponsegromab 300 mg versus
placebo on the physical function of 
participants with HF and any serum 
GDF-15 concentration.
Change from baseline in 6MWD at 
Week 22.
Not applicable.
To compare the effect of 
ponsegromab 300 mg versus
placebo on fatigue reported by 
participants with HF and any serum 
GDF-15 concentration.
Change from baseline in PROMIS 
Fatigue 7a at Week 22.
Not applicable.
To compare the effect of 
ponsegromab versus placebo on HF 
disease-specific health status in 
participants with HF.
Response as defined by a ≥10-point 
and ≥15-point increase in 
KCCQ-23 CSS, OSS, TSS, and 
physical limitation at Week 22.
Not applicable.
To describe the effect of 
ponsegromab on impressions of 
disease severity and change in 
participants with HF.
Absolute and change from baseline 
in PGI-S at Week 22.
Absolute PGI-C at Week 22.
Not applicable.
To compare the effect of 
ponsegromab versus placebo on 
body weight in participants with 
HF.
Change from baseline in body 
weight at Week 22.
Not applicable.
To compare the effect of 
ponsegromab versus placebo on 
daily activity measures based on 
accelerometry in participants with 
HF.
Change from baseline in daily 
activity measures based on 
accelerometry at Week 22.
Not applicable.
To evaluate the PK of ponsegromab
in participants with HF.
Serum unbound and total 
ponsegromab concentrations on 
Day 1 (predose) and Weeks 4, 8, 
12, 16, 20, 22, 24, and 32.
Not applicable.
To compare the effect of 
ponsegromab versus placebo on 
GDF-15 concentrations in 
participants with HF.
Serum concentrations of GDF-15 
on Day 1 and Weeks 4, 8, 12, 16, 
20, 22, 24, and 32.
Not applicable.
To characterize the immunogenicity 
of ponsegromab in participants with 
HF.
Incidence of anti-ponsegromab
antibodies, and neutralizing 
antibodies.
Not applicable.
To compare the effect of 
ponsegromab versus placebo on 
markers to check HF risk, acute MI, 
Fold change from baseline in 
NT-proBNP, hsCRP, albumin and
pre-albumin at Week 22.
Not applicable.
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Objectives
Endpoints
Estimands
inflammation, and nutritional status 
in participants with HF.
To compare the effect of 
ponsegromab versus placebo on 
in participants with 
HF.
Fold change from baseline in
at Weeks 12 and 22.
Fold change from baseline in 
at Weeks 12 and 22 
(Cohorts C and D only).
Not applicable.
To compare the effect of 
ponsegromab versus placebo on 
clinical outcomes of cardiovascular 
death, hospitalization for HF, or 
urgent HF visit and on days alive 
and out of the hospital in 
participants with HF.
Hierarchical composite endpoint: 

Time to cardiovascular death;

Number of worsening HF 
events (hospitalization for HF, 
or urgent HF visit);

Time to first worsening HF 
event (hospitalization for HF, 
or urgent heart visit);

Change from baseline in 
KCCQ-23 CSS at Week 22.
Time to first occurrence of the 
clinical composite of cardiovascular 
death, hospitalization for HF, or 
urgent heart visit.
Total number of days alive and out 
of the hospital over 22 weeks.
Total number of hospitalizations for 
HF and urgent HF visits over 
22 weeks.
Not applicable.
3.2. Open-Label, PK Cohort (Cohort B)
Objectives
Endpoints
Estimands
Secondary: 
Secondary:
Secondary: 
To evaluate the safety and 
tolerability of ponsegromab in 
participants with HF and elevated 
circulating GDF-15 concentrations.
Incidence of TEAEs, TESAEs, 
abnormal laboratory results, and 
vital signs.
There are no defined estimands for 
the incidence of TEAEs, TESAEs, 
abnormal laboratory results, and 
vital signs, and these endpoints 
will be analyzed using Pfizer data 
standards as applicable.
Tertiary/Exploratory: 
Tertiary/Exploratory:
Tertiary/Exploratory: 

To evaluate the PK of ponsegromab 
following repeated SC 
administration in participants with 
HF and elevated circulating GDF-
15 concentrations.
Serum unbound and total 
ponsegromab PK parameters after 
1st dose on Day 1 and 4th dose on 
Day 85: AUCtau, Cmax, Tmax and as 
data permit, t½, CL/F, Vz/F, PTR
after 4th dose.
There are no defined estimands for 
PK endpoints.
To characterize the effect of 
ponsegromab on circulating GDF-
15 concentrations in participants 
Serum concentrations of GDF-15 
on Day 1 and Weeks 1, 2, 3, 4, 8, 
12, 13, 14, 15, 16 and 18. 
Not applicable
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Final Protocol Amendment 2, 18 July 2024
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 42
Objectives
Endpoints
Estimands
with HF and elevated circulating 
GDF-15 concentrations.
To characterize the immunogenicity 
of ponsegromab in participants with 
HF and elevated circulating GDF-15 
concentrations.
Incidence of ADA, and NAb.
Not applicable.
To evaluate the effect of 
ponsegromab on NT-proBNP in 
participants with HF and elevated 
circulating GDF-15 concentrations.
Fold change from baseline in NT-
proBNP at Weeks 12 and 16. 
Not applicable.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 2, parallel-group, randomized, double-blind, placebo-controlled study to
evaluate the effect of ponsegromab on HRQL, physical activity, and circulating biomarkers 
in adult participants with HF and elevated circulating GDF-15. 
For the Main Cohort (Cohort A), Cohort C, and Cohort D, following the 56-day screening 
period to confirm eligibility, the study will include a 22-week treatment period (from Day 1 
to Week 20, and Week 22 for primary endpoint collection), and a 10-week follow-up period 
for a total study duration of 32 weeks not including the screening period.
Approximately 416 participants will be enrolled into the Main Cohort (Cohort A) and
randomized to one of 3 doses of ponsegromab (100 mg [n=18], 200 mg [n=18], or 300 mg 
[n=190]) or to matched placebo (n=190). Approximately 195 additional participants may be 
enrolled into optional Cohort C and randomized in a 2:1 ratio to either 100 mg ponsegromab 
(n~130) or to matched placebo (n~65). The participants in optional Cohort C will allow for a 
more comprehensive evaluation of the safety and efficacy of the ponsegromab 100 mg dose 
level compared to placebo. For each of these cohorts, blinded study drug will be administered 
SC Q4W for a total of 6 doses during the 22-week treatment period.
Participant randomization will be stratified based on 
: 
KCCQ-23 CSS: <45 or ≥45.
The primary endpoint for the study is the change from baseline at Week 22 in 
KCCQ-23 CSS, an HRQL PRO instrument.
Approximately 100 participants (maximum of approximately 150) who meet all eligibility 
criteria for Cohorts A and C, except the requirement for serum GDF-15 concentration
pg/mL, may be enrolled into the optional Cohort D and randomized in a 1:1 ratio to either 
300 mg ponsegromab (n~50) or to matched placebo (n~50), administered SC Q4W for a total 
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of 6 doses during the 22-week treatment period. Participant randomization in Cohort D will 
be stratified by KCCQ-23 CSS: <45 or ≥45. The purpose of this optional cohort is for a 
supportive assessment of efficacy and safety endpoints across the spectrum of GDF-15 
concentrations in participants with HF.
This study will use an unblinded E-DMC to monitor the safety of participants and an 
unblinded IRC to monitor the efficacy and safety of participants. A blinded Steering 
Committee will monitor the proportion of study participants with various NYHA classes, left 
ventricular ejection fractions, GDF-15 concentrations, KCCQ-23 CSS scores, and the relative 
proportions qualifying under the cachexia, fatigue, and functional impairment criteria and 
may cap one or more to ensure a broad population.
This study will also use a separate blinded adjudication committee consisting of independent 
external experts who will be responsible for adjudication of all deaths and investigator-
reported HF hospitalizations and urgent HF visits.
Open-label, PK Cohort (Cohort B): The primary purpose of this open-label, PK cohort is 
to facilitate a more comprehensive assessment of PK characteristics and PK/PD relationship 
of ponsegromab following single and repeated SC administration in participants with HF and 
elevated circulating GDF-15 concentrations.
Approximately 20 participants, after confirmation of eligibility, will be randomized to one of 
3 dose levels of open-label ponsegromab (100 mg [n=4], 200 mg [n=8], or 300 mg [n=8]) 
administered SC Q4W for a total of 4 doses, with last dose at Week 12 and follow-up to 
Week 22.
4.2. Scientific Rationale for Study Design
The primary purpose of this study is to assess the effect of repeated SC administration of 
ponsegromab on frequency, severity, and burden of symptoms as well as physical limitations 
in participants with HF and elevated circulating GDF-15 (
 pg/mL). The assessments to 
be performed to achieve these objectives are described in detail in Section 8. The study will 
also assess the safety, tolerability, PK, PD, and immunogenicity of ponsegromab. A separate, 
open-label, PK cohort, with more frequent PK and GDF-15 collection after single and 
multiple SC administration of ponsegromab, will be enrolled at certain participating sites to 
facilitate a more comprehensive assessment of PK characteristics and PK/PD relationship for 
GDF-15 in participants with HF. In addition, an optional cohort (Cohort D) will enroll 
participants with circulating GDF-15
 pg/mL to enable a supportive assessment of 
efficacy and safety endpoints across the spectrum of GDF-15 concentrations in participants 
with HF.
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Ponsegromab and GDF-15 concentrations will be measured in this study to 
(1) assess ponsegromab exposure in this population; (2) understand the range of baseline 
GDF-15 values and variability in this population; and (3) provide preliminary information on 
the magnitude of GDF-15 suppression after ponsegromab treatment. As ponsegromab is a 
monoclonal antibody, immunogenicity samples will be collected for the determination of 
ADA and NAb.
The rationale for stratification by GDF-15 and KCCQ-23 is an attempt to balance these key 
parameters across the different treatment groups.
The sample sizes for the ponsegromab 300 mg and placebo dose groups in the Main Cohort 
(Cohort A) and for the ponsegromab 100 mg dose group in optional Cohort C were chosen to 
provide acceptable operating characteristics for the primary endpoint for both doses, and 
thereby support dose-finding efforts for any subsequent clinical studies. The smaller sample 
size in the ponsegromab 100 mg and 200 mg Q4W arms in the Main Cohort (Cohort A) was
chosen empirically to provide sufficient data to gain a preliminary understanding of the 
PK/PD relationship in this population. The sample size for the open-label, PK cohort (Cohort 
B) has been chosen empirically to provide sufficient evaluable participants to adequately 
evaluate the PK of ponsegromab following repeated SC administration to participants with 
HF and elevated circulating GDF-15 concentrations. The sample size for the optional Cohort 
D was chosen empirically to provide data on participants with GDF-15 levels
pg/mL 
for supportive analyses.
4.2.1. KCCQ-23 Heart Failure Patient Reported Outcome Instrument
The KCCQ-23 is a self-administered questionnaire that quantifies physical limitations, 
symptoms, self-efficacy, social interference, and quality of life for participants with HF.14
The KCCQ-23 is sensitive to clinical change, and is a straightforward instrument for 
participants to complete. The benefit and importance of functional status and PRO data are 
recognized as key clinical endpoints in HF research.
4.2.2. Patient Input Into Design
Participant input was leveraged based on interviews conducted in patients with various types 
of cancer. Although this patient population is different from a HF population, the 
GDF-15-related symptoms overlap in the HF population, including:

Fatigue/tiredness.

Physical activity limitations (eg, limited activities of daily living, difficulty walking, 
reduced physical strength).

Weight loss/fluctuations.
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
Loss of appetite/anorexia.

Gastric problems (nausea, vomiting).
Twelve patients with cancer (prostate, NSCLC, colorectal, or pancreatic) and their caregivers 
were interviewed to better understand their burdensome symptoms and resulting impact on
clinical trial participation. This targeted patient population emphasized the need to improve 
appetite and reduce fatigue. Combined with the prognostic associations of circulating 
GDF-15 with HF morbidity and mortality, the primary objective focusing on KCCQ-23 CSS
is appropriate.
Based on feedback from these patients and caregivers, this study incorporated the following 
elements:

Including qualitative phone interviews as a holistic assessment so patients may share 
their overall experiences with the study treatment with the Sponsor. 

Incorporating important aspects of the disease and the potential social and 
psychological impact in training.
4.2.3. Diversity of Study Population
Reasonable attempts will be made to enroll participants who are representative of the patient 
population that will be treated with ponsegromab in clinical practice. The team will follow 
best practices for diverse study population enrollment and retention. The following strategies 
may be explored in support of diverse recruitment efforts:

Inclusion of diversity questions into the Feasibility Survey and Pre-Trial Assessment 
to identify sites with access to diverse patient populations.

Discussion with investigator sites ahead of selection to assess preparedness, 
mitigation strategies for reaching diversity goals, and active inclusion.

Encouragement of investigator sites to complete the Investigator Site Recruitment 
Plan.

Provide investigator sites with site kit materials designed for use with diverse patient 
populations.

Implement as needed targeted digital outreach to diverse patient groups.

Have proactive discussions with investigator sites throughout the enrollment period to 
assess and reevaluate site specific strategies as needed to best position each site for 
the most diverse representation enrollment outcomes.
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
Monitor diverse enrollment to identify potential opportunities to include diverse 
populations.
4.2.4. Choice of Contraception/Barrier Requirements
Studies to evaluate the developmental toxicity of ponsegromab have not been conducted. 
Therefore, the use of a highly effective method of contraception is required (see Appendix 4).
4.2.5. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
In the Main Cohort (Cohort A), ponsegromab will be administered at doses of 100, 200 or 
300 mg, or matched placebo, Q4W SC for a total of 6 doses. In Cohort C, ponsegromab will 
be administered at a dose of 100 mg, or matched placebo, SC Q4W SC for a total of 6 doses. 
In Cohort D, ponsegromab will be administered at a dose of 300 mg, or matched placebo, SC 
Q4W for a total of 6 doses. The proposed doses have been determined considering all 
relevant information obtained from nonclinical safety studies, safety, tolerability, PK and PD 
data from the 2 completed studies in healthy participants (C3651001 and C3651002, see IB)
and 
 These doses 
should facilitate an assessment of the PK/PD relationship between ponsegromab exposure 
and GDF-15 suppression.
Based on preliminary population PK/PD simulations, the proposed 100 mg Q4W SC dose is 
expected to suppress the unbound GDF-15 concentration in HF patients with assumed 
median baseline of 2820 pg/mL in
%  
% of the patients for
weeks, 
respectively. The proposed 200 mg Q4W SC dose is expected to suppress the unbound 
GDF-15 concentration in 
%,
% of the patients for
weeks, respectively. 
The proposed high dose of 300 mg Q4W SC dose is expected to suppress the unbound 
GDF-15 concentration in
% of HF patients for
weeks.
Based on the t½ of the total and unbound ponsegromab and duration of the study, the 
exposures are expected to have reached steady state after
doses administered Q4W. Based 
on these preliminary PK/PD simulations, the predicted steady state total ponsegromab Cmax, 
AUCtau and Cavg, following Q4W SC doses of 100, 200 and 300 mg, along with the 
corresponding safety margins calculated using exposure data from the 6-month toxicology 
study in monkeys (See IB), and exposure multiples calculated using total exposure data 
following a single 300 mg dose to healthy participants in study C3651001, are summarized in
Table 3. The corresponding steady state unbound ponsegromab exposures and exposure 
multiples calculated using unbound exposure data from study C3651001, are summarized in
Table 4.
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Final Protocol Amendment 2, 18 July 2024
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Table 3.
Summary of Predicted Steady State Total Ponsegromab Exposures and 
Associated Safety Margins and Exposure Multiples Following Q4W SC 
Doses
SC Dose 
(mg, Q4W)
Cmax
(µg/mL)
AUCtau
(µg•day/mL)
Cavg
(µg/mL)
Safety Margina
Exposure Multipleb
Cmax
Cavg
Cmax
AUCtau
100 
200
300
a.
Based on the predicted steady state total Cmax and Cavg following Q4W SC doses of ponsegromab at 100, 200 or 300 
mg relative to the NOAEL Cmax (
µg/mL) and Cavg
µg/mL) observed in the 6-month toxicology study in 
monkey (IB).
b.
Based on the predicted steady state total Cmax and AUCtau following Q4W SC doses of ponsegromab at 100, 200 or 
300 mg relative to the Cmax, (
µg/mL) and AUCinf (
µg•day/mL) observed following the 300 mg single dose 
in C3651001.
Table 4.
Summary of Predicted Steady State Unbound Ponsegromab Exposures 
and Associated Exposure Multiples Following Q4W SC Doses
SC Dose 
(mg, Q4W)
Cmax
(µg/mL)
AUCtau
(µg•day/mL)
Cavg
(µg/mL)
Exposure Multiplea
Cmax
AUCtau
100
200
300
a.
Based on the predicted steady state unbound Cmax and AUCtau following Q4W SC doses of ponsegromab at 100, 
200, and 300 mg relative to the unbound Cmax (
µg/mL) and AUCinf (
µg•day /mL) observed following the 
300 mg single SC dose in study C3651001.
Given the observed safety data in healthy participants from studies C3651001 and C3651002, 
and the preliminary safety data from ongoing studies C351009 and C3651010, the proposed 
100, 200, and 300 mg Q4W SC doses are expected to have an acceptable safety and 
tolerability profile.
The same dose levels (100, 200 and 300 mg SC Q4W) as in the Main Cohort (Cohort A) will 
be studied in the open-label PK cohort (Cohort B). A total of 4 doses will be administered 
during the 12-week treatment period. Ponsegromab exposures are expected to be close to 
steady state after 4 doses administered Q4W (>
% of steady state).
4.4. End of Study Definition
The end of the study is defined as the date of the last visit in the SoA of the last participant
active in either the Main Cohort (Cohort A), open-label, PK cohort (Cohort B), Cohort C, or 
Cohort D (whichever is the latest).
A participant is considered to have completed the study if he/she has completed all periods of 
the study, including the last visit in the SoA.
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The PCD is the date when the last participant in the Main Cohort (Cohort A), Cohort C (if 
enrolled) or Cohort D (if enrolled), whichever is latest, has
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. 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:
Age and Sex:
1. Participants aged 18 years or older (or the minimum age of consent in accordance 
with local regulations) at screening.  
a.
A female participant is eligible to participate if she is not pregnant or 
breastfeeding.
b. Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Disease Characteristics:
2. Clinical evidence of HF with each of the following criteria:
a.
LVEF <50% on most recent measurement, within 12 months of screening.
Note: An assessment of LVEF in the prior 12 months is not required in situations 
where LVEF has been persistently <50% on prior assessments obtained at least 3 
months apart (including the most recent measurement).
b. NYHA class II-IV at screening.
c.
NT-proBNP ≥400 pg/mL at screening (Note: Does not apply to open-label, PK 
cohort [Cohort B]).
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3. Serum GDF-15 concentration
pg/mL at screening.

Cohort D only: Serum GDF-15 concentration
pg/mL at screening.
4. KCCQ-23 CSS <75 at screening (Note: Does not apply to open-label, PK cohort
[Cohort B]).
5. Evidence of cachexia or fatigue or functional impairment, as demonstrated by at least 
one of the following at screening (Note: Does not apply to open-label, PK cohort
[Cohort B]):
a.
Non-edematous unintentional weight loss ≥5% in the last 6 months or current 
BMI <20 kg/m2, associated with subjective fatigue or anorexia; or
b. Fatigue at least 3 times per week AND at least moderately bothersome fatigue in 
the past 2 weeks based on the KCCQ-23 administered at screening; or
c.
A score of <60 on the Physical Limitations Domain of the KCCQ-23 
administered at screening.
Other Inclusion Criteria:
6. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures (including
but not limited to subcutaneous injection of study intervention).
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Acute decompensated HF within 1 month prior to SV1 or during the screening period.
2. Implantation of a cardiac resynchronization therapy device or valve repair or 
replacement within 3 months prior to randomization or intent to do so during the trial.

For the open-label, PK cohort (Cohort B) only: implantation of a cardiac 
resynchronization therapy device more than 1 month prior to randomization is 
permitted.
3. History of heart transplantation, currently listed for heart transplant, current/planned 
mechanical circulatory support, or current/planned use of intravenous inotropes (eg, 
dobutamine, milrinone).
4. Acute coronary syndrome within 1 month prior to randomization.
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5. Coronary revascularization (percutaneous coronary intervention or coronary artery 
bypass grafting) within 3 months prior to randomization or intent to undergo coronary 
revascularization during the trial.

For the open-label, PK cohort (Cohort B) only: coronary revascularization 
more than 1 month prior to randomization is permitted.
6. Untreated indication for an implantable cardiac defibrillator or pacemaker to treat a 
cardiac rhythm abnormality (ie, tachyarrhythmia or bradyarrhythmia).
7. History of allergic or anaphylactic reaction to any therapeutic or diagnostic 
monoclonal antibody (IgG protein) or molecules made of components of monoclonal 
antibody.
8. Other medical (eg, severe, uncorrected aortic stenosis; active malignancy) 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, may limit life expectancy to less than 
1 year and/or make the participant inappropriate for the study.
Prior/Concomitant Therapy:
9. Current use of any prohibited concomitant medication(s). Refer to Section 6.9 Prior 
and Concomitant Therapy.
Prior/Concurrent Clinical Study Experience:
10. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives (whichever is 
longer) preceding the first dose of study intervention used in this study. Treatment 
with an investigational biologic agent within 6 months or 5 half-lives (whichever is 
longer) of Day 1.
11. Previous exposure to ponsegromab in a prior clinical study.
Diagnostic Assessments:
12. Renal disease requiring ongoing dialysis.
13. Cirrhosis with evidence of portal hypertension not due to HF, or the following LFT 
abnormalities at the time of screening, confirmed by a repeat test if deemed 
necessary: AST or ALT level ≥3 x ULN, or total bilirubin level ≥2 x ULN (unless 
history of Gilbert’s syndrome).
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Other Exclusion Criteria:
14. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
5.3. Lifestyle Considerations
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
from the permitted list of contraception methods (see Appendix 4, Section 10.4.4) and will
confirm that the participant has been instructed in its consistent and correct use. At time 
points indicated in the SoA, the investigator or designee will inform the participant of the 
need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception,
considering that their risk for pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, and any SAE.
Main Cohort (Cohort A)/Cohort C/Cohort D: Individuals who qualify for these cohorts
but are not randomized for administrative reasons, may be re-screened. Individuals who do 
not meet the criteria for participation in these cohorts may be re-screened once if, in the 
judgment of the investigator, the reason for initial ineligibility is considered to be resolved, or 
there has been a change in eligibility status. Individuals who were already screened on two 
occasions for the Main Cohort (Cohort A), and screen-failed on one or both occasions due to 
serum GDF-15 concentration 
pg/mL, may be re-screened on one further occasion for 
potential eligibility for Cohort D. Given that eligibility criteria are identical for Cohorts C 
and D (with the exception of the serum GDF-15 concentration requirement), individuals can 
undergo a common screening period for inclusion in these cohorts, with cohort ultimately 
determined by the result of the screening GDF-15 assessment. For individuals who are re-
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screened for any reason, all screening procedures should be repeated, unless otherwise agreed 
with the Sponsor in advance, and the participant assigned a new 8-digit SSID.
Open-label, PK cohort (Cohort B): At certain sites, participants may be considered for 
enrollment in the open-label, PK cohort. This may include participants who screen fail for the 
Main Cohort (Cohort A) or Cohort C at any time during screening (SV1 or SV2). In such 
circumstances, screening for the open-label, PK cohort may be performed during the same 
site visit or on a separate day. Participants will be assigned a new 8-digit SSID. Signed and 
dated ICD will be required prior to any study-specific activity specified in the SoA for this 
open-label, PK cohort (Table 2). Screening procedures that were already performed during 
screening for a different cohort may not need to be repeated for screening for the open-label, 
PK cohort, if within the screening window. Participants who are screened twice for a 
different cohort can still be screened for the open-label, PK cohort. However, participants can 
only be screened once for the open-label, PK cohort, unless randomization is deferred for 
administrative reasons.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and non-investigational products, 
medical devices, and other interventions (eg, surgical and behavioral) intended to be 
administered to the study participants during the study conduct.
For the purposes of this protocol, study intervention refers to ponsegromab (PF-06946860,
IMP), and placebo (IMP).
Study Interventions Administered
Intervention Name
Ponsegromab (PF-06946860)
Placebo
Arm Name
(group of participants
receiving a specific treatment 
or no treatment)
Ponsegromab double-blind treatment
Placebo double-blind 
treatment
Type
Biologic
Placebo
Dose Formulation
Solution for injection
Solution for injection
Unit Dose Strength(s)
100 mg/mL
Placebo
Dosage Level(s)
100, 200 or 300 mg Q4W
Placebo Q4W
Route of Administration
SC
SC
Use
Experimental 
Placebo
IMP or NIMP/AxMP
IMP
IMP
Sourcing
Provided centrally by the sponsor
Provided centrally by the 
sponsor
Packaging and Labeling
Study intervention will be provided in 6-mL 
glass vial with an up to 1 mL withdrawal
volume. Each vial will be labeled as required 
per country requirement. Each vial is for 
single use only.
Study intervention will be 
provided in 6-mL glass 
vial with an up to 1 mL 
withdrawal volume. Each 
vial will be labeled as 
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Intervention Name
Ponsegromab (PF-06946860)
Placebo
required per country 
requirement. Each vial is 
for single use only.
Study Arms for Main Cohort (Cohort A) a
Arm Title
Ponsegromab or Placebob
100 mg
Ponsegromab or 
Placebob 200 mg
Ponsegromab or Placebob
300 mg
Arm Type
Experimental
n=18
Placebo
n=6
Experimental
n=18
Placebo
n=6
Experimental
n=190
Placebo
n=178
Arm Description
Participants 
will receive 
100 mg 
Q4W SC
Participants 
will receive
placebo
Q4W SC
Participants 
will receive 
200 mg 
Q4W SC
Participant
s will 
receive
placebo
Q4W SC
Participants 
will receive 
300 mg 
Q4w SC
Participants will 
receive placebo
Q4W SC
Associated 
Intervention 
Labels
Ponsegromab 
100 mg
Placebo
Ponsegromab 
200 mg
Placebo
Ponsegromab 
300 mg
Placebo
a.
A total of 6 doses will be administered from Day 1 to Week 20.
b.
As different volumes are required for the different dose levels of ponsegromab, each study arm will have 
a volume-matched placebo to maintain blinding within each study arm. Each dose will be administered as 
2 SC injections of equal volume. In addition, during SV2, all participants will receive 2 SC injections of 
open-label placebo (equivalent of highest possible dose, 300 mg) to assess injection tolerability.
Study Arms for Open-label, PK Cohort (Cohort B) a,b
Arm Title
Ponsegromab 100 mg
Ponsegromab 200 mg
Ponsegromab 300 mg
Arm Type
Experimental
n=4
Experimental
n=8
Experimental
n=8
Arm Description
Participants will receive 100 
mg Q4W SC
Participants will receive 200 
mg Q4W SC
Participants will receive 300 
mg Q4W SC
Associated 
Intervention 
Labels
Ponsegromab 100 mg
Ponsegromab 200 mg
Ponsegromab 300 mg
a.
A total of 4 doses will be administered from Day 1 to Week 12.
b.
If not previously administered, participants will receive 2 SC injections of open-label placebo (equivalent 
of highest possible dose, 300 mg) during the screening period to assess injection tolerability.
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Study Arms for Cohort C a
Arm Title
Ponsegromab or Placebob 100 mg
Arm Type
Experimental
n~130
Placebo
n~65
Arm Description
Participants will receive 100 mg Q4W SC
Participants will receive placebo Q4W SC
Associated 
Intervention 
Labels
Ponsegromab 100 mg
Placebo
a.
A total of 6 doses may be administered from Day 1 to Week 20.
b.
Each dose will be administered as 2 SC injections of equal volume. In addition, during SV2, all 
participants will receive 2 SC injections of open-label placebo (equivalent of highest possible dose, 
300 mg) to assess injection tolerability.
Study Arms for Cohort D a
Arm Title
Ponsegromab or Placebob 300 mg
Arm Type
Experimental
n~50
Placebo
n~50
Arm Description
Participants will receive 300 mg Q4W SC
Participants will receive placebo Q4W SC
Associated 
Intervention 
Labels
Ponsegromab 300 mg
Placebo
a.
A total of 6 doses may be administered from Day 1 to Week 20.
b.
Each dose will be administered as 2 SC injections of equal volume. In addition, during SV2, all 
participants will receive 2 SC injections of open-label placebo (equivalent of highest possible dose, 
300 mg) to assess injection tolerability.
6.1. Administration
Each dose of investigational product must be administered by appropriately qualified 
personnel. 
Study intervention will be administered in a divided dose requiring 2 separate SC injections 
given in rapid succession every 4 weeks. The permitted injection sites are the abdomen, 
upper arm (right or left) and the thigh (right or left). The following combination of injection 
sites are provided as examples:

Two injections in the abdomen (each injection should be administered into a different 
quadrant and separated by at least 3 cm),

One injection into each upper arm

One injection into each thigh
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
One injection into the arm (right or left) and one injection in the leg (right or left), or

One injection in arm or leg (left or right) and one in the abdomen.
The injections can be rotated with each administration for participant comfort. If participants 
are receiving other, non-study intervention injectable agents, those interventions should be 
administered in a quadrant different from where the study intervention was administered. 
Additionally, areas with scarring, redness, tattoos, or other visible marks should be avoided.
Please refer to the IP manual for specific instructions on the handling, preparation, and 
administration of study intervention.
Premedication is permitted for all participants, consistent with institutional guidelines, and 
may include an antihistamine, anti-inflammatory agent, or pain reliever.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions 
(eg, temperature) have been maintained during transit for all study interventions
received and any discrepancies are reported and resolved before use of the study 
intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to labeled storage conditions, as 
soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to
report for each excursion will be provided to the site in the IP Manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. Site staff will instruct participants on the proper storage 
requirements for take-home study intervention. 
6. Study interventions should be stored in their original containers.
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7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record. Returned study intervention must not be re-dispensed to the participants.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP Manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
Investigational Product, ponsegromab (100 mg/mL) and placebo will be prepared in a 
blinded fashion by qualified personnel according to the IP manual. The study intervention 
will be administered in a blinded fashion by qualified personnel to the participants. A second 
staff member will verify the dispensing.
Open-label, PK cohort (Cohort B) only: Open-label ponsegromab will be prepared as per 
treatment assignment by qualified personnel according to the IPM, and administered by 
qualified personnel to the participants. A second staff member will verify the dispensing.
6.3. Assignment to Study Intervention
Allocation of participants to treatment groups in Main Cohort (Cohort A), Cohort C and 
Cohort D will proceed through the use of an IRT system. The site personnel (study 
coordinator or specified designee) will be required to enter or select information including 
but not limited to the user’s ID and password, the protocol number, and the participant 
number. Randomization is stratified based on KCCQ-23 CSS score (Main Cohort [Cohort 
A], Cohort C and Cohort D) and GDF-15 concentrations (Main Cohort [Cohort A] and 
Cohort C only) from SV1 assessments; these data points will be required to be entered in the 
IRT system to ensure appropriate randomization allocations.
The site personnel will then be provided with a randomization number corresponding to the 
assigned treatment group, and DU or container number(s) when study intervention is being 
supplied via the IRT system. The IRT system will provide a confirmation report containing 
the participant number, randomization number, and DU or container number assigned. The 
confirmation report must be stored in the site’s files. 
Study intervention will be administered at the study visits summarized in the SoA. 
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The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
Open-label, PK cohort (Cohort B): This is an open-label cohort; however, the specific 
treatment assignment (ie, 100 mg, 200 mg, or 300 mg open-label dose arm) will be assigned 
using the IRT system. Randomization for this cohort is not stratified.
6.4. Blinding (Main Cohort [Cohort A]/Cohort C/Cohort D)
This is a double-blind study, with blinding of ponsegromab versus placebo for each dose 
level. 
6.4.1. Blinding of Participants (Main Cohort [Cohort A]/Cohort C/Cohort D)
Participants and their caregivers will be blinded to their assigned study intervention.
6.4.2. Blinding of Site Personnel (Main Cohort [Cohort A]/Cohort C/Cohort D)
Investigators and other site staff will be blinded to participants’ assigned study intervention, 
including the site staff assigned to prepare and administer the study intervention. Pharmacists 
and site personnel will be blinded to study intervention versus placebo within each study 
arm.
6.4.3. Blinding of the Sponsor (Main Cohort [Cohort A]/Cohort C/Cohort D)
Sponsor staff will be blinded to participants’ assigned study intervention, except for sponsor 
staff involved in the assignment or distribution of study intervention.
Sponsor staff who are not directly involved with the conduct of this study will prepare 
analyses and documentation containing unblinded data while the study is ongoing to support 
interactions with the E-DMC and IRC as documented in the respective charters.
6.4.4. Breaking the Blind (Main Cohort [Cohort A]/Cohort C/Cohort D)
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the TIMI Hotline (available 24/7) or the 
study medical monitor prior to unblinding a participant’s treatment assignment unless this 
could delay further management of the participant. If a participant’s treatment assignment is 
unblinded, the sponsor must be notified within 24 hours after breaking the blind. The date 
and reason that the blind was broken must be recorded in the source documentation and the 
CRF.
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
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6.5. Study Intervention Compliance
The study intervention will be administered to participants directly by an appropriately 
qualified individual. In this study, participants are dosed at the site, and they will receive 
study intervention directly from the investigator or designee, under medical supervision. The 
date and time of each dose administered in the clinic will be recorded in the source 
documents and recorded in the CRF. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study intervention if the study intervention is 
administered at the clinic. 
The site will complete the required dosage Preparation Record located in the IP Manual. The 
use of the Preparation Record is preferred, but it does not preclude the use of an existing 
appropriate clinical site documentation system. The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose. This may be used in place of the Preparation Record after 
approval from the sponsor and/or designee.
Deviation(s) from the protocol-specified dosage regimen should be recorded in the CRF. In 
exceptional circumstances and with agreement from the Sponsor, the study intervention may 
be administered outside of the window for a given dosing visit with appropriate consideration 
of timing of any subsequent dosing visit; in such circumstances, the rationale should be 
recorded in the CRF.
A record of the number of vials and syringes dispensed to and taken by each participant must 
be maintained and reconciled with study intervention and compliance records. Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions, will also 
be recorded in the CRF.
6.6. Dose Modification
There is no dose modification of ponsegromab anticipated in this study.
6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation.
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician.
6.8. Treatment of Overdose
For this study, any dose of ponsegromab greater than 700 mg within a 4-week period will be 
considered an overdose.
There is no specific treatment for an overdose.
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In the event of an overdose, the investigator should:
1. Contact the study medical monitor or TIMI Hotline within 24 hours.
2. Closely monitor the participant for any AEs/SAEs as medically appropriate and at 
least until the next scheduled follow-up.
3. Document the quantity of the excess dose as well as the timeframe (eg, frequency) of 
overdose(s) in the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK, GDF-15, and/or immunogenicity analysis within 
5-7 days from the date of the last dose of study intervention if requested by the study 
medical monitor (determined on a case-by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant.
6.9. Prior and Concomitant Therapy
Participants in this study will be allowed to be on concomitant medications that have been 
prescribed according to their label. Attempts should be made not to alter the doses and 
regimens of the background medications after randomization and for the duration of 
participation in this study, except in circumstances where a change in dose is deemed 
medically necessary. Any changes must be captured in the CRF. Additionally, many 
over-the-counter medications are also permitted during this study. 
Treatments taken within 56 days in either cohort before the first dose of IP will be 
documented as prior treatment. Treatments taken after the first dose of IP will be documented 
as concomitant treatment. 
All concomitant treatments, both prescription and over-the-counter taken during the study 
must be recorded with indication, daily dose, and start and stop dates of administration. All 
participants will be questioned about concomitant treatment at each clinic visit. 
Use of investigational therapies is prohibited during the study. See Appendix 9 for details
regarding prohibited concomitant medications due to potential DDI.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
Background biologics are permitted as indicated by the label (not contra-indicated for 
combination with an investigational mAb).
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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
The study intervention must be permanently discontinued for the following reasons:

Severe allergic reaction to study intervention.

Intent to become pregnant or pregnancy confirmed by -hCG testing.

Drug-induced liver injury as described in Section 10.6, Appendix 6, Liver Safety: 
Suggested Actions and Follow-up Assessments.

The study participant undergoes heart transplantation or requires mechanical 
circulatory support.

The investigator has determined that continuation of the administration of the study 
intervention is no longer feasible or appropriate.
Other reasons that may prompt consideration for permanent discontinuation of study 
intervention include the following:

ECG Findings of potential concern as described in Section 10.8, Appendix 8, ECG 
Findings of Potential Clinical Concern.

If a participant experiences serious or severe AEs judged by the Investigator as 
related to randomized study intervention, the study intervention will be temporarily 
discontinued until the treatment-related AEs return to a moderate level or less. If the 
treatment-related AEs return to a moderate level or less, or resolve within 4 weeks, 
continuation of dosing with study intervention may be considered. If these AEs do not 
return to moderate within 4 weeks, and after discussion with the TIMI Hotline, the 
participant will be permanently discontinued from the study intervention.
Any planned or potential discontinuation of study drug should be discussed with the TIMI 
Hotline (available 24/7). Note that discontinuation of study intervention does not represent 
withdrawal from the study. If it is confirmed that the participant will permanently discontinue 
study intervention following discussion with the TIMI Hotline, an Early Termination visit 
should be performed, which should include assessments of patient-reported outcomes, 
physical activity (6MWT), and laboratory assessments. In addition, a follow-up visit (F/U1)
should be completed approximately 28 days and another follow-up visit (F/U2) should be 
completed ideally no more than 94 days for the Main Cohort (Cohort A)/Cohort C/Cohort D, 
and ideally no more than 75 calendar days for the open-label, PK cohort (Cohort B), after 
discontinuing study intervention primarily for the purpose of assessing resolution of any 
treatment-related AEs. See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up for any further evaluations that need to be completed.
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Again, it is important to first contact the TIMI Hotline before classifying a subject as 
‘Discontinued from Study Intervention’ and completing an Early Termination visit.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
Follow-Up:
At approximately 28 calendar days (F/U1), and again ideally no more than 94 calendar days
for the Main Cohort (Cohort A)/Cohort C/Cohort D and ideally no more than 75 calendar 
days for the open-label, PK cohort (Cohort B) (F/U2) after discontinuation of study 
intervention, participants should return to undergo review of concomitant treatments, vital 
signs, and assessment for resolution of any treatment-related AEs. Participants continuing to 
experience AEs at this point following discontinuation of treatment will continue to be 
followed at least every 4 weeks until resolution or determination, in the clinical judgment of 
the investigator, that no further improvement is expected. If the unresolved AE is considered 
by the investigator as possibly related to or associated with ADA formation, the participant 
will be asked to return for drug concentration and ADA blood sampling at up to 3-month 
intervals, until the last follow-up of the AE.
7.1.1. COVID-19
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Study treatment should continue 
unless the investigator/treating physician is concerned about the safety of the participant, in 
which case, temporary or permanent discontinuation may be required.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the TIMI Hotline.
7.2. Discontinuation From the Study
Reasons for discontinuation from the study include the following:

Participant refused further follow-up (refer to Section 7.2.1);

Lost to follow-up (refer to Section 7.3);

Death;

Study terminated by sponsor.
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At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue study intervention will remain in the study and 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 them 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 investigator should inform the TIMI Hotline of any 
potential withdrawal of consent.
A participant may withdraw from the study at any time at their own request. If a participant 
withdraws from the study, they 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 consent for disclosure of future information, no further 
evaluations should be performed and no additional data should be collected. The sponsor 
may retain and continue to use any data collected before such withdrawal of consent. 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. 
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is only from further receipt of study intervention or 
also from study procedures and/or posttreatment study follow-up, and entered on the 
appropriate 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.
7.3. Lost to Follow-Up 
To prevent participants being lost to follow-up, their contact details, including next of kin 
contacts should be collected initially, if permitted, and updated regularly by the site staff or 
representative. The Investigator should educate the participant on the importance of contact 
with the Investigator throughout the study. Repeated attempts will be made to locate and 
obtain pertinent medical information for participants who are potentially lost to follow-up. 
If a participant fails to return to the clinic for/attend a required study visit, the site must 
attempt to contact the participant and reschedule the missed visit as soon as possible. Counsel 
the participant on the importance of maintaining the assigned visit schedule, and ascertain 
whether the participant wishes to and/or should continue in the study. 
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Where permissible by local regulations, the ICD will include language to grant the option to 
employ outside companies to assist in obtaining updated contact information or 
ascertainment of vital status of lost participants using publicly available source.
A participant will be classified as lost to follow up only if he/she/they has failed to return for 
the required study visits and his/her/their vital status remains unknown despite multiple 
attempts to contact him/her/them via telephone, fax, email, certified letter or through patient 
locator agencies (if allowed by local regulations). These contact attempts should be 
documented in the participant’s medical record. The participant will then be considered lost 
to follow-up and discontinuation of study will be documented in source data and CRF as the 
date of last contact.
8. STUDY ASSESSMENTS AND PROCEDURES
All study assessments and procedures conducted on scheduled dosing visits per the SoA
should be completed prior to study intervention administration, unless otherwise specified. 
8.1. Administrative 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.
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.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
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Laboratory results that have been collected for the purposes of this study and could unblind 
the study will not be reported to investigative sites or other blinded personnel until the study 
has been unblinded.
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 
274 mL for the Main Cohort (Cohort A)/Cohort C/Cohort D (approximately 184 mL for 
participants enrolled in the open-label, PK cohort [Cohort B]). 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 56 consecutive days.
8.1.1. Screening Procedures
Screening assessments will be collected in at least two visits, as noted below:
1. SV1: Signed and dated ICD will be collected prior to any study-specific activity.
Following consent, the KCCQ-23 PRO will be completed by the participant using an 
electronic hand-held device. Following KCCQ-23 PRO completion, the Investigator
will assess Inclusion Criterion #5a (Section 5.1) through 3 questions about
(1) non-edematous unintentional weight loss ≥5% in the last 6 months, (2) current
BMI <20 kg/m2, and (3) associated with subjective fatigue or anorexia, and enter the
information into the electronic hand-held device.
Afterwards, a serum sample will be collected to evaluate GDF-15 concentrations and 
a plasma sample will be collected to evaluate NT-proBNP concentrations. The 
GDF-15 
) and NT-proBNP samples should be submitted for analysis 
immediately, as the results of this lab test will inform eligibility to continue to SV2.
Additional assessments will be performed as per the SoA for the Main Cohort(Cohort 
A)/Cohort C/Cohort D (Table 1).
2. SV2: Eligible participants will return to complete remaining screening procedures at a 
minimum of 15 days prior to first dose, when feasible. SV2 will collect all remaining 
Screening assessments, including activity monitoring (see below), placebo injection 
to assess tolerability and other assessments. Please refer to the SoA for the Main 
Cohort (Cohort A)/Cohort C/Cohort D (Table 1) for additional details.

Of note, a digital wrist device should be dispensed to participants at SV2. A 
minimum of 14 days of activity monitoring should be collected prior to Day 1, 
which should be taken into consideration when scheduling SV2.
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Open-label, PK Cohort (Cohort B) Only: At certain sites, where permitted, participants
may be considered for enrollment in the open-label, PK cohort. This may include participants
who screen fail for the Main Cohort (Cohort A) or Cohort C at any time during screening 
(SV1 or SV2). In such circumstances, participants will be eligible during that same visit or 
on a separate day to undergo screening to enroll in the open-label, PK cohort (Section 5.4). 
Signed and dated ICD for this cohort will be collected prior to any study-specific activity. 
Please refer to the SoA for this open-label, PK cohort (Table 2). Screening procedures that 
were already performed during screening for a different cohort may not need to be repeated 
for screening for the open-label, PK cohort, if within the screening window.
8.1.2. Contracted Home Health Visits (Open-Label, PK Cohort [Cohort B] Only)
A home health care service may be contracted and utilized to facilitate only the open-label, 
PK cohort at specified visits. Home visits may include a home healthcare service conducting 
an in-person study visit at the participant’s home or current residence rather than an in-person 
study visit at the site. The following may be performed during a home visit (see the open-
label, PK cohort SoA [Table 2]):

PK, PD and/or ADA sample collection.
8.2. Efficacy Assessments (Main Cohort [Cohort A]/Cohort C/Cohort D)
8.2.1. Patient Reported Outcomes
All PRO assessments are completed electronically by study participants at the clinic as per 
the SoA and Table 5. Every effort should be made to have the study participant complete all 
PRO assessments before any other clinical assessments that take place at the clinical site. 
There are no PRO assessments in the open-label, PK cohort.
Additional details are provided in the PRO/eCOA Training Manual.
Table 5.
PRO Assessments
PRO Measure 
Assessment schedule
Number 
of 
Questions
Completion 
Time
KCCQ-23
SV1, W0 (baseline), W4, W8, W12, 
W16, W20, W22, or early term.
23
~6 minutes
PROMIS Fatigue 7a (“Past 7 days” recall 
version)
W0 (baseline), W12, W22, or early 
term.
7
~2 minutes
PGI-S 
W0 (baseline), W4, W8, W12, W16, 
W20, W22, or early term.
4
~1 minute
PGI-C 
W12, W22, or early term.
4
~1 minute
8.2.1.1. Kansas City Cardiomyopathy Questionnaire
The KCCQ is a self-reported 23-item questionnaire that assesses HRQL in participants with 
HF. Items assess physical limitations, symptoms (frequency, severity, and recent change over 
time), QoL, social interference, and self-efficacy. Response options vary by question. There 
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are 10 summary scores within KCCQ-23: physical limitation, symptom stability, symptom 
frequency, symptom burden, total symptom score, self-efficacy, quality of life, social 
limitation, overall summary score, and clinical summary score. Raw summary scores are 
transformed to a 0-100 scale where higher scores indicate better health.15
8.2.1.2. PROMIS Fatigue (Version 7a)
The PROMIS Fatigue 7a is a self-reported measure that assesses a range of symptoms in the 
past 7 days from mild subjective feelings of tiredness to an overwhelming, debilitating, and 
sustained sense of exhaustion that likely decreases one’s ability to execute daily activities 
and function normally in family or social roles.16
The short form 7A consists of 7 items that study participants will rate from 1: “Never” to 
5: “Always”. A global raw score ranging from 7 to 35 is calculated and can be translated into 
a T-score (Mean = 50, SD = 10) using the applicable score conversion table provided in the 
PROMIS User’s Manual.
8.2.1.3. Patient’s Global Impression of Severity
The PGI-S is a measure consisting of 4 questions that ask the study participants to evaluate 
the severity of their fatigue, shortness of breath, overall symptoms of HF, and daily activity 
limitations over the past 14 days on a 5-point verbal response scale that ranges from “None” 
to “Very severe”.
The PGI-S is recommended by the FDA for use as an anchor measure to generate an 
appropriate threshold that represents meaningful within-individual change in the target 
patient population.17
8.2.1.4. Patient’s Global Impression of Change
The PGI-C is a measure consisting of 4 questions that ask study participants to rate the 
overall change in their fatigue, shortness of breath, overall symptoms of HF, and ability to do 
daily activities on a 5-point verbal rating scale ranging from “Much better” to Much worse”.  
The PGI-C is recommended by FDA for use as an anchor measure to generate an appropriate 
threshold that represents meaningful within-individual change in the target patient 
population.17
8.2.1.5. Qualitative Exit Interviews
Qualitative exit interviews with a select group of US English-speaking participants (up to 50) 
at selected sites will be conducted by telephone, as indicated in the SoA. The interviews will 
be conducted by trained moderators, that are not part of study site staff, will be audio 
recorded and transcribed, and are anticipated to be approximately 60 minutes in duration. 
The transcripts and interviewer field notes will be used to examine changes in symptoms and 
impacts experienced over the period of study duration, to describe treatment experience, and 
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the importance of any improvement reported by the study participants. Following the 
analysis of the qualitative data, a summary report that describes the study objectives, 
methods, participants, and results of the qualitative interviews will be reported separately 
from the CSR.
8.2.2. 6MWT
The 6MWT is a submaximal exercise test that entails measurement of distance walked over a 
span of 6 minutes.18 The 6MWD (distance traveled in meters) provides a measure for 
integrated global response of multiple cardiopulmonary and musculoskeletal systems 
involved in exercise. Additional training information will be provided in Firecrest regarding 
the appropriate methodology for observation and data collection.
8.2.3. Body Weight
Weight will be recorded using a calibrated scale (with the same scale used if possible for the 
duration of the study) reporting weight in either lb or kg, and accuracy to the nearest 0.2 lb. 
(or 0.1 kg); that is, the device must be able to distinguish a difference between 150.4 lb. 
(68.4 kg) versus 150.2 lb. (68.3 kg). The scale must be placed on a stable, flat surface.
Weight measurement should be taken under the following conditions:

After void of urine;

After removal of shoes, bulky layers of clothing and jackets so that only light clothing 
remains; 

While remaining still during the measurement.
Body weight is not considered an efficacy assessment for the open-label, PK cohort.
8.2.4. Activity Monitoring (Main Cohort [Cohort A]/Cohort C/Cohort D)
An activity monitor should be placed on the participant’s non-dominant wrist from SV2 to 
Day 1 and from Week 20 to Week 22. The participant should be asked to wear the activity 
monitor continuously during these periods. Please refer to the activity monitoring guide for 
detailed instructions.
Activity monitoring data will capture real-life activities and movement patterns.
8.2.5. Clinical Outcomes
Details of deaths occurring during trial follow-up will be collected in the CRF and/or 
separate adjudication packages. Investigators will classify deaths as cardiovascular or non-
cardiovascular according to the primary cause of death, which is the underlying disease or 
injury that initiated the train of events resulting in death. In addition, all deaths will be 
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adjudicated by a blinded adjudication committee consisting of independent external experts. 
Cardiovascular death includes:

Death resulting from an acute myocardial infarction

Sudden cardiac death

Death due to heart failure or cardiogenic shock

Death due to stroke

Death due to cardiovascular hemorrhage

Death due to other cardiovascular cause (eg, pulmonary embolism, peripheral artery 
disease)
Worsening heart failure events occurring during the trial (after randomization) will be 
collected in the eCRF and/or separate adjudication packages. Worsening heart failure events 
include both heart failure hospitalizations and urgent heart failure visits. Please refer to the 
eCRF completion requirements for the clinical criteria needed to classify an event as a heart 
failure hospitalization or urgent heart failure visit. All investigator-reported worsening heart 
failure events will be adjudicated by a blinded adjudication committee consisting of 
independent external experts.
The occurrence of potential clinical outcome will trigger the compilation of a dossier that 
includes anonymized supporting medical record information that will be sent to the 
adjudication committee.
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
Although not observed so far with ponsegromab, injection site reactions and delayed 
hypersensitivity reactions are theoretically possible in response to injected monoclonal
antibodies. Participants should be monitored after receiving injections for clinical signs of 
systemic immune reactions, and any such reactions assessed and reported as part of standard 
safety/AE monitoring, including adverse events that are manifestations of injection site 
reactions. Additional assessments may be conducted at investigator discretion and/or until 
any symptoms resolve. If deemed appropriate by the investigator, a consultation with a 
dermatologist may be performed. Documentation of a reaction may include items such as 
investigator notes, photographs, dermatologist report and/or clinic notes. As part of the safety 
analysis, any cases of potential anaphylaxis will be assessed by the sponsor against the 
Sampson criteria.19
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8.3.1. Physical Examinations
A brief physical examination will include, at a minimum, assessments of the lungs, 
cardiovascular system, and abdomen. Height and weight will also be measured and recorded.
Height will only be captured once, at the initial screening assessment. Please refer to 
Section 8.2.3 for details regarding collection of body weight.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.2.1. Blood Pressure and Pulse Rate
BP and PR measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available.
BP and PR measurements should be preceded by at least 5 minutes of rest with the 
participant in a supine position, before the collection of laboratory tests, in a quiet setting 
without distraction (eg, television, cell phones) and the results recorded in the CRF. It would 
not be considered a protocol deviation if BP and PR measurements are collected after 
laboratory tests.
8.3.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex.
If the site does not have an ECG machine that performs automated interval calculations, the 
investigator is permitted to calculate the standard intervals.
8.3.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
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Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or up to the time of the final planned follow-up visit after the last 
dose of study intervention should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
8.3.5. Pregnancy Testing 
A serum pregnancy test is required at the initial screening visit and will be sent to the central 
lab. Following screening, pregnancy tests may be urine or serum tests, and must have a 
sensitivity of at least 25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times 
listed in the SoA. Following a negative pregnancy test result at screening, appropriate 
contraception must be commenced and a second negative pregnancy test result will be 
required at the baseline visit prior to the participant’s receiving the study intervention. 
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected) and at the end of the 
study. Pregnancy tests may also be repeated if requested by IRBs/ECs or if required by local 
regulations. Pregnancy test results must be reviewed and confirmed as negative, in order to 
continue dosing with study intervention (see also Section 7.1).
8.3.5.1. At-Home Pregnancy Testing
If a participant requiring pregnancy testing cannot visit the study site for a follow-up visit 
(F/U1 and/or F/U2), a home urine pregnancy testing kit with a sensitivity of at least 
25 mIU/mL may be used by the participant to perform the test at home or current residence, 
if compliant with local regulatory requirements. The pregnancy test outcome should be 
documented in the participant’s source documents/medical records and relevant data 
recorded on the CRF. Confirm that the participant is adhering to the contraception method(s) 
required in the protocol.
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8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention, through and including the time of the final planned follow-up visit, except as 
indicated below, after the last administration of the study intervention. 
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
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Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
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possible causality. Any information relevant to the event, such as concomitant medications 
and 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 Safety. 
Further information on follow-up procedures is provided in Appendix 3.
8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner.
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
A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by eg, skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by eg, skin contact then inseminates his female partner prior to or 
around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until the time of 
the final planned follow-up visit.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
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for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental exposure during breastfeeding is a female family member or 
healthcare provider who reports that she is breastfeeding after having been exposed to 
the study intervention by inhalation or skin contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant enrolled in the study, so the 
information is not recorded on a CRF. However, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
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8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form, regardless of 
whether there is an associated SAE. Since the information about the occupational exposure
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.
8.4.6. Cardiovascular and Death Events
Not applicable.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
Not applicable.
8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy of the underlying disease (HF) is not expected 
in the study population with the study intervention.
8.4.9. Medical Device Deficiencies
Not applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;
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
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics 
Blood samples of approximately 4 mL, to provide a minimum of 1.5 mL serum, will be 
collected for measurement of serum unbound and total concentrations of ponsegromab as 
specified in the respective SoA (ie, Table 1 for the Main Cohort (Cohort A)/Cohort C/Cohort 
D and Table 2 for the open-label, PK cohort). 
In addition, in the Main Cohort (Cohort A)/Cohort C/Cohort D, if the participant consents to 
the extra sample collection, a flexible PK sample may be collected at 1 week (±2 days) post 
any dose (ie, collect a sample at Week 1, Week 5, Week 9, Week 13, Week 17, or Week 21
for a dose administered on Day 1, Week 4, Week 8, Week 12, Week 16 or Week 20, 
respectively), in conjunction with the flexible PD sample collection (see Section 8.7.1). It 
will not be considered a protocol deviation if the participant chooses not to have this 
additional visit. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. In some instances, as specified in the respective SoAs, the samples 
from the participant may be collected at their home or current residence.
The actual times may change, but the number of samples will remain the same. Collection of 
samples within the protocol-allowed visit window, as defined in SoA or noted above will not 
be captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF.
Samples will be used to evaluate the PK of ponsegromab. Samples collected for analyses of 
ponsegromab serum concentrations may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, or for other internal exploratory purposes.
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Genetic analyses will not be performed on these serum samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of serum concentrations of ponsegromab (unbound and 
total) will be analyzed using a validated analytical method(s) in compliance with applicable 
SOPs. 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
Drug concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics (Main Cohort [Cohort A]/Cohort 
C/Cohort D)
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected on Day 1 prior 
to first dose, as local regulations and IRBs/ECs allow. 
Retained Research Samples may be used for research related to the study intervention(s) and 
HF. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using 
the retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual.
8.6.3. Retained Research Samples for Future Genetic Research by TIMI (Main Cohort
[Cohort A]/Cohort C/Cohort D)
A 4-mL blood sample optimized for DNA isolation in K2EDTA will be collected on Day 1, 
as local regulations and IRBs/ECs allow. 
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These samples may be used for research related to the study intervention(s), and HF by the 
TIMI Study Group. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may 
be studied using the stored samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the central laboratory manual.
8.7. Biomarkers
Collection of samples for biomarker research is also part of this study. 
The following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA:

Serum GDF-15 (Section 8.7.1);

NT-proBNP, hsCRP, albumin and pre-albumin (Section 8.7.2).

 ratio for Cohorts C and D only (Section 8.7.2)
8.7.1. GDF-15
Blood samples of approximately 6 mL, to provide a minimum of 2 mL serum, will be 
collected for measurement of serum concentrations of 
GDF-15 at time 
points specified in the respective SoA (ie, Table 1 for the Main Cohort (Cohort A)/Cohort 
C/Cohort D and Table 2 for the open-label, PK cohort). 
In addition, in the Main Cohort (Cohort A)/Cohort C/Cohort D, if the participant consents to 
the extra sample collection, a
 
 
, in conjunction with the flexible PK sample collection (see Section 8.5). It will 
not be considered a protocol deviation if the participant chooses not to have this additional
visit. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. In some instances, as specified in the respective SoAs, samples 
from the participant may be collected at their home or current residence.
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At the initial screening visit,
 GDF-15 (
)
sample will be analyzed using the IUO
GDF-15 assay, for determination of 
enrollment eligibility. In addition, this sample may be used to help support development of a 
potential companion diagnostic test for ponsegromab. This screening assay will be validated 
in a CLIA accredited central laboratory.
 
 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
The actual times may change, but the number of samples will remain the same. Collection of 
samples within the protocol-allowed visit window, as defined in SoA or above will not be 
captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF.
Samples will be used to evaluate the PD of ponsegromab. Samples collected for PD analyses 
may also be used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study, and/or evaluation of bioanalytical methods, or for other internal exploratory 
purposes.
The PD samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PD sample 
handling procedure (eg, sample collection and processing steps, interim storage, or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
GDF-15 concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.7.2. Exploratory Biomarkers
These analytes will be used for exploratory research to measure the effect of ponsegromab on 
biomarkers of hemodynamic stress (NT-proBNP), inflammation (hsCRP), 
for Cohorts C and D only, and nutritional status (albumin and pre-albumin).
Samples will be collected according to the SoA. All samples collected on Day 1 must be 
collected prior to study intervention administration.
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Laboratory/analyte results from albumin, pre-albumin, NT-proBNP, and hsCRP samples 
collected after the first dose of study intervention through EOT that could unblind the study 
will not be reported to investigator sites or other blinded personnel until the study has been 
unblinded.
Other exploratory plasma biomarkers may also be analyzed.
8.7.3. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.7.4. Specified Protein Research 
Specified protein research is not included in this study.
8.7.5. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.7.6. Retained Research Samples for Biomarkers (Main Cohort [Cohort A]/Cohort 
C/Cohort D)
These Retained Research Samples will be collected in this study:

2.5-mL whole blood (Prep R1 optimized for RNA); 

10-mL whole blood (Prep B2 optimized for serum); 

10-mL whole blood (Prep B1 optimized for plasma).
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA. 
Retained Research Samples may be used for research related to the study intervention and 
HF. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using 
the retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual. 
8.7.7. Retained Research Samples for Future Biomarker Research by TIMI (Main 
Cohort [Cohort A]/Cohort C/Cohort D)
The following samples will be collected in this study for future research by TIMI group:

One 10-mL whole blood will be collected and isolated plasma retained in K2EDTA.
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
One 10-mL whole blood will be collected and isolated serum retained with no 
additive.
Samples will be collected as local regulations and IRB/ECs allow according to the SoA.
These samples may be used for research related to the study intervention(s) and HF by the 
TIMI Study Group. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may 
be studied using the stored samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the central laboratory manual.
8.7.8. Samples for Exploratory Plasma Biomarker Research by Pfizer (Main Cohort
[Cohort A]/Cohort C/Cohort D)
One 4-ml whole blood sample will be collected and isolated plasma retained in lithium 
heparin.
Samples will be collected according to the SoA, as local regulations and IRBs/ECs allow.
These samples may be used for research related to the study intervention(s), and HF disease 
by Pfizer.
8.8. Immunogenicity Assessments
Blood samples of approximately 4 mL, to provide a minimum of 1.5 mL serum, will be 
collected for determination of ADA and NAb as specified in the SoA. Participants found to 
have anti-ponsegromab antibodies still present at the end of study may be requested to 
provide additional immunogenicity samples (either at the site or at home/current residence) at 
approximately 90-day intervals until ADA titers return to baseline levels or up to 
approximately 12 months from the last dose administered if no safety concerns associated 
with the ADA.
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
Samples collected for determination of ADA and NAb may also be used for additional 
characterization of the immune response and/or evaluation of the bioanalytical method, or for 
other internal exploratory purposes. These data will be used for internal exploratory 
purposes.
Genetic analyses will not be performed on these serum samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
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Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs. Samples determined to be positive for ADA may be further characterized for NAb, if 
feasible.
The immunogenicity samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity. Any deviations from the 
immunogenicity sample handling procedure (eg, sample collection and processing steps, 
interim storage, or shipping conditions), including any actions taken, must be documented 
and reported to the sponsor. On a case-by-case basis, the sponsor may make a determination 
as to whether sample integrity has been compromised.
Immunogenicity information that would unblind the study will not be reported to investigator 
sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
The null hypothesis of no difference between ponsegromab and placebo will be tested for 
each primary and selected secondary and tertiary endpoints. The alternative hypothesis is that 
ponsegromab is superior to placebo. There is no hypothesis testing planned for the open-
label, PK cohort.
9.1.1. Estimands
Details of all the estimands and analyses will be presented in the SAP.
9.1.1.1. Primary Estimands
The primary estimand is applied to the comparison between ponsegromab 300 mg and 
placebo only.
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Estimand related to the HF disease-specific health status primary objective (Main Cohort
[Cohort A] only):
Estimand 1 (similar to “hypothetical”) is intended to provide a population level estimate of 
the treatment effect on the change from baseline in KCCQ-23 CSS for ponsegromab 
compared with placebo in all evaluable participants in the Main Cohort, under the scenario of 
no discontinuation of study intervention and without the potential confounding effect of 
prohibited procedures or participants’ non-compliance with dosing (ie, using the censored 
analysis set for the Main Cohort as defined in Section 9.1.1.3).

Population: Participants with HF, elevated circulating GDF-15 concentrations and 
KCCQ-23 CSS <75.

Endpoint: Change from baseline in KCCQ-23 CSS at Week 22.

Intercurrent Events:
a.
Discontinuation of study intervention: Data collected after a participant has 
discontinued study intervention will be censored and treated as missing data.
b. Prohibited procedures: Data collected after a participant has undergone prohibited 
procedures, that would modulate the primary endpoint will be censored and 
treated as missing data. Any procedures will be reviewed prior to database lock to 
determine which would be classed as “prohibited” for this estimand.
c.
Inadequate compliance: Data collected after a participant has missed a dose will 
be censored and treated as missing data. For participants who resume dosing, their 
subsequent data may be included in the analysis following a review of their 
compliance prior to database lock. Details will be provided in the SAP. 
Missing data due to censoring, study withdrawal or other reasons, are assumed to 
be missing at random in the analysis.

Population-level summary: Difference in mean change from baseline for the 
KCCQ-23 CSS at Week 22 between ponsegromab and placebo.
Alternative estimands (eg, one similar to “treatment policy”, using a complete analysis set 
where all observations post-discontinuation, prohibited procedure or inadequate compliance,
will be included) for the primary objective may be used in order to examine the robustness of 
the results and will be detailed in the SAP.
9.1.1.2. Secondary Estimands
The secondary estimands are applied to the comparisons between each ponsegromab dose 
and placebo. Data from the Main Cohort (Cohort A) will be used for comparisons between 
ponsegromab 300 mg and placebo. Data from the Main Cohort (Cohort A) and Cohort C, 
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combined (ie, Cohort A + Cohort C), will be used for comparisons between ponsegromab 
100, 200 and 300 mg (as appropriate) and placebo. See Section 9.3.1 for more details.
Estimand related to the HF disease-specific health status secondary objective (Main Cohort
[Cohort A] ± Cohort C):
Estimand 2 will be similar to Estimand 1, except for the following:

Endpoint: Change from baseline in each of KCCQ-23 CSS*, OSS, TSS and physical 
limitation score at Week 22.

Population-level summary: Difference in mean change from baseline for the 
KCCQ-23 CSS, OSS, TSS, or physical limitation score at Week 22 between 
ponsegromab and placebo.
* Note: For KCCQ-23 CSS, comparisons between ponsegromab 100 or 200 mg and placebo 
are based on data from the Main Cohort (Cohort A) and Cohort C combined, only.
Estimand related to the HF disease-specific health status (responses as defined by a ≥
5-point increase from baseline) secondary objective (Main Cohort [Cohort A] ± Cohort C):
Estimand 3 will be similar to Estimand 1, except for the following:

Endpoint: Responses as defined by a ≥5-point increase in each of KCCQ-23 CSS, 
OSS, TSS, and physical limitation score at Week 22.

Population-level summary: Odds ratio for the proportions of study participants with 
≥5-point increase in KCCQ-23 CSS, OSS, TSS, and physical limitation score at 
Week 22 between ponsegromab and placebo.
Estimand related to the physical function secondary objective (Main Cohort [Cohort A] ± 
Cohort C ): 
Estimand 4 will be similar to Estimand 1, except for the following:

Endpoint: Change from baseline in the 6MWD at Week 22.

Population-level summary: Difference in mean change from baseline for the 6MWD 
at Week 22 between ponsegromab and placebo.
Estimand related to the Fatigue secondary objective (Main Cohort [Cohort A] ± Cohort C): 
Estimand 5 will be similar to Estimand 1, except for the following:

Endpoint: Change from baseline in PROMIS Fatigue 7a at Week 22.
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
Population-level summary: Difference in mean change from baseline for PROMIS 
Fatigue 7a at Week 22 between ponsegromab and placebo.
Estimands related to the safety and tolerability secondary objective (All Cohorts):
There are no defined estimands for the incidence of treatment-emergent adverse events and 
treatment-emergent serious adverse events, abnormal laboratory results and vital signs, and 
these endpoints will be reported using Pfizer data standards as applicable. The Main Cohort 
(Cohort A) and Cohort C will be reported combined; the open-label, PK cohort (Cohort B) 
will be reported separately; Cohort D will be reported separately.
9.1.1.3. Tertiary/Exploratory Estimands
Tertiary/exploratory endpoints may be analyzed using similar estimands or analyzed in a 
descriptive manner without reference to an estimand. Other supporting estimands may be 
used for some of the primary and secondary endpoints as a means to examine the robustness 
of results, compare to available literature and/or be used for future study planning as needed.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention 
"Enrolled" means a participant's agreement to participate in 
a clinical study following completion of the informed 
consent process and randomization. A participant will be 
considered enrolled if the informed consent is not 
withdrawn prior to participating in any study activity after 
screening. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
Evaluable 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention, for the given 
part of the study (Main Cohort [Cohort A], open-label, PK 
cohort [Cohort B], Cohort C or Cohort D). Participants will 
be analyzed according to the randomized intervention.
Safety Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention, for the given 
part of the study (Main Cohort [Cohort A], open-label, PK 
cohort [Cohort B], Cohort C or Cohort D). Participants will 
be analyzed according to the product they actually received. 
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Defined Analysis Set
Description
Censored
All evaluable participants. For participants who discontinue 
study intervention or receive a prohibited procedure, all 
observations post-discontinuation, or post-procedure, will be 
censored and treated as missing data. For participants who 
miss a dose, all observations post-missed dose will be 
censored. For participants who resume dosing, their 
subsequent data may be included in the analysis following a 
review of their compliance prior to database lock. Details 
will be provided in the SAP. 
PK concentration
All participants randomly assigned to study intervention and 
who take at least 1 dose of ponsegromab and in whom at 
least 1 PK concentration value is reported, for the given part 
of the study (Main Cohort [Cohort A], open-label, PK 
cohort [Cohort B], Cohort C or Cohort D).
PK parameter (open-label, 
PK cohort [Cohort B]
only)
All participants randomly assigned to study intervention and 
who take at least 1 dose of ponsegromab and have at least 1 
of the PK parameters of interest calculated.
PD
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom 
at least 1 PD (GDF-15) concentration value is reported for 
any PD endpoint, for the given part of the study (Main 
Cohort [Cohort A], open-label, PK cohort [Cohort B], 
Cohort C or Cohort D).
Immunogenicity 
All participants randomly assigned to study intervention and 
who take at least 1 dose of ponsegromab and in whom at 
least 1 ADA result is reported, for the given part of the 
study (Main Cohort [Cohort A], open-label, PK cohort
[Cohort B], Cohort C or Cohort D). 
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
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9.3.1. General Considerations
The open-label, PK cohort (Cohort B) will be presented separately from the Main Cohort
(Cohort A), Cohort C and Cohort D.
Following PCD, the data will be analyzed and reported in a CSR. The results for the open-
label, PK cohort (Cohort B) may be reported separately.
The main efficacy analyses for the 300 mg ponsegromab treatment group will be performed 
using data from the Main Cohort (Cohort A) only; statistical models will include data from 
the 300 mg ponsegromab treatment group and placebo only. The main statistical analyses for 
the 100 mg and 200 mg ponsegromab treatment groups will be performed using combined 
data from the Main Cohort (Cohort A) and Cohort C; statistical models will include data 
from all three ponsegromab treatment groups and placebo, with these analyses also providing 
sensitivity analyses for the 300 mg ponsegromab treatment group.
For safety analyses, the Main Cohort (Cohort A) and Cohort C will be reported combined; 
the open-label, PK cohort (Cohort B) will be reported separately; Cohort D will be reported 
separately.
9.3.1.1. Analyses for Continuous Endpoints
The MMRM model will include participant as a random term, and baseline, time (as a 
factor), baseline-by-time interaction, treatment and treatment-by-time interaction as fixed 
terms in the model. An unstructured covariance matrix will be fitted to the repeated times 
within subject (other covariance matrices will be considered if necessary), and the 
Kenward-Roger approximation will be used for estimating degrees of freedom. Additional 
terms may be fitted in the model (eg, cohort, LVEF, log GDF-15 concentrations, log NT-
proBNP), as appropriate.
9.3.1.2. Analyses for Binary Endpoints
The logistic regression model will include baseline and treatment as fixed terms in the model. 
Additional terms may be fitted in the model (eg, cohort, LVEF, log GDF-15 concentrations, 
log NT-proBNP), as appropriate.
9.3.2. Primary Endpoints Analysis
Main Cohort (Cohort A): KCCQ-23 CSS at Week 22
Change from baseline in KCCQ-23 CSS at Week 22 will be analyzed using Estimand 1 and 
an MMRM model (as per Section 9.3.1.1). The MMRM model will be fitted to the change 
from baseline at all post-treatment timepoints up to Week 22 using the Censored analysis set
for the Main Cohort (Cohort A). The analysis will include data from the 300 mg 
ponsegromab treatment group and placebo only. Additional terms for LVEF, GDF-15 
concentrations and NT-proBNP will be fitted in the model. Least squares means (and 90% 
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CIs) and mean differences versus placebo (and 90% CIs and p-values) will be provided. No 
adjustments will be made for multiplicity.
9.3.3. Secondary Endpoints Analysis
Endpoint
Statistical Analysis Methods
Main Cohort (Cohort A)/Cohort C/Cohort D
Change from baseline in KCCQ-23 CSS, OSS, TSS 
and physical limitation score at Week 22
Change from baseline in KCCQ-23 CSS, OSS, 
TSS, and physical limitation scores will be 
analyzed separately using Estimand 2 and an 
MMRM model (as per Section 9.3.1.1). The 
MMRM model will be fitted to the change from 
baseline at all post-treatment timepoints up to 
Week 22 using the Censored analysis set for the 
Main Cohort (Cohort A) ± Cohort C.
Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs and 
p-values) will be provided. No adjustments will be 
made for multiplicity.
Responses as defined by a ≥5-point increase from 
baseline in KCCQ-23 CSS, OSS, TSS and physical 
limitation score at Week 22.
Responses as defined by a ≥5-point increase in 
KCCQ-23 CSS, OSS, TSS, and physical limitation 
score will be analyzed separately using Estimand 3 
and a logistic regression model (as per 
Section 9.3.1.2). The model will be fitted to the 
data at Week 22 using the Censored analysis set for 
the Main Cohort (Cohort A) ± Cohort C.
Proportions (and 90% CIs), odds (and 90% CIs) 
and odds ratios versus placebo (and 90% CIs and 
p-values) will be provided. No adjustments will be 
made for multiplicity.
Change from baseline in 6MWD at Week 22.
Change from baseline in 6MWD will be analyzed 
using Estimand 4 and an MMRM model (as per 
Section 9.3.1.1). The MMRM model will be fitted 
to the change from baseline at all post-treatment 
timepoints up to Week 22 using the Censored 
analysis set for the Main Cohort (Cohort A) ±
Cohort C.
Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs and 
p-values) will be provided. No adjustments will be 
made for multiplicity.
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Endpoint
Statistical Analysis Methods
Main Cohort (Cohort A)/Cohort C/Cohort D
Change from baseline in PROMIS Fatigue 7a at Week 
22.
Change from baseline in PROMIS Fatigue 7a will 
be analyzed using Estimand 5 and an MMRM 
model (as per Section 9.3.1.1). The MMRM model 
will be fitted to the change from baseline at all 
post-treatment timepoints up to Week 22 using the 
Censored analysis set for the Main Cohort (Cohort 
A) ± Cohort C.
Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs and 
p-values) will be provided. No adjustments will be 
made for multiplicity.
Incidence of TEAEs, TESAEs, abnormal laboratory 
results, and vital signs.
All safety analyses will be performed on the safety 
population for the Main Cohort (Cohort A), Cohort 
C and Cohort D. The safety data will be 
summarized in accordance with Pfizer Data 
Standards. All safety data will be summarized 
descriptively through appropriate data tabulation, 
descriptive statistics, categorical summaries, and 
graphical presentations, as appropriate. The Main 
Cohort (Cohort A) and Cohort C will be reported 
combined; Cohort D will be reported separately.
Open-Label, PK Cohort (Cohort B)
Incidence of TEAEs, TESAEs, abnormal laboratory 
results, and vital signs.
All safety analyses will be performed on the safety 
population for the open-label, PK cohort (Cohort 
B). The safety data will be summarized in 
accordance with Pfizer Data Standards. All safety 
data will be summarized descriptively through 
appropriate data tabulation, descriptive statistics, 
categorical summaries, and graphical presentations, 
as appropriate.
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis
Details on the analyses of Tertiary/Exploratory endpoints will be described in the SAP.
9.3.5. Other Safety Analyses
All safety analyses will be performed on the corresponding safety population.
9.3.6. Other Analyses 
Selected data collected at Screening may be reported. These data include demographic data, 
prior and concomitant medications, LVEF, NYHA classification, GDF-15 concentrations, 
height, weight, BMI and KCCQ-23 scores. In addition, a subset of medical history data will 
be reported; this may include time since diagnosis, time since last HF hospitalization, body 
weight history (eg, evidence of cachexia), where feasible. Other data collected at screening 
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that are used for inclusion/exclusion criteria, such as laboratory data, will be considered 
source data, and will not be required to be reported, unless otherwise noted.
As permitted by data, and determined by the sponsor, the PK/PD relationship between serum 
ponsegromab concentration and the effect on primary, secondary and/or tertiary endpoints 
may be explored using a population PK/PD approach. The population PK/PD analysis, if 
conducted, will be reported in a separate report.
Qualitative exit interviews with a selected group of participants (up to 50) at selected sites 
will be conducted by telephone at the end of the Main Cohort (Cohort A), Cohort C and 
Cohort D, after Week 22, as indicated in the SoA. Interviews will be conducted by trained 
moderators and are anticipated to be approximately 60 minutes in duration. Using the 
transcripts and interviewer field notes, dominant trends will be identified in each interview 
and compared across all the interviews to describe the participant experience with a focus on 
the themes or patterns in the way the treatment experience is described, and the importance 
of any improvements reported. These results will be reported in a separate report.
Pharmacogenomic or biomarker data from Retained Research Samples or other exploratory 
plasma biomarker data may be collected during or after the trial and retained for future 
analyses; the results of such analyses are not planned to be included in the CSR. 
9.4. Interim Analyses
Interim analyses will be performed at least once while the study is ongoing to assess efficacy 
and/or safety after at least approximately 25% of the planned participants in the ponsegromab 
300 mg and placebo arms in the Main Cohort (Cohort A), ie, approximately 80 participants, 
complete their study participation through at least Week 12 of the Main Cohort (Cohort A). 
Interim analysis results may be used for internal business decisions including, but not limited 
to, future study planning, stopping for futility, stopping for early success, conducting a 
sample size re-estimation, or adapting the study after the interim analysis. Participants may 
be discontinued from the study intervention/study as a result of the interim analysis, as 
described in Section 9.3.2.
Before any interim analysis is performed, the details of the objectives, decision criteria, 
dissemination plan, and method of maintaining the study blind (if applicable) as per Pfizer’s 
SOPs will be documented and approved in an IRC charter and/or data access plan. In 
addition, the analysis details will be documented and approved in the SAP or an additional 
interim analysis SAP.
In addition, ongoing monitoring of the safety of participants will be performed by an 
E-DMC. Further details are provided in Section 10.1.5.2 and will be further documented in 
an E-DMC charter.
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9.4.1. PK/PD Unblinding Plan
If needed, a PK/PD unblinding plan will be developed for the Main Cohort (Cohort A), 
Cohort C and Cohort D, to safeguard the study blind for members of the study team. These 
procedures will be in accordance with applicable Pfizer SOPs for releasing randomization 
codes and breaking the study blind. Under this plan, a limited number of individuals, not on 
the study team, will be unblinded, with the purpose of composing PK/PD and/or 
immunogenicity analysis sets and conducting PK/PD analysis that will not be made available 
to the study team until after database lock.
9.5. Sample Size Determination
The planned total sample size for the study is up to approximately 781 randomized 
participants.
Main Cohort (Cohort A)
A sufficient number of participants will be screened to achieve a total of approximately 
416 randomized participants, with 380 participants randomly assigned to ponsegromab 
300 mg Q4W and placebo Q4W in approximately a 1:1 ratio, plus an additional 
36 participants randomly assigned to ponsegromab 100 mg Q4W and 200 mg Q4W in 
approximately a 1:1 ratio. Participants will be randomized initially in a 1:1:1:1 ratio to all
four treatment arms (until approximately 72 participants are randomized), followed by a 
1:1 ratio to the 300 mg Q4W and placebo arms only. This planned number of randomized 
participants is expected to ensure completion of the Main Cohort (Cohort A) of 
approximately 161 evaluable participants in the 300 mg Q4W and placebo Q4W treatment 
arms and approximately 15 evaluable participants in the 100 mg and 200 mg Q4W treatment 
arms, assuming a discontinuation rate of 15% (if this rate is higher, or there is a high rate of 
non-compliance, more participants may be randomized to ensure the required number of
evaluable participants). 
The sample size in the ponsegromab 300 mg Q4W and placebo arms is based
 
 
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The sample size in the ponsegromab 100 mg and 200 mg Q4W arms has been chosen 
empirically to provide sufficient data to gain a preliminary understanding of the PK/PD 
relationship in this population, and is not based on the primary endpoint.
Open-Label, PK Cohort (Cohort B)
Approximately 20 additional participants will be randomly assigned to open-label 
ponsegromab 100 mg, 200 mg and 300 mg Q4W in approximately a 1:2:2 ratio. This sample 
size has been chosen empirically to provide sufficient evaluable participants (approximately 
15) to adequately evaluate the PK of ponsegromab following repeated SC administration to 
participants with HF and elevated circulating GDF-15 concentrations, assuming a 15% 
discontinuation rate (if this rate is higher, or there is a high rate of non-compliance, more 
participants may be randomized to ensure the required number of evaluable participants).
Cohort C (optional)
A sufficient number of participants will be screened to achieve a total of approximately 
195 randomized participants, with 130 participants randomly assigned to ponsegromab 
100 mg Q4W and 65 to placebo Q4W in approximately a 2:1 ratio. This planned number of 
randomized participants is expected to ensure completion in Cohort C of approximately 110 
evaluable participants in the 100 mg Q4W and 55 in the placebo Q4W treatment arms, 
assuming a discontinuation rate of 15% (if this rate is higher, or there is a high rate of 
non-compliance, more participants may be randomized to ensure the required number of 
evaluable participants). This sample size of 165 completers is based on the primary efficacy 
endpoint and, when combined with the completing 100 mg Q4W and placebo Q4W 
participants in the Main Cohort (Cohort A), gives similar acceptable Operating 
Characteristics to those for the 300 mg Q4W arm in the Main Cohort.
 
Cohort D (optional)
Approximately 100 participants will be randomly assigned to ponsegromab 300 mg Q4W or 
placebo in approximately a 1:1 ratio in Cohort D. This sample size has been estimated based 
on the number of participants being screened for Cohort C and the anticipated screen-fail 
rate. The actual sample size may be lower or higher than estimated, with a maximum of 
approximately 150 total participants in this cohort. Enrollment into Cohort D will stop 
approximately when enrollment into Cohort C stops.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 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 CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, 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.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation 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;

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 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process 
The investigator or their representative will explain the nature of the study, including the 
risks and benefits, 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, privacy and data protection 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 their 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 their 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 their
right to access and correct their 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 on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
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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.
Participants who are rescreened are required to sign a new ICD.
10.1.4. 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 will 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 participants 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 ID. 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.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Steering Committee
A steering committee chaired by the TIMI Study Group and consisting of physicians from 
Pfizer and the National Lead Investigators for participating countries will provide academic 
leadership, will monitor the proportion of study participants with various NYHA classes, left 
ventricular ejection fractions, GDF-15 concentrations, KCCQ-23 CSS scores, and the relative 
proportions qualifying under the cachexia, fatigue, and functional impairment criteria and 
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may cap one or more to ensure a broad population. Additional details will be provided in the 
charter.
10.1.5.2. Data Monitoring Committee 
This study will use an E-DMC. The E-DMC is independent of the study team and includes
external members with expertise in the disease state and clinical trials. The E-DMC charter 
describes the role of the E-DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. The E-DMC will review blinded and unblinded safety data 
prepared by an independent statistician who is not part of the study team. The 
recommendations made by the E-DMC will be forwarded to the appropriate authorized Pfizer 
personnel for review and final decision. Pfizer will communicate such decisions, which may 
include summaries of aggregate analyses of endpoint events and of safety data that are not 
endpoints, to regulatory authorities and investigators, as appropriate.
10.1.5.3. Internal Review Committee
This study will also use an IRC. The IRC is independent of the study team and may include a 
mix of external and internal members. The IRC charter describes the role of the IRC in more 
detail.
The IRC will be responsible for ongoing monitoring of the efficacy and safety of participants 
in the study according to the charter. The IRC will review blinded and unblinded efficacy and 
safety data prepared by an independent statistician who is not part of the study team. The 
recommendations made by the IRC will be forwarded to the appropriate authorized Pfizer 
personnel for review and final decision. Pfizer will communicate such decisions, which may 
include summaries of aggregate analyses of endpoint events and of safety data to regulatory 
authorities and investigators, as appropriate. 
10.1.5.4. Use of Adjudication Committee(s)
This protocol will use an independent adjudication committee to determine whether certain 
investigator-reported events meet standardized definitions for the clinical outcomes described 
in Section 8.2.5. Further information about this endpoint adjudication committee is provided 
in a charter, including a description of the scope of the committee’s responsibilities, the 
process and definitions to be utilized by the committee for adjudication, and communication 
plan including timelines.
The occurrence of potential clinical outcome events as defined in Section 8.2.5 will trigger 
the compilation of a dossier that includes anonymized supporting medical record information 
that will be sent to the adjudication committee.
The results of the adjudication committees’ decisions will be databased and be used for the 
statistical analyses of these endpoints.  The details of these analyses will be described in the 
SAP.
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10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. 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 (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
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.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents.
This 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, including definition of study-critical data items and 
processes (eg, 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 non-compliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
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.
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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.
10.1.8. 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 eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be 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 and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring 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 guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
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, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
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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 sponsor 
or designee/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 the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
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 therapy and/or 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.
10.1.10. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
academic leadership and Pfizer reporting the primary endpoint(s) of the study covering all 
study sites. An analogous approach will be taken for secondary analyses covering data from 
all study sites.
Individual study site investigators agree to refer to the primary publication in any subsequent 
publications. Pfizer will not provide any financial compensation for the investigator’s 
participation in the preparation of the primary congress abstract, poster, presentation, or 
primary manuscript for the study.
Individual site investigators are free to publish individual center results that they deem to be 
clinically meaningful after publication of the overall results of the study or 12 months after 
primary completion date or study completion at all sites, whichever occurs first, subject to 
the other requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
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submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer 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-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.11. Sponsor’s Medically Qualified Individual 
The sponsor will designate a medically qualified individual (MQI, also known as the medical 
monitor) to advise the investigator on study-related medical questions. The contact 
information for the study medical monitor is documented in the Study Team Contact List 
located in the Investigator Site File or equivalent. 
Participants are provided with a Pfizer study information card at the time of informed consent 
which includes contact information for their investigator in case of study-related medical 
questions. The study information card contains, at a minimum, (a) study number, (b) 
participant’s study identification number, and (c) principal investigator contact information.
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Hematology
Chemistry
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Urea and creatinine
CystatinC (at baseline only)
Sodium
Potassium
AST, ALT
Total bilirubin
Alkaline phosphatase
Total protein
Glucose (non-fasting)
Lipid panel:

Total cholesterol

HDL-cholesterol

Non-HDL-cholesterol

Calculated LDL-cholesterol

Triglycerides.
c
At screening:

FSHa
Per SoA or as needed:
Pregnancy test (-hCG, or urine test)b
a.
For confirmation of postmenopausal status only.
b.
Serum -hCG will be collected at screening for female participants of childbearing potential. Local urine 
testing will be standard for the protocol unless serum testing is required by local regulation or IRB/EC.
c.
Only for Cohort C and Cohort D.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

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.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
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suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
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serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or nonpathogenic  
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; 
(2) nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure to 
the product under study to 
a nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
nonparticipant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the CT SAE Report Form and EDP Supplemental Form; if the EDP is associated with 
an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, which would also include details
of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form. 
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
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing discomfort,
but poses no significant or permanent risk of harm to the research participant.  

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.  
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, SEVERE, or VERY SEVERE to describe the maximum intensity of the 
AE. The severity of the AE should be determined using the Toxicity Grading Scale: 
MILD
Does not interfere with participant’s usual function.
MODERATE
Interferes to some extent with participant’s usual function.
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SEVERE
Interferes significantly with participant’s usual function.
VERY SEVERE
Unacceptable and intolerable events or events which are irreversible 
or cause the participant to be in imminent danger of death.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment.

For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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
If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT.

If the electronic system is unavailable, then the site will use the paper SAE DCT
(see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.
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
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic DCT has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or 
to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies. 
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definition in Section 10.4.3).
OR

Is a WOCBP and agrees to use a highly effective contraceptive method (failure rate of 
<1% per year) during the intervention period and for at least 8 weeks after the last 
dose of study intervention, which corresponds to the time needed to eliminate any 
reproductive safety risk of the study intervention(s). If a highly effective, user-
dependent method is chosen, she agrees to concurrently use an effective barrier 
method of contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for reviewing the woman’s medical history, menstrual history, 
and recent sexual activity in order to decrease the risk of enrolling a woman with an early, 
undetected pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following: 

Documented hysterectomy;
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
Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to use 
one of the highly effective nonestrogen hormonal contraception methods if she 
wishes to continue her HRT during the study. Otherwise, she must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
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5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral + barrier*;

Intravaginal + barrier*;

Transdermal + barrier*.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral + barrier*;

Injectable + barrier*.
8. Sexual Abstinence: 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:

Male or female condom with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).
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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to ponsegromab or study interventions of this class to 
understand treatments for the disease under study or the disease itself.

The results of genetic analyses may be reported in CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Retained samples will be stored indefinitely or for another period as per local 
requirements.

Retained samples for TIMI will be stored indefinitely, or for another period as per 
local requirements. 

Participants may withdraw their consent for the storage and/or use of their 
Retained Research Samples at any time by making a request to the investigator; in 
this case, any remaining material will be destroyed. Data already generated from 
the samples will be retained to protect the integrity of existing analyses.

Samples for genetic research will be labeled with a code. The key between the 
code and the participant’s personally identifying information (eg, name, address) 
will be held securely at the study site. 
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below.
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to T bili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value 
≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).
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
Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: Kidney Safety Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr measurement to eGFR [Scr-based eGFR] or [eCrCl]). Baseline and 
postbaseline Scys makes it feasible to distinguish AKI from other causes of Scr increase. If 
Scr increase is confirmed after baseline, then reflex measurement of Scys is indicated to 
estimate the combined Scr-Scys eGFR calculation (for adults only).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
2021 
CKD-EPI 
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
N/A
eGFR = 143 × (Scr/0.7)-0.241 × (0.9938)Age
Female
if >0.7
N/A
eGFR = 143 × (Scr/0.7)-1.200 × (0.9938)Age
Male
if ≤0.9
N/A
eGFR = 142 × (Scr/0.9)-0.302 × (0.9938)Age
Male
if >0.9
N/A
eGFR = 142 × (Scr/0.9)-1.200 × (0.9938)Age
2021 
CKD-EPI 
Scr-Scys 
Combined
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
if ≤0.8
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if ≤0.7
if >0.8
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age
Female
if >0.7
if ≤0.8
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if >0.7
if >0.8
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if ≤0.9
if ≤0.8
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if ≤0.9
if >0.8
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if >0.9
if ≤0.8
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if >0.9
if >0.8
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
Inker LA et al. N Engl J Med. 2021;385:1737-49.
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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB (QRS complex >120 ms).

New-onset right bundle branch block (QRS complex >120 ms).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).
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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(HR <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as
torsades de pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all-inclusive of what to be reported as AEs/SAEs.
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10.9. Appendix 9: Prohibited Concomitant Medications 
Ponsegromab, a humanized mAb directed against GDF-15, is not expected to affect the PK 
of small molecule drugs either via cytokine-mediated effects on CYP enzymes or 
transporters.
The below investigational products are not permitted:

Investigational products (drug or vaccine) are not permitted within 30 days (or as 
determined by the local requirement) or 5 half-lives (whichever is longer) of Day 1 
through Week 32.  

Investigational biologic agents are not permitted within 6 months or 5 half-lives 
(whichever is longer) of Day 1 through Week 32.
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgment on the ongoing 
participation of any participant with prohibited medication use during the study.
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10.10. Appendix 10: Protocol Amendment History
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below:
Amendment 1 (06 June 2023)
Overall Rationale for the Amendment: The overall rationale for this amendment is to 
incorporate an open-label, PK cohort, clarifications to eligibility criteria and other sections, 
remove the Heart Failure Daily Diary, and simplify approach to activity monitoring.
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Inclusion of Open-label, 
PK Cohort, which includes 
the following unique items 
separate from the main 
cohort:

Study rationale

Study design

Study schema

SoA

Inclusion/Exclusion 
criteria

Study arms and 
duration

Objectives/endpoints

Contracted Home 
Health Visits
Open-label, PK cohort 
added to facilitate a more 
comprehensive assessment 
of PK characteristics and 
PK/PD relationship at each 
ponsegromab dose level in 
participants with heart 
failure and elevated GDF-
15 levels, in response to a 
regulatory request.
1 – Protocol Summary
2 – Introduction
3.2 – Objectives, Endpoints, 
and Estimands (Open-label, 
PK cohort)
4 – Study Design
5 – Study Population
6 – Study Intervention(s) 
and Concomitant Therapy
7 – Discontinuation of 
Study Intervention and 
Participant 
Discontinuation/Withdrawal
8 – Study Assessments and 
Procedures
9 – Statistical 
Considerations
Removal of HF Daily 
Diary
Early feedback from 
sites/investigators that this 
ePRO was an excessive 
burden on participants and 
sites. Strategic 
reassessment concluded 
that this ePRO did not
provide incremental  value
1 – Protocol Summary
3.1 – Objectives, Endpoints, 
and Estimands (Main 
cohort)
8.1.1 – Screening 
Procedures
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Description of Change
Brief Rationale
Section # and Name
beyond other ePROs 
included in the protocol.
8.2.1 – Patient Reported 
Outcomes (Main Cohort 
Only)
9 – Statistical 
Considerations
Exclusion Criteria
#3: Excluded
current/planned use of 
intravenous inotropes (eg, 
dobutamine, milrinone)
#8: Specified the exclusion 
of severe, uncorrected 
aortic stenosis; active 
malignancy and reduced 
life expectancy to less than 
1 year.
#11: Excluded participants 
with “Previous exposure to 
ponsegromab in a prior 
clinical study.”
#13: Excluded participants 
with the following LFT 
abnormalities at the time of 
screening, confirmed by a 
repeat test if deemed 
necessary: AST or ALT 
level ≥ 3 x ULN, or total 
bilirubin level ≥ 2 x ULN 
(unless history of Gilbert’s 
syndrome).
Clarifications offered to 
existing exclusion criteria 
to reduce likelihood of 
enrolling participants who 
would not be appropriate 
for study. 
1 – Protocol Summary
5.2 – Exclusion Criteria
Inclusion Criteria
#2: Added note that 12-
month window is not 
required if LVEF has been 
persistently <50% on prior 
assessments.
Clarifications offered to 
existing inclusion criteria 
to ensure likelihood of 
enrolling participants who 
would be appropriate for 
study.
1 – Protocol Summary
5.1 – Inclusion Criteria
Reduced frequency of 
activity monitoring to the 
following periods: from 
Feedback provided from 
sites and participants that 
original requirement for 
continuous wear through 
1.3  – Schedule of Activities
3.1 – Objectives, Endpoints, 
and Estimands (Main 
cohort)
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Description of Change
Brief Rationale
Section # and Name
SV2 to Day 1 and from 
Week 20 to Week 22
Week 22 was an excessive 
burden. Strategic 
reassessment favored 
reduced frequency. 
8.1.1 – Screening 
Procedures
8.2.4 – Activity Monitoring 
(Main Cohort Only)
Main cohort SoA: 
Added Early Termination 
Hematology & Chemistry 
Panel
Added Week 24 
contraception check.
Additional safety 
measurement.
1.3  – Schedule of Activities
Main cohort SoA: Added 
Lipid panel assessment
Requested safety 
measurement from a 
regulatory authority.
1.3  – Schedule of Activities
10.2 – Appendix 2: Clinical 
Laboratory Tests
Main cohort SoA: Added 
NT-proBNP in plasma 
assessment at Week 12
Align with Week 12 
assessment of other 
efficacy endpoints.
1.3  – Schedule of Activities
Updated clinical overview, 
including summary of 
safety data, 
pharmacokinetics, GDF-15 
response and 
immunogenicity from 
completed clinical studies.
Updates in line with 
updates to the IB.
2.2.2 – Clinical Overview
2.3 – Benefit/Risk 
Assessment
Revised discontinuation 
criteria to clarify scenarios 
when study intervention 
must be permanently 
discontinued and 
considerations for 
permanent discontinuation. 
Updates requested by 
regulatory authority.
7.1 – Discontinuation of 
Study Intervention
Removed legal guardian 
and legally authorized 
representative
Legal guardians and 
legally authorized 
representatives  not 
permitted to act on behalf 
of participants.
8.4 – Adverse Events, 
Serious Adverse Events, and 
Other Safety Reporting
9.2 – Analysis Set
10.1.3 – Informed Consent 
Process
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Description of Change
Brief Rationale
Section # and Name
10.4.2 – Modified
contraception intervention 
period from at least 22 
weeks to at least 8 weeks 
after the last dose of study 
intervention.
8.4.5.1 – Modified follow-
up time period for 
pregnancy from at least 5
terminal half-lives after the 
last dose to up to the time 
of the final planned follow-
up visit.
Updated to clarify 
intention to collect data on 
pregnancy through the 
duration of follow-up 
which incorporates the 5 
half-lives window (11.1 
days) of unbound
ponsegromab noted in 
Section 2.2.2.2 – Summary 
of Pharmacokinetics.
10.4.2 – Female Participant 
Reproductive Inclusion 
Criteria
8.4.5.1 – Exposure During 
Pregnancy
Updated inclusion criteria 
for female participation.
Update reflects current 
recommendation based on 
nonclinical and clinical 
data.
10.4.2 – Female Participant 
Reproductive Inclusion 
Criteria
Non-substantial Modification(s)
Streamlined text to 
emphasize that no injection 
site reactions or delayed 
hypersensitivity reactions 
have been observed in the 
completed clinical studies.
Clarification
2.3.1– Risk Assessment
Inclusion Criterion #2a: 
Modified text to state, 
“LVEF <50% on most 
recent measurement, within 
12 months of screening.”
Clarification
1 – Protocol Summary
5.1 – Inclusion Criteria
Inclusion Criterion
#5: Clarified that all
criteria should be met at 
screening.
#5b: Specified that criteria 
is based on the KCCQ-23 
administered at 
screening.
Clarification
1 – Protocol Summary
5.1 – Inclusion Criteria
Exclusion Criterion #1: 
Modified text to state, 
Clarification
1 – Protocol Summary
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Description of Change
Brief Rationale
Section # and Name
“Acute decompensated HF 
within 1 month prior to 
SV1 or during the 
screening period.”
5.2 – Exclusion Criteria
Exclusion Criterion #12: 
Modified text to state, 
"Renal disease requiring 
ongoing dialysis.”
Clarification
1 – Protocol Summary
5.2 – Exclusion Criteria
Modified text to emphasize 
that SV2 should commence 
at a minimum of 15 days 
prior to Day 1, when
feasible.
Clarification
1.3 – Schedule of Activities
Extended the time period 
for use of prior treatments 
from 28 to 56 days.
Time period reflects 
screening period and 
ensures consistency with 
other language throughout 
protocol.
6.9 – Prior and Concomitant 
Therapy
Clarified Early 
Termination and Follow-up 
Visits requirements 
following discontinuation 
of study intervention.
Clarification to align with 
CRF completion 
requirements 
7.1 – Discontinuation of 
Study Intervention
Added instructional 
language for COVID-19 
safety reporting
Clarification
7.1.1 – COVID-19
Updated measures for 
participants lost to follow-
up
Clarified text to minimize 
loss to follow up, and 
procedures in event of loss 
to follow-up.
7.3 – Lost to Follow-up
Total blood sampling 
updated to 274 mL (main 
cohort) and 184 mL (open-
label, PK cohort)
Updates reflective of
changes in protocol 
amendment
8.1 – Administrative 
Procedures
Added language for home 
health care services for the 
open-label, PK cohort 
Contracting outside vendor 
to perform blood sampling 
at participant home or 
8.1.2 – Contracted Home 
Health Visits (Open-Label, 
PK Cohort Only)
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Description of Change
Brief Rationale
Section # and Name
current residence as per 
SoA
Added language specific to 
classification of deaths as 
cardiovascular or non-
cardiovascular according to 
the primary cause of death
Clarification to align with 
CRF completion 
requirements
8.2.5 – Clinical Outcomes
Added “The investigator 
should inform the TIMI 
Hotline of any potential 
withdrawal of consent.”
Clarification to align with 
CRF completion 
requirements
7.2.1 – Withdrawal of 
Consent
Added “If the site does not 
have an ECG machine that 
performs automated 
calculations, the 
investigator is permitted to 
calculate the standard 
intervals.”
Clarification
8.3.3 – Electrocardiograms
Added language specific to 
male participants who 
inseminate a female partner
Language inadvertently 
omitted in initial protocol.
8.4.5.1 – Exposure During 
Pregnancy
Updated blood sample 
volume to 4 mL.
Volume consistent with 
laboratory manual.
8.6.3 – Retained Research 
Samples for Future Genetic 
Research by TIMI
Added “Participants who 
are rescreened are required
to sign a new ICD.”
Clarification
10.1.3 – Informed Consent 
Process
Removed “eg, implantation 
of a pacemaker, coronary 
revascularization and heart 
transplant.”
Language aligns with SAP
9.1.1.1 – Primary Estimands
Updated model language to 
state log GDF-15 
concentrations and log NT-
proBNP
Language aligns with SAP
9.3.1 – General 
Considerations
Removed “…and their 
partner(s)…” in the first 
sentence.
Language inadvertently 
included. No contraception 
is required for male 
partner(s) of female study 
5.3.1 – Contraception
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Description of Change
Brief Rationale
Section # and Name
participants that are 
WOCBP.
Added text “A second staff 
member will verify the 
dispensing.”
Clarification to coincide 
with language in IP 
manual.
6.2.1 – Preparation and 
Dispensing
Modified details of the 
PK/PD unblinding plan.
Clarification of the 
specifics of the PK/PD 
unblinding plan.
9.4.1 – PK/PD Unblinding 
Plan
Modified to “Response as 
defined by a ≥10-point and 
≥15-point increase in...”
Correction: Protocol 
Administrative Change 
Letter dated 03 Aug 2022
3 – Objectives, Endpoints, 
and Estimands
Modifications to language 
to reflect steady state 
exposures, not exposures 
after 6 Q4W SC doses.
Clarification: Protocol 
Administrative Change 
Letter dated 03 Aug 2022
4.3 – Justification for Dose
Language modified for 
clarification.
Clarification: Protocol 
Administrative Change 
Letter dated 03 Aug 2022
6.1– Administration
Modified follow-up time 
period for laboratory test 
values considered clinically 
significant and abnormal 
from 28 days to up to the 
time of the final planned 
follow-up visit
Clarification: Protocol 
Administrative Change 
Letter dated 03 Aug 2022
8.3.4 – Clinical Safety 
Laboratory Assessments
Revised text to emphasize
that only follow-up visits 
(F/U1, F/U2), the flexible 
PK/PD visit, and any 
additional immunogenicity 
sampling may be 
conducted at the 
participant’s home or 
current residence by 
qualified personnel.
Clarification; Protocol 
Administrative Change 
Letter dated 11 Oct 2022
1.3 – Schedule of Activities 
– Table 1, Study Schedule 
of Assessment for the Main 
Cohort
2.3.1 – Risk Assessment
8.3.5.1 – At-Home 
Pregnancy Testing
8.5 – Pharmacokinetics
8.7.1 – GDF-15 
8.8 – Immunogenicity 
Assessments
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Description of Change
Brief Rationale
Section # and Name
Added the following text in
bold, “In addition, this 
sample may be used to 
help support development 
of a potential companion 
diagnostic test for 
ponsegromab. This 
screening assay will be 
validated in a CLIA 
accredited central 
laboratory.”
Additional details: 
Protocol Administrative 
Change Letter dated 11 
Oct 2022
8.7.1 – GDF-15 
Added the following text in 
bold, “Samples will be 
collected according to the 
SoA, as local regulations 
and IRB/ECs allow.”
Clarification: Protocol 
Administrative Change 
Letter dated 11 Oct 2022
8.7.8 – Samples for 
Exploratory Plasma 
Biomarker Research by 
Pfizer
Modified language to 
emphasize that glucose 
sampling is non-fasting
Clarification: Protocol 
Administrative Change 
Letter dated 11 Oct 2022
10.2 – Appendix 2: Clinical 
Laboratory Tests
Modified active collection 
period from 28 days to up 
to the time of the final 
planned follow-up visit.
Clarification; Protocol 
Administrative Change 
Letter dated 27 Jan 2023
8.4.1 – Time Period and 
Frequency for Collecting 
AE and SAE Information
Provided text clarification 
and corrections.
Minor clarifications and 
editorial/typographical 
changes have been made 
throughout, including 
those through new 
regulatory guidance.
Various sections of the 
protocol
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10.11. Appendix 11: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
6MWD
6-Minute Walk Distance
6MWT
6-Minute Walk Test
ADA
anti-drug antibodies
ADL
activity/activities of daily living
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUCinf
area under the serum concentration time profile from time zero 
extrapolated to infinite time
AUClast
area under the serum concentration time profile from time zero to 
the time of the last quantifiable concentration
AUCtau
area under the serum concentration-time curve over the dosing 
interval tau
AV
atrioventricular
-hCG
-human chorionic gonadotropin
BD
business day
BP
blood pressure
bpm
beats per minute
Cavg
average concentration
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology 
CL/F
apparent clearance
CLIA
Clinical Laboratory Improvements Amendments
Cmax
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CSR
Clinical Study Report
CSS
Clinical Summary Score
CT
computed tomography;clinical trial
CTIS
Clinical Trial Information System
CTR
Clinical Trials Regulation
CYP
cytochrome P450
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Abbreviation
Term
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram or electrocardiography
eCOA
electronic clinical outcome assessment
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
Emax
maximal effect
EOT
end of treatment
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
F/U1
follow-up visit 1
F/U2
follow-up visit 2
GCP
Good Clinical Practice
GDF-15
growth differentiation factor 15
GGT
gamma-glutamyl transferase
HDL
high-density lipoprotein
HF
heart failure
HFrEF
heart failure with reduced ejection fraction
HR
heart rate
HRQL
health-related quality of life
HRT
hormone replacement therapy
hsCRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ID
identification
IgG
immunoglobulin g
IMP
investigational medicinal product
IND
Investigational New Drug
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Abbreviation
Term
INR
international normalized ratio
IP
investigational product
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
IRB
Institutional Review Board
IRC
internal review committee
IRT
Interactive Response Technology
KCCQ-23
Kansas City Cardiomyopathy Questionnaire
KDIGO
Kidney Disease: Improving Global Outcomes
LBBB
left bundle branch block
LDL
low-density lipoprotein
LFT
liver function test
LLOQ
lower limit of quantitation
LVEF
left ventricular ejection fraction
mAbs
monoclonal antibodies
MI
myocardial infarction
MIC-1
Macrophage Inhibitory Cytokine 1
MMRM
mixed models repeated measures
MQI
medically qualified individual
N/A
Not Applicable
NAb
neutralizing antibodies
NIMP
noninvestigational medicinal product
NOAEL
no observed adverse effect level
NSCLC
non-small cell lung cancer
NT-proBNP
N-terminal pro-B type natriuretic peptide
NYHA
New York Heart Association
OSS
Overall Summary Score
PAX
paired box
PCD
primary completion date
PD
pharmacodynamic(s)
PGI-C
Patient Global Impression of Severity
PGI-S
Patient Global Impression of Change
PK
pharmacokinetic(s)
PR
pulse rate
PRO
patient reported outcomes
PROMIS
Patient-Reported Outcomes Measurement Information System
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PTR
peak-to-trough ratio
PVC
premature ventricular contraction
Q3W
every three weeks
Q4W
every four weeks
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Abbreviation
Term
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
QTL
quality tolerance limit
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous(ly)
Scr
serum creatinine
SD
standard deviation
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single-reference safety document
SSID
single subject identifier
SUSAR
Suspected Unexpected Serious Adverse Reaction
SV1
Screening visit 1
SV2
Screening visit 2
t½
terminal elimination half-life
T bili
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TGF-
transforming growth factor beta
TIMI
TIMI Study Group, an academic research organization
Tmax
time for C
TSS
Total Symptom Score
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman/women of childbearing potential
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11. REFERENCES
1
Hollenberg SM, Warner Stevenson L, Ahmad T, et al. 2019 ACC Expert Consensus 
Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients 
Hospitalized With Heart Failure: A Report of the American College of Cardiology 
Solution Set Oversight Committee. J Am Coll Cardiol. 2019 Oct 15;74(15):1966-2011.
2
Virani SS, Alonso A, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2020 
Update: A Report From the American Heart Association. Circulation. 
2020;141(9):e139-e596.
3
Bottner M, Suter-Crazzolara C, Schober A, et al. Expression of a novel member of the 
TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting 
cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res. 1999;297(1):103-10.
4
Albertoni M, Shaw PH, Nozaki M, et al. Anoxia induces macrophage inhibitory 
cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1. Oncogene. 
2002;21(27):4212-9.
5
Akiyama M, Okano K, Fukada Y, et al. Macrophage inhibitory cytokine MIC-1 is 
upregulated by short-wavelength light in cultured normal human dermal fibroblasts. 
FEBS Lett. 2009;583(5):933-7.
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Ponsegromab, PF-06946860
Protocol C3651011
Final Protocol Amendment 2, 18 July 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 135
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