Clinical trial NCT05478603
Conditions: Hepatic Impairment Healthy Volunteers
Keywords: Hepatic impairment Healthy volunteers
Sponsor: Pfizer
Start date: 2022-08-01; Completion date: 2023-04-05
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to understand the effects of liver functional impairment on the study medicine (PF-07081532). People with liver functional impairment may process the study medicine differently from healthy people.

We are seeking participants who:

* Are between 18 and 70 years of age;
* Have a BMI (body mass index) of 17.5 to 38.0 kg/m2, inclusive, and a total body weight \>50 kg (110 lbs.).

Participants will take the study medicine as a tablet once at the study clinic, and then will stay onsite for about 7 days. During this time, the study team will monitor their treatment experience and take some blood samples to test the level of PF-07081532. This will help us understand if certain level of liver functional impairment could affect the study medicine being processed in the body.

Detailed description:

Arms: arm 1: Participants without hepatic impairment will receive a single 20 mg dose of PF-07081532, administered orally as 1 PF-07081532 20 mg tablet. arm 2: Participants with mild hepatic impairment will receive a single 20 mg dose of PF-07081532, administered orally as 1 PF-07081532 20 mg tablet arm 3: Participants with moderate hepatic impairment will receive a single 20 mg dose of PF-07081532, administered orally as 1 PF-07081532 20 mg tablet. arm 4: Participants with severe hepatic impairment will receive a single20 mg dose of PF-07081532, administered orally as 1 PF-07081532 20 mg tablet.
Interventions: intervention 1: PF-07081532
Intervention descriptions: intervention 1: PF-07081532 20 milligrams (mg), 1 tablet orally, once on Day 1

Protocol documents:
Prot_000.pdf: 
PF-07081532 
Protocol C3991009 
Final Protocol, 18 May 2022 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
Title Page 
 
 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL GROUP STUDY TO 
COMPARE THE PHARMACOKINETICS OF PF-07081532 IN ADULT 
PARTICIPANTS WITH VARYING DEGREES OF HEPATIC IMPAIRMENT 
RELATIVE TO PARTICIPANTS WITHOUT HEPATIC IMPAIRMENT 
 
 
Study Intervention Number: 
PF-07081532 
Study Intervention Name: 
NA 
US IND Number: 
CCI 
 
EudraCT/CTIS Number: 
NA 
ClinicalTrials.gov ID: 
Not available 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C3991009 
Phase: 
1 
Brief Title: A Study to Investigate the Effects of Hepatic Impairment on the 
Pharmacokinetics of PF-07081532 
 
 
 
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. 


PF-07081532 
Protocol C3991009 
Final Protocol, 18 May 2022 
PFIZER CONFIDENTIAL 
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Document History 
 
Document 
Version Date 
Original protocol 
18 May 2022 


PF-07081532 
Protocol C3991009 
Final Protocol, 18 May 2022 
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................... 8 
1. PROTOCOL SUMMARY .................................................................................................... 9 
1.1. Synopsis .................................................................................................................... 9 
1.2. Schema.................................................................................................................... 16 
1.3. Schedule of Activities ............................................................................................. 16 
2. INTRODUCTION ............................................................................................................... 19 
2.1. Study Rationale ....................................................................................................... 19 
2.2. Background ............................................................................................................. 19 
2.2.1. Nonclinical Pharmacology ......................................................................... 19 
2.2.2. Nonclinical Pharmacokinetics and Metabolism ......................................... 19 
2.2.3. Nonclinical Safety ...................................................................................... 20 
2.2.4. Clinical Overview ...................................................................................... 20 
2.2.4.1. Clinical Safety .......................................................................... 21 
2.2.4.2. Clinical Pharmacokinetics ........................................................ 21 
2.3. Benefit/Risk Assessment ........................................................................................ 23 
2.3.1. Risk Assessment ........................................................................................ 23 
2.3.2. Benefit Assessment .................................................................................... 25 
2.3.3. Overall Benefit/Risk Conclusion ............................................................... 25 
3. OBJECTIVES AND ENDPOINTS .................................................................................... 25 
4. STUDY DESIGN ................................................................................................................ 26 
4.1. Overall Design ........................................................................................................ 26 
4.2. Scientific Rationale for Study Design .................................................................... 27 
4.2.1. Choice of Contraception/Barrier Requirements ......................................... 29 
4.2.2. Collection of Retained Research Samples .................................................. 29 
4.3. Justification for Dose .............................................................................................. 30 
4.4. End of Study Definition .......................................................................................... 30 
5. STUDY POPULATION ..................................................................................................... 30 
5.1. Inclusion Criteria .................................................................................................... 31 
5.1.1. Participants in All Groups .......................................................................... 31 
5.1.2. Additional Inclusion Criteria for Group 1 Only (without Hepatic 
Impairment) ..................................................................................................... 31 


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5.1.3. Additional Inclusion Criteria for Groups 2, 3 & 4 Only (Hepatic 
Impairment) ..................................................................................................... 32 
5.2. Exclusion Criteria ................................................................................................... 32 
5.2.1. Participants in All Groups .......................................................................... 32 
5.2.2. Additional Exclusion Criteria for Group 1 Only (without Hepatic 
Impairment) ..................................................................................................... 34 
5.2.3. Additional Exclusion Criteria for Groups 2, 3 & 4 Only (Hepatic 
Impairment) ..................................................................................................... 35 
5.3. Lifestyle Considerations ......................................................................................... 36 
5.3.1. Contraception ............................................................................................. 36 
5.3.2. Meals and Dietary Restrictions .................................................................. 37 
5.3.3. Caffeine, Alcohol, and Tobacco ................................................................. 38 
5.3.4. Activity ...................................................................................................... 38 
5.4. Screen Failures ........................................................................................................ 38 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................. 39 
6.1. Study Intervention(s) Administered ........................................................................ 39 
6.1.1. Administration ............................................................................................ 40 
6.2. Preparation, Handling, Storage, and Accountability .............................................. 40 
6.2.1. Preparation and Dispensing ........................................................................ 41 
6.3. Assignment to Study Intervention .......................................................................... 42 
6.4. Blinding .................................................................................................................. 42 
6.4.1. Blinding of Participants .............................................................................. 42 
6.4.2. Blinding of Site Personnel .......................................................................... 42 
6.4.3. Blinding of the Sponsor ............................................................................. 42 
6.5. Study Intervention Compliance .............................................................................. 42 
6.6. Dose Modification .................................................................................................. 42 
6.7. Continued Access to Study Intervention After the End of the Study ..................... 43 
6.8. Treatment of Overdose ........................................................................................... 43 
6.9. Prior and Concomitant Therapy .............................................................................. 43 
6.9.1. Participants in Group 1 Only (without Hepatic Impairment) ..................... 44 
6.9.2. Participants in Groups 2, 3 & 4 Only (Hepatic Impairment)..................... 44 
6.9.3. Rescue Medicine ........................................................................................ 44 


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 45 
7.1. Discontinuation of Study Intervention .................................................................... 45 
7.2. Participant Discontinuation/Withdrawal From the Study ...................................... 45 
7.2.1. Withdrawal of Consent .............................................................................. 45 
7.3. Lost to Follow-up ................................................................................................... 46 
8. STUDY ASSESSMENTS AND PROCEDURES .............................................................. 46 
8.1. Administrative Procedures ...................................................................................... 46 
8.2. Efficacy Assessments ............................................................................................. 47 
8.3. Safety Assessments ................................................................................................. 47 
8.3.1. Physical Examinations ............................................................................... 47 
8.3.2. Vital Signs .................................................................................................. 48 
8.3.2.1. Blood Pressure and Pulse Rate ................................................. 48 
8.3.3. Electrocardiograms ..................................................................................... 49 
8.3.4. Clinical Safety Laboratory Assessments .................................................... 49 
8.3.5. Management of Hypoglycemia .................................................................. 50 
8.3.5.1. Definition and Severity of Hypoglycemic Adverse Event 
(HAE) ............................................................................................... 50 
8.3.6. COVID-19 Specific Assessments .............................................................. 52 
8.3.7. Pregnancy Testing ...................................................................................... 52 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting ................. 52 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information ...... 53 
8.4.1.1. Reporting SAEs to Pfizer Safety .............................................. 53 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF .................. 53 
8.4.2. Method of Detecting AEs and SAEs .......................................................... 54 
8.4.3. Follow-Up of AEs and SAEs ..................................................................... 54 
8.4.4. Regulatory Reporting Requirements for SAEs .......................................... 54 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure .................................................... 55 
8.4.5.1. Exposure During Pregnancy ..................................................... 55 
8.4.5.2. Exposure During Breastfeeding ................................................ 56 
8.4.5.3. Occupational Exposure ............................................................. 57 


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8.4.6. Cardiovascular and Death Events ................................................................ 57 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 57 
8.4.8. Adverse Events of Special Interest ............................................................. 57 
8.4.8.1. Lack of Efficacy ........................................................................ 57 
8.4.9. Medical Device Deficiencies ...................................................................... 57 
8.4.10. Medication Errors ...................................................................................... 58 
8.5. Pharmacokinetics ..................................................................................................... 58 
8.5.1. Plasma for Analysis of PF-07081532 .......................................................... 58 
8.5.2. Plasma for Determination of PF-07081532 Unbound Fraction .................. 59 
8.6. Genetics ................................................................................................................... 60 
8.6.1. Specified Genetics ....................................................................................... 60 
CCI 
 
8.7. Biomarkers ............................................................................................................... 60 
CCI 
 
8.7.2. Specified Gene Expression (RNA) Research ............................................. 60 
8.7.3. Specified Protein Research .......................................................................... 61 
8.7.4. Specified Metabolomic Research ................................................................ 61 
8.8. Immunogenicity Assessments ................................................................................. 61 
8.9. Health Economics .................................................................................................... 61 
9. STATISTICAL CONSIDERATIONS ................................................................................. 61 
9.1. Statistical Hypotheses .............................................................................................. 61 
9.2. Analysis Sets ............................................................................................................ 61 
9.3. Statistical Analyses .................................................................................................. 62 
9.3.1. General Considerations ............................................................................... 62 
9.3.1.1. Analyses for PK Endpoints ........................................................ 62 
9.3.2. Primary Endpoint(s) Analysis ..................................................................... 62 
9.3.2.1. Definition of Endpoint(s) ........................................................... 62 
9.3.2.2. Main Analytical Approach ......................................................... 63 
9.3.2.3. Supplementary Analyses ........................................................... 64 
9.3.3. Secondary Endpoint Analysis - Safety Analyses ........................................ 64 
9.3.3.1. Electrocardiogram Analyses ...................................................... 65 


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9.4. Interim Analyses ..................................................................................................... 65 
9.5. Sample Size Determination .................................................................................... 65 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.......................................................................................................... 67 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 67 
10.1.1. Regulatory and Ethical Considerations .................................................... 67 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 67 
10.1.2. Financial Disclosure ................................................................................. 68 
10.1.3. Informed Consent Process ....................................................................... 68 
10.1.4. Data Protection ......................................................................................... 69 
10.1.5. Committees Structure ............................................................................... 69 
10.1.5.1. Data Monitoring Committee ................................................... 69 
10.1.6. Dissemination of Clinical Study Data ...................................................... 70 
10.1.7. Data Quality Assurance ............................................................................ 71 
10.1.8. Source Documents ................................................................................... 72 
10.1.9. Study and Site Start and Closure .............................................................. 72 
10.1.10. Publication Policy .................................................................................. 73 
10.1.11. Sponsor’s Medically Qualified Individual ............................................. 74 
10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 75 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ..................................................................... 77 
10.3.1. Definition of AE ....................................................................................... 77 
10.3.2. Definition of an SAE ................................................................................ 78 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ........................................................................... 79 
10.3.4. Reporting of SAEs ................................................................................... 83 
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................ 84 
10.4.1. Male Participant Reproductive Inclusion Criteria ................................... 84 
10.4.2. Female Participant Reproductive Inclusion Criteria ................................ 84 
CCI 


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10.4.3. Woman of Childbearing Potential ............................................................ 84 
10.4.4. Contraception Methods ............................................................................ 85 
CCI 
 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ....... 89 
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................ 91 
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury ............................................................................. 91 
10.7.2. Age-Specific Kidney Function Calculation Recommendations ............... 91 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations13 ...................................................................................................................................... 91 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities .................................................................................................. 91 
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ................................... 92 
CCI 
 
10.10. Appendix 10: Other Prohibited Prior/Concomitant Medications ........................ 97 
10.11. Appendix 11: Child-Pugh Classification (CPC) of Liver Dysfunction .............. 98 
10.12. Appendix 12: Abbreviations ............................................................................... 99 
11. REFERENCES ................................................................................................................ 103 
 
LIST OF TABLES 
Table 1. 
Study Schedule of Assessments ............................................................... 17 
Table 2. 
Hepatic Function Categories Based on Child-Pugh Score ....................... 26 
Table 3. 
Plasma PK Parameters ............................................................................. 63 
Table 4. 
Expected Widths of the 90% CIs (with 80% Coverage Probability) 
for Different Possible Estimated Effects ................................................... 66 
Table 5. 
Protocol-Required Safety Laboratory Assessments .................................. 75 
Table 6. 
Scoring for Child-Pugh Classification14 .............................................................................. 98 
Table 7. 
Derivation of Child-Pugh Classification Score ......................................... 98 
Table 8. 
Determination of Encephalopathy Grade .................................................. 98 


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
A Phase 1, Open-Label, Single-Dose, Parallel Group Study to Compare the Pharmacokinetics 
of PF-07081532 in Adult Participants With Varying Degrees of Hepatic Impairment Relative 
to Participants Without Hepatic Impairment 
Brief Title: 
A Study to Investigate the Effects of Hepatic Impairment on the Pharmacokinetics of 
PF-07081532 
Regulatory Agency Identification Number(s): 
 
US IND Number: 
CCI  
EudraCT/CTIS Number: 
NA 
ClinicalTrials.gov ID: 
Not available 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C3991009 
Phase: 
1 
Rationale: 
The primary purpose of this study is to characterize the effect of varying degrees of hepatic 
impairment on the plasma PK of PF-07081532 following administration of a single oral dose 
of PF-07081532. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To compare the PK of PF-07081532 following administration 
of a single oral dose in adult participants with varying degrees 
of hepatic impairment relative to age- and body 
weight-matched participants without hepatic impairment. 
• 
Plasma: Cmax, AUCinf, AUClast*, fu, Cmax,u, 
AUCinf,u and AUClast,u*, as data permit. 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of a single oral dose of 
PF-07081532 when administered to adult participants with 
varying degrees of hepatic impairment and in age- and body 
weight-matched participants without hepatic impairment. 
• 
Assessment of treatment emergent AEs, clinical 
laboratory abnormalities, vital signs, ECG 
parameters. 
* AUClast and AUClast,u will be treated as primary endpoints if data do not permit robust estimation of AUCinf and AUCinf,u, 
otherwise they will be treated as tertiary endpoints. 


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Overall Design: 
This is an open-label, single-dose, parallel-group, multicenter study to investigate the effect 
of varying degrees of hepatic function on the plasma PK of PF-07081532 after a single, oral 
20 mg dose administered in the fed state (standard breakfast). Safety and tolerability will be 
evaluated throughout the study. 
Number of Participants: 
Approximately 24 participants will be enrolled to receive study intervention. 
Note: "Enrolled" means a participant's, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process and 
assignment to study intervention. A participant will be considered enrolled if the informed 
consent is not withdrawn prior to participating in any study activity after screening. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol. 
Study Population: 
Key inclusion and exclusion criteria are listed below: 
Key Inclusion Criteria 
Participants must meet the following key inclusion criteria to be eligible for study 
enrollment: 
All Groups 
• Male or female between the ages of 18 (or the minimum country-specific age of 
consent if >18) and 70 years, inclusive at the screening visit. 
• Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, 
lifestyle considerations, and other study procedures. 
• BMI of 17.5 to 38.0 kg/m2, inclusive, and a total body weight >50 kg (110 lb). 
• Capable of giving signed informed consent. 
Additional for Group 1 Only (without Hepatic Impairment) 
• At screening, no clinically relevant abnormalities identified by a detailed medical 
history, complete PE, including BP and pulse rate measurement, 12-lead ECG and 
clinical laboratory tests. 


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• At screening, meet the demographic-matching criteria, including body weight within 
±10 kg and age within ±5 years, of the average of the pooled hepatic impairment 
groups, as provided by the sponsor. 
• No known or suspected hepatic impairment and meet all the following criteria based 
on screening laboratory tests: ALT ≤ ULN, AST ≤ ULN, T bili ≤ ULN, Albumin 
≤ ULN, PT ≤ ULN. 
Additional for Groups 2, 3 & 4 Only (Hepatic Impairment) 
• Stable hepatic impairment that meets criteria for Class A, B, or C of the Child-Pugh 
classification with no clinically significant change in disease status within 28 days 
before screening. 
• Stable concomitant medications for the management of individual participant’s 
medical history. 
Key Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded: 
All Groups 
• Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection). 
• At screening, a positive result for HIV antibodies. 
• Personal or family history of MTC or MEN2, or participants with suspected MTC per 
the investigator’s judgement. 
• History of acute pancreatitis within 6 months before the screening visit or any history 
of chronic pancreatitis. 
• Other medical or psychiatric condition or laboratory abnormality that may increase 
the risk of study participation or make the participant inappropriate for the study. 
• Use of specific prohibited prior/concomitant therapies as outlined in the protocol. 
• Use of an investigational product within 30 days (or local requirement) or 5 half-lives 
(whichever longer), or 14 days plus 5 half-lives for strong CYP3A inducers or 
time-dependent inhibitors, before study dose. 
• eGFR<60 mL/min/1.73m2 (calculated with the 2021 CKD-EPI Scr-Scys combined 
equation) at screening. 


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• A positive urine drug test at screening or Day -1; however, participants in Groups 
2-4, only, who have been medically prescribed medications and report use at 
screening may be allowed after sponsor approval. 
• At screening or Day -1, a positive breath alcohol test. 
• For females, pregnancy, as indicated by a positive serum pregnancy test at screening 
and/or positive urine pregnancy test in WOCBP at Day -1. 
Additional Group 1 Only (without Hepatic Impairment) 
• Evidence of chronic liver disease including history of hepatitis, hepatitis B, or 
hepatitis C. 
• History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of screening. 
• Screening supine 12-lead ECG demonstrating QTcF interval >450 ms or a QRS 
interval >120 ms. 
• Screening seated SBP ≥140 mm Hg or DBP ≥90 mm Hg, following ≥5 minutes of 
seated rest. 
• Use of chronic prescription medications within 7 days or 5 half-lives (whichever 
longer) before Day 1, or for prohibited medications, use within the required 
washout/restriction period in protocol. 
Additional Exclusion Criteria for Groups 2, 3 & 4 Only (Hepatic Impairment) 
• Hepatic carcinoma or hepatorenal syndrome or limited predicted life expectancy 
(defined as <1 year in Groups 2 & 3 and <6 months for Group 4 only). 
• A diagnosis of hepatic dysfunction secondary to any acute ongoing hepatocellular 
process that is documented by medical history, PE, liver biopsy, hepatic ultrasound, 
CT scan, or MRI. 
• History of surgery that would be expected to alter absorption, distribution, 
metabolism, or excretion properties of PF-07081532. 
• History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less 
than 4 weeks prior to screening. 
• Signs of clinically active Grade 3 or 4 hepatic encephalopathy (ie, > Grade 2 Portal 
Systemic Encephalopathy score). 


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• Severe ascites and/or pleural effusion, except for those categorized in Group 4 who 
may be enrolled provided participant is medically stable, per the investigator’s 
judgment. 
• Previously received a kidney, liver, or heart transplant. 
• Screening supine 12-lead ECG demonstrating a QTcF interval >470 ms or a QRS 
interval >120 ms. 
• At screening, Day -1 or pre-dose on Day 1, persistent severe, uncontrolled 
hypertension. 
• ALT or AST >5x ULN on clinical laboratory tests at screening. 
Study Arms and Duration: 
A total of approximately 24 participants with varying degrees of hepatic function will be 
administered a single, oral 20 mg dose of PF-07081532 in the fed state as shown in the table 
below. 
Hepatic Function Categories Based on Child-Pugh-Score 
 
Group 
Description 
Child-Pugh Score 
Number of Participants 
1 
Without hepatic impairment 
Not Applicable 
6a 
2 
Mild hepatic impairment 
Class A (5 to 6 points) 
6 
3 
Moderate hepatic impairment 
Class B (7 to 9 points) 
6 
4 
Severe hepatic impairment 
Class C (10 to 15 points) 
6b 
a. 
Additional participants may be dosed to a maximum of 8 participants to ensure mean age ±5 years and 
mean body weight ±10 kg of this group is aligned with the pooled average assessed when approximately 
≥75% of participants are dosed across the other 3 groups. 
b. If recruitment across the sites selected proves to be prohibitive, study may dose 4-6 participants in this 
group. 
 
Categorization of participants into Groups 2-4 will be done based on Child-Pugh scores 
determined at the screening visit. 
Staged Enrollment of Study Groups 
Participants will be dosed in a staged manner as follows: 
• Participants with moderate and severe hepatic impairment (Groups 3 and 4) will be 
enrolled first. 
• Recruitment of participants with mild hepatic impairment (Group 2) will initiate 
when approximately 50% of the participants across Groups 3 and 4 have been dosed. 


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Sponsor approval is required before proceeding with recruitment of Group 2. 
• An average value for age and weight for the 3 hepatic impairment groups 
(Groups 2-4) will be determined and participants without hepatic impairment 
(Group 1) will be recruited to match the average demographics (at a minimum, age 
and weight, and as much as practically possible gender) across the pooled 
Groups 2-4. 
• Recruitment for healthy participants in Group 1 (without hepatic impairment) may 
start when approximately 75% of total participants across Groups 2-4 
(ie, approximately 12-13 participants) have been dosed. 
Sponsor approval is required before proceeding with recruitment of Group 1. 
For individual participants, the total duration of participation from the screening visit to the 
follow-up visit will range from approximately 5 weeks (minimum) to approximately 9 weeks 
(maximum). The study consists of an initial screening period of up to 28 days, a 7-day 
inpatient stay at the CRU which includes administration of a single oral dose of 
PF-07081532, and a follow up contact that will occur 28-35 days after PF-07081532 
administration. 
PF-07081532 will be supplied by Pfizer as 20 mg tablets in open-label bulk bottles along 
with individual dosing containers, as necessary, for unit dosing. For the 20 mg dose 
administered in this study, participants will take 1 PF-07081532 20-mg tablet orally with the 
morning meal. 
 
Study Intervention(s) 
Intervention Name 
PF-07081532 
Arm Name 
(group of participants receiving a 
specific treatment or no treatment) 
Group 1, Group 2, Group 3, Group 4 
Unit Dose Strength(s) 
20 mg 
Route of Administration 
Oral 
Use 
Experimental 
IMP or NIMP/AxMP 
IMP 


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Study Arm(s) 
Arm Title 
Group 1 
Group 2 
Group 3 
Group 4 
Arm Type 
Experimental 
Experimental 
Experimental 
Experimental 
Arm 
Participants without 
Participants with 
Participants with 
Participants with 
Description 
hepatic impairment 
mild hepatic 
moderate hepatic 
severe hepatic 
will receive a single 
impairment will 
impairment will 
impairment will 
20 mg dose of 
receive a single 
receive a single 
receive a single 
PF-07081532, 
20 mg dose of 
20 mg dose of 
20 mg dose of 
administered orally 
PF-07081532, 
PF-07081532, 
PF-07081532, 
as 1 PF-07081532 
administered orally 
administered orally 
administered orally 
20 mg tablet 
as 1 PF-07081532 
as 1 PF-07081532 
as 1 PF-07081532 
20 mg tablet 
20 mg tablet 
20 mg tablet 
Statistical Methods: 
A sample size of approximately 24 participants (approximately 6 participants per group, with 
varying degrees of hepatic function in each of the 4 groups) has been selected to provide 
sufficient precision to detect a 2-fold difference in AUCinf between each Test group (with 
hepatic impairment) and the Reference group (without hepatic impairment). 
The effect of varying degrees of hepatic impairment on PK parameters will be assessed by 
constructing 90% CI around the estimated difference between each of the Test (hepatic 
impaired) groups and the Reference (without hepatic impairment) group. A one-way 
ANOVA will be used to compare the natural log transformed PF-07081532 AUCinf, Cmax, 
AUClast, fraction unbound (fu), and associated unbound parameters (AUCinf,u, Cmax,u, 
AUClast,u ), as data permit, for each of the hepatic impairment groups (Test) to the group 
without hepatic impairment (Reference). Estimates of the adjusted mean differences 
(Test - Reference), and corresponding 90% CIs, will be obtained from the model. These will 
be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CIs for the ratios. 
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 following 
Sponsor standards. 


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Ethical Considerations: 
A single dose of PF-07081532 administered in this study is not expected to provide any 
clinical benefit to study participants. This study is designed primarily to characterize the 
effect of varying degrees of hepatic impairment on the PK of PF-07081532. Results from this 
study will be used in conjunction with collective safety, tolerability, efficacy, and PK/PD 
data from other PF-07081532 studies to develop dosing recommendations for the target 
patient populations with varying degrees of hepatic function. 
1.2. Schema 
 
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. 


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Table 1. 
Study Schedule of Assessments 
 
Visit Identifier/Day 
[list of abbreviations in Appendix 12] 
Screen 
≤-28 to -2 
Day 
-1 
Day 1 
Day 2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
ET 
Follow-upa 
Day 29-36 
Hours Post Dose 
-- 
0 
0.5 
1 
2 
4 
6 
8 
10 
12 14 
15 
24 
36 
48 
72 
96 
120 
144 
-- 
-- 
Informed consent & demography 
x 
COVID-19 testing/risk assessmentb 
See footnote 
Outpatient visit 
x 
Inpatient stay at CRU 
x 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ → 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
x 
Eligibility assessment 
x 
x 
x 
Medical history 
x 
Child-Pugh Classification scoring 
x 
PE (height & weight at screening only)c 
x 
x 
x 
x 
Breath alcohol & Urine drug test 
x 
x 
Alcohol/tobacco & contraception used 
x 
x 
x 
x 
x 
(Update) prior/concomitant treatments 
x 
x 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ → 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
x 
x 
Single, supine 12-lead ECGe 
x 
xe 
x 
x 
Single, seated vital signs (BP, pulse rate)e 
x 
x 
xe 
x 
x 
x 
x 
AE monitoring (non-serious & SAEs) 
x 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ → 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
x 
x 
x 
Standard meals/optional snacksf 
xf 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study intervention administrationg 
x 
Blood & Urine for clinical laboratory testsh 
x 
xk 
x 
x 
x 
Serology for FSH (all females), HIV, 
HBsAg, HCVAb/RNA 
x 
Serum pregnancy test (all females) 
x 
Urine pregnancy test (WOCBP only)i 
x 
x 
x 
Prep D1.5 Retained Research Samplesj 
xk 
Blood for PK sampling for PF-07081532 
xk 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CCI 
k 
Blood for fu of PF-07081532 in plasma 
xk 
x 
a. 
Follow-up visit to be performed as telephone contact and must occur in the window of 28 to 35 days (ie, Day 29-36) from administration of study intervention. A clinic visit 
may be performed in place of telephone contact, if deemed necessary by the investigator, eg, for follow-up of abnormal laboratory tests and/or open AEs. 
b. 
Assessment of risk for, symptoms of or testing for COVID-19 may be performed at screening, admission to the CRU and/or at other times during the study at investigator 
discretion and according to local site policies. 
c. 
Complete PE at screening; at all other time points limited PE, at investigator discretion (see Section 8.3.1). 
d. 
In confirmation of appropriate contraception use only. 


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e. 
If done around the time of a blood draw, ECG and vital sign assessments (BP and pulse rate) should be collected before the blood draw. ECG and vital signs on Day 1 at 
Time 0H must be done before collection of the pre-dose blood samples. If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments (BP and 
pulse rate) should be collected before insertion of the catheter. 
f. 
Meals/snacks to be served at clock times matching approximately 0H, 4H, 6H (optional snack), 10H, and 14H (optional snack) relative to dosing on Day 1, while inpatient. 
Meals/snacks on Day -1 must be timed such that there is at least an 8 hour fast prior to collection of the pre-dose PK sample on Day 1 (see Section 5.3.2). 
g. 
Dosing to occur with standard morning meal provided approximately 30 minutes prior to 0H, and meal completed approximately 10 minutes prior to dosing. 
h. 
Safety related laboratory tests collected on Day -1, if performed at investigator discretion, must be reviewed prior to dosing and must reflect the participant to be in stable 
medical condition. 
i. 
Test result must be reviewed and deemed acceptable (ie, negative) to continue participation in the study. 
j. 
If not collected on the designated collection day, collect at the next available time point when biospecimens are collected in conjunction with a participant visit. 
k. 
Samples at Time 0 on Day 1 must be collected pre-dose. 


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2. INTRODUCTION 
GLP-1 is a neuroendocrine hormone that is predominantly released from the small intestine 
in response to food intake.1 Activation of the GLP-1R stimulates insulin release, inhibits 
glucagon secretion in a glucose-dependent manner, and delays gastric emptying.2,3 In 
addition, GLP-1 has been shown to increase satiety and suppress food intake.4 
PF-07081532 is a potent and selective, orally administered, small molecule GLP-1R agonist 
that is currently being developed as an adjunct to diet and exercise to improve glycemic 
control in adults with T2DM. 
2.1. Study Rationale 
The primary purpose of this study is to characterize the effect of varying degrees of hepatic 
impairment on the plasma PK of PF-07081532 following administration of a single oral dose 
of PF-07081532. 
2.2. Background 
2.2.1. Nonclinical Pharmacology 
 
Details of the nonclinical pharmacology program are included in the IB. 
2.2.2. Nonclinical Pharmacokinetics and Metabolism 
 
 


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Further details of the nonclinical PK and metabolism program are included in the IB. 
2.2.3. Nonclinical Safety 
PF-07081532 was administered PO to Wistar Han rats and cynomolgus monkeys in studies 
up to 6 and 9 months in duration, respectively. All in vitro and in vivo studies used the Tris 
salt form of PF-07081532 (78% – 82.5% active moiety across all lots). The high dose 
(100 mg/kg/day for rats and monkeys) in the pivotal toxicity studies were selected based on 
toleration and findings from earlier repeat-dose and exploratory studies. 
 
 
The NOAELs in the 6-month rat or 9-month monkey pivotal toxicity studies were 
100 mg/kg/day in both species, with associated unbound Cmax and unbound AUC24 of 
and CCI 
respectively. CCI 
in rats and CCI 
and CCI 
in monkeys, 
 
 
 
 
 
 
 
 
Further details of the nonclinical toxicology program are included in the IB. 
2.2.4. Clinical Overview 
Two clinical studies (C3991001 and C3991002) have been completed with PF-07081532 in 
which a total of 88 participants have been randomized. Across these 2 studies, 22 healthy 
adult participants, 51 adult participants with T2DM and 15 adult participants with obesity 
have been randomized, with a total of 74 unique participants exposed to at least 1 dose of 
PF-07081532. 
CCI 


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CCI 
One Phase 1 study, C3991003, is ongoing. This in-patient study is enrolling participants with 
T2DM inadequately controlled on metformin and participants with obesity to receive 
PF-07081532 or placebo daily for 42 days. The starting dose for the first cohort of this study 
is 20 mg of PF-07081532, with subsequent dose levels to be determined based on emerging 
data, and dosing is in progress. While final clinical data from this study are not yet available 
as of issuance of this protocol, there have been no deaths, SAEs or AEs of severe intensity 
reported. 
2.2.4.1. Clinical Safety 
The safety profile of PF-07081532 has been assessed in 2 completed clinical studies. To date, 
administration of PF-07081532 at single doses up to 200 mg and multiple doses up to 
180 mg QD for up to 42 days has been considered safe, with a tolerability profile consistent 
with the mechanism of action. The majority of TEAEs have been mild in intensity and in the 
Gastrointestinal Disorders SOC. 
Following single dose administration to healthy adult participants in study C3991001, the 
most frequently reported all-causality TEAEs across all treatment groups were nausea and 
vomiting, with an increased incidence of gastrointestinal AEs noted at the dose of 200 mg. In 
the multiple ascending dose study, C3991002, the most frequently reported all causality 
TEAEs included nausea in participants with T2DM, and nausea and constipation in 
participants with obesity. Higher incidences of gastrointestinal TEAEs were observed in the 
higher dose groups of PF-07081532 (120 mg QD and 180 mg QD) compared to placebo. 
There were no clinically significant adverse trends in safety laboratory tests, vital signs or 
ECG parameters in either study with increasing PF-07081532 doses. 
Refer to the IB for more detail on these studies, and the known drug class effects of marketed 
GLP-1R agonists. 
2.2.4.2. Clinical Pharmacokinetics 
The clinical pharmacokinetics of PF-07081532 have been evaluated to date in 2 completed 
studies (C3991001 and C3991002), the results of which are provided in the IB. 
 


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2.3. Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably expected AEs of PF-07081532, and the 
drug class effects of marketed GLP-1R agonists, may be found in the IB, which is the SRSD for this study. 
2.3.1. Risk Assessment 
 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention PF-07081532 
Gastrointestinal adverse reactions 
The potential risks are based on product labeling for injectable 
GLP-1R agonists (ie, liraglutide, exenatide, semaglutide and 
dulaglutide). 
In addition, gastrointestinal adverse events, the majority of which 
were mild in severity, have been observed in the clinical program 
with PF-07081532. 
The single dose and dose level administered in 
this study minimize any potential risk. 
Participants are monitored during the clinical 
studies to prevent potential sequelae of any 
severe gastrointestinal reactions, eg, dehydration. 
Hypoglycemia 
Clinical trials with injectable GLP-1R agonists have not 
demonstrated an increased risk for hypoglycemia. However, when 
administered in combination with anti-diabetic agents that are 
known to have an increased risk of hypoglycemia (such as insulin 
or sulfonylureas), an increased risk for hypoglycemia was 
observed. 
The single dose and dose level administered in 
this study minimize any potential risk. 
Study includes inpatient monitoring of the 
participants following administration of a single 
dose of the investigational product. 
Increased heart rate 
Based on the product labeling for the injectable GLP-1R agonist 
liraglutide for obesity, mean increases in resting heart rate ranged 2 
to 3 bpm in clinical trials, with some participants experiencing 
greater increases in resting heart rate, up to 10-20 bpm. 
Following single dose administration of PF-07081532 in the 
completed FIH study, variable increases in heart rate were 
observed; the majority of individual values remained within normal 
ranges, and, throughout the study, no AEs or clinical symptoms 
related to vital sign parameters were reported. 
The single dose and dose level administered in 
this study minimize any potential risk. 
Study includes inpatient monitoring of the 
participants following administration of a single 
dose of the investigational product. 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential risks associated with 
long-term dosing of marketed 
GLP-1R agonists include 
thyroid C-cell tumors, pancreatitis, 
impairment in renal function, 
diabetic retinopathy complications, 
acute gallbladder disease, 
The potential risks are based on product labeling for injectable 
GLP-1R agonists (ie, liraglutide, dulaglutide, exenatide and 
semaglutide); additional information is provided in the IB. 
The single dose and dose level administered in 
this study minimize any potential risk. 
Study includes inpatient monitoring of the 
participants following administration of a single 
dose of the investigational product. 
Participants with a personal or family history of 
medullary thyroid carcinoma or MEN2; with 
acute pancreatitis or a history of chronic 
pancreatitis are not eligible for study entry. 
Other 
Risk of COVID-19 exposure during 
study. 
During the pandemic, study participants could be exposed to the 
SARS-CoV-2 virus during study participation. This could lead to 
increased health risk for this participant and others in the study. 
Assessment of risk for, symptoms of or testing 
for COVID-19 may be performed at screening, 
admission to the CRU and/or at other times 
during the study at investigator discretion and 
according to local site policies. 


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2.3.2. Benefit Assessment 
A single dose of PF-07081532 is not expected to provide any clinical benefit to study 
participants. This study is designed primarily to characterize the effect of varying degrees of 
hepatic impairment on the PK of PF-07081532 to support further clinical development of 
PF-07081532 as a potential treatment of T2DM. Results from this study will be used in 
conjunction with collective safety, tolerability, efficacy, and PK/PD data from other 
PF-07081532 studies to develop dosing recommendations for the target patient population 
with varying degrees of hepatic function. 
2.3.3. Overall Benefit/Risk Conclusion 
In line with the clinical profile of marketed GLP-1R agonists,6 the most frequently reported 
AEs in the 2 completed clinical studies with PF-07081532 administration have been in the 
Gastrointestinal Disorders SOC (Section 2.2.4). In addition, as has been reported for 
marketed GLP-1R agonists,7,8 modest increases in heart rate have been observed with 
PF-07081532 administration, with most heart rate values within the normal range. Based on 
available clinical data (Section 2.2.4 and current IB), a single 20 mg PF-07081532 dose is 
anticipated to be safe and well tolerated, including in participants with varying degrees of 
hepatic impairment, even if increased plasma concentrations were to be observed 
(Section 4.3). 
Based on the profile of PF-07081532 observed in nonclinical and clinical studies to date, and 
taking into account the measures to minimize risk to study participants, the potential risk to 
the participants in this study is deemed to be minimal and is justified by the anticipated 
benefits that may be afforded to patients with varying degrees of hepatic impairment 
receiving PF-07081532 in the future. 
3. OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To compare the PK of PF-07081532 following administration 
of a single oral dose in adult participants with varying degrees 
of hepatic impairment relative to age- and body 
weight-matched participants without hepatic impairment. 
• 
Plasma: Cmax, AUCinf, AUClast*, fu, Cmax,u, 
AUCinf,u and AUClast,u*, as data permit. 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of a single oral dose of 
PF-07081532 when administered to adult participants with 
varying degrees of hepatic impairment and in age- and body 
weight-matched participants without hepatic impairment. 
• 
Assessment of treatment emergent AEs, clinical 
laboratory abnormalities, vital signs, ECG 
parameters. 
CCI 
 
 
 


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Objectives 
Endpoints 
• 
CCI 
 
 
* AUClast and AUClast,u will be treated as primary endpoints if data do not permit robust estimation of AUCinf and AUCinf,u, 
otherwise they will be treated as tertiary endpoints. 
 
4. STUDY DESIGN 
4.1. Overall Design 
This is an open-label, single-dose, parallel-group, multicenter study to investigate the effect 
of varying degrees of hepatic function on the plasma PK of PF-07081532 after a single, oral 
20 mg dose administered in the fed state (standard breakfast). Safety and tolerability will be 
evaluated throughout the study. A total of approximately 24 participants with varying 
degrees of hepatic function will be dosed in the study as shown in Table 2. If recruitment of 
participants with severe hepatic impairment proves prohibitive, the number of participants to 
be enrolled in this group may be flexible (4-6 participants). 
Table 2. 
Hepatic Function Categories Based on Child-Pugh Score 
 
Group 
Description 
Child-Pugh Score 
Number of Participants 
1 
Without hepatic impairment 
Not Applicable 
6a 
2 
Mild hepatic impairment 
Class A (5 to 6 points) 
6 
3 
Moderate hepatic impairment 
Class B (7 to 9 points) 
6 
4 
Severe hepatic impairment 
Class C (10 to 15 points) 
6b 
a. 
Additional participants may be dosed to a maximum of 8 participants to ensure mean age ±5 years and 
mean body weight ±10 kg of this group is aligned with the pooled average assessed when approximately 
≥75% of participants are dosed across the other 3 groups. 
b. If recruitment proves to be prohibitive, study may dose 4-6 participants in this group. 
 
Categorization of participants into Groups 2-4 will be done based on Child-Pugh scores 
determined, as described in Appendix 11 at the screening visit. 
Staged Enrollment of Study Groups 
Participants will be dosed in a staged manner as follows: 
• Participants with moderate and severe hepatic impairment (Groups 3 and 4) will be 
enrolled first. 
• Recruitment of participants with mild hepatic impairment (Group 2) will initiate 
when approximately 50% of the participants across Groups 3 and 4 have been dosed. 


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Sponsor approval is required before proceeding with recruitment of Group 2. 
• An average value for age and weight for the 3 hepatic impairment groups 
(Groups 2-4) will be determined, and participants without hepatic impairment 
(Group 1) will be recruited to match the average demographics (at a minimum, age 
and weight, and as much as practically possible gender) across the pooled 
Groups 2-4. 
• Recruitment for healthy participants in Group 1 (without hepatic impairment) may 
start when approximately 75% of total participants across Groups 2-4 
(ie, approximately 12-13 participants) have been dosed. 
Sponsor approval is required before proceeding with recruitment of Group 1. 
Participants who prematurely discontinue before completing all assessments may be 
replaced, at the discretion of the investigator and sponsor study team. 
The overall study design is presented as a schematic in Section 1.2. For individual 
participants, the total duration of participation from the screening visit to the follow-up visit 
will range from approximately 5 weeks (minimum) to approximately 9 weeks (maximum). 
The study consists of an initial screening period of up to 28 days, a 7-day inpatient stay at 
the CRU which includes administration of a single oral dose of PF-07081532, and a 
follow up contact that will occur 28-35 days after PF-07081532 administration. 
4.2. Scientific Rationale for Study Design 
The purpose of this study is to characterize the effect of varying degrees of hepatic 
impairment on the PK, safety and tolerability of PF-07081532. PF-07081532 is an oral 
GLP-1R agonist that is currently being investigated as a chronic therapy to improve glycemic 
control in adult participants with T2DM. Based on review of the effect of hepatic impairment 
on human PK CCI 
impaired hepatic function is generally associated with increased drug 
exposures in plasma CCI 
 
 
 
As such, this study will enroll participants with varying degrees of hepatic 
impairment, and participants without hepatic impairment (matched for age as well as body 
weight and gender as much as practically possible) in order to allow a robust assessment of 
PK across the entire spectrum of hepatic function. A single dose of PF-07081532 is 
proposed, as single dose plasma PK of PF-07081532 is generally predictive of exposure upon 
repeated dosing. 


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Following administration of single oral doses of PF-07081532 under either fasted or fed 
conditions in Study C3991001 (non-Japanese cohorts), the arithmetic mean terminal t½ of 
PF-07081532 ranged approximately from 17 to 21 hours. Therefore, in this study, serial PK 
samples will be collected up to 144 hours post-dose in order to allow adequate 
characterization of the elimination phase of the plasma concentration-time profile should any 
increased half-life (up to 2-fold) in participants with varying degrees of hepatic impairment 
be observed. 
Available PK data with PF-07081532 administered under fasted or fed conditions indicate 
that PF-07081532 may be administered without regard to food. In this study, a single dose of 
PF-07081532 will be administered with a standard breakfast to reflect the conditions for 
anticipated use of PF-07081532 in future trials and the target patient population. 
PF-07081532 is extensively bound to plasma proteins with a fu of 0.000376 in humans and, 
as such, plasma protein binding may be affected in patients with chronic liver disease. To 
assess the in vivo protein binding of PF-07081532 with varying degrees of hepatic 
impairment, the fu of PF-07081532 will be determined in all participants at approximately 
the expected Tmax. 
 
In general, participants with normal hepatic function (Group 1) will abstain from 
concomitant treatments, except for the treatment of adverse events. Use of selected limited 
prescription and non-prescription medications may be permitted (refer to Section 6.9 for 
details). Participants with impaired hepatic function (Groups 2, 3 and 4) are permitted to be 
on stable doses of background medications for the management of their concomitant medical 
condition(s) with some exclusions (see Appendix 9 and Appendix 10). 
 
To minimize the risks of COVID 19 related complications to participants and the study site 
personnel, assessment of risk for, symptoms of or testing for COVID-19 may be performed at 
screening, admission to the CRU and/or at other times during the study at investigator 
discretion and according to local site policies. 


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The Child-Pugh Classification (CPC; refer to Appendix 11) will be used to define the 
3 groups of participants with varying degrees of hepatic impairment. This study will include 
participants with mild (Child-Pugh Class A, Group 2), moderate (Child-Pugh Class B, 
Group 3), and severe (Child-Pugh Class C, Group 4) hepatic impairment as well as 
demographically matched control participants without hepatic impairment (Group 1). All 
participants will be required to provide their own consent to participate in this study, hence 
participants with clinically active Grade 3 or Grade 4 encephalopathy will be excluded. 
However, participants who have a previous history of Grade 3 or 4 encephalopathy but are 
currently receiving an intervention (eg, lactulose or lactitol, alone or in combination with 
rifaximin, and/or neomycin) to manage their encephalopathy-related signs and symptoms are 
eligible provided the on-treatment encephalopathy grading at the screening visit is Grade 2 or 
lower, thereby permitting them to provide their own informed consent. Acknowledging the 
medical state of the population enrolled, certain eligibility criteria for participants with 
hepatic impairment are distinctly different, with no specific exclusion of participants with 
Hepatitis B and Hepatitis C in Groups 2, 3, or 4. 
Although urinary recovery of PF-07081532 is low, with less than 0.2% of the dose recovered 
in the 24-hour dosing interval (Section 2.2.4.2), 
10 Therefore, in order to 
enable a robust assessment of the effect of hepatic impairment on PF-07081532 PK, 
participants will be excluded if there is concomitant clinical evidence of renal impairment, 
defined as eGFR <60 mL/min/1.73m2. 
4.2.1. Choice of Contraception/Barrier Requirements 
Both women of childbearing potential, as well as those who are of non-childbearing 
potential, may be enrolled given the availability of EFD toxicity studies with PF-07081532. 
However, as marketed GLP-1R agonists are listed as contraindicated in pregnancy, measures 
will be taken to limit the risk of pregnancy in the female population enrolled (see SoA and 
Section 10.4). 
The potential risk of exposure to PF-07081532 in a sexual partner of a male participant in 
this study via ejaculate is low, and therefore no contraception (condom) use in male 
participants is warranted. The calculated safety margin is ≥100 fold between the estimated 
partner exposure due to seminal transfer and the NOAEL for serious manifestations of 
developmental toxicity in nonclinical studies. The safety margin of 100 fold is based on 
applying a 10 fold safety factor for interspecies extrapolation and a 10 fold safety factor for 
susceptible populations.11 
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. 


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4.3. Justification for Dose 
A single oral dose of 20 mg will be used in this study. This dose has been selected based on 
prior experience in clinical studies with PF-07081532 (Section 2.2.4) and also taking into 
account safety considerations for the participants with varying degrees of hepatic impairment 
in whom an increase in plasma PF-07081532 exposure may be observed. 
In Study C3991001, a single dose of 30 mg was very well tolerated with an AE profile that 
did not differ from placebo. In the same study, single ascending doses up to 200 mg were 
tested and were considered safe and had a tolerability profile in line with expectations for the 
mechanism of action, with the majority of AEs being mild in severity and in the 
Gastrointestinal Disorders SOC (with nausea and vomiting the most frequently observed). 
For participants that experienced vomiting (observed at the 100 and 200 mg dose levels, with 
increased incidence at 200 mg), this generally occurred after the attainment of Cmax and with 
no apparent impact on PF-07081532 exposure. In addition, the dose proposed in the current 
study (20 mg) reflects adequate safety margins compared to nonclinical toxicity studies. 
After accounting for species differences in plasma protein binding, this dose represents an 
exposure in participants with healthy hepatic function that is approximately CCI 
 
for Cmax and AUC respectively, lower than the exposure observed at the NOAEL in 
the pivotal 9-month toxicology study in monkeys (Section 2.2.3). Given the above, it is 
anticipated that potential increases in plasma exposure in participants with varying degrees of 
hepatic impairment in the current study, if encountered, are not anticipated to pose an undue 
safety risk. 
Although doses up to 260 mg QD may be evaluated in future clinical studies with 
PF-07081532, the proposed dose of 20 mg is viewed as appropriate for this study, given the 
potential of increased exposures in participants with hepatic impairment. Since no greater 
than dose-proportional increases in exposure of PF-07081532 have been observed over the 
range of clinical doses tested so far (up to single dose of 200 mg and up to 180 mg QD), the 
results from this study may be used to extrapolate and inform the effect of hepatic 
impairment on PK for doses exceeding 20 mg. 
4.4. End of Study Definition 
The end of the study is defined as the date of the follow up visit as shown in the SoA for the 
last participant in the trial globally. 
A participant is considered to have completed the study if they have completed all phases of 
the study, including the follow up visit (telephone contact or onsite visit per Investigator 
discretion) as shown in the SoA. 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. Use of a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 


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permitted under local regulations, age, sex, and race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
5.1.1. Participants in All Groups 
Age and Sex: 
1. Male or female between the ages of 18 (or the minimum country-specific age of 
consent if >18) and 70 years, inclusive, at the screening visit. 
Women may be of child-bearing potential, however, cannot be pregnant, 
breastfeeding, or planning to become pregnant while participating in the study. Refer 
to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
Other Inclusion Criteria: 
2. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, 
lifestyle considerations (as described in Section 5.3), and other study procedures. 
3. BMI of 17.5 to 38.0 kg/m2, inclusive; and a total body weight >50 kg (110 lb), at the 
screening visit; with a single repeat assessment of total body weight (and hence BMI), 
on a separate day before Day -1 permitted to assess eligibility, if needed. 
4. 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. 
5.1.2. Additional Inclusion Criteria for Group 1 Only (without Hepatic Impairment) 
1. At screening, no clinically relevant abnormalities identified by a detailed medical 
history, complete PE, including BP and pulse rate measurement, 12-lead ECG and 
clinical laboratory tests, as assessed by the sponsor approved laboratory. 
2. At screening, participants must meet the demographic-matching criteria, including: 
• A body weight that is within ±10 kg of the average of the pooled hepatic 
impairment groups (Groups 2, 3, and 4), as provided by the sponsor; 


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• An age that is within ±5 years of the average of the pooled hepatic impairment 
groups (Groups 2, 3, and 4), as provided by the sponsor; 
• Attempts will be made to ensure that the male-to-female distribution in Group 1 is 
comparable to that in the pooled hepatic impairment groups (Groups 2, 3, and 4). 
3. No known or suspected hepatic impairment, and meet all the following criteria at 
screening, as assessed by the sponsor approved laboratory, with a single repeat 
permitted to assess eligibility, if needed: 
• ALT ≤ ULN; 
• AST ≤ ULN; 
• T bili ≤ ULN; 
NOTE: Participants with a history of Gilbert syndrome (and hence elevated T bili) 
are eligible provided direct bilirubin level is ≤ ULN plus ALT and AST are ≤ ULN 
plus alkaline phosphatase, hemoglobin, and reticulocyte count are all ≤ ULN. 
• Albumin ≤ ULN; 
• PT ≤ ULN. 
5.1.3. Additional Inclusion Criteria for Groups 2, 3 & 4 Only (Hepatic Impairment) 
1. Stable hepatic impairment that meets the criteria for Class A, B, or C of the 
Child-Pugh classification (refer to Appendix 11) with no clinically significant change 
in disease status within the 28 days prior to the screening visit, as documented by the 
participant’s recent medical history (eg, no worsening clinical signs of hepatic 
impairment, no worsening of T bili or PT by more than 50%). 
2. Stable concomitant medications for the management of individual participant’s 
medical history; on a case-by-case basis, with approval from the sponsor, participants 
receiving fluctuating concomitant medication/treatment may be considered if the 
underlying disease is under control. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. Participants in All Groups 
Medical Conditions: 
1. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection). 


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CCI 
NOTE: Participants who have undergone cholecystectomy and/or appendectomy are 
eligible for this study as long as the surgery occurred more than 6 months prior to 
screening. 
2. At screening, a positive result for HIV antibodies, as assessed by sponsor approved 
laboratory, with a single repeat permitted to assess eligibility, if needed. 
3. Personal or family history of MTC or MEN2, or participants with suspected MTC per 
the investigator’s judgement. 
4. History of acute pancreatitis within 6 months before the screening visit or any history 
of chronic pancreatitis. 
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 specific prohibited prior/concomitant therapies as outlined in Section 6.9, 
Appendix 9 and Appendix 10. 
Prior/Concurrent Clinical Study Experience: 
7. Previous administration with an investigational product (drug or vaccine) 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). 
 
 
8. Known prior participation (ie, received at least 1 dose of study intervention) in a 
study involving PF-07081532. 
Diagnostic Assessments: 
9. eGFR < 60 mL/min/1.73m2 (calculated with the 2021 CKD-EPI Scr-Scys combined 
equation, see Appendix 7), at the screening visit, as assessed by the sponsor approved 
laboratory, and confirmed by a single repeat test, if deemed necessary. 
10. A positive urine drug test at screening or Day -1. However, participants in 
Groups 2-4, only, who have been medically prescribed medications, 
eg, opiates/opioids, cannabinoids, benzodiazepines, methylphenidate (or similar), and 
report the use of these drugs to the investigator at the screening visit may be allowed 
to participate, after approval from the sponsor, and if in line with protocol 


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specifications regarding prohibited medications (see Section 6.9, Appendix 9 and 
Appendix 10). 
NOTE: repeat urine drug testing to assess study eligibility at screening or Day -1 is 
not permitted in this study. 
11. At screening or Day -1, a positive breath alcohol test, as assessed using kits approved 
by sponsor; for the screening test, a single repeat (which may be on a separate day) 
before Day -1 is permitted to assess eligibility, if needed. 
12. For females, pregnancy, as indicated by a positive serum pregnancy test at screening 
and/or positive urine pregnancy test in WOCBP at Day -1. 
13. If performed at investigator discretion, safety related laboratory tests collected on 
Day -1, upon review prior to dosing reflect the participant not to be in stable medical 
condition. 
Other Exclusion Criteria: 
14. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing and until the follow-up contact. 
15. History of sensitivity to heparin or heparin-induced thrombocytopenia, only if heparin 
is used to flush IV catheters used during serial blood collections. 
16. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
5.2.2. Additional Exclusion Criteria for Group 1 Only (without Hepatic Impairment) 
1. Evidence of chronic liver disease including history of hepatitis, hepatitis B, or 
hepatitis C or evidence of any of the following, as assessed by sponsor approved 
laboratory, with a single repeat, permitted to assess eligibility, if needed: 
• Hepatitis B virus, defined by presence of HBsAg; 
NOTE: while not part of the tests assessed in this study, a previously positive 
hepatitis B surface antibody result due to vaccination is permissible. 
• Hepatitis C infection, defined by presence of HCVAb and HCV RNA. 


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2. 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) and 4 (female) 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). 
3. Screening supine 12-lead ECG demonstrating QTcF interval >450 ms or a QRS 
interval >120 ms. If QTcF exceeds 450 ms, or QRS exceeds 120 ms, 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. 
4. Screening seated SBP ≥140 mm Hg or DBP ≥90 mm Hg, following ≥5 minutes of 
seated rest. If SBP is ≥140 mm Hg or DBP ≥90 mm Hg, the BP assessment should be 
repeated 2 more times and the average of the 3 BP values should be used to determine 
eligibility. 
5. Use of chronic prescription medications within 7 days or 5 half-lives (whichever is 
longer) prior to Day 1, or for prohibited medications, use within the required 
washout/restriction period provided in Appendix 9 and Appendix 10. 
NOTE: Use of selected, limited prescription and non-prescription medications may 
be permitted on a case-by-case basis after approval from the sponsor (refer to 
Section 6.9 for details). 
5.2.3. Additional Exclusion Criteria for Groups 2, 3 & 4 Only (Hepatic Impairment) 
1. Hepatic carcinoma or hepatorenal syndrome or limited predicted life expectancy 
(defined as <1 year in Groups 2 & 3 and <6 months for Group 4 only). 
2. A diagnosis of hepatic dysfunction secondary to any acute ongoing hepatocellular 
process that is documented by medical history, PE, liver biopsy, hepatic ultrasound, 
CT scan, or MRI. 
3. History of surgery that would be expected to alter absorption, distribution, 
metabolism, or excretion properties of PF-07081532 (eg, status post porta-caval shunt 
surgery). 
NOTE: Participants with a transjugular intrahepatic portosystemic shunt are 
permitted provided that they meet the Child-Pugh criteria. 
4. History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less 
than 4 weeks prior to the screening visit. 
5. Signs of clinically active Grade 3 or 4 hepatic encephalopathy (ie, > Grade 2 Portal 
Systemic Encephalopathy score; refer to Appendix 11). 


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6. Severe ascites and/or pleural effusion, except for those categorized in Group 4 who 
may be enrolled provided participant is medically stable, per the investigator’s 
judgment. 
7. Previously received a kidney, liver, or heart transplant. 
8. Screening supine 12-lead ECG demonstrating a QTcF interval >470 ms or a QRS 
interval >120 ms. If QTcF exceeds 470 ms, or QRS exceeds 120 ms, the ECG should 
be repeated 2 more times and the average of the 3 QTcF or QRS values should be 
used to determine eligibility. 
9. At screening, Day -1 or pre-dose on Day 1, persistent severe, uncontrolled 
hypertension as outlined below: 
• Groups 2, 3 and 4 at screening or Day -1: seated SBP ≥180 mm Hg or 
DBP ≥105 mm Hg after ≥5-minute of seated rest, with a single repeat permitted to 
assess eligibility, if needed, at each of these 2 visits; if done, the repeat 
assessment overrides initial results. 
NOTE: For participants with SBP ≥160 and ≤179 mm Hg or DBP ≥100 and 
≤104 mm Hg at screening, the period between screening and Day -1 may be used 
to refine the doses of the agents used for management of BP with the aim of 
having stable BP by Day -1. 
• Groups 2 and 3 only, at Day 1: seated SBP ≥160 mm Hg or DBP ≥100 mm Hg 
after ≥5-minute of seated rest, with a single repeat permitted to assess eligibility, 
if needed; if done, the repeat assessment overrides initial results. 
• Group 4 only, at Day 1: seated SBP ≥ 160 mm Hg or DBP ≥105 mm Hg after 
≥5-minute of seated rest, with a single repeat permitted to assess eligibility, if 
needed; if done, the repeat assessment overrides initial results. 
10. ALT or AST >5x ULN on clinical laboratory tests at screening, as assessed by the 
sponsor approved laboratory, with a single repeat permitted to assess eligibility, if 
needed. 
5.3. Lifestyle Considerations 
After confirmation of eligibility, participants will be instructed to maintain the guidelines 
described below for the duration of participation in the study. 
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
from the permitted list of contraception methods (see Appendix 4, Section 10.4.4) and will 
confirm that the participant has been instructed in its consistent and correct use. At time 


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points indicated in SoA, the investigator or designee will inform the participant of the need to 
use highly effective contraception consistently and correctly and document the conversation 
and the participant’s affirmation in the participant’s chart. Participants need to affirm their 
consistent and correct use of at least 1 of the selected methods of contraception, considering 
that their risk for pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner. 
5.3.2. Meals and Dietary Restrictions 
• Participants must abstain from all food and drink (except water) at least 4 hours prior 
to all fasting clinical laboratory evaluations and at least 8 hours prior to the collection 
of the pre-dose PK sample on Day 1. 
• Water may be consumed as desired (ad libitum). 
• While inpatient, all meals will be standardized as follows: 
• On Day 1, following an overnight fast of at least 8 hours, participants should 
begin breakfast approximately 30 minutes prior to PF-07081532 administration. 
The breakfast will be consumed over approximately a 20-minute period with 
PF-07081532 administered within approximately 10 minutes after completion of 
the meal. Participants will be encouraged to complete the entire breakfast. There 
will be no water restrictions prior to dosing. 
• Standard morning meal, lunch, an optional afternoon snack, an evening meal, and 
an optional evening snack will be provided at a similar clock time to the clock 
time when these meals are provided relative to dosing on Day 1 while inpatient 
ie, approximately 0H, 4H, 6H (optional snack), 10H, and 14H (optional snack). 
• The total daily nutritional composition should be approximately 
55% carbohydrate, 30% fat and 15% protein. The nutritional macronutrient 
composition consumed by each participant should be maintained, as much as 
practically possible. 
• The daily caloric intake per participant should not exceed approximately 
3200 kcal. 
• Participants will refrain from consuming red wine, grapefruit, or 
grapefruit-related citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 
7 days prior to Day 1 and until collection of the final PK blood sample. 


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• When a meal or snack is scheduled at the same time as an ECG and/or vital sign 
assessments, the meal will be provided after the ECG and/or vital sign 
assessments are completed. 
5.3.3. Caffeine, Alcohol, and Tobacco 
• Participants will abstain from alcohol for ≥24 hours prior to admission for inpatient 
stay (and for red wine abstain for at least 7 days prior to Day 1), plus have a negative 
breath alcohol test on Day -1, and continue abstaining from alcohol until collection of 
the final PK blood sample. 
• Participants will undergo breath alcohol tests at timepoints indicated in the SoA, 
additional tests may be conducted at investigator discretion 
• Consumption of caffeinated drinks and tobacco (or nicotine containing products) is 
permitted during participation in the study; however, there may be a need for brief 
interruption while at the site, depending on local site policy. 
In addition: 
• Participants must abstain from caffeine-containing products for a minimum of 2 hours 
prior to all vital signs and ECG measurements conducted throughout study 
participation (from screening to the final follow-up visit). 
• Smoking may not be permitted when it would interfere with the timing of scheduled 
study procedures. In addition, participants must abstain from use of tobacco- or 
nicotine-containing products: for a minimum of 2 hours prior to all vital signs and 
ECG measurements; for a minimum of 2 hours prior to and following administration 
of study intervention. 
5.3.4. Activity 
• Participants will not be permitted to engage in physically strenuous exercise (eg, 
heavy lifting, weight training, calisthenics, and aerobics) within 48 hours before each 
blood sample collection for clinical laboratory tests while participating in the study; 
physical activity at an individual participant’s normal pace is permitted. 
• In order to standardize the conditions on PK sampling days, all participants will be 
required to refrain from lying down (except if required for study procedures, 
eg, ECG), eating, and drinking beverages other than water during the first 4 hours 
after dosing. 
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. 


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In this study, participants may be rescreened only after contact with a sponsor Clinical 
representative. This may be permitted when, for example due to logistical constraints or 
administrative reasons, the maximum period between screening visit and Day 1, of 28 days, 
is exceeded. In addition, for participants in Groups 2-4 only, rescreening may be appropriate 
following mild intercurrent illness after the condition has resolved. Otherwise, individuals 
who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
In cases where rescreening is permitted, all screening procedures must be repeated and the 
participant assigned a new 8-digit SSID number. Participants must be deemed to meet all the 
eligibility criteria under the new 8-digit SSID before progressing to Day 1. Reconsent is 
required. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study interventions are all prespecified investigational products, medical devices, and other 
interventions (eg, surgical and behavioral) intended to be administered to the study 
participants during the study conduct. 
For the purposes of this protocol, study intervention refers to PF-07081532. 
6.1. Study Intervention(s) Administered 
 
Study Intervention(s) 
Intervention Name 
PF-07081532 
Arm Name 
(group of participants receiving a 
specific treatment or no treatment) 
Group 1, Group 2, Group 3, Group 4 
Type 
Drug 
Dose Formulation 
Tablet 
Unit Dose Strength(s) 
20 mg 
Dosage Level(s) 
20 mg, single dose 
Route of Administration 
Oral 
Use 
Experimental 
IMP or NIMP/AxMP 
IMP 
Sourcing 
Provided centrally by the sponsor. Refer to the IPM. 
Packaging and Labeling 
Study intervention will be provided as open-label supply in bulk bottles 
along with individual dose containers, as necessary, for unit dosing. 
Current/Former Name(s) or Alias(es) 
PF-07081532 20 mg tablets 


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Study Arm(s) 
Arm Title 
Group 1 
Group 2 
Group 3 
Group 4 
Arm Type 
Experimental 
Experimental 
Experimental 
Experimental 
Arm 
Description 
Participants 
without hepatic 
impairment will 
receive a single 
20 mg dose of 
PF-07081532, 
administered orally 
as 1 PF-07081532 
20 mg tablet 
Participants with 
mild hepatic 
impairment will 
receive a single 
20 mg dose of 
PF-07081532, 
administered orally 
as 1 PF-07081532 
20 mg tablet 
Participants with 
moderate hepatic 
impairment will 
receive a single 
20 mg dose of 
PF-07081532, 
administered orally 
as 1 PF-07081532 
20 mg tablet 
Participants with 
severe hepatic 
impairment will 
receive a single 
20 mg dose of 
PF-07081532, 
administered orally 
as 1 PF-07081532 
20 mg tablet 
Associated 
Intervention 
Labels 
PF-07081532 
PF-07081532 
PF-07081532 
PF-07081532 
PF-07081532 will be supplied by Pfizer as 20 mg tablets in open-label bulk bottles along 
with individual dosing containers, as necessary, for unit dosing. For the 20 mg dose 
administered in this study, participants will take 1 PF-07081532 20-mg tablet, orally, with 
the morning meal as described in Section 5.3.2. 
6.1.1. Administration 
Following an overnight fast of at least 8 hours, participants will receive breakfast as outlined 
in Section 5.3.2 (Meals and Dietary Restrictions). The participants will then receive study 
intervention at approximately 08:00 hours (plus or minus 2 hours) on Day 1. Investigator site 
personnel will administer study intervention with ambient temperature water to a total 
volume of approximately 120 mL. Participants will swallow the study intervention whole, 
and will not manipulate or chew the study intervention prior to swallowing. 
6.2. Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm that appropriate conditions 
(eg, temperature) have been maintained during transit for all study interventions 
received and any discrepancies are reported and resolved before use of the study 
intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 


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indicate the minimum and maximum temperatures since previously documented upon 
return to business. 
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
as soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to 
report for each excursion will be provided to the site in the IPM. 
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
6. Study interventions should be stored in their original containers. 
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record. 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IPM. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer. 
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM. 
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 
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. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities. 
Tablets will be prepared at the CRU in the individual dosing containers by 2 operators, 1 of 
whom is an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist). 
The tablets will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements. 


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6.3. Assignment to Study Intervention 
This is an open-label study in which each participant dosed will receive a single 20 mg dose 
of PF-07081532. Following completion of informed consent at the screening visit, each 
participant will be assigned a single 8 digit SSID number by the site staff. The first 4 digits of 
the SSID will reflect the sponsor-assigned site number and the remaining 4 digits will reflect 
each participant’s unique number assigned in chronological order of when informed consent 
is obtained. Each participant who is dosed with study intervention will also be assigned a 
separate, distinct number (as provided to the site by the sponsor), to enable execution of the 
sponsor’s standard processes for analysis of PK samples. 
6.4. Blinding 
This is an open-label study. 
6.4.1. Blinding of Participants 
Participants will be unblinded to their assigned study intervention. 
6.4.2. Blinding of Site Personnel 
Investigators and other site staff will be unblinded to participants’ assigned study 
intervention. 
6.4.3. Blinding of the Sponsor 
Sponsor staff will be unblinded to participants’ assigned study intervention. 
6.5. 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. 
A record of the number of study intervention tablets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. 
6.6. Dose Modification 
Dose modification of PF-07081532 is not allowed. 


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6.7. Continued Access to Study Intervention After the End of the Study 
No study intervention will be provided to participants at the end of their study participation. 
6.8. Treatment of Overdose 
For this study, any dose of PF-07081532 greater than CCI  within a 24-hour time period will 
be considered an overdose. This dose is projected to result in exposure that will exceed that 
observed at the NOAEL in the pivotal 9-month toxicology study in monkeys, after 
accounting for species differences in plasma protein binding. 
There is no specific treatment for an overdose. 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the study medical monitor within 24 hours. 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
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 3 days from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis). 
6.9. Prior and Concomitant Therapy 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit. 
Treatments taken within 28 days before study intervention dosing on Day 1 will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments. 
Females using hormonal contraceptives or taking hormone replacement therapy are eligible 
to participate in this study. See Appendix 4 for hormonal contraceptives that are permitted in 
this study. 
Participants on certain medications are excluded from the study (see CCI 
 for list of 
prohibited medications CCI 
 and Appendix 10 for a list of 
other prohibited medications. 


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CCI 
Sites are encouraged to contact the sponsor should there be questions as to whether a 
medication is permitted or prohibited. 
6.9.1. Participants in Group 1 Only (without Hepatic Impairment) 
In general, participants in Group 1 (without hepatic impairment) will abstain from all 
concomitant treatments, except for the treatment of AEs. Of note, are the following 
restrictions: 
• Acetaminophen/paracetamol may be used at doses of ≤1 g/day; 
• Herbal supplements must be discontinued at least 28 days prior to Day 1 and until the 
follow-up contact; 
• Limited use of prescription and nonprescription medications that are not believed to 
affect the overall results of the study may be permitted on a case-by-case basis after 
approval from the sponsor study team. 
6.9.2. Participants in Groups 2, 3 & 4 Only (Hepatic Impairment) 
Participants in Groups 2, 3 & 4 (with hepatic impairment) are permitted to be on stable doses 
of background medications for the management of their concomitant medical condition(s), as 
long as this is in line with protocol specifications regarding prohibited medications as 
described above in Section 6.9 and in Appendix 9 and Appendix 10. On a case-by-case basis, 
with approval from the sponsor, participants receiving fluctuating concomitant 
medication/treatment may be considered if the underlying disease is under control. Whenever 
possible, attempts must be made to not add new medications or alter the doses and regimens 
of the concomitant medications after enrollment and for the duration of participation in this 
study, except in circumstances where a change is deemed medically necessary. Any changes 
must be captured in the CRF. 
Participants may receive any permitted background medications according to their stable 
medication routine at their usual dosing times. This is with the exception of 
which must 
not be administered within the 8 hours before study intervention dosing or within the 4 hours 
after study intervention dosing on Day 1. On Day 1, the investigator will determine the 
appropriate time to administer medications that are to be taken on an empty stomach. 
Otherwise, permitted concomitant medications that may be administered under fed 
conditions can be taken with breakfast on the morning of Day 1. On all other study days, 
participants are to receive their background medications at their usual times. 
6.9.3. Rescue Medicine 
There is no rescue therapy to reverse AEs observed with PF-07081532; standard medical 
supportive care must be provided to manage any 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. 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following: safety, behavioral, compliance or 
administrative reasons, or if the study is terminated by sponsor. 
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 and then are 
prematurely withdrawn from the study. Participants should be questioned regarding their 
reason for withdrawal. The participant will be permanently discontinued from the study 
intervention and the study at that time. 
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. 
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will 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 them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The 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. 


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7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if the participant 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 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record; 
• Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1. Administrative Procedures 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants may be rescreened after contact with a sponsor Clinical 
representative as described in Section 5.4. 


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Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner. 
If done around the time of a blood draw, ECGs and vital sign assessments (BP and pulse rate) 
should be collected before the blood draw. If an IV catheter is utilized for blood sample 
collections, ECGs and vital sign assessments (BP and pulse rate) should be collected before 
insertion of the catheter. 
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 
170 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days. 
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol. 
8.2. Efficacy Assessments 
Not applicable. 
8.3. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues. 
8.3.1. Physical Examinations 
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
neck, 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 per the SoA and recorded in the CRF. 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 8.4.1 to 8.4.3. 
8.3.2. Vital Signs 
8.3.2.1. Blood Pressure and Pulse Rate 
Blood pressure and pulse rate will be measured as defined in the SoA. 
• Single, seated BP and pulse rate will be measured with the participant’s arm 
supported at the level of the heart, and recorded to the nearest mmHg, following a rest 
of ≥5 minutes; 
• Same arm (preferably the dominant arm) will be used for BP/pulse rate assessment 
throughout the study; 
• BP/pulse rate assessment should not be taken from the arm with an IV catheter, if 
placed; 
• Participants should be instructed not to speak during BP/pulse rate 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. 
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Section 8.4.1 to 8.4.3. 


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8.3.3. Electrocardiograms 
Supine standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. 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 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms 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 QTcF 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. 
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
values 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 8. 
8.3.4. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 


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The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 5 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 study medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI. 
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities. 
8.3.5. Management of Hypoglycemia 
While GLP-1R agonists typically are not associated with hypoglycemia unless 
co-administered with anti-diabetic agents that can cause hypoglycemia (such as insulin or 
sulfonylureas), participants will be monitored for signs and symptoms of hypoglycemia. 
Blood glucose concentrations may be measured via a glucometer, at investigator discretion. 
Any episode of hypoglycemia must be captured on the AE CRF with specific details captured 
on the HAE Form CRF. For the definition of a hypoglycemic episode and severity 
categorization see Section 8.3.5.1 below. 
8.3.5.1. Definition and Severity of Hypoglycemic Adverse Event (HAE) 
The investigator must assess any glucose values, if measured, as well as any signs or 
symptoms reported by the study participant. 
HAE is defined as one of the following:12 
a. Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a glucose value of <70 mg/dL (3.9 mmol/L) using either glucometer 
(fingerstick blood glucose) at the study site or sponsor approved laboratory (plasma 
glucose). 


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b. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose value of <70 mg/dL (3.9 mmol/L), using 
glucometer (fingerstick blood glucose) at the study site or sponsor approved 
laboratory (plasma glucose), and the clinical picture includes prompt resolution with 
food intake, subcutaneous glucagon, or IV glucose. 
c. Probable symptomatic hypoglycemia: An event during which symptoms of HAE are 
not accompanied by a glucose determination but was presumably caused by a glucose 
concentration of <70 mg/dL (3.9 mmol/L), and the clinical picture includes prompt 
resolution with food intake, subcutaneous glucagon, or IV glucose. 
Each episode of HAE must be categorized with respect to severity. In order to characterize 
the event as severe, all 3 criteria below must be met: 
1. The participant was unable to treat him/herself. Neurologic impairment, and not the 
age of the participant, is the explanation for why the participant could not treat 
him/herself and required the assistance of another person. 
2. The participant exhibited at least 1 of the following neurological symptoms: 
• Memory loss; 
• Confusion; 
• Uncontrolled behavior; 
• Irrational behavior; 
• Unusual difficulty in awakening; 
• Suspected seizure; 
• Seizure; 
• Loss of consciousness. 
3. Either: 
• If blood glucose was measured and was ≤54 mg/dL (2.7 mmol/L) using 
glucometer (or laboratory); or 
• If blood glucose was not measured, the clinical manifestations were reversed by 
oral carbohydrates, subcutaneous glucagon, or IV glucose. 
Events that do not meet all the criteria above for severe HAE are characterized as mild or 
moderate in severity. 


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8.3.6. COVID-19 Specific Assessments 
Assessment of risk for, symptoms of or testing for COVID-19 may be performed at 
screening, admission to the CRU and/or at other times during the study at investigator 
discretion and according to local site policies. 
8.3.7. Pregnancy Testing 
A serum pregnancy test is required in all females at screening. Following screening, 
pregnancy tests may be urine or serum tests, and must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. In 
WOCBP, following a negative pregnancy test result at screening, appropriate contraception 
must be commenced or continued and a second negative pregnancy test result will be 
required at Day -1 prior to the participant’s receiving the study intervention on Day 1. 
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected) and at the end of the 
study. Pregnancy tests may also be repeated if requested by IRBs/ECs or if required by local 
regulations. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded if the serum 
pregnancy result is positive. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Appendix 3. 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (see Section 7.2). 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 


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8.4.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including 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 the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator. 
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant permanently discontinues or temporarily discontinues study 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 they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form. 
8.4.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available. 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 


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As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4. 
8.4.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. Follow-Up of AEs and SAEs 
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is provided in Appendix 3. 
8.4.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 


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An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure. 
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 
8.4.5.1. Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
• A male participant who is receiving or has discontinued study intervention 
inseminates a female partner. 
• A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 
• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion. 
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/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 


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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 should be reported 
as an SAE; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
8.4.5.2. Exposure During Breastfeeding 
An EDB occurs if: 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
• A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 


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that she is breastfeeding after having been exposed to the study intervention by 
ingestion. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant enrolled in the study, so the 
information is not recorded on a CRF. However, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file. 
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB. 
8.4.5.3. Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form regardless of 
whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file. 
8.4.6. Cardiovascular and Death Events 
Not applicable. 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
8.4.8. Adverse Events of Special Interest 
Not applicable. 
8.4.8.1. Lack of Efficacy 
This section is not applicable because efficacy is not expected in the study population. 
8.4.9. Medical Device Deficiencies 
Not applicable. 


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8.4.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Medication errors are recorded and reported as follows: 
 
Recorded on the 
Medication Error Page 
of the CRF 
Recorded on the 
Adverse Event Page 
of the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
All (regardless of whether 
associated with an AE) 
Any AE or SAE associated 
with the medication error 
Only if associated with an 
SAE 
Medication errors include: 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of PF-07081532 
Blood samples of approximately 3 mL, to provide a minimum volume of 1 mL plasma, will 
be collected into appropriately labeled tubes containing K2EDTA for measurement of plasma 
concentrations of PF-07081532 as specified in the SoA. 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. 


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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. 
Samples will be used to evaluate the PK of PF-07081532. 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. 
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained. 
Samples collected for measurement of plasma concentrations of PF-07081532 will be 
analyzed using a validated analytical method in compliance with applicable SOPs. Potential 
metabolites may be analyzed with either validated or exploratory methods. 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
8.5.2. Plasma for Determination of PF-07081532 Unbound Fraction 
During the study, blood samples of approximately 10 mL to provide sufficient plasma 
(approximately 4 mL) for unbound fraction determination, will be collected into 
appropriately labeled tubes containing K2EDTA, as specified in the SoA. Instructions for the 
collection and handling of biological samples will be provided in the laboratory manual or by 
the sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
The actual times may change, but the number of samples will remain the same. 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. 


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Samples collected for analyses of PF-07081532 plasma protein binding 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 analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained. 
Samples collected for measurement of PF-07081532 plasma protein binding will be analyzed 
using a validated analytical method in compliance with applicable SOPs. Potential 
metabolites may be analyzed with either validated or exploratory methods. 
The samples for determination of PF-07081532 plasma protein binding 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. 
8.6. Genetics 
8.6.1. Specified Genetics 
Specified genetic analyses are not evaluated in this study. 
 
 
 
 
8.7. Biomarkers 
 
 
8.7.2. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study. 


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8.7.3. Specified Protein Research 
Specified protein research is not included in this study. 
8.7.4. Specified Metabolomic Research 
Specified metabolomic research is not included in this study. 
8.8. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
8.9. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 
9.1. Statistical Hypotheses 
No formal statistical hypothesis testing will be performed in this study. 
9.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis 
Set 
Description 
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
assignment to study intervention. 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. 
Safety analysis set 
All participants assigned to study intervention and who take at 
least 1 dose of study intervention. 


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Participant Analysis 
Set 
Description 
PK Concentration Set 
The PK concentration population is defined as all participants 
who received at least 1 dose of PF-07081532 and in whom at 
least 1 plasma concentration value is reported. 
PK Parameter Set 
The PK parameter analysis population is defined as all 
participants who received at least 1 dose of PF-07081532 and 
have at least 1 of the PK parameters of interest calculated. 
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 
Endpoints will be reported and analyzed according to the hepatic function group that 
participants fall into based upon their Child-Pugh score at screening. 
9.3.1.1. Analyses for PK Endpoints 
Natural log-transformed PK parameters will be analyzed using an ANOVA model including 
hepatic function group as fixed effect. Estimates of the adjusted means and of the adjusted 
mean differences (Test-Reference) with their corresponding 90% CIs will be obtained before 
being exponentiated to provide estimates of the adjusted geometric means and of the ratio of 
adjusted geometric means (Test/Reference). 
9.3.2. Primary Endpoint(s) Analysis 
9.3.2.1. Definition of Endpoint(s) 
The plasma PK parameters for PF-07081532 following single dose administration will be 
derived from the concentration-time profiles as detailed in Table 3. Actual PK sampling 
times will be used in the derivation of PK parameters. In the case that actual PK sampling 
times are not available, nominal PK sampling time will be used in the derivation of PK 
parameters. The fraction of PF-07081532 unbound in plasma (fu) will be determined by the 
analytical lab and reported for each participant. 


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Table 3. 
Plasma PK Parameters 
Parameter 
Definition 
Method of Determination 
AUClast 
Area under the plasma 
concentration-time profile from 
Linear/Log trapezoidal method. 
time zero to the time of the last 
quantifiable concentration (Clast) 
AUCinf* 
Area under the plasma 
AUClast + (Clast*/kel), where Clast* is the predicted 
concentration-time profile from 
plasma concentration at the last quantifiable time 
time zero extrapolated to infinite 
point estimated from the log-linear regression 
time 
analysis. 
Cmax 
Maximum plasma concentration 
Observed directly from data. 
 
 
 
 
 
 
 
 
 
 
 
fu 
Fraction of unbound drug in 
plasma 
Cu/C (where Cu represents unbound 
concentration and C represents total 
concentration). 
AUClast,u 
Unbound AUClast 
fu∙AUClast. 
AUCinf,u* 
Unbound AUCinf 
fu∙AUCinf. 
Cmax,u 
Unbound Cmax 
fu∙Cmax. 
CCI 
 
* as data permit 
9.3.2.2. Main Analytical Approach 
The effect of varying degrees of hepatic impairment on PK parameters will be assessed by 
constructing 90% CIs around the estimated difference between each of the Test (hepatic 
impaired) groups and the Reference (without hepatic impairment) group. A one-way 
ANOVA will be used to compare the natural log transformed PF-07081532 AUCinf, Cmax, 
AUClast, fraction unbound (fu), and associated unbound parameters (AUCinf,u, Cmax,u, 
AUClast,u), as data permit, for each of the hepatic impairment groups (Test) to the group 
without hepatic impairment (Reference). Estimates of the adjusted mean differences 
(Test - Reference), and corresponding 90% confidence intervals, will be obtained from the 
model. These will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% confidence intervals for the ratios. 


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Individual PF-07081532 concentrations will be listed and summarized descriptively by 
nominal PK sampling time and hepatic function group. Individual participant and summary 
profiles of the concentration-time data (using actual and nominal times, respectively) will be 
plotted by hepatic function group for both total plasma PF-07081532 and unbound 
PF-07081532. 
Box and whisker plots for individual PK parameters (AUCinf, AUClast, Cmax, fu, AUCinf,u, 
AUClast,u and Cmax,u) will be constructed by hepatic function group and overlaid with 
geometric means. PK parameters of PF-07081532 will be summarized descriptively by 
hepatic function group. Unbound fraction (fu) will be listed and summarized descriptively 
by hepatic function group. 
9.3.2.3. Supplementary Analyses 
Additional analysis using linear regression may be used to analyze the potential relationship 
between appropriate PK parameters (eg, AUCinf, AUClast, Cmax, fu, AUCinf,u, AUClast,u, Cmax,u) 
and hepatic function (eg, serum albumin concentration, PT or T bili). Plots of PK parameters 
(eg, AUCinf, AUClast, Cmax, fu, AUCinf,u, AUClast,u, Cmax,u) versus hepatic function will be 
constructed, with a regression line and 90% confidence region included. Estimates of the 
slope and intercept, together with a 90% CI, and the coefficient of determination 
(ie, R-squared and adj-R-squared) may be obtained from the model. 
Additionally, as an exploratory analysis, age and body weight may be explored as additional 
covariates/factors in the models, as appropriate. 
9.3.3. Secondary Endpoint Analysis - 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 
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. 
COVID-19 specific assessments data will be considered source data and will not be required 
to be reported. 


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9.3.3.1. Electrocardiogram Analyses 
Changes from baseline for the ECG parameters HR, QTcF, PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated. 
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
 
Safety QTcF Assessment 
 
Degree of Prolongation 
Mild (ms) 
Moderate (ms) 
Severe (ms) 
Absolute value 
>450-480 
>480-500 
>500 
Increase from baseline 
30-60 
>60 
 
 
 
 
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 modeling, and/or supporting clinical 
development. 
9.5. Sample Size Determination 
A sample size of approximately 24 participants (approximately 6 participants per group, with 
varying degrees of hepatic function in each of the 4 groups) has been selected to provide 
sufficient precision to detect a 2-fold difference in AUCinf between each Test group (with 
hepatic impairment) and the Reference group (without hepatic impairment). Table 4 presents 
the 90% CIs (with 80% coverage probability) for various possible effects on AUCinf. The 
same table would be applicable for possible effects on Cmax. 


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Table 4. 
Expected Widths of the 90% CIs (with 80% Coverage Probability) for 
Different Possible Estimated Effects 
 
Estimated Effect 
(Test/Reference) 
AUCinf 
Probable 90% CI 
Probable CI Width 
CCI 
These estimates are based on an assumed conservative standard deviation of CC for 
logeAUCinf (also applicable to logeCmax) based on data from internal previousI studies with 
PF-07081532 administered either as a single dose in the fed/fasted state in healthy 
participants (C3991001) or as multiple doses in the fed state in participants with T2DM 
(C3991002). 
Participants who discontinue from the study before completing all assessments may be 
replaced at the discretion of the investigator and sponsor. 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines; 
• Applicable ICH GCP guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated. 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations. 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of. 
10.1.2. Financial Disclosure 
Investigators and 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 the investigator’s 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 participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data. 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
The investigator further must ensure that each study participant is fully informed about their 
right to access and correct their personal data and to withdraw consent for the processing of 
their 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 IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations. 
A copy of the ICD(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICD. 
10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law. 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
10.1.5. Committees Structure 
A data monitoring committee or independent oversight committee will not be utilized. 
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC. 


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10.1.6. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
EudraCT/CTIS 
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements. 
www.pfizer.com 
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized. 
Documents within marketing applications 
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized. 
Data sharing 
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized. 


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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 
10.1.7. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document. 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties. 
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. 


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
10.1.8. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor. 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements. 
10.1.9. Study and Site Start and Closure 
The study start date is the date 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, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 


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closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed. 
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants. 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines; 
• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
10.1.10. Publication Policy 
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study. 
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section. 
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 


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comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication. 
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication. 
10.1.11. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI 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 their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, participants are provided with 
an 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 participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they 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 5. 
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) 
Coagulation 
aPTT,PT,INR 
PT control 
BUN 
Creatinine (Scr) 
Cystatin C (Scys) 
eGFRa 
Plasma Glucose 
(fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (Bicarbonate) 
AST 
ALT 
Alkaline phosphatase 
GGT 
T bili 
Direct bilirubinb,c 
Indirect bilirubinb,c 
Creatine kinaseb,d 
Uric acid 
Albumin 
Total protein 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte 
esterase 
Urobilinogen 
Urine bilirubin 
Microscopye 
Other tests as part of clinical laboratory tests: 
At times specified in SoA: 
• Urine pregnancy test (WOCBP only)f 
At screening only: 
• Serology: HBsAg, HCVAb (if positive, HCV 
RNA) and HIV 
• Serum FSH (all females) 
• Serum pregnancy test (β-hCG) (all females) 
• Reticulocyte count (Abs) 
• Total bile acids 
• Amylase 
• Lipase 
At screening and Day -1 only: 
• Breath alcohol testg 
• Urine drug testh 
For suspected DILI: 
• AST, ALT 
• T bili, direct and indirect bilirubin 
• Total bile acids, GGT 
• Albumin 
• Alkaline phosphatase 
• CK 
• PT, INR 
• Acetaminophen/paracetamol or 
protein adduct levels 
For suspected DICI/DIKI: 
Creatinine (Scr) 
Cystatin C (Scys) 
eGFRa 
Spot (dipstick) UACR 
a. 
eGFR should be calculated using the 2021 CKD-EPI Scr-Scys combined equations, see Appendix 7. 
b. 
At screening and Day 1 only, unless conditions for testing are met after Day 1 per notes “c” and “d” below. 
c. 
After Day 1, direct and indirect bilirubin assessed only when T bili is > ULN. 
d. 
After Day 1, creatine kinase assessed only when ALT is > ULN. 
e. 
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase. 
f. 
Performed on-site using kits approved by sponsor. 
g. 
Performed on-site using kits approved by sponsor. 
h. 
Minimum testing requirements include cocaine, THC, opiates and opioids, benzodiazepines and amphetamines. 


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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 an 
increase in either frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
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 
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. 
* 
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the CT SAE Report Form and EDP Supplemental Form; if the EDP is associated with 
an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, which would also include details 
of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form. 
• 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. 
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 EDP or EDB 
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF 
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)* 
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)** 
Environmental or 
occupational exposure to 
the product under study 
to a nonparticipant (not 
involving EDP or EDB) 
None. Exposure to a study 
non-participant is not 
collected on the CRF 
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported*** 


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• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
• Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL. 
• Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing discomfort, 
but poses no significant or permanent risk of harm to the research participant. 
• Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
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. 


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• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment. 
• For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor. 
• The investigator may change their opinion of causality in light of -follow-up 
information and send an SAE -follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
• 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. 


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• New or updated information will be recorded in the originally submitted 
documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via an Electronic DCT 
• The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT. 
• If the electronic system is unavailable, then the site will use the paper SAE DCT 
(see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available. 
• After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic DCT has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or 
to Pfizer Safety by telephone. 
 
 
SAE Reporting to Pfizer Safety via the CT SAE Report Form 
• Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety. 
• In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames. 


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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies. 
10.4.2. Female Participant Reproductive Inclusion Criteria 
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she (a) is not pregnant or breastfeeding; and 
(b) agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for 28 days after 
last dose of study intervention; and (c) at least 1 of the following conditions applies: 
• Is not a WOCBP (see definition in Section 10.4.3). 
OR 
• Is a WOCBP and agrees to use a contraceptive method that is highly effective (failure 
rate of <1% per year) with low user dependency during the intervention period and 
agrees to use it for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate any reproductive safety risk of the study 
intervention(s). The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
OR 
• Is a WOCBP and agrees to use a highly effective (failure rate of <1% per year) 
user-dependent method of contraception during the intervention period and for at 
least 28 days after the last dose of study intervention, which corresponds to the time 
needed to eliminate any reproductive safety risk of the study intervention(s). In 
addition to her use of the highly effective method above, she agrees to concurrently 
use an effective barrier method. The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study intervention. 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 


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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to a medical cause other than the above 
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
2. Postmenopausal female. 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition: 
• A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years 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 highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 


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The following contraceptive methods are appropriate for this study: 
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device. 
3. Intrauterine hormone-releasing system. 
4. Bilateral tubal occlusion. 
5. Vasectomized partner. 
• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral + barrier*; 
• Intravaginal + barrier*; 
• Transdermal + barrier*. 
7. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral + barrier*; 
• Injectable + barrier*. 
8. Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 


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* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following: 
• Male or female condom with or without spermicide; 
• Cervical cap, diaphragm, or sponge with spermicide; 
• A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods). 


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CCI 


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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.” 
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to T bili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
• Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value 
≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available. 
• For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller). 
• Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller). 


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Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 


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10.7. Appendix 7: Kidney Safety: Monitoring Guidelines 
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury 
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine. Additionally, baseline and postbaseline serum Scys makes it feasible to 
distinguish AKI from other causes of Scr increase. In this study, eGFR will be determined 
using the 2021 CKD-EPI Scr-Scys combined equation (see Section 10.7.2.1 below) and both 
Scr and Scys will be measured as part of the protocol-required safety laboratory assessments 
at all times specified in the SoA. 
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care. 
10.7.2. Age-Specific Kidney Function Calculation Recommendations 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations13 
 
2021 CKD-EPI 
Scr-Scys 
Combined 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤0.7 
if ≤0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if ≤0.7 
if >0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age 
Female 
if >0.7 
if ≤0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if >0.7 
if >0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if ≤0.9 
if ≤0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if ≤0.9 
if >0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if >0.9 
if ≤0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if >0.9 
if >0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities 
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO 
criteria. 


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10.8. Appendix 8: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• New PR interval prolongation >280 ms. 
• New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms from baseline. 
• New-onset atrial flutter or fibrillation, with controlled ventricular response rate: 
ie, rate <120 bpm. 
• New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration. 
• Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes. 
ECG Findings That May Qualify as SAEs 
• QTcF prolongation >500 ms. 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset LBBB (QRS complex>120 ms). 
• New-onset right bundle branch block (QRS complex>120 ms). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 
• In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
• Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 


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• Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR 
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as 
torsades de pointes]). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heart block. 
ECG Findings That Qualify as SAEs 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyarrhythmias (>30 seconds’ duration). 
• Second- or third-degree AV block requiring pacemaker placement. 
• Asystolic pauses requiring pacemaker placement. 
• Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion. 
• Ventricular fibrillation/flutter. 
• At the discretion of the investigator, any arrhythmia classified as an adverse 
experience. 
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all-inclusive of what to be reported as AEs/SAEs. 


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10.10. Appendix 10: Other Prohibited Prior/Concomitant Medications 
The following medications are prohibited until the follow-up contact, unless stated otherwise. 
If a participant receives a prohibited medication, the investigator should contact the sponsor 
clinician or sponsor medical monitor to determine if the participant should be included in the 
study/continued in the study. 
 
Drug Classes and/or Drugs 
Timeframe of Restriction 
Other GLP-1R agonists 
90 days prior to screening visit until final follow 
up contact 
DPP-4 inhibitors, pramlintide, repaglinide 
Screening visit until final follow-up contact 
Systemic glucocorticoids such as prednisone, 
dexamethasone, triamcinolone, budesonide, 
betamethasone. Note: As an exception, steroid- 
containing inhalers, nasal sprays and topical formulations 
are permitted. 
Screening visit until final follow-up contact 
Immunosuppressants such as cyclosporine and 
tacrolimus. 
Screening visit until final follow-up contact 
Cannabinoids (eg, medically prescribed THC) 
Screening visit until final follow-up contact 


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10.11. Appendix 11: Child-Pugh Classification (CPC) of Liver Dysfunction 
Table 6. 
Scoring for Child-Pugh Classification14 
Group 
CPC 
Level of 
dysfunction 
Total Score 
(tally based on assessment of 
parameters in Table 7) 
1 
Not Applicable 
Without hepatic 
impairment 
Not Applicable 
2 
A 
Mild 
5-6 
3 
B 
Moderate 
7-9 
4 
C 
Severe 
≥10 
Table 7. 
Derivation of Child-Pugh Classification Score 
 
Assessment Parameters 
Assigned score for observed findings 
1 point 
2 points 
3 points 
Encephalopathy gradea 
(refer to Table 8 below) 
0 
1 or 2 
3 or 4a 
Ascites 
Absent 
Asymptomatic 
Requiring intervention 
Serum T bili, mg/dL 
<2 
2 to 3 
>3 
Serum albumin, g/dL 
>3.5 
2.8 to 3.5 
<2.8 
PT, sec prolonged 
<4 
4 to 6 
>6 
a. 
Participants with a prior history of Grade 3 or 4 encephalopathy who are currently receiving 
an intervention [eg, lactulose or lactitol, alone or in combination with rifaximin, and/or neomycin] to 
manage encephalopathy related signs and symptoms should be scored for encephalopathy grading based 
on their presentation while on intervention at the screening visit and can be included in Study C3991009 
as long as they do not have clinically active Grade 3 or 4 encephalopathy. 
 
Table 8. 
Determination of Encephalopathy Grade 
 
Encephalopathy Grade 
Definition 
0 
Normal consciousness, personality, neurological exam 
1 
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting 
2 
Lethargic, time-disoriented, inappropriate, asterixis, ataxia 
3a 
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity 
4a 
Unrousable coma, no personality/behavior, decerebrate 
a. 
Participants with clinically active Grade 3 or 4 encephalopathy are excluded. 


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10.12. Appendix 12: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
Abs 
absolute 
ADL 
activity/activities of daily living 
AE 
adverse event 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC24 
area under the plasma concentration-time profile over 24 hours 
AUCinf 
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time 
AUCinf,u 
unbound area under the plasma concentration-time profile from 
time zero extrapolated to infinite time 
AUClast 
area under the plasma concentration-time profile from time zero to 
the time of the last quantifiable concentration 
AUClast,u 
unbound area under the plasma concentration-time profile from 
time zero to the time of the last quantifiable concentration 
AUCtau 
area under the plasma concentration-time profile over tau, the 
dosing interval, where tau = 24 hours 
AV 
atrioventricular 
AxMP 
auxiliary medicinal product 
-hCG 
-human chorionic gonadotropin 
BBS 
Biospecimen Banking System 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
cAMP 
cyclic adenosine monophosphate 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
chronic kidney disease epidemiology 
CL 
total clearance of drug from eg, plasma 
CCI 
Clast 
last quantifiable concentration 
Cmax 
maximum plasma concentration 


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Abbreviation 
Term 
Cmax,u 
unbound maximum plasma concentration 
CO2 
carbon dioxide (bicarbonate) 
COVID-19 
coronavirus disease 2019 
CPC 
Child-Pugh Classification 
CCI 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
Clinical Study Report 
CT 
clinical trial 
CTIS 
Clinical Trial Information System 
CT scan 
computed tomography scan 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DCT 
data collection tool 
DDI 
drug-drug interaction 
DICI 
drug-induced creatinine increase 
DIKI 
drug-induced kidney injury 
DILI 
drug-induced liver injury 
CCI 
DPP-4 
dipeptidyl peptidase-4 
EC 
ethics committee 
ECC 
emergency contact card 
ECG 
electrocardiogram or electrocardiography 
eCrCl 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
E-DMC 
External Data Monitoring Committee 
EDP 
exposure during pregnancy 
EFD 
embryo-fetal development 
eGFR 
estimated glomerular filtration rate 
eSAE 
electronic serious adverse event 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database) 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
fu 
fraction of unbound drug in plasma 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP-1 
glucagon-like peptide-1 
GLP-1R 
glucagon-like peptide-1 receptor 


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Abbreviation 
Term 
H 
hour 
HAE 
hypoglycemic adverse event 
HBsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C antibody 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ID 
identification 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPAL 
Investigational Product Accountability Log 
IPM 
investigational product manual 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
IVGTT 
intravenous glucose tolerance test 
K2EDTA 
dipotassium edetic acid (ethylenediaminetetraacetic acid) 
kel 
first-order elimination rate constant 
KDIGO 
Kidney Disease Improving Global Outcomes 
LBBB 
left bundle branch block 
LFT 
liver function test 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MEN2 
multiple endocrine neoplasia type 2 
MQI 
medically qualified individual 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid carcinoma 
NA 
Not Applicable 
NIMP 
noninvestigational medicinal product 
NOAEL 
no observed adverse effect level 
NRU 
neutral red uptake 
OATP 
organic anion transporting polypeptide 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PK 
pharmacokinetic(s) 
PO 
per os (by mouth) 
PPI 
proton pump inhibitor 


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Abbreviation 
Term 
PSSA 
Pfizer's Serious Adverse Event Submission Assistant 
PT 
prothrombin time 
PVC 
premature ventricular contraction/complex 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QTc corrected using Fridericia’s formula 
qual 
qualitative 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
Scr 
serum creatinine 
Scys 
serum cystatin C 
SoA 
schedule of activities 
SOC 
System Organ Class 
SOP 
standard operating procedure 
SRSD 
Single Reference Safety Document 
SSID 
single subject identifier 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
terminal phase half-life 
T2DM 
Type 2 Diabetes Mellitus 
T bili 
total bilirubin 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
CCI 
UACR 
urine albumin/creatinine ratio 
UGT 
uridine 5’-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
CCI 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 


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11. REFERENCES 
1. 
Orskov C, Holst JJ, Knuhtsen S, et al. Glucagon-like peptides GLP-1 and GLP-2, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology. 1986;119(4):1467-75. 
2. 
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet. 1987;2(8571):1300-4. 
3. 
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 
1997;273(5):E981-8. 
4. 
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest. 1998;101(3):515-20. 
5. 
US Food and Drug Administration. Guidance for industry: S10 Photosafety evaluation 
of pharmaceuticals. Rockville, MD: Center for Biologics Evaluation and Research; Jan 
2015. 
6. 
Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of 
type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102. 
7. 
Drucker DL. The ascending GLP-1 road from clinical safety to reduction of 
cardiovascular complications. Diabetes.2018;67:1710-9. 
8. 
Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon-like peptide-1 
receptor agonists on heart rate. Cardiovasc Diabetol.2017;16:6. 
9. 
Hachad H, Ragueneau-Majlessi I and Levy RH. A useful tool for drug interaction 
evaluation: the University of Washington Metabolism and Transport Drug Interaction 
Database. Hum Genomics. 2010;5(1):61-72. 
10. Tan ML, Yoshida K, Zhao P, et al. Effect of chronic kidney disease on nonrenal 
elimination pathways: a systematic assessment of CYP1A2, CYP2C8, CYP2C9, 
CYP2C19, and OATP. Clin Pharmacol Ther. 2018; 103(5):854-67. 
11. Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update.Clin 
Transl Med 2016;5(1):23-37. 
12. American Diabetes Association. Standards of medical care in diabetes -2019. Diabetes 
Care 2019;42(Suppl 1):S1-S193. 
13. Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. N Engl J Med. 2021;385:1737-49. 


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14. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for 
bleeding oesophageal varices. Br J Surg. 1973;60(8):646-9. 

SAP_001.pdf: 
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Protocol C3991009 
 
 
 
 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL GROUP STUDY TO 
COMPARE THE PHARMACOKINETICS OF PF-07081532 IN ADULT 
PARTICIPANTS WITH VARYING DEGREES OF HEPATIC IMPAIRMENT 
RELATIVE TO PARTICIPANTS WITHOUT HEPATIC IMPAIRMENT 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
Version: 
1 
Date: 
10Aug-2022 


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TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................3 
LIST OF FIGURES ....................................................................................................................4 
APPENDICES ........................................................................................................................... 4 
1. VERSION HISTORY ........................................................................................................... 5 
2. INTRODUCTION ................................................................................................................ 5 
2.1. Modifications to the Analysis Plan Described in the Protocol ................................. 5 
2.2. Study Objectives, Endpoints, and Estimands ........................................................... 5 
2.2.1. Primary Estimand(s) .................................................................................... 6 
2.2.2. Secondary Estimand(s) ................................................................................ 6 
2.2.3. Additional Estimand(s) ................................................................................ 6 
2.3. Study Design ............................................................................................................ 6 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS .................................................................................................................. 7 
3.1. Primary Endpoint(s) ................................................................................................. 7 
3.2. Secondary Endpoint(s) ............................................................................................. 8 
 
 
 
3.4. Baseline Variables .................................................................................................... 9 
3.5. Safety Endpoints ..................................................................................................... 10 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ................................................... 10 
5. GENERAL METHODOLOGY AND CONVENTIONS ................................................... 10 
5.1. Hypotheses and Decision Rules .............................................................................. 11 
5.2. General Methods .................................................................................................... 11 
5.2.1. Analyses for Continuous Endpoints ........................................................... 11 
5.2.2. Analyses for Categorical Endpoints ........................................................... 11 
5.2.3. One-way Analysis of Variance (ANOVA) ................................................ 11 
5.2.4. Linear Regression PK Parameters versus Hepatic Function ...................... 11 
5.3. Methods to Manage Missing Data .......................................................................... 12 
5.3.1. Pharmacokinetic Concentrations Below the Limit of Quantification ........ 12 
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5.3.2. Pharmacokinetic Deviations, Missing Concentrations and 
Anomalous Values ........................................................................................... 13 
5.3.3. Pharmacokinetic Parameters ....................................................................... 13 
6. ANALYSES AND SUMMARIES ...................................................................................... 13 
6.1. Primary Endpoint(s) ................................................................................................ 13 
6.1.1. PF-07081532 PK Parameters ...................................................................... 13 
6.1.1.1. Main Analysis ............................................................................ 13 
6.1.1.2. Sensitivity/Supplementary Analyses ......................................... 14 
6.2. Secondary Endpoint(s) ............................................................................................ 14 
6.2.1. Adverse Events ........................................................................................... 15 
6.2.2. Laboratory Data .......................................................................................... 15 
6.2.3. Vital Signs .................................................................................................. 15 
6.2.4. ECG ............................................................................................................ 15 
 
 
 
 
6.4. Subset Analyses ...................................................................................................... 17 
6.5. Baseline and Other Summaries and Analyses ......................................................... 17 
6.5.1. Baseline Summaries .................................................................................... 17 
6.5.2. Study Conduct and Participant Disposition ................................................ 17 
6.5.3. Study Treatment Exposure ......................................................................... 17 
6.5.4. Concomitant Medications and Nondrug Treatments .................................. 17 
6.6. Safety Summaries and Analyses ............................................................................. 18 
7. INTERIM ANALYSES ....................................................................................................... 18 
7.1. Introduction ............................................................................................................. 18 
7.2. Interim Analyses and Summaries ............................................................................ 18 
8. REFERENCES .................................................................................................................... 18 
APPENDICES .......................................................................................................................... 19 
LIST OF TABLES 
Table 1. 
Summary of Changes .................................................................................. 5 


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Table 2. 
Hepatic Function Categories Based on Child-Pugh Score......................... 6 
Table 3. Summary of Plasma PK Parameters of PF-07081532 to be calculated ........................ 7 
Table 4. Summary of Plasma PK parameters of Unbound PF-07081532 to be calculated ........ 8 
Table 7. Summary statistics to be produced for Plasma PK Parameters of PF-07081532 ....... 14 
 
 
 
 
 
 
No table of figures entries found. 
 
 
 
 
LIST OF FIGURES 
 
 
APPENDICES 
Table 1. 
Summary of Changes .................................................................................. 5 
Table 2. 
Hepatic Function Categories Based on Child-Pugh Score ......................... 6 
Table 3. Summary of Plasma PK Parameters of PF-07081532 to be calculated ........................ 7 
Table 4. Summary of Plasma PK parameters of Unbound PF-07081532 to be calculated ........ 8 
Table 7. Summary statistics to be produced for Plasma PK Parameters of PF-07081532 ....... 14 
Appendix 1. Statistical Methodology Details .......................................................................... 19 
Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern ...... 20 
Appendix 3. List of Abbreviations ........................................................................................... 21 
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1. VERSION HISTORY 
 
 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1 
10 AUG2022 
Original 
18 May 2022 
N/A 
N/A 
 
2. INTRODUCTION 
PF-07081532 is an oral GLP-1R agonist that is currently being investigated as a chronic 
therapy to improve glycemic control in adult participants with T2DM. Based on review of the 
effect of hepatic impairment on human PK for compounds cleared in a similar manner to PF- 
07081532 (OATP-mediated hepatic uptake), impaired hepatic function is generally 
associated with increased drug exposures in plasma. 
Therefore, the primary purpose of this study is to characterize the effect of varying degrees of 
hepatic impairment on the plasma PK of PF-07081532 following administration of a single 
oral dose of PF-07081532. 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3991009. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
Not Applicable 
 
2.2. Study Objectives, Endpoints, and Estimands 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To compare the PK of PF-07081532 following administration 
of a single oral dose in adult participants with varying degrees 
of hepatic impairment relative to age- and body 
weight-matched participants without hepatic impairment. 
• 
Plasma: Cmax, AUCinf, AUClast*, fu, Cmax,u, 
AUCinf,u and AUClast,u*, as data permit. 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of a single oral dose of 
PF-07081532 when administered to adult participants with 
varying degrees of hepatic impairment and in age- and body 
weight-matched participants without hepatic impairment. 
• 
Assessment of treatment emergent AEs, clinical 
laboratory abnormalities, vital signs, ECG 
parameters. 


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* AUClast and AUClast,u will be treated as primary endpoints if data do not permit robust estimation of AUCinf and AUCinf,u, 
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2.2.1. Primary Estimand(s) 
Not applicable because C3991009 is a Phase 1 study with no estimands on PK endpoints 
2.2.2. Secondary Estimand(s) 
Not applicable because C3991009 is a Phase 1 study with no estimands on safety endpoints 
2.2.3. Additional Estimand(s) 
Not applicable because C3991009 is a Phase 1 study with no estimands on safety endpoints 
2.3. Study Design 
This is an open-label, single-dose, parallel-group, multicenter study to investigate the effect 
of varying degrees of hepatic function on the plasma PK of PF-07081532 after a single, oral 
20 mg dose administered in the fed state (standard breakfast). Safety and tolerability will be 
evaluated throughout the study. A total of approximately 24 participants with varying 
degrees of hepatic function will be dosed in the study as shown in Table 2. If recruitment of 
participants with severe hepatic impairment proves prohibitive, the number of participants to 
be enrolled in this group may be flexible (4-6 participants). 
Table 2. 
Hepatic Function Categories Based on Child-Pugh Score 
 
Group 
Description 
Child-Pugh Score 
Number of Participants 
1 
Without hepatic impairment 
Not Applicable 
6a 
2 
Mild hepatic impairment 
Class A (5 to 6 points) 
6 
3 
Moderate hepatic impairment 
Class B (7 to 9 points) 
6 
4 
Severe hepatic impairment 
Class C (10 to 15 points) 
6b 
a. Additional participants may be dosed to a maximum of 8 participants to ensure mean age ±5 years and 
mean body weight ±10 kg of this group is aligned with the pooled averageassessed when approximately 
≥75% of participants are dosed across the other 3 groups. 
b. If recruitment proves to beprohibitive, study may dose 4-6 participants in this group. 
 
Categorization of participants into Groups 2-4 will be done based on Child-Pugh scores 
determined at the screening visit , as described in Appendix 11 of the protocol. 
 
 
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Staged Enrollment of Study Groups 
Participants will be dosed in a staged manner as follows: 
• Participants with moderate and severe hepatic impairment (Groups 3 and 4) will be 
enrolled first. 
• Recruitment of participants with mild hepatic impairment (Group 2) will initiate 
when approximately 50% of the participants across Groups 3 and 4 have been dosed. 
Sponsor approval is required before proceeding with recruitment of Group 2. 
• An average value for age and weight for the 3 hepatic impairment groups 
(Groups 2-4) will be determined, and participants without hepatic impairment 
(Group 1) will be recruited to match the average demographics (at a minimum, age 
and weight, and as much as practically possible gender) across the pooled 
Groups 2-4. 
• Recruitment for healthy participants in Group 1 (without hepatic impairment) may 
start when approximately 75% of total participants across Groups 2-4 
(ie, approximately 12-13 participants) have been dosed. 
Sponsor approval is required before proceeding with recruitment of Group 1. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
Baseline is defined as the last pre-dose assessment for all endpoints, unless otherwise 
specified. 
3.1. Primary Endpoint(s) 
• PF-07081532 Plasma Pharmacokinetic parameters: Cmax, AUCinf, AUClast, fu, Cmax,u, 
AUCinf,u, AUClast,u as data permit. 
The plasma PK parameters in Table 3 will be derived from concentration-time profiles using 
standard non-compartmental analysis methods (with the exception of fu that will be directly 
determined by the analytical lab): 
Table 3. Summary of Plasma PK Parameters of PF-07081532 to be calculated 
 
Parameter 
Analysis 
Scale 
PF-07081532 20mg 
Cmax 
ln 
A, D 
AUCinf* 
ln 
A, D 
AUClast+ 
ln 
A, D 
fu 
R 
A, D 
Cmax,u 
ln 
A, D 


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AUCinf,u* 
ln 
A, D 
AUClast,u+ 
ln 
A, D 
*=if data permits. +AUClast and AUClast,u will be treated as primary endpoints if data do not permit robust estimation 
of AUCinf and AUCinf,u, 
Abbreviations: A = analyzed using a statistical model; D=displayed with descriptive statistics 
as outlined in Table 7 in Section 6.1.1.1 ; ln=natural-log transformed; R=raw 
(untransformed). 
The plasma PK parameters for unbound PF-07081532 will be calculated as described in 
Table 4: 
Table 4. Summary of Plasma PK parameters of Unbound PF-07081532 to be calculated 
 
Parameter 
Method of Determination 
AUClast,u+ 
fu × AUClast 
AUCinf,u* 
fu × AUCinf* 
Cmax,u 
fu × Cmax 
*=if data permits. +AUClast and AUClast,u will be treated as primary endpoints if data do not permit robust estimation 
of AUCinf and AUCinf,u, 
 
 
 
 
 
3.2. Secondary Endpoint(s) 
Assessment of treatment emergent AEs, clinical laboratory abnormalities, vital signs, 
ECG parameters. 
An adverse event is considered treatment emergent (TEAE) relative to a given treatment if: 
• the event starts during the effective duration of treatment (i.e. starting on or after the 
dose of PF-07081532 but before this dose plus lag time) 
The effective duration of treatment is determined by the lag time. Any event occurring within 
the lag time is attributed to the corresponding treatment. The lag time is defined by the Pfizer 
Standard of 365 days post last dose of IP. 
A 3-tier approach for summarizing AEs will not be used due to the low number of 
participants planned to be recruited. 
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. 


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For laboratory, vital signs and ECG data, baseline will be defined as the last pre-dose 
measurement, unless otherwise specified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4. Baseline Variables 
Not Applicable. 


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3.5. Safety Endpoints 
See Section 3.2 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures. 
For purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis Set 
Description 
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
assignment to study intervention. 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. 
Safety analysis set 
All participants assigned to study intervention and who take at 
least 1 dose of study intervention. 
PK Concentration Set 
The PK concentration population is defined as all participants 
who received at least 1 dose of PF-07081532 and in whom at 
least 1 plasma concentration value is reported. 
PK Parameter Set 
The PK parameter analysis population is defined as all 
participants who received at least 1 dose of PF-07081532 and 
have at least 1 of the PK parameters of interest calculated. 
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5. GENERAL METHODOLOGY AND CONVENTIONS 
The following group labels (or similar) will be used for tables and figures unless otherwise 
stated: 
 
Group 
Description of Group 
Label 
1 
Normal hepatic function 
Without Hepatic Impairment 
2 
Mild hepatic impairment 
Mild Hepatic Impairment 
3 
Moderate hepatic impairment 
Moderate Hepatic Impairment 
4 
Severe hepatic impairment 
Severe Hepatic Impairment 


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5.1. Hypotheses and Decision Rules 
There is no statistical hypothesis testing planned for this study and no statistical decision 
rules will be applied. 
5.2. General Methods 
5.2.1. Analyses for Continuous Endpoints 
Unless otherwise stated, continuous endpoints and relevant safety endpoints will be presented 
using summary statistics: number of observations, arithmetic mean, standard deviation, 
median, minimum and maximum values. 
5.2.2. Analyses for Categorical Endpoints 
Categorical endpoints and relevant safety endpoints will be presented using summary statistics: 
number of observations, counts and percentages. 
5.2.3. One-way Analysis of Variance (ANOVA) 
The one-way analysis of variance (ANOVA) model will include group as a factor. 
Estimates of the adjusted mean differences (Test - Reference), and corresponding 90% CIs, 
will be obtained from the model. These will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Example 
SAS code is given in Appendix 1. 
Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report. If there are major 
deviations from normality or outliers (where studentized residuals are greater than 3 or less 
than - 3) then the effect of these on the conclusions may be investigated through alternative 
transformations and/or analyses excluding outliers. Justification for any alternative to the 
planned analysis will be given in the report of the study if applicable. 
 
5.2.4. Linear Regression PK Parameters versus Hepatic Function 
Linear regression will be used to analyze the potential relationship between appropriate PK 
parameters (eg, AUCinf, AUClast, Cmax, fu, AUCinf,u, AUClast,u, Cmax,u) and hepatic function as a 
continuous explanatory variable (using either continuous serum albumin, prothrombin time 
or total bilirubin, each modelled separately). Estimates of the slope and intercept, together 


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with a 90% CI, and the coefficient of determination (i.e. R-squared and adj-R-squared) may 
be obtained from the model. Example SAS code is given in Appendix 1. 
Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report. If there are major 
deviations from normality or outliers (where studentized residuals are greater than 3 or less 
than - 3) then the effect of these on the conclusions may be investigated through alternative 
transformations and/or analyses excluding outliers. Alternative model structure may also be 
considered. Justification for any alternative to the planned analysis will be given in the report 
of the study if applicable. 
 
 
 
 
5.3. Methods to Manage Missing Data 
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied. 
5.3.1. Pharmacokinetic 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. 


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5.3.2. Pharmacokinetic Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median/mean 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/clinical team. 
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing. 
5.3.3. Pharmacokinetic Parameters 
Actual PK sampling times will be used in the derivation of PK parameters. 
If a PK parameter cannot be derived from a participant’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 participant discontinues. 
In analysis and 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 participant 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/figures and will not be included in the 
calculation of summary statistics or statistical analyses. 
6. ANALYSES AND SUMMARIES 
Data collected before baseline will only be listed, unless otherwise stated. 
Unless otherwise stated, all analyses, summaries and listings will be produced by group (as 
outlined in Section 5) which would include all 4 groups in the same analysis/output. 
6.1. Primary Endpoint(s) 
6.1.1. PF-07081532 PK Parameters 
• Estimand strategy: Not applicable 
• Analysis set: PF-07081532 Concentration and Pharmacokinetic Parameter Set 
6.1.1.1. Main Analysis 
Cmax, AUCinf (if data permit), AUClast, fu, AUCinf,u, AUClast,u and Cmax,u will be listed, 
summarized descriptively and analyzed by group for participants in the PK parameter set (as 
defined in Section 4). Missing values will be handled as detailed in Section 5.3. 


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A one-way analysis of variance (ANOVA) described in Section 5.2.3, that includes all 4 
groups in the same model, will be used to compare the natural log transformed of Cmax, 
AUCinf, AUClast, fu, AUCinf,u, AUClast,u, and Cmax,u of PF-07081532 separately, for each of 
the hepatic impairment groups (Test, Groups 2, 3, 4) to the healthy normal hepatic function 
group (Reference, Group 1). 
For summary statistics and median or mean plots by sampling time, the nominal PK 
sampling time will be used. For individual participant plots by time, the actual PK sampling 
time will be used. The plasma PK parameters of PF-07081532 for each group will be 
summarized as specified in Table 7 below. 
Table 7. Summary statistics to be produced for Plasma PK Parameters of PF-07081532 
 
Parameter 
Summary Statistics 
Cmax, AUCinf *, AUClast, fu, 
AUCinf,u*, AUClast,u, and 
Cmax,u 
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%. 
* if data permits 
The following plots will be presented: 
• Box and whisker plots for individual PK parameters (AUCinf, AUClast, Cmax, fu, AUCinf,u, 
AUClast,u and Cmax,u)) will be constructed by group and overlaid with geometric means. 
6.1.1.2. Sensitivity/Supplementary Analyses 
 
Plots of PK parameters (eg, AUCinf, AUClast, Cmax, fu, AUCinf,u, AUClast,u and Cmax,u) versus 
hepatic function at baseline (e.g. serum albumin, prothrombin time or total bilirubin, plotted 
separately) will be constructed, with a regression line and 90% confidence region included 
from the main linear regression model. 
6.2. Secondary Endpoint(s) 
Any clinical laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern 
will be described. 
No formal analyses are planned for safety data. 
The safety endpoints detailed in Section 3.2 will be listed and summarized in accordance 
with sponsor reporting standards based on the safety population (as defined in Section 4), 
with more details provided below. 


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6.2.1. Adverse Events 
Adverse events will be summarised by group and overall, in accordance with sponsor 
reporting standards using the safety population defined in Section 4. 
If applicable, subject discontinuations due to adverse events will be detailed and 
summarized. 
6.2.2. Laboratory Data 
Laboratory data will be listed and summarized by group and overall, in accordance with the 
sponsor reporting standards using the safety population defined in Section 4. Baseline is as 
defined in Section 3.2. 
6.2.3. Vital Signs 
Absolute values and changes from baseline in seated systolic and diastolic blood pressure 
and pulse rate will be summarised by group, according to sponsor reporting standards using 
the safety population defined in Section 4. Baseline is as defined in Section 3.2. 
Maximum and minimum absolute values and maximum changes from baseline for seated 
vital signs will also be summarised descriptively by group using categories as defined in 
Appendix 2. Numbers and percentages of participants meeting the categorical criteria will be 
provided. All planned and unplanned post dose time points will be counted in these 
categorical summaries. All values meeting the criteria of potential clinical concern will be 
listed. 
6.2.4. ECG 
Absolute values and changes from baseline in QT interval, heart rate, QTcF interval, PR 
interval and QRS interval will be summarised by group using sponsor reporting standards 
and the safety population defined in Section 4. Tables will be paged by parameter. Baseline 
is as defined in Section 3.2. 
Maximum absolute values and changes from baseline for QTcF, PR and QRS will also be 
summarised descriptively by group using categories as defined in Appendix 2. Numbers and 
percentages of participants meeting the categorical criteria will be provided. All planned and 
unplanned post dose time points will be counted in these categorical summaries. All values 
meeting the criteria of potential clinical concern will be listed. 
 
 
 
 


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6.4. Subset Analyses 
No subset analyses will be performed. 
6.5. Baseline and Other Summaries and Analyses 
Data will be reported in accordance with the sponsor reporting standards. 
6.5.1. Baseline Summaries 
Demographics data (age, biological sex, race, ethnicity, weight, body mass index and height) 
will be summarized by group and overall, as outlined in Sections 5.2.1 and 5.2.2 as 
applicable. 
6.5.2. Study Conduct and Participant Disposition 
Participant evaluation groups will show end of study participant disposition by group and 
will show which participants were analyzed for pharmacokinetics and safety, which may not 
be produced in one table. Frequency counts and percentages will be supplied for participant 
discontinuation(s) by group. 
6.5.3. Study Treatment Exposure 
Not applicable. 
6.5.4. Concomitant Medications and Nondrug Treatments 
All prior and concomitant medication(s) as well as non-drug treatment(s) will be provided in 
listings. 


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6.6. Safety Summaries and Analyses 
See Section 6.2. 
7. INTERIM ANALYSES 
7.1. Introduction 
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 modeling, and/or supporting clinical 
development. 
7.2. Interim Analyses and Summaries 
Not applicable. 
8. REFERENCES 
None. 


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APPENDICES 
Appendix 1. Statistical Methodology Details 
An example of SAS code for ANOVA: 
proc mixed data = tab.pk; 
class group; 
model l&var = group /residual; 
lsmeans group/diff cl alpha=0.1; 
ods output lsmeans = lsmeans&var; 
ods output diffs=diffs&var; 
run; 
An example of SAS code for the PROC REG code for linear regression analyses: 
proc reg data=tab.pk; 
model l&var=clcr/clb alpha=0.1; 
ods output ParameterEstimates = param&var; 
ods output FitStatistics = fit&var; 
ods output ANOVA = reg&var; 
run; 
An example of SAS code for stepwise regression with model selection using AIC: 
proc glmselect data=tab.pk analysis plot=ALL; 
model pk_p = albumin age weight/ selection=stepwise (select = AIC stop = AIC) 
include=1 hierarchy=none showpvalues; 
run; 


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Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern 
Categories for QTcF 
Absolute value of 
QTcF (msec) 
 450 and 480 
>480 and 500 
>500 
Increase from baseline in 
QTcF (msec) 
 30 and 60 
>60 
Categories for PR and QRS 
 
PR (ms) 
max. ≥300 
PR (ms) increa se 
from baseline 
Baseline >200 
and max. ≥25% 
increase 
Baseline ≤200 and 
max. ≥50% increase 
QRS (ms) 
max. ≥140 
QRS (ms) increa se 
from baseline 
≥50% increase 
Categories for Vital Signs 
 
Systolic BP (mm Hg) 
min. <90 
Systolic BP (mm Hg) change 
from baseline 
max. decrease ≥30 
max. increase ≥30 
Dia stolic BP (mm Hg) 
min. <50 
Dia stolic BP (mm Hg) change 
from baseline 
max. decrease ≥20 
max. increase ≥20 
Seatedpulse rate (bpm) 
min. <40 
max. >120 
Measurements that fulfill these criteria are to be listed in the report. 


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Appendix 3. List of Abbreviations 
 
Abbreviation 
Term 
AE 
adverse event 
Ae 
Amount excreted 
ANOVA 
analysis of variance 
AUC 
area under the curve 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
CI 
confidence interval 
CL 
Clearance 
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Cmax 
maximum observed concentration 
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CSR 
clinical study report 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
IP 
Investigational Product 
LLQ 
Lower limit of quantitation 
Ln 
Natural log 
N/A 
not applicable 
NC 
not calculated 
ND 
not done 
NS 
no sample 
PK 
pharmacokinetic(s) 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
SAP 
statistical analysis plan 
SOA 
Schedule of activities 
TEAE 
Treatment emergent adverse events 
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