Clinical trial NCT05286281
Conditions: Healthy
Keywords: LMNA-related DCM Cardiomyopathy Lamin Type A Heart failure ARRY-371797
Sponsor: Pfizer
Start date: 2022-03-31; Completion date: 2022-05-26
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the pharmacokinetics, excretion, mass balance and metabolism of PF-07265803 (formerly known as ARRY-371797) in approximately 6 healthy adult male participants.

Detailed description:

Arms: arm 1: PF-07265803 is a p38 inhibitor formulated for oral delivery.
Interventions: intervention 1: PF-07265803
Intervention descriptions: intervention 1: PF-07265803 is a p38 inhibitor formulated for oral delivery.

Protocol documents:
Prot_000.pdf: 
PF-07265803
Protocol C4411010
Final  Protocol, 26-January-2022
PFIZER CONFIDENTIAL
Page 1
Title Page
A PHASE 1, OPEN-LABEL, SINGLE-PERIOD, NON-RANDOMIZED STUDY TO 
EVALUATE THE PHARMACOKINETICS, EXCRETION, MASS BALANCE AND 
METABOLISM OF [14C]PF-07265803 ADMINISTERED ORALLY TO HEALTHY 
ADULT MALE PARTICIPANTS
Study Intervention Number:
PF-07265803
Study Intervention Name:
N/A
US IND Number:
118,677
EudraCT Number:
N/A
ClinicalTrials.gov ID:  
TBD
Protocol Number:
C4411010
Phase:
1
Brief Title: A Phase 1 Radiolabel Pharmacokinetics, Excretion, Mass Balance and Metabolism 
Study of [14C]PF-07265803.
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.


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Protocol C4411010
Final  Protocol, 26-January-2022
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Original protocol
26 January 2022


PF-07265803
Protocol C4411010
Final  Protocol, 26-January-2022
PFIZER CONFIDENTIAL
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................10
1.3. Schedule of Activities .............................................................................................11
2. INTRODUCTION ...............................................................................................................14
2.1. Study Rationale .......................................................................................................14
2.2. Background .............................................................................................................14
2.2.1. Nonclinical Studies with PF-07265803......................................................14
2.2.2. Nonclinical Pharmacology..........................................................................15
2.2.3. Nonclinical Pharmacokinetics and Metabolism .........................................15
2.2.4. Nonclinical Safety ......................................................................................16
2.2.5. Clinical Overview.......................................................................................16
2.3. Benefit/Risk Assessment.........................................................................................17
2.3.1. Risk Assessment.........................................................................................18
2.3.2. Benefit Assessment.....................................................................................19
2.3.3. Overall Benefit/Risk Conclusion................................................................19
3. OBJECTIVES AND ENDPOINTS.....................................................................................19
4. STUDY DESIGN.................................................................................................................19
4.1. Overall Design.........................................................................................................19
4.2. Scientific Rationale for Study Design.....................................................................20
4.2.1. Choice of Contraception/Barrier Requirements .........................................20
4.2.2. Collection of Retained Research Samples..................................................21
4.3. Justification for Dose ..............................................................................................21
4.3.1. Dosimetry Calculations ..............................................................................21
4.4. End of Study Definition ..........................................................................................22
5. STUDY POPULATION......................................................................................................22
5.1. Inclusion Criteria.....................................................................................................22
Age and Sex:.........................................................................................................22
Type of Participant and Disease Characteristics: .................................................22


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Weight: .................................................................................................................23
Informed Consent: ................................................................................................23
5.2. Exclusion Criteria....................................................................................................23
Medical Conditions:..............................................................................................23
Prior/Concomitant Therapy: .................................................................................23
Prior/Concurrent Clinical Study Experience: .......................................................24
Diagnostic Assessments: ......................................................................................24
Other Exclusions:..................................................................................................24
5.3. Lifestyle Considerations..........................................................................................25
5.3.1. Meals and Dietary Restrictions...................................................................25
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................26
5.3.3. Activity .......................................................................................................26
5.3.4. Contraception..............................................................................................26
5.4. Screen Failures ........................................................................................................27
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................27
6.1. Study Intervention(s) Administered........................................................................27
6.1.1. Administration............................................................................................27
6.2. Preparation, Handling, Storage, and Accountability...............................................27
6.2.1. Preparation and Dispensing........................................................................28
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................29
6.3.1. Allocation to Study Intervention ................................................................29
6.4. Study Intervention Compliance...............................................................................29
6.5. Dose Modification...................................................................................................29
6.6. Continued Access to Study Intervention After the End of the Study......................29
6.7. Treatment of Overdose............................................................................................29
6.8. Concomitant Therapy..............................................................................................30
6.8.1. Rescue Medicine.........................................................................................30
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................31
7.1. Discontinuation of Study Intervention ....................................................................31
7.1.1. Potential Cases of Acute Kidney Injury .....................................................31
7.2. Participant Discontinuation/Withdrawal From the Study.......................................31


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7.2.1. Withdrawal of Consent...............................................................................32
7.3. Lost to Follow up ....................................................................................................32
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................33
8.1. Efficacy Assessments..............................................................................................34
8.2. Safety Assessments .................................................................................................34
8.2.1. Physical Examinations................................................................................34
8.2.2. Vital Signs ..................................................................................................35
8.2.3. Electrocardiograms.....................................................................................35
8.2.4. Clinical Safety Laboratory Assessments ....................................................36
8.2.5. COVID-19 specific assessments.................................................................37
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................37
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......37
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................38
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................38
8.3.2. Method of Detecting AEs and SAEs ..........................................................38
8.3.3. Follow-Up of AEs and SAEs......................................................................38
8.3.4. Regulatory Reporting Requirements for SAEs...........................................39
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................39
8.3.5.1. Exposure During Pregnancy......................................................39
8.3.5.2. Exposure During Breastfeeding ................................................41
8.3.5.3. Occupational Exposure .............................................................41
8.3.6. Cardiovascular and Death Events...............................................................41
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................42
8.3.8. Adverse Events of Special Interest.............................................................42
8.3.8.1. Lack of Efficacy........................................................................42
8.3.9. Medical Device Deficiencies......................................................................42
8.3.9.1. Medication Errors......................................................................42
8.4. Pharmacokinetics ....................................................................................................43
8.4.1. Plasma Analysis of Non-Radiolabeled PF-07265803 ................................43
8.4.2. Metabolite Profiling/ID ..............................................................................44


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8.4.2.1. Plasma for Metabolite Profiling/ID...........................................44
8.4.2.2. Urine for Metabolite Profiling/ID .............................................44
8.4.2.3. Feces for Metabolite Profiling/ID .............................................44
8.4.3. Radioactivity...............................................................................................45
8.4.3.1. Sample Collection .....................................................................45
8.4.3.2. Plasma/Blood Sample Collection for Total Radioactivity........45
8.4.3.3. Urine Sample Collection for Total Radioactivity .....................45
8.4.3.4. Fecal Sample Collection for Total Radioactivity......................45
8.4.3.5. Emesis Sample Collection for Total Radioactivity....................45
8.5. Genetics...................................................................................................................46
8.5.1. Specified Genetics ......................................................................................46
8.5.2. Retained Research Samples for Genetics ...................................................46
8.6. Biomarkers ..............................................................................................................46
8.6.1. Specified Gene Expression (RNA) Research .............................................46
8.6.2. Specified Protein Research.........................................................................46
8.6.3. Specified Metabolomic Research ...............................................................46
8.7. Immunogenicity Assessments.................................................................................46
8.8. Health Economics ...................................................................................................46
9. STATISTICAL CONSIDERATIONS ................................................................................46
9.1. Statistical Hypotheses .............................................................................................47
9.2. Analysis Sets ...........................................................................................................47
9.3. Statistical Analyses .................................................................................................47
9.3.1. General Considerations...............................................................................47
9.3.2. Primary Endpoint(s)....................................................................................48
9.3.2.1. Metabolic Profiling/Identification.............................................48
9.3.3. Secondary Endpoint(s)................................................................................48
9.3.3.1. Pharmacokinetic Parameters .....................................................48
9.3.4. Other Safety Analyses ................................................................................49
9.3.4.1. Electrocardiogram Analyses......................................................50
9.3.4.2. Other Analyses ..........................................................................50
9.4. Interim Analyses .....................................................................................................50


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9.5. Sample Size Determination.....................................................................................50
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................51
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............51
10.1.1. Regulatory and Ethical Considerations ....................................................51
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................51
10.1.2. Financial Disclosure .................................................................................52
10.1.3. Informed Consent Process ........................................................................52
10.1.4. Data Protection .........................................................................................53
10.1.5. Committees Structure ...............................................................................53
10.1.5.1. Data Monitoring Committee ...................................................53
10.1.6. Dissemination of Clinical Study Data ......................................................53
10.1.7. Data Quality Assurance ............................................................................55
10.1.8. Source Documents....................................................................................56
10.1.9. Study and Site Start and Closure ..............................................................56
10.1.10. Publication Policy...................................................................................57
10.1.11. Sponsor’s Qualified Medical Personnel .................................................58
10.2. Appendix 2: Clinical Laboratory Tests .................................................................59
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................60
10.3.1. Definition of AE .......................................................................................60
10.3.2. Definition of an SAE ................................................................................61
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................62
10.3.4. Reporting of SAEs....................................................................................66
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................67
10.4.1. Male Participant Reproductive Inclusion Criteria....................................67
10.4.2. Female Participant Reproductive Inclusion Criteria.................................67
10.4.3. Woman of Childbearing Potential ............................................................67
10.4.4. Contraception Methods.............................................................................68
10.5. Appendix 5: Genetics............................................................................................70
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......71


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................73
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI.......75
10.9. Appendix 9: Abbreviations ...................................................................................75
11. REFERENCES ..................................................................................................................79
LIST OF TABLES
Table 1.
Blood Sampling Volume ..........................................................................34
Table 2.
Analysis Sets.............................................................................................47
Table 3.
Pharmacokinetic Parameters.....................................................................49
Table 4.
Protocol-Required Safety Laboratory Assessments .................................59


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Protocol C4411010
Final  Protocol, 26-January-2022
PFIZER CONFIDENTIAL
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title
A Phase 1 Radiolabel Pharmacokinetics, Excretion, Mass Balance and Metabolism Study of 
[14C]PF-07265803.
Rationale
The purpose of this Phase 1 study is to assess the pharmacokinetics, excretion, mass balance 
and metabolism of PF-07265803 (formerly known as known as ARRY-371797) in healthy 
adult male participants. Only males will be included in this study given the use of 
radiolabeled substance and the desire to enroll a homogeneous population given the small 
sample size of this study.
Administration of the investigational product, [14C]PF-07265803 in this study will be via the 
oral route to reflect the intended route of administration in the treatment of lamin A/C gene 
mutation (LMNA)-related DCM. PF-07265803 will be administered as an extemporaneously 
prepared liquid formulation in this study. In order to limit the confounding of absorption, 
[14C]PF-07265803 will be administered following an overnight fast of at least 10 hours.
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
To characterize rate and extent of excretion of total
radioactivity in urine and feces, following a single
oral dose of [14C]PF-07265803 administered to
healthy adult male participants.
Mass Balance: cumulative recovery of urinary, 
fecal, and total excretion of radioactivity over time 
expressed as percentage of total radioactive dose 
administered.
To characterize metabolic profile and identify 
circulating and excreted metabolites following 
administration of a single oral dose of [14C]PF-
07265803 to healthy adult male participants.
Metabolic profiling/identification and determination 
of relative abundance of PF-07265803 and the 
metabolites of PF-07265803 in plasma, urine, and 
feces.
Secondary: 
Secondary: 
To quantify plasma concentrations and 
pharmacokinetic parameters of PF-07265803, its 
known circulating metabolites (PF-07327859, PF-
07327860, PF-07327890) and total radioactivity in 
plasma following administration of a single oral 
dose of [14C]PF-07265803 to healthy adult male 
participants.
Pharmacokinetics parameter AUClast, AUCinf, CL/F, 
Vz/F, Cmax, Tmax, and t½ to describe single dose PK 
of: PF-07265803 and where appropriate PF-
07327859, PF-07327860, PF-07327890.
Total radioactivity in plasma; PF-07265803, PF-
07327859, PF-07327860 and PF-07327890
concentrations in plasma.
To evaluate safety and tolerability of a single oral 
dose of [14C]PF-07265803 administered to healthy 
adult male participants.
Safety endpoints including physical examinations, 
adverse events, clinical laboratory measurements, 
vital signs and ECG.


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Final  Protocol, 26-January-2022
PFIZER CONFIDENTIAL
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Overall Design
This is a Phase 1, open-label, single-period, single-center, non-randomized study in healthy 
adult male participants.
Brief Summary
In this study, mass balance and metabolism of 400 mg PF-07265803 containing 100 µCi 
[14C]PF-07265803 will be assessed.  Healthy participants will be screened up to 28 days prior 
to dosing to determine eligibility. 
Number of Participants
Approximately 6 participants will be enrolled to study intervention.
Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. 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.
Intervention Groups and Duration
The duration of this non-randomized Phase 1, open-label, single-center, single-dose study is 
approximately 7 days, with a 30-day safety follow up. The maximum period of confinement 
is expected to be 14 days. The minimum period of confinement is expected to be 3 days.  
Data Monitoring Committee or Other Independent Oversight Committee: No
This study will not use a DMC or IOC.
Statistical Methods
There will be no formal hypothesis testing in this study. The sample size of 6 participants, for 
this study, was not based on empirical data or hypothesis testing criteria. The sample size has 
been selected to ensure that at least 4 participants provide evaluable data; with intent not to 
replace participants who prematurely withdraw (or offer non-evaluable or partially evaluable 
data).
1.2. Schema
Not applicable.


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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. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifier
Abbreviations used in this table may 
be found in 10.9.
Screening
Period 1
Follow-Up 
Early Termination/
Discontinuation
Days Relative to Day 1
Day -28 to 
Day -2
Day -1
Day 1
Day 
2
Day
3
Day 
4
Day 
5
Day
6-14
28-35 Daysb
Informed consent
X
CRU confinementa
X
X
X
X
X
X
Xa
Inclusion/exclusion criteria
X
X
Medical/medication history
X
X
Physical examb
X
Xc
X
Safety laboratoryi
X
X
Xc
X
Demography
X
Height and Weight
X
Urine drug/alcohol/cotinine testingk
X
X
12-Lead ECG
X
Xg,j
Xc
X
Blood pressure and pulse rate 
X
Xh,j
Xc
X
Contraception check
X
HIV, HBsAg, HCVAb 
X
COVID-19 CRU Internal 
Procedured
X
X
X
X
X
X
X
Xc
X
Study intervention administration
X
Standard Mealse
X
X
X
X
X
X
X
Spot Collection for Urinalysis (and
Microscopy, if needed)
X
X
Xc
X
Retained Research Sample for 
Genetics (Prep D1)f
X
CRU discharge 
Xa
Serious and nonserious AE
monitoring
X
X
X
X
X
X
X
X
X
X


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Final  Protocol, 26-January-2022
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Visit Identifier
Abbreviations used in this table may 
be found in 10.9.
Screening
Period 1
Follow-Up 
Early Termination/
Discontinuation
Days Relative to Day 1
Day -28 to 
Day -2
Day -1
Day 1
Day 
2
Day
3
Day 
4
Day 
5
Day
6-14
28-35 Daysb
a.
Inpatient stay must be extended until >90% radioactive dose administered has been recovered or <1% is excreted in total (urine and feces) in any 24H period for two 
consecutive days. Maximum confinement will be 14 days.
b.
Complete physical examination will be conducted at Day -1 (Period 1); otherwise brief physical exam envisioned for findings during previous PE or new/open AEs, at 
Investigator discretion. Follow-up over the phone may be conducted if no new/open AE’s at Investigators discretion.
c.
Procedures to be completed at time of discharge (approximately 144 hours post dose) only, with clinical laboratory tests conducted only after criteria for discharge 
(footnote “a”) are satisfied
d.
Assessments for COVID-19 infection will be done per CRU standards for testing and those described in Section 8.2.5
e.
Starting at enrollment, meals to be served, at clock times matching approximately 0H, 4H, and 9H relative to dosing on Day 1. No meal administered on Day 1 0 h in 
accordance with the fasted window. To help assure regularity in bowel movements, nutritional composition should contain at least 15 g of fiber per 1000 kcal or fiber 
capsules containing the equivalent amount of fiber may be administered daily (beginning at least 8 hr after dosing).
f.
Prep D1 Retained Research Samples for Genetics: If not collected on the designated collection day, collect at the next available time point when biospecimens are being 
collected in conjunction with a participant visit. Sample should be collected prior to dose.
g.
ECG assessment will occur prior to dosing (approximately 1 hour).
h.
Pre-dose vital sign measurements. Predose (approximately 1 hour) vital sign measurements on Day 1.
i.
Safety laboratories consistent with those described in Section 10.2
j.
ECG and vital signs assessment for eligibility may be considered at both screening and Day 1 visit (predose).
k.
Urine drug screen and cotinine conducted at screening and check-in, and urine alcohol conducted at check-in only.


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Visit Identifier 
Period 1
Study Day
1
2
3
4
5
6
Early Termination/
Discontinuation
Hours Before/After Dose
0a
0.5
1
2
3
4
6
9
12
24
36
48
72
96
120
Study intervention administration
X
PK blood sampling 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Radioactivity and metabolite ID in blood  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Interval collection for radioactivity and metabolite ID 
in urineb
X





X

X
X

X
X
X
X
Interval collection for radioactivity and metabolite ID 
in fecesc
X







X
X

X
X
X
X
Emesis Collection for Radioactivity Measurement, if 
Occurs
X





X


a.
Predose sample collection
b.
“Blank” spot urine sample to be collected anytime predose (Day 1) and postdose in intervals of 0-6H, 6-12H, 12-24H, 24-48H, 48-72H, 72-96H, and each subsequent 24H 
interval up to discharge.
c.
“Blank” fecal sample to be collected prior to dosing but post admission to CRU and in intervals of each 24H period post dose up to discharge


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2. INTRODUCTION
PF-07265803 (formerly known as known as ARRY-371797) is a potent and selective, oral 
small molecule inhibitor of the α isoform of p38 MAPK. Mutations in the LMNA gene 
encoding nuclear lamina components cause nuclear envelope dysfunction leading to altered 
nuclear activity, impaired structural dynamics and aberrant cell signaling including activation 
of p38α MAPK signaling pathways.  Structural alterations in the nuclear envelope and 
connected cytoskeleton resulting from LMNA mutations make cardiomyocytes highly 
susceptible to damage even by physiological mechanical stress, leading to a disease specific 
maladaptive activation of the p38α MAPK. Up-regulation of p38 MAPK has been observed 
in the hearts of animal models and adult patients with LMNA-related DCM compared to wild-
type/healthy individuals. Inhibition of p38 MAPK in this disease setting may halt aberrant 
apoptosis and cardiac remodeling resulting in improved cardiac function.
2.1. Study Rationale 
The purpose of this Phase 1 study is to assess the pharmacokinetics, excretion, mass balance
and metabolism of PF-07265803 (formerly known as ARRY-37197) in healthy adult male 
participants. Only males will be included in this study given the use of radiolabeled 
substance and the desire to enroll a homogeneous population given the small sample size of 
this study.
Administration of the investigational product, [14C]PF-07265803 in this study will be via the 
oral route to reflect the intended route of administration in the treatment of lamin A/C gene 
mutation (LMNA)-related DCM. PF-07265803 will be administered as an extemporaneously 
prepared liquid formulation in this study. In order to limit the confounding of absorption,
[14C]PF-07265803 will be administered following an overnight fast of at least 10 hours.
2.2. Background 
In the completed Phase 2 study ARRAY-797-231, treatment with PF-07265803 resulted in 
rapid (<4 weeks), sustained increases in functional capacity in participants with LMNA-
related DCM. Improvements on the 6MWT compared to baseline, the primary endpoint, 
were mirrored by favorable changes in NT-proBNP levels, LVEF, and RV fractional area. 
PF-07265803 was generally well tolerated. The AEs for most participants were mild to 
moderate, and only 1 participant discontinued the study because of a treatment-related AE. 
Based on these clinical data, inhibition of p38 MAPK with the selective p38 inhibitor PF-
07265803 may provide a novel therapeutic approach and has the potential to fill an unmet 
medical need for the treatment of symptomatic LMNA-related DCM and is being evaluated in 
the Phase 3 study, C4411002.
2.2.1. Nonclinical Studies with PF-07265803
Detailed information regarding nonclinical studies of PF-07265803 is presented in the IB.


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2.2.2. Nonclinical Pharmacology
Numerous in vitro and in vivo studies were performed to evaluate and confirm the ability of 
PF-07265803 to interact with its intended target, p38 MAPK. In enzyme studies, PF-
07265803 inhibits p38a with a half-maximal inhibitory concentration (IC50) of 8.2 nM. In 
cellular studies, PF-07265803 is a potent inhibitor of p38-mediated downstream 
phosphorylation of HSP27 in HeLa cells with an IC50 of 17 nM. This compound has 
demonstrated little to no activity against over 201 enzymes, receptors, channels, and 
transporters.
Two in vivo murine models of LMNA-related DCM have allowed exploration of 
pathophysiologic mechanisms of disease progression and novel therapies for these 
conditions. In vivo studies have demonstrated that p38 MAPK is activated in murine models 
of LMNA-related DCM and that this activation of p38 MAPK precedes the development of 
cardiac dysfunction. PF-07265803 has been tested in the homozygous LMNA H222P model 
of EDMD with cardiomyopathy (EDMD2, MIM:181350) and in the homozygous LMNA 
N195K model of LMNA-related DCM, one of the original LMNA mutations linked to familial 
DCM with conduction defects1. These 2 nonclinical models bracket the spectrum of 
phenotypes (EDMD2: cardiac and skeletal muscle disease and DCM: cardiac disease only). 
Results from these studies confirm that treatment with PF-07265803 improves cardiac 
structure and function and reduces myocardial apoptosis. 
2.2.3. Nonclinical Pharmacokinetics and Metabolism
Multiple Phase 1 enzymes (CYPs, FMOs, amidases, and esterases) are involved in the 
metabolism of PF-07265803.
In vitro experiments indicated that PF-07265803 has moderate membrane permeability and 
may be a substrate for active efflux. PF-07265803 was moderately, but reversibly, bound to 
plasma proteins in vitro across mouse, monkey, and human plasma, as was AR00420643, the 
principal metabolite in vivo. PF-07265803 was predicted to have moderate-to-good stability 
in humans with respect to hepatic metabolism. The principal metabolite in vivo, 
AR00420643, is formed in in vitro incubations with liver microsomes, hepatocytes, plasma, 
or blood.
CYP-mediated metabolism was primarily by CYP3A4 and CYP2D6; however, these 
enzymes do not generate the principal metabolite in vivo. In vivo, other Phase 1 enzymes 
(FMOs, amidases, and esterases) are involved in the metabolism of PF-07265803, with the 
major mechanism of clearance thought to be through an unidentified hydrolase enzyme. PF-
07265803 and its metabolites were weak inhibitors of 5 major CYP isoforms in vitro 
(CYP2C19, CYP2C9, CYP1A2, CYP2D6, CYP3A4. PF-07265803 is a weak time-dependent 
inhibitor of CYP3A4. In in vitro studies in human hepatocytes, PF-07265803 and its
metabolites are inducers of CYP3A, while only metabolites AR00420643 and AR00428028 
induce CYP2B6.  Based on potential for mixed induction/inhibition of CYP3A4, the net 
effect of PF-07265803 interaction with drugs that are identified as CYP3A4 cannot be 
predicted. PF-07265803 has the potential to inhibit P-gp, but overall data suggest that PF-
07265803 is not a very potent P-gp inhibitor.


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PF-07265803 is not a substrate or inhibitor of recombinant MAO-A or MAO-B. 
AR00420643 is a principal metabolite from in vitro incubations with liver microsomes, 
hepatocytes, plasma, or blood. Other, less abundant, metabolites that are found in vitro or in 
vivo are a result of oxidative metabolism. No glucuronide conjugates were detected in 
hepatocyte incubations
2.2.4. Nonclinical Safety
Preclinical toxicological studies have indicated that PF-07265803 was well-tolerated at 
multiple doses of up to 100 mg/kg BID in rats and monkeys, with GI side effects and 
minimal clinical pathology changes. Associated histopathology changes were reversible in 
monkeys treated with doses of up to 100 mg/kg BID for 28 days. Histopathology findings in 
rats receiving PF-07265803 for 28 days were partially reversible with respect to severity and 
incidence at the 100 mg/kg BID (200 mg/kg/day) dose level. In the chronic dosing studies for 
up to 6 months in the rat and 9 months in the monkey at doses up to 30 mg/kg BID, there 
were no significant adverse histopathology findings. In general, administration of PF-
07265803 at doses of up to 30 mg/kg BID was tolerated in-life in rats and monkeys in 
chronic safety studies. Administration of PF-07265803 to rats for up to 3 months was 
associated with microscopic findings of skeletal muscle fiber changes, with no effects on 
clinical chemistry. These skeletal muscle changes were reversible after dosing cessation and 
with continued dosing for up to 6 months. Evidence of gastric irritation and increased gastric 
fluid secretion was observed in rats after a single oral dose of 100 mg/kg of PF-07265803. 
After treatment with PF-07265803 for multiple days, evidence of changes in stool 
consistency, ranging from loose stools to diarrhea was observed in monkeys. The GI 
disturbances were mild to moderate in the lower dose groups. In most dose groups, these GI 
effects resolved within 28 days after discontinuation of treatment with PF-07265803.
2.2.5. Clinical Overview
PF-07265803 is currently undergoing investigation in a Phase 3, multinational, randomized, 
placebo controlled study in which patients with symptomatic LMNA-related DCM (planned 
N=160) are randomized 1:1 to receive PF-07265803 400 mg BID or placebo.
PF-07265803 has been investigated in 12 completed clinical studies including a Phase 2 
study in patients with LMNA-related DCM and long-term rollover extension to the Phase 2.
In addition, 5 studies (one Phase 1b and four Phase 2) in patients with painful inflammatory 
conditions have been completed as well as five Phase 1 studies in healthy subjects.
In 5 clinical studies in healthy subjects, PF-07265803 demonstrated an acceptable safety 
profile when administered at single doses up to 900 mg QD, up to 400 mg/day for 14 days 
and up to 2000 mg/day for 7 days. In these studies, the most commonly reported AEs in 
subjects receiving PF-07265803 were dizziness, headache, diarrhea, nausea and acne; the 
incidence of these AEs was not clearly related to the PF-07265803 dose or to the duration of 
exposure.
Detailed information regarding clinical studies of PF-07265803 is presented in the IB.


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2.3. Benefit/Risk Assessment
PF-07265803 as a single dose is not expected to provide any clinical benefit to healthy 
participants. This study is designed primarily to generate safety, tolerability, and 
pharmacokinetic data for further clinical development.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-07265803 may be found in the Investigator’s Brochure, 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) PF-07265803
An identified risk associated with this study 
intervention is stomatitis. It is a common (≥1/100 to 
<1/10) event in the protocol population.
The potential risks are based on adverse events 
reported in early studies of PF-07265803 (ARRY-
371797).
AEs will be monitored on an ongoing basis. 
Instructions for managing potential cases of 
stomatitis can be discussed with the sponsor.
First time clinical administration of [14C]PF-
07265803

Single oral doses up to 900 mg of PF-
07265803 observed to be well tolerated;
single, oral dose of PF-07265803 in this study
(400 mg) represents is >2-fold lower

The maximum whole-body exposure of 
humans to radioactivity from a 100 μCi (3.7
MBq) PO dose of [14C] PF-07265803PF-
07265803, which was predicted using this 
rodent tissue distribution data was 0.39 mrem.
This was approximately 0.013% of the 3 to 5 
rem limit specified for whole-body exposure 
by the Code of Federal Regulations. The 
predicted exposure of the blood-forming
organs, gonads and 29 other tissues to 
radioactivity from an PO dose of 100 μCi of 
[14C]PF-07265803 to humans were each less 
than 1.0% of the 3 to 5 rem limits specified 
by the Code of Federal Regulations.

Administration of PF-07265803 will occur in
an inpatient setting under close supervision

Clear communication via ICD of negligible
risk with the [14C]PF-07265803 doses
administered relative to previously
administered oral doses.


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2.3.2. Benefit Assessment
The participants in this study are not expected to obtain any specific benefit beyond 
contributing to the process of developing new therapies in an area of unmet need. They will 
receive close monitoring of their safety via study procedures undertaken (eg. Physical 
examination, 12-lead ECGs, vital signs) which will occur as outlined in this protocol.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with PF-07265803 are justified by the anticipated benefits that may 
be afforded to participants with LMNA-related DCM.The overall benefit:risk profile for PF-
07265803 supports continued clinical development and the conduct of this study.
3. OBJECTIVES AND ENDPOINTS
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, open-label, single-period, single-center, non-randomized single oral dose 
study administering a liquid formulation with 400 mg of PF-07265803 containing 100 µCi of 
[14C]PF-07265803 to healthy male participants. Participants will be screened for participation 
in this study within 28 days before dosing on Day 1 to confirm that they meet the 
inclusion/exclusion criteria specified in Section 5.1.
Objectives
Endpoints
Primary: 
Primary: 
To characterize rate and extent of excretion of total
radioactivity in urine and feces, following a single
oral dose of [14C]PF-07265803 administered to
healthy adult male participants.
Mass Balance: cumulative recovery of urinary, 
fecal, and total excretion of radioactivity over time 
expressed as percentage of total radioactive dose 
administered.
To characterize metabolic profile and identify 
circulating and excreted metabolites following 
administration of a single oral dose of [14C]PF-
07265803 to healthy adult male participants.
Metabolic profiling/identification and determination 
of relative abundance of PF-07265803 and the 
metabolites of PF-07265803 in plasma, urine, and 
feces.
Secondary: 
Secondary: 
To quantify plasma concentrations and 
pharmacokinetic parameters of PF-07265803, its 
known circulating metabolites (PF-07327859, PF-
07327860, PF-07327890) and total radioactivity in 
plasma following administration of a single oral 
dose of [14C]PF-07265803 to healthy adult male 
participants.
Pharmacokinetic parameters AUClast, AUCinf, CL/F, 
Vz/F, Cmax, Tmax, and t½ to describe single dose PK 
of: PF-07265803 and where appropriate PF-
07327859, PF-07327860, PF-07327890.
Total radioactivity in plasma; PF-07265803, PF-
07327859, PF-07327860 and PF-07327890 
concentrations in plasma.
To evaluate safety and tolerability of a single oral 
dose of [14C]PF-07265803 administered to healthy 
adult male participants.
Safety endpoints including physical examinations, 
adverse events, clinical laboratory measurements, 
vital signs and ECG.


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The duration of this non-randomized Phase 1, open-label, single-center, single-dose study is 
approximately 7 days, with a 30-day safety follow up. The maximum period of confinement 
is expected to be 14 days. The minimum period of confinement is expected to be 3 days. 
Inpatient stay must be extended until >90% radioactive dose administered has been recovered 
or <1% is excreted in total (urine and feces) in any 24H period for two consecutive days. 
Maximum confinement will be 14 days
The expected duration of participation from Screening to the follow-up telephone contact 
will be approximately 5 weeks (minimum) to 8 weeks (maximum). Approximately 6 
participants will be enrolled to study intervention.
On Day-1, participants will be admitted in order to ensure that a group of 6 participants are 
dosed on Day 1.  The study will dose 6 adult male participants in order to ensure that at least
4 participants provide evaluable data. There are no plans to replace participants who are 
prematurely withdrawn.
4.2. Scientific Rationale for Study Design
This study will investigate the ADME of [14C]PF-07265803 and characterize plasma, fecal
and urinary radioactivity and identify any metabolites of [14C]PF-07265803 in male 
participants. Only nonsmokers will be enrolled to minimize any potential effect on 
metabolism by smoking. Oral dosing will be administered in the absence of food, as food has 
been shown to potentially decrease exposures of PF-07265803 and mimics how PF-
07265803 is being administered in the clinical program. Female subjects will be excluded to 
align with regulatory guidance. The ‘as low as (is) reasonably achievable’ (ALARA) 
principle prescribed by the FDA recommends that radiation exposure to subjects should be 
kept ALARA; therefore, if no specific reason exists to include females (ie, no available data 
suggest metabolism of the PF-07265803 is different in females versus males), then the 
radiation exposure to female subjects should ideally be kept at zero by not including females 
in this radioactivity study and only enrolling and dosing male subjects.
The potential risk of exposure to PF-07265803 in a sexual partner of a male participant in 
this study via ejaculate is possible, and therefore contraception (condom) use in male 
participants is warranted. The embryo-fetal developmental toxicity studies support the 
exclusion of pregnant women from clinical studies of PF-07265803 and the continued 
consideration that partners of study participants who are WOCBP use appropriate 
contraception in addition to condom use.
Banked Biospecimens will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.2.1. Choice of Contraception/Barrier Requirements 
Nonclinical studies suggest risk for severe manifestations of developmental toxicity at 
relevant clinical exposures for PF-07265803. Therefore, the use of a highly effective method 
of contraception is required (see Appendix 4).


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4.2.2. 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 more than 100 healthy participants and relatively healthy participants, 400 mg BID PF-
07265803 has proven to be a well-tolerated dose. In Study ARRAY-797-223, 41 participants 
with OA of the knee received 400 mg BID for 28 days, and this dosing regimen was well 
tolerated. In PD studies using clinical samples, 400 mg QD doses of PF-07265803 provided 
inhibition of PD markers p38 pathway inhibition (cytokines, CRP) of greater than 80% 
(Study ARRAY-797-101). In a clinical study of pain relief (Study ARRAY 797-221), 400 
mg QD of PF-07265803 provided maximal effect (associated with p38 MAPK inhibition), 
with 200 mg PF-07265803 providing significantly less benefit.
Doses utilized in the nonclinical studies of LMNA-related DCM, where positive effects on 
cardiovascular function and survival were demonstrated, provided exposure consistent with 
clinical exposure observed with 200 to 400 mg BID of PF-07265803. Study ARRAY-797-
231 was a Phase 2, two-arm study designed to investigate the efficacy and safety of 48 weeks 
of treatment with PF-07265803 in 12 stable participants with DCM secondary to LMNA
mutations. In this study, participants were alternately assigned to receive PF-07265803) at 
100 mg BID or 400 mg BID resulting in n = 6 per dose group. Participants in the 100 mg 
BID dose group were allowed to dose escalate to 400 mg BID after 24 weeks of treatment. 
Three participants dose escalated to 400 mg BID after their Week 24 visits and all 3 
remained at the 400 mg BID dose through Week 48. In this study PF-07265803 was 
generally well tolerated; most AEs were mild and only 1 participant discontinued due to a 
study intervention-related AE. There was also an apparent trend towards a dose response 
with greater efficacy observed with the 400 mg BID dose. Finally, the 400 mg BID dose of 
ARRY-371797 (PF-07265803) appeared to be associated with larger favorable changes in 
NT-proBNP concentration than the 100 mg BID dose in an analysis of aggregated mean 
change from baseline at all time points. 
4.3.1. Dosimetry Calculations
Dosimetry calculations for this proposed [14C]PF-07265803 ADME study in healthy, male
subjects are based on a tissue distribution study conducted with Sprague Dawley and Long
Evans male rats receiving an oral dose of PF-07265803.  Pharmacokinetic parameters and 
dosimetry projections were calculated for blood and tissues, including (but not limited to)
International Commission on Radiological Protection (ICRP) 30 critical tissues of bones, 
bone marrow, lungs, testes (gonads), and thyroid and the four tissues with highest 
concentrations of radioactivity in tissues including the gastrointestinal tract, liver, renal 
cortex, and renal medulla.
The maximum whole-body exposure of humans to radioactivity from a 100 μCi PO dose of 
[14C]PF-07265803, which was predicted using this rodent tissue distribution data, was
0.00039 rem. This was approximately 0.013% of the 3 to 5 rem limit specified for whole-
body exposure by the Code of Federal Regulations. The predicted exposure of the blood-


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forming organs, gonads and 29 other tissues to radioactivity from an PO dose of 100 μCi of 
[14C]PF-07265803 to humans were each less than 1.0% of the 3 to 5 rem limits specified by 
the Code of Federal Regulations.
The planned radioactive dose in the current study is 100 µCi of [14C]PF-07265803; based on 
ICRP 30 weighting factors, this would result in an effective dose to the whole body of 
0.39 mrem. The planned radioactive dose of approximately 100 μCi of [14C]PF-07265803 is 
expected to provide a sufficient radioactive signal to achieve the study objectives with 
minimal radiation risk to subjects.
4.4. End of Study Definition
A participant is considered to have completed the study if he has completed all phases of the 
study, including the last scheduled procedure shown in SoA (ie, follow-up phone call).
The end of the study is defined as the date of the last scheduled procedure shown in SoA for 
the last participant in the trial.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants must be male and ≥18 years of age at the time of signing the ICD.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1)
participants.
Type of Participant and Disease Characteristics:
2. Male participants who are overtly healthy as determined by medical evaluation 
including medical history, physical examination, laboratory tests, and ECG
monitoring.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests , lifestyle considerations , and other study procedures.


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Weight:
4. BMI of 18.0 to 32 kg/m2; and a total body weight >50 kg (110 lb).
Informed Consent:
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy, 
gastric bypass, duodenotomy, colectomy, history of inflammatory bowel disease).
3. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
or HCVAb. Hepatitis B vaccination is allowed.
4. Participants with a history of irregular bowel movements; e.g., less than 1 bowel 
movement per day, regular episodes of diarrhea or constipation, irritable bowel 
syndrome (IBS) or lactose intolerance.
5. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic (eg. Contact with positive case)] that may 
increase the risk of study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study.
Prior/Concomitant Therapy:
6. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention with the exception of moderate/potent CYP3A inducers which are
prohibited within 14 days plus 5 half-lives prior to the first dose of study
intervention..  (Refer to Section 6.8 Concomitant Therapy for additional details).
7. Current use of any prohibited concomitant medication(s) or those unwilling/unable to 
use a permitted concomitant medication(s). Refer to Section 6.8 Concomitant 
Therapy.


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Prior/Concurrent Clinical Study Experience:
8. 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
used in this study (whichever is longer). 
Diagnostic Assessments:
9. A positive urine drug test.
10. Screening and baseline supine BP >140 mm Hg (systolic) or >90 mm Hg (diastolic), 
following at least 5 minutes of supine rest. If BP is >140 mm Hg (systolic) or 
>90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of 
the 3 BP values should be used to determine the participant’s eligibility.
11. Screening and baseline standard 12-lead ECG that demonstrates clinically relevant 
abnormalities that may affect participant safety or interpretation of study results (eg,
baseline QTcF interval >450 msec, atrial fibrillation, complete LBBB, signs of an 
acute or indeterminate-age myocardial infarction, ST-T interval changes suggestive of 
myocardial ischemia, second- or third-degree AV block, or serious bradyarrhythmias 
or tachyarrhythmias). If the baseline uncorrected QT interval is >450 msec, this 
interval should be rate-corrected using the Fridericia method and the resulting QTcF 
should be used for decision making and reporting. If QTcF exceeds 450 msec, or 
QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of 
the 3 QTcF or QRS values should be used to determine the participant’s eligibility.
Computer-interpreted ECGs should be overread by a physician experienced in 
reading ECGs before excluding a participant.
12. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 

AST or ALT level ≥1.5 × ULN;

Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is≤ULN.
Other Exclusions:
13. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake 
should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce 
(30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
14. Positive urine drug screen or cotinine at screening or check-in, and positive urine 
alcohol at check-in.


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15. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
16. History of sensitivity to heparin or heparin-induced thrombocytopenia.
17. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
18. 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.
19. Subjects with exposure to significant diagnostic or therapeutic radiation (eg, serial 
x-ray, computed tomography scan, barium meal) or current employment in a job 
requiring radiation exposure monitoring within 12 months prior to check-in.
20. Subjects who have participated in more than 3 radiolabeled drug studies in the last 
12 months (previous study to be at least 4 months prior to check-in to the study site 
where exposures are known to the investigator, or 6 months prior to check-in to the 
study site for a radiolabeled drug study where exposures are not known to the 
investigator). The total 12-month exposure from this study and a maximum of 2 other 
previous radiolabeled studies within 4 to 12 months prior to this study will be within 
the Code of Federal Regulations (CFR) recommended levels considered safe, per 
United States (US) Title 21 CFR 361.1.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 8 hours prior to the collection of the predose 
PK sample.

Water is permitted until 1 hour prior to study intervention administration.  Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices—see below) may be 
consumed with meals and the evening snack.

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.


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
Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos) from 7 days prior to the first dose of study 
intervention until collection of the final PK blood sample.  

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.

To help assure regularity in bowel movements, nutritional composition should 
contain at least 15 g of fiber per 1000 kcal or fiber capsules containing the equivalent 
amount of fiber may be administered daily (beginning at least 8 hr after dosing).
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample.  

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample. Participants may undergo urine alcohol test at the discretion 
of the investigator.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
3 months prior to dosing and during confinement in the CRU.
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing;
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) 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 


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the last visit. In addition, the investigator or designee will instruct the participant to call 
immediately if the selected contraception method is discontinued 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. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-07265803.
6.1. Study Intervention(s) Administered
One batch of GMP [14C]PF-07265803 API will be prepared with the oral dose being fully 
radio-diluted (100 µCi / 400 mg (~0.25 µCi/mg)) to the overall specific activity requirements 
for oral dosing. A bulk bottle of this will be shipped to the CRU from the radiochemical 
vendor.
[14C]PF-07265803 components for oral administration will be supplied by Pfizer as bulk API 
and, where necessary, bulk excipients for the manufacture of the oral formulation. The final 
product composition and presentation will be detailed in a separate Extemporaneous 
Dispensing Record (EDR) for the [14C] labeled oral formulation.
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive study intervention
at approximately 0800 hours (plus or minus 2 hours). Investigator site personnel will 
administer study intervention according to the EDR.
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 


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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. 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 for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, 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 definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the EDR/Roles and Responsibilities Matrix.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. See the EDR and the IP manual for storage conditions of the study intervention once 
reconstituted and/or diluted.
7. The investigator, institution, or the head of the medical institution (where applicable) 
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 as detailed in the IP manual.
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 as detailed in the IP manual.
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
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 


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staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant in accordance with this protocol and the IP Manual. Local health authority 
regulations or investigator site guidelines may use alternative terms for these activities.
PF-07265803 oral dosing formulation will be prepared in the CRU by 2 operators, 1 of whom 
is a pharmacist. Details of dose preparation will be given in a separate EDR located in the IP 
Manual. Prepared doses will be provided in unit dose containers and labeled in accordance 
with Pfizer regulations and the investigator site’s labeling requirements.
6.3. Measures to Minimize Bias: Randomization and Blinding
This study is an open-label study.
6.3.1. Allocation to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
6.4. Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
When participants are dosed at the site, 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. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5. Dose Modification
Not applicable.
6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. Treatment of Overdose
For this study, any dose of PF-07265803 greater than 400 mg (+/- 10% based on the 
preparation of the final oral dosing formulation) within a 24-hour time period [±2 hours] 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/treating physician should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-07265803 (whichever 
is longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within as soon as possible from the date of the 
last dose of study intervention if requested by the medical monitor (determined on a 
case-by-case basis).
6.8. Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of 
study intervention with the exception of moderate/potent CYP3A inducers which are
prohibited within 14 days plus 5 half-lives prior to the first dose of study intervention. 
Limited use of nonprescription medications that are not believed to affect participant 
safety or the overall results of the study may be permitted on a case-by-case basis (e.g. to 
treat an AE) following approval by the sponsor. 
If an individual participant has not experienced a bowel movement within a 36 – 48 hour 
window following dose administration, fluid intake should be increased and 
administration of a mild laxative (e.g., prune juice, milk of magnesia or a mild stool 
softener) should be implemented, with the goal to facilitate at least one daily bowel 
movement. A mild laxative may also be used prior to dosing to assist with collection of a 
pre-dose fecal sample, irrespective of the time of last bowel movement.
Acetaminophen/paracetamol may be used at doses of ≤1 g/day.
Treatments taken within 28 days before the first dose of study intervention will be
documented as a prior treatment. Treatments taken after the first dose of study intervention
will be documented as concomitant treatments.
6.8.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with PF-07265803; standard medical 
supportive care must be provided to manage the AEs. 


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Since this is a single-dose study, this section is not applicable.
7.1.1. Potential Cases of Acute Kidney Injury
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness.
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants in a given period are noted to have 2 consecutive 
SCr results of ≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the finding may be 
considered an adverse drug reaction should be undertaken.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;

Lost to follow-up;

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. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.  
If a participant withdraws from the study, he may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of 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 him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from 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 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to 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;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 


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address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
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.
Healthy participants will be screened up to 28 days prior to dosing to determine eligibility. If 
the time between screening and dosing exceeds 28 days as a result of unexpected delays (eg, 
delayed drug shipment), then participants do not require rescreening if the laboratory results 
obtained prior to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, banked biospecimens, may 
be used without repeat collection, as appropriate.
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 may 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 he or she has 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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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 
312 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 500 mL during any period of 56 consecutive 
days.
Table 1.
Blood Sampling Volume
Sample Type
Sample
Volume
(mL)
Number of Sampling Times
Total
Volume
(mL)
Screening
Study Period
Clinical Laboratory Tests
16
1
16
Clinical Laboratory Tests
8
2
16
PK of PF-07265803
4
15
60
Total radioactivity (post-dose)
4
14
56
Total radioactivity (pre-dose)
10
1
10
Metabolite ID
10
15
150
Banked Biospecimen for DNA – Prep D1
4
1
4
TOTAL
312
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
There are no efficacy assessments included in this protocol.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 


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Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
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 8.3.1 to 8.3.3.
8.2.2. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
8.2.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads should be collected at times specified in the SoA
section of this protocol using an ECG machine that automatically calculates the heart rate and 
measures PR, QT, and QTc intervals and QRS complex. Alternative lead placement 
methodology using torso leads (eg, Mason-Likar) should not be used given the potential risk 
of discrepancies with ECGs acquired using standard limb lead placement. All scheduled 
ECGs should be performed after the participant has rested quietly for at least 5 minutes in a 
supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥60 msec from the baseline (predose) and is 
>450 msec; or b) an absolute QT value is ≥500 msec for any scheduled ECG.  If either of 
these conditions occurs, then 2 additional ECGs will be collected approximately 2 to 
4 minutes apart to confirm the original measurement. If the QTc values from these repeated 
ECGs remain above the threshold value, then a single ECG must be repeated at least hourly 
until QTc values from 2 successive ECGs fall below the threshold value that triggered the 
repeat measurement.


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If either of these conditions occurs, then a single ECG measurement must be repeated at least 
hourly until QTc values from 2 successive ECGs fall below the threshold value that triggered 
the repeat measurement.
If a) a postdose QTcF interval remains ≥60 msec from the baseline and is >450 msec; or b) 
an absolute QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator); or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring (e.g. holter monitor) and 
consultation with a cardiologist. A cardiologist should be consulted if QTcF intervals do not 
return to less than the criteria listed above after 8 hours of monitoring (or sooner, at the 
discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. 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. 
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 relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which 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 significantly abnormal during 
participation in the study or within 28 days 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 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 
drug-induced liver injury.


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Participants may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention.
8.2.5. COVID-19 specific assessments
Participants will be tested for SARS-COVID-19 infection by PCR at screening and at the 
time of being admitted to the clinic for confinement. Additional testing may be required by 
local regulations or by the Principal Investigator.
8.3. 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 (see Section 7.1). 
During the active collection period as described in Section 8.3.1, 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.
8.3.1. 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 the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.


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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 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.
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 he/she 
considers 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.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 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 it being available.
8.3.1.2. 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 8.3.1, 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.
Reporting of AEs and SAEs for participants who fail screening are participant to the CRF 
requirements as described in Section 5.4.
8.3.2. 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.
8.3.3. 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).


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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 
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 given in Appendix 3.
8.3.4. 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.
8.3.5. 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 exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:  

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.


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
A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:  

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then exposes 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 a 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 28 days after 
the last dose.

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 
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 


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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.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female 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 ingestion, inhalation, or skin contact.  
The investigator must report exposure during breastfeeding 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 exposure during 
breastfeeding 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 exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. 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.
8.3.6. Cardiovascular and Death Events
Not applicable.


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8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.9.1. 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.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

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.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
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.


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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Pharmacokinetics 
The samples collected for PK (non-radiolabeled PF-07265803 concentrations), radioactivity
(total 14C) and/or metabolite profiling assessment must be processed and shipped as indicated
in the instructions provided to the investigator site to maintain sample integrity. Any
deviations from the 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. Samples collected for PK, radioactivity
and/or metabolite profiling/ID 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. Genetic analysis will not 
be performed on these samples unless consent for this was included in the informed consent.  
Participant confidentiality will be maintained.
8.4.1. Plasma Analysis of Non-Radiolabeled PF-07265803
Blood samples of approximately 4 mL, will be collected into appropriately labeled tubes 
containing K2EDTA at times specified in the SoA of the protocol to provide approximately
1.5 mL plasma, will be collected for measurement of plasma concentrations of PF-07265803
and metabolites as specified in the Bioanalytical Plan. 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 
concetrations of “cold” PF-07265803 will be measured by a validated LCMS method.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) 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. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing 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. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples collected for analyses of  plasma concentration 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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8.4.2. Metabolite Profiling/ID
8.4.2.1. Plasma for Metabolite Profiling/ID
Blood samples (10 mL) to provide plasma, will be collected into appropriately labeled tubes
containing K2EDTA at times specified in the SoA section of the protocol. Handling of 
plasma samples, including procedures to stabilize metabolites will be addressed in the 
Laboratory Manual. 
8.4.2.2. Urine for Metabolite Profiling/ID
Urine will be collected over intervals described in the SoA section of the protocol. Handling 
of urine samples, including procedures to stabilize metabolites will be addressed in the 
Laboratory Manual.

Prior to dosing on Day 1 at any time, each subject must empty his urinary bladder, and
an aliquot from this urine will serve as the “urine blank”. Approximately 10 mL of urine 
will be collected predose for analysis. 

Following dosing on Day 1, each void post dose will be collected and saved in a 
container and stored in refrigerated conditions (ie, 2-8°C) for the duration of the
collection interval. An aliquot of approximately 100 mL from each collection interval 
will be withdrawn for measurement of metabolite concentrations/profiling.

At the end of the collection interval, subjects will attempt to empty bladder prior to the 
start of the next interval with this void included as part of the interval collection;

If end of urine collection interval coincides with a meal, subjects will attempt to void
prior to initiation of the meal; in such cases, so long as the actual time of forced void
is recorded, for practical reasons, the fact that this collection may be more than 30-
minutes (and up to 45-minutes) prior to end of collection interval is acceptable and
will not be considered as protocol deviation.

The urine container will be mixed thoroughly and total weight of the urine collected
during the interval recorded
8.4.2.3. Feces for Metabolite Profiling/ID

All feces will be collected over intervals described in the SoA section of the protocol. 
A pre-dose sample will also be collected. When feces are being collected, all  toilet 
paper that come in contact with the subject’s feces will also be collected for possible 
analysis in appropriately labelled containers stored at approximately -20°C.  In the 
event of diarrhea during the study, all diarrhea including any swabbing and 
contaminated linen should be collected, labeled, and stored in appropriate containers 
at approximately -20°C for possible analysis of radioactivity. Prior to dosing on Day
1 at any time, each subject must complete a fecal void. A mild laxative may be used 
to promote a bowel movement and complete fecal void to improve radiolabel material 
recovery. Approximately 15 g of feces will be collected predose for analysis.For 


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each collection interval, an aliquot of 40 g will be withdrawn for metabolic
identification and profiling. A mild laxative may be used to promote a bowel 
movement in concordance with the guidance in Section 6.8. Detailed sample handling 
instructions will be provided separately to the site before the start of the study.
8.4.3. Radioactivity
8.4.3.1. Sample Collection
It is extremely important to quantitatively collect all scheduled blood, urine, feces and 
emesis samples.  The separate collection of urine and feces is critical to the success of this 
study.  If urine and feces becomes mixed at any collection, note the weight and add the 
feces-contaminated urine to the feces collection.  Samples missed or lost for any reason
should be documented on the case report forms (CRFs).
8.4.3.2. Plasma/Blood Sample Collection for Total Radioactivity
Blood samples (4 mL) to provide plasma (10 mL predose), will be collected into 
appropriately labeled tubes containing K2EDTA at times specified in the SoA section of the 
protocol and submitted for analysis of total radioactivity. Detailed sample handling 
instructions will be provided separately to the site before the start of the study and described 
in the Laboratory Manual.
8.4.3.3. Urine Sample Collection for Total Radioactivity
Urine will be collected over intervals described in the SoA. A predose aliquot of 10 mL will 
be collected. Following dosing, a 25 mL aliquot from each post dose collection interval will 
be withdrawn for total radioactivity analysis. Detailed sample handling instructions will be
provided separately to the site before the start of the study and described in the Laboratory 
Manual.
8.4.3.4. Fecal Sample Collection for Total Radioactivity
Feces will be collected over intervals described in the SoA. A predose aliquot of 15 g will be 
collected. For each post dose collection interval, an aliquot of 100 g will be withdrawn for 
total radioactivity measurements. Detailed sample handling instructions will be provided 
separately to the site before the start of the study and described in the Laboratory Manual.
8.4.3.5. Emesis Sample Collection for Total Radioactivity
If emesis occurs within the first 24 hours post dosing, vomitus will be collected for potential 
analysis of radioactivity. Approximately 4 mL should be collected if emesis occurs. All 
emesis discharge including any swabbing, contaminated linens  and facial tissues used to 
collect bodily discharge (eg, nose bleeding clean-up tissue and any emesis related clean-up) 
should be collected and stored in a labeled emesis bag at minimally -20°C for possible 
analysis of radioactivity.  Detailed sample handling instructions will be provided separately 
to the site before the start of the study.


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8.5. Genetics
8.5.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.5.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1will be collected according to the 
SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
banked samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in Laboratory Manual.
8.6. Biomarkers
Biomarkers are not evaluated in this study.
8.6.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.6.2. Specified Protein Research 
Specified protein research is not included in this study.
8.6.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. 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 a 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.


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9.1. Statistical Hypotheses
No statistical hypothesis is tested in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined in the table below:
Table 2.
Analysis Sets
Participant Analysis 
Set
Description
Enrolled
"Enrolled" means all participants who complete the informed 
consent process.
Safety Analysis Set
All participants assigned to study intervention and who take at 
least 1 dose of study intervention. Participants will be analyzed 
according to the product they actually received.
PK Concentration
The PK concentration population for PF-07265803 is defined 
as all participants who receive at least 1 dose of PF-07265803 
and who have at least 1 measurable concentration of PF-
07265803. The PK concentration population for 14C is defined 
as all participants dosed with [14C]PF-07265803, who have at 
least one 14C measurement.
Extent of Excretion
Extent of excretion population is defined as all participants
who have received 1 dose of [14C]PF-07265803 and who have
evaluable total radioactivity concentration (urinary and fecal) 
data and who had no protocol deviations or AEs (such as 
vomiting of the dose, diarrhoea or severe constipation) that 
may have affected the extent of excretion analysis.
PK Parameter
The PK parameter analysis population for PF-07265803 is
defined as all participants treated who have at least 1 of the PF-
07265803 PK parameters of interest. The PK parameter 
analysis population for 14C analysis is defined as all 
participants treated who have at least one of the 14C parameters 
of interest. The PK concentration and PK parameter analysis
sets may differ.
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.
9.3.1. General Considerations
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 


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data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints.
9.3.2. Primary Endpoint(s)
Radioactivity excreted in urine and/or feces will be reported as the percentage of the 
administered radioactivity excreted at each time interval, cumulatively through that interval 
and the total percent of dose recovered in urine and/or feces.
Percent recovery and cumulative recovery of total radioactivity in urine, feces and emesis (if 
any) will be determined based on total administered dose.
Individual participant and median data profiles will be graphically presented for the
cumulative recovery of radioactivity in urine, feces and their combination. The total 
recovery of radioactivity in urine, feces and their combination will be listed and summarized
using descriptive statistics. Where possible, the rate of excretion of radioactivity will be
estimated.
9.3.2.1. Metabolic Profiling/Identification
Plasma, urine and fecal samples will be analyzed for metabolites and/or chiral inversion
of PF-07265803. Major metabolites and/or stereoisomers of PF-07265803 in plasma, 
urine, and feces following oral dose of [14C] PF-07265803 will be identified.  
Contributions of each major metabolite to total radioactivity recovered and to circulating 
radioactivity in plasma will be approximated. Results of the metabolic profiling analysis
will be detailed in a separate report and will be summarized within the CSR.
9.3.3. Secondary Endpoint(s)
9.3.3.1. Pharmacokinetic Parameters
9.3.3.1.1. Plasma
The PK parameters for PF-07265803 and for known circulating metabolites PF-07327859, 
PF-07327860, PF-07327890 and total radioactivity will be derived following a single dose 
administration of [14C] PF-07265803, where appropriate, from the concentration-time
profiles as outlined below. Additional PK parameters may be included at the discretion of 
the sponsor and described in the Statistical Analysis Plan.
The PF-07265803 (including  circulating metabolites PF-07327859, PF-07327860, PF-
07327890) and total radioactivity (plasma) concentrations and parameters (below) will 
be listed and summarized using descriptive statistics. Individual subject and median
concentration-time profiles will be graphically presented.


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Table 3.
Pharmacokinetic Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the plasma
concentration-time profile from
time zero to time of the last 
quantifiable concentration 
Linear/Log trapezoidal rule
AUCinf a
Area under the concentration-
time curve from time zero to 
infinity
AUClast + (Clast*/kel), where Clast* is the
predicted plasma concentration at the
last quantifiable time point estimated 
from the log-linear regression analysis
Cmax
Maximum observed 
concentration
Observed directly from data
Tmax
Time of maximum observed 
concentration
Observed directly from data as time of
first occurrence
t½a
Terminal elimination half-life
Loge(2)/kel, where kel is the terminal
phase rate constant calculated by a linear 
regression of the loglinear concentration
time curve. Only those data points
judged to describe the terminal loglinear
decline will be used in the regression
CL/Fa (oral)
Apparent clearance of drug from 
e.g.,plasma, for extravascular 
routes of administration
Dose/AUCinf
Vz/Fa (oral)
Apparent volume of distribution, 
estimated from terminal phase, 
for extravascular dosing
Dose/(AUCinf*kel)
a. Where appropriate
9.3.4. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants. Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 


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described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
9.3.4.1. Electrocardiogram Analyses
Absolute value and changes from baseline for the ECG parameters QT interval, heart rate, 
QTc interval, PR interval, and QRS complex will be listed by treatment and time.
9.3.4.2. Other Analyses
Pharmacogenomic or biomarker data from Banked Biospecimens 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
No formal interim analysis will be conducted for this study. As this is an open-label 
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development. 
9.5. Sample Size Determination
A sample size of 6 male participants has been chosen based on the industry standard sample 
size for ADME Mass Balance studies and radiolabeled tracer studies2. This sample size was 
not chosen based on any empirical data or hypothesis testing criteria. The sample size has 
been selected to ensure that at least 4 participants provide evaluable data; with intent not to 
replace participants who prematurely withdraw (or offer non-evaluable or partially evaluable 
data).


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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 (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), 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 subinvestigators 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 his/her 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 his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant  is fully informed about his 
or her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date 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.
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.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use a DMC or IOC.
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, and/or 
www.pfizer.com, and other public registries 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.


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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
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data sharing
Pfizer provides researchers secure access to patient-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 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
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.


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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 clinical study 
report.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data 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 noncompliance 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.
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 


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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.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes source data and its origin can be found in Study Monitoring 
Plan, 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.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the 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.
If the sponsor decides to terminate the study for a reason unrelated to the safety of PF-
07265803, participants may continue to receive PF-07265803 per the investigator’s 
judgement and protocol-specified safety assessments will continue to be performed for these 
participants until the end of study as defined in Section 4.4. The following non-safety-related 
study procedures and assessments may be stopped upon written notification from the 
sponsor:
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
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications,
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.


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For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study 
documentation/study portal or other electronic system. 
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 
the time of informed consent. The ECC contains, at a minimum, (a) protocol and study 
intervention identifiers, (b) participant’s study identification number, (c) site emergency 
phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site.


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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.
Table 4.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubinc
Alkaline phosphatase
Uric acid
Albumin
Total protein
Local Dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy and 
Culturea
COVID-19 testing
At screening only:

Hepatitis B surface antigen

Hepatitis C antibody

Human immunodeficiency 
virus
At screening and admission
(check-in) only:

Urine cotinine

Urine drug screeningb
At admission (check-in) only:

Urine alcohol
a. Microscopy will be conducted if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
Culture only conducted if bacteriuria present upon microscopy.
b.The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific).
c. Direct and indirect bilirubin will be measured if total bilirubin is elevated
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.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.


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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 either an 
increase in 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 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.


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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 
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.


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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 non-pathogenic, is considered serious.  
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.
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. 


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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/SAEs associated 
with exposure during 
pregnancy or breastfeeding
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 non-participant (not 
involving EDP or EDB).
None.  Exposure to a study 
non-participant 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 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. 

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 


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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: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.

Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.

Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self 
care ADL. Self care ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden.
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 


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administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has 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 his/her 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.

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 


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of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

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 data collection tool 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 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, 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
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 30 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s) plus an additional 90 days (a spermatogenesis cycle): 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent;
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

Use of an additional highly effective contraceptive method with a failure rate of 
<1% per year as described below in Section 10.4.4 for a female partner of 
childbearing potential.
10.4.2. Female Participant Reproductive Inclusion Criteria
Females are not eligible to enroll in this study
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. Premenarchal.
2. 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 an alternate 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.
3. 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 old 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 nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they 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.
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 (eg, bilateral tubal ligation).


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5. Vasectomized partner.

A 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;

Intravaginal;

Transdermal;
7. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.
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.
One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent:

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
Genetics (specified analyses) are not evaluated in this study.


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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 TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample). In rare instances, by the time TBili 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 TBili 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 TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili 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 TBili 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 TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili 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 TBili 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 
TBili 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: 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 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec 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 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

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).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 


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PFIZER CONFIDENTIAL
Page 74
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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PFIZER CONFIDENTIAL
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10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI  
Concomitant medications are not allowed in this study
10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
6MWT
six minute walk time distance
Abs
absolute
ADE
adverse device effect
ADL
activities of daily living
ADME
absorption, distribution, metabolism, excretion
AE
adverse event
AESI
adverse events of special interest
ALARA
as low as reasonably achievable
ALT
alanine aminotransferase
API
active pharmaceutical ingredient
AST
aspartate aminotransferase
AUC
area under the curve
AUCinf
area under the concentration-time curve from time zero to infinity
AUClast
area under the  concentration -time curve from zero to time of last 
measurable concentration
AV
atrioventricular
BA
bioavailability
BBS
Biospecimen Banking System
BE
bioequivalence
BID
twice-a-day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
Clast
last observable concentration
CL/F
Apparent clearance of drug from e.g.,plasma, for extravascular 
routes of administration
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization


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Abbreviation
Term
CRP
c-reactive protein
CRU
clinical research unit
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial; computed tomography
CYP
cytochrome P450
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DMD
Duchenne muscular dystrophy
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDMD
Emery-Dreifuss Muscular Dystrophy
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FMO
flavin monooxoygenase
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GMP
Good Manufacturing Practice
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
HSP28
heat shock protein 28
IB
Investigator’s Brochure
IBS
irritable bowel syndrome
IC50
concentration corresponding to 50% inhibition
ICD
informed consent document
ICH
International Council for Harmonisation of Technical Requirements 


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Abbreviation
Term
for Pharmaceuticals for Human Use
ID
identification
ICRP
International Commision on Radiological Protection
IND
Investigational New Drug 
INR
international normalized ratio
IOC
independent oversight committee
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IV
intravenous
Kel
Rate constant for terminal phase
LBBB
left bundle branch block
LFT
liver function test
Loge
natural logarithm
LVEF
left ventricular ejection fraction
MAPK
mitogen-activated protein kinase
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
msec
millisecond
N/A
not applicable
NT-proBNP
N-terminal pro b-type natriuretic peptide
p38α MAPK
p38-alpha mitogen activated protein kinase
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic(s)
PO
oral
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
once daily
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
QTL
quality tolerance limit
qual
qualitative
RNA
ribonucleic acid
RV
right ventricular
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan


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Abbreviation
Term
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
THC
tetrahydrocannabinol
Tmax
time of maximum observed concentration
t1/2
terminal elimination half-life
TOC
table of contents
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
Vz/F
Apparent volume of distribution, estimated from terminal phase, for 
extravascular dosing
WBC
white blood cell
WOCBP
woman/women of childbearing potential


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11. REFERENCES
1.
Fatkin D, MacRae C, Sasaki T et al. Missense mutations in the rod domain of the lamin 
A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J 
Med. 1999;341(23):1715-24.
2.
Penner N, Klunk L, Prakash C. Human Radiolabeled mass balance studies: objectives, 
otilities and limitations. Biopharm Drug Dispos. 2009;30:185–203.

SAP_001.pdf: 
Protocol C4411010 (PF-07265803) Statistical Analysis Plan
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PFIZER CONFIDENTIAL
Protocol C4411010
A PHASE 1, OPEN-LABEL, SINGLE-PERIOD, 
NON-RANDOMIZED STUDY TO EVALUATE THE 
PHARMACOKINETICS, EXCRETION, MASS BALANCE AND 
METABOLISM OF [14C]PF-07265803 ADMINISTERED 
ORALLY TO HEALTHY ADULT MALE PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
Date:
18-Feb-2022
PPD


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PFIZER CONFIDENTIAL
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1.0
February 18, 2022
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD


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PFIZER CONFIDENTIAL
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................5
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................7
2.2.1. Primary Objectives .......................................................................................7
2.2.2. Secondary Objective.....................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................7
5.1.1. PK Concentration Analysis Set ....................................................................7
5.1.2. PK Parameter Analysis Set...........................................................................8
5.1.3. Extent of Excretion Analysis Set..................................................................8
5.2. Pharmacodynamic Analysis Set................................................................................8
5.3. Safety Analysis Set....................................................................................................8
5.4. Other Analysis Sets ...................................................................................................8
5.5. Treatment Misallocations..........................................................................................8
5.6. Protocol Deviations...................................................................................................8
5.6.1. Deviations Assessed Prior to Randomization...............................................8
5.6.2. Deviations Assessed Post-Randomization....................................................9
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .......................................................................................................9
6.3. Other Endpoints.........................................................................................................9
6.3.1. PK Endpoints................................................................................................9
6.3.2. Mass Balance..............................................................................................10


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PFIZER CONFIDENTIAL
6.3.3. Metabolic Profiling and Metabolite Identification .....................................10
6.3.4. PD Endpoints..............................................................................................10
6.4. Covariates................................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................10
7.1. Concentrations Below the Limit of Quantification.................................................11
7.2. Deviations, Missing Concentrations and Anomalous Values .................................11
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................11
8.1. Statistical Methods ..................................................................................................11
8.2. Statistical Analyses .................................................................................................11
8.2.1. Pharmacokinetic Analysis ..........................................................................11
8.2.2. Mass Balance..............................................................................................13
8.3. Safety Analysis........................................................................................................13
8.3.1. Treatment and Disposition of Subjects.......................................................13
8.3.2. Demographic and Clinical Examination Data............................................14
8.3.3. Discontinuation(s).......................................................................................14
8.3.4. Adverse Events...........................................................................................14
8.3.5. Laboratory Data..........................................................................................14
8.3.6. Vital Signs Data..........................................................................................14
8.3.7. ECG Data....................................................................................................14
8.3.8. Other Safety Data .......................................................................................14
8.3.9. Concomitant Treatments.............................................................................15
8.3.10. COVID-19 Specific Assessments.............................................................15
8.3.11. Screening and Other Special Purpose Data ..............................................15
9. REFERENCES ....................................................................................................................15
10. APPENDICES ...................................................................................................................15
LIST OF TABLES
Table 1.
Noncompartmental PK Parameters of Plasma..........................................10
Table 2.
PK Parameters to be Summarized Descriptively......................................12


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PFIZER CONFIDENTIAL
LIST OF FIGURES
None.
APPENDICES
None. 


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
PF-07265803 (formerly known as known as ARRY-371797) is a potent and selective, oral
small molecule inhibitor of the α isoform of p38 MAPK. Mutations in the LMNA gene
encoding nuclear lamina components cause nuclear envelope dysfunction leading to altered
nuclear activity, impaired structural dynamics and aberrant cell signaling including 
activation of p38α MAPK signaling pathways. Structural alterations in the nuclear envelope 
and connected cytoskeleton resulting from LMNA mutations make cardiomyocytes highly
susceptible to damage even by physiological mechanical stress, leading to a disease specific
maladaptive activation of the p38α MAPK. Up-regulation of p38 MAPK has been observed
in the hearts of animal models and adult patients with LMNA-related DCM compared to 
wild-type/healthy individuals. Inhibition of p38 MAPK in this disease setting may halt 
aberrant apoptosis and cardiac remodeling resulting in improved cardiac function.
2.1. Study Design
This is a Phase 1, open-label, single-period, single-center, non-randomized single oral dose
study administering a liquid formulation with 400 mg of PF-07265803 containing 100 μCi of
[14C]PF-07265803 to healthy male participants. Participants will be screened for 
participation in this study within 28 days before dosing on Day 1 to confirm that they meet 
the inclusion/exclusion criteria specified in protocol Section 5.1.
The duration of this non-randomized Phase 1, open-label, single-center, single-dose study is
approximately 7 days, with a 30-day safety follow up. The maximum period of confinement is 
expected to be 14 days. The minimum period of confinement is expected to be 3 days.
Inpatient stay must be extended until >90% radioactive dose administered has been 
recovered or <1% is excreted in total (urine and feces) in any 24H period for two 
consecutive days. Maximum confinement will be 14 days.
The expected duration of participation from Screening to the follow-up telephone contact will 
be approximately 5 weeks (minimum) to 8 weeks (maximum). Approximately 6 participants 
will be enrolled to study intervention.
On Day-1, participants will be admitted in order to ensure that a group of 6 participants are
dosed on Day 1. The study will dose 6 adult male participants in order to ensure that at least
4 participants provide evaluable data. There are no plans to replace participants who are
prematurely withdrawn.


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2.2. Study Objectives
2.2.1. Primary Objectives

To characterize rate and extent of excretion of total radioactivity in urine and feces, 
following a single oral dose of [14C]PF-07265803 administered to healthy adult male 
participants.

To characterize metabolic profile and identify circulating and excreted metabolites 
following administration of a single oral dose of [14C]PF-07265803 to healthy adult 
male participants.
2.2.2. Secondary Objective

To quantify plasma concentrations and pharmacokinetic parameters of 
PF-07265803, its known circulating metabolites (PF-07327859, PF-07327860, 
PF-07327890) and total radioactivity in plasma following administration of a single 
oral dose of [14C]PF-07265803 to healthy adult male participants.

To evaluate safety and tolerability of a single oral dose of [14C]PF-07265803 
administered to healthy adult male participants.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. PK Concentration Analysis Set
The PK concentration population for PF-07265803 is defined as all participants who receive 
at least 1 dose of PF-07265803 and who have at least 1 measurable concentration of 
PF-07265803 (Or its known circulating metabolites PF-07327859, PF-07327860, 
PF-07327890). The PK concentration population for 14C is defined as all participants dosed 
with [14C]PF-07265803, who have at least one 14C measurement.


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5.1.2. PK Parameter Analysis Set
The PK parameter analysis population for PF-07265803 is defined as all participants treated 
who have at least 1 of the PF- 07265803(Or its known circulating metabolites PF-07327859, 
PF-07327860, PF-07327890) PK parameters of interest. The PK parameter analysis 
population for 14C analysis is defined as all participants treated who have at least one of the 
14C parameters of interest. The PK concentration and PK parameter analysis sets may differ.
5.1.3. Extent of Excretion Analysis Set
Extent of excretion population is defined as all participants who have received 1 dose of 
[14C]PF-07265803 and who have evaluable total radioactivity concentration (urinary and 
fecal) data and who had no protocol deviations or AEs (such as vomiting of the dose,
diarrhoea or severe constipation) that may have affected the extent of excretion analysis.
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All participants assigned to study intervention and who take at least 1 dose of study 
intervention. Participants will be analyzed according to the product they actually received.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
This is a nonrandomized study. All subjects will receive the same treatment.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg, lack of compliance with 
dosing) may be excluded from the PK analysis. At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 5.1 and 5.2 of the protocol.


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5.6.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure. Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
An adverse event will be considered a Treatment-emergent Adverse Event (TEAE) if the 
event started during the effective duration of treatment. All events that starts on or after the 
first dosing day and time/start time, if collected, but before the last dose plus the lag time 
(28 days) will be flagged as TEAEs. The algorithm will not consider any event that started 
prior to the first dose date. Any event occurring following start of treatment or increasing in 
severity will be counted as treatment emergent.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

adverse events,

laboratory data,

vital signs data,

ECG results.
6.3. Other Endpoints
6.3.1. PK Endpoints
Plasma PK Parameters
Blood samples will be collected according to the Schedule of Activities given in the protocol.
Plasma samples will be analyzed for concentrations of PF-07265803 and its known 
circulating metabolites PF-07327859, PF-07327860, PF-07327890 and total radioactivity.
PK parameters will be determined from concentration-time data for plasma. The following 
parameters will be determined using standard noncompartmental methods:


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PFIZER CONFIDENTIAL
Table 1.
Noncompartmental PK Parameters of Plasma
Parameter
Analysis Scale
Plasma
PF-07265803 (and known 
circulating metabolites 
PF-07327859, 
PF-07327860, 
PF-07327890)
Plasma
Radioactivity
AUCinf*
ln
D
D
AUClast
ln
D
D
Cmax
ln
D
D
Tmax
R
D
D
t1/2*
R
D
D
CL/F*,†
ln
D
D
VZ/F*,†
ln
D
D
Key: A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits, †=where 
appropriate.
6.3.2. Mass Balance
Mass Balance: cumulative recovery of urinary, fecal, and total excretion of radioactivity 
over time expressed as percentage of total radioactive dose administered.
6.3.3. Metabolic Profiling and Metabolite Identification
Plasma, urine and fecal samples will be analyzed for metabolites and/or chiral inversion of 
PF-07265803. Major metabolites and/or stereoisomers of PF-07265803 in plasma, urine, 
and feces following oral dose of [14C] PF-07265803 will be identified.
Contributions of each major metabolite to total radioactivity recovered and to circulating 
radioactivity in plasma will be approximated. Results of the metabolic profiling analysis will 
be detailed in a separate report and will be summarized within the CSR.
6.3.4. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.


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7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification). 
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular group with ≥3 evaluable measurements.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
The PK and radioactivity data will be summarized using descriptive statistics.
8.2. Statistical Analyses
8.2.1. Pharmacokinetic Analysis
The PK parameters detailed in Section 6.3 will be listed and summarized for subjects in the 
appropriate analysis sets (as defined in Section 5.1.2). Missing values will be handled as 
detailed in Section 7.


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PK parameters will be summarized as specified in the table below. All parameters will be 
presented in the same table using separate columns for plasma PK, plasma radioactivity.
Table 2.
PK Parameters to be Summarized Descriptively
Parameter
Summary Statistics
AUClast, AUCinf, Cmax, 
CL/F* and VZ/F*
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
t1/2
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum.

For PF-07265803 only.
Box and whisker plots for individual subject parameters (AUCinf, AUClast and Cmax) be 
presented and overlaid with geometric means.
Supporting data from the estimation of t½ and AUCinf will be listed:  terminal phase rate 
constant (kel); goodness of fit statistic from the log-linear regression (r2); the percent of
AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of time points 
used in the estimation of kel. This data may be included in the clinical study report.
Presentations for PK and total radioactivity (plasma) concentrations will include:

A listing of all concentrations sorted by subject id and nominal time postdose. The 
listing of concentrations will include the actual times. Deviations from the nominal 
time will be given in a separate listing.  

A summary of concentrations by nominal time postdose, where the set of statistics 
will include n, mean, median, standard deviation, coefficient of variation (cv) and the 
number of concentrations above the lower limit of quantification.

A plot of median PK and radioactivity concentrations against nominal time postdose 
(based on the summary of concentrations by time postdose), where the median 
concentration-time profiles for plasma PK, and plasma radioactivity will be presented 
together on the same plot.

A log-linear plot of the median concentrations against nominal times postdose, as 
described above.

Plots of individual concentrations against actual time postdose, where profiles for 
plasma PK, and plasma radioactivity, will be presented together on the same plot.


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
Log-linear plots of individual concentrations against nominal times postdose, as 
described above.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
8.2.2. Mass Balance
Radioactivity excreted in urine and/or feces will be reported as the percentage of the
administered radioactivity excreted at each time interval, cumulatively through that interval
and the total percent of dose recovered in urine and/or feces.
Percent recovery and cumulative recovery of total radioactivity in urine, feces and emesis (if
any) will be determined based on total administered dose.
Individual participant and median data profiles will be graphically presented for the
cumulative recovery of radioactivity in urine, feces and their combination. The total recovery 
of radioactivity in urine, feces and their combination will be listed and summarized using 
descriptive statistics. Where possible, the rate of excretion of radioactivity will be estimated.
8.3. Safety Analysis
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on
an ongoing basis during the study to evaluate the safety of participants. Any clinical
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be
described. Safety data will be presented in tabular and/or graphical format and summarized
descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as
applicable, collected during the course of the study will be considered source data and will
not be required to be reported, unless otherwise noted. However, any untoward findings
identified on physical and/or neurological examinations conducted during the active
collection period will be captured as AEs, if those findings meet the definition of an AE. Data 
collected at screening that are used for inclusion/exclusion criteria, such as laboratory data, 
ECGs, and vital signs, will be considered source data, and will not be required to be
reported, unless otherwise noted. Demographic data collected at screening will be reported.
8.3.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data). Frequency counts will be supplied for subject discontinuation(s).
Data will be reported in accordance with the sponsor reporting standards.


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8.3.2. Demographic and Clinical Examination Data
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
and height. Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Subject discontinuation due to adverse events will be detailed and summarized.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
8.3.5. Laboratory Data
Laboratory data will be listed in accordance with the sponsor reporting standards.
8.3.6. Vital Signs Data
The baseline measurement is the last predose measurement.
Blood pressure and pulse rate will be measured as per the schedule of activities mentioned in 
the protocol.
For each planned timepoint, baseline values and change from baseline values will be 
summarized with descriptive statistics (using sponsor default standards).
These data will be listed in accordance with the sponsor reporting standards.
8.3.7. ECG Data
The baseline measurement is the predose measurement.
Absolute value and changes from baseline for the ECG parameters QT interval, heart rate,
QTc interval, PR interval, and QRS complex will be listed by treatment and time.
These data will be listed in accordance with the sponsor reporting standards.
8.3.8. Other Safety Data
Pharmacogenomic or biomarker data from Banked Biospecimens 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.


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8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.10. COVID-19 Specific Assessments
Participants will be tested for SARS-COVID-19 infection by PCR at screening and at the
time of being admitted to the clinic for confinement. Additional testing may be required by
local regulations or by the Principal Investigator.
This data will be provided in listings.
8.3.11. Screening and Other Special Purpose Data
If the screening data is brought in-house, then will be listed.
9. REFERENCES
None.
10. APPENDICES