Clinical trial NCT05745701
Conditions: Healthy
Sponsor: Pfizer
Start date: 2023-02-22; Completion date: 2023-05-29
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1, open-label, fixed-sequence, 3-period study to evaluate the effect of multiple doses of itraconazole and a single dose of cyclosporine on the single-dose PK of PF-07081532 in otherwise healthy, overweight or obese, adult female and male participants.

The 3 study periods will be conducted consecutively without a break.

Detailed description:

Arms: arm 1: Participants will receive PF-07081532 as a single dose on Day 1. arm 2: Participants will receive a single dose of PF-07081532 and a single dose of cyclosporine on Day 1. arm 3: Participants will receive itraconazole daily for 9 days plus a single dose of PF-07081532 on Day 4.
Interventions: intervention 1: PF-07081532 intervention 2: Cyclosporine intervention 3: Itraconazole
Intervention descriptions: intervention 1: Oral Tablet intervention 2: Oral Solution intervention 3: Oral Capsule

Protocol documents:
Prot_000.pdf: 
PF-07081532 
Protocol C3991041 
Final Protocol 31 January 2023 
PFIZER CONFIDENTIAL 
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022) 
Page 1 
 
 
 
 
 
 
A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE STUDY TO EVALUATE THE 
EFFECT OF ITRACONAZOLE AND CYCLOSPORINE ON THE SINGLE-DOSE 
PHARMACOKINETICS OF PF-07081532 IN OVERWEIGHT OR OBESE ADULT 
PARTICIPANTS 
 
 
 
 
 
Study Intervention Number: 
PF-07081532 
Study Intervention Name: 
NA 
US IND Number: 
CCI  
EudraCT/EU CT Number: 
NA 
ClinicalTrials.gov ID: 
NA 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C3991041 
Phase: 
1 
Brief Title: A Drug-Drug Interaction Study to Examine the Impact of Itraconazole and 
Cyclosporine on PF-07081532 Pharmacokinetics in Overweight or Obese Adult 
Participants. 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 


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Protocol C3991041 
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CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022) 
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Document History 
 
Document 
Version Date 
Original protocol 
31 January 2023 


PF-07081532 
Protocol C3991041 
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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 8 
1. PROTOCOL SUMMARY ..................................................................................................... 9 
1.1. Synopsis ..................................................................................................................... 9 
1.2. Schema..................................................................................................................... 15 
1.3. Schedule of Activities .............................................................................................. 16 
2. INTRODUCTION ................................................................................................................ 21 
2.1. Study Rationale ........................................................................................................ 21 
2.2. Background .............................................................................................................. 21 
2.2.1. Nonclinical Pharmacology .......................................................................... 22 
2.2.2. Nonclinical Pharmacokinetics and Metabolism .......................................... 22 
2.2.3. Nonclinical Safety ....................................................................................... 22 
2.2.4. Clinical Overview ....................................................................................... 23 
2.2.4.1. Clinical Pharmacokinetics ......................................................... 23 
2.3. Benefit/Risk Assessment ......................................................................................... 24 
2.3.1. Risk Assessment ......................................................................................... 25 
2.3.2. Benefit Assessment ..................................................................................... 28 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 28 
3. OBJECTIVES AND ENDPOINTS ..................................................................................... 28 
4. STUDY DESIGN ................................................................................................................. 29 
4.1. Overall Design ......................................................................................................... 29 
4.2. Scientific Rationale for Study Design ...................................................................... 29 
4.2.1. Choice of Contraception/Barrier Requirements .......................................... 30 
4.2.2. Collection of Retained Research Samples ................................................... 30 
4.3. Justification for Dose ............................................................................................... 30 
4.4. End of Study Definition ........................................................................................... 31 
5. STUDY POPULATION ...................................................................................................... 31 
5.1. Inclusion Criteria ..................................................................................................... 31 
5.2. Exclusion Criteria .................................................................................................... 32 
5.3. Lifestyle Considerations .......................................................................................... 35 
5.3.1. Contraception .............................................................................................. 36 
5.3.2. Meals and Dietary Restrictions ................................................................... 36 


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Protocol C3991041 
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5.3.3. Caffeine, Alcohol, and Tobacco ................................................................. 37 
5.3.4. Activity ...................................................................................................... 37 
5.4. Screen Failures ........................................................................................................ 37 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................. 37 
6.1. Study Intervention(s) Administered ........................................................................ 38 
6.1.1. Administration ............................................................................................ 39 
6.2. Preparation, Handling, Storage, and Accountability .............................................. 39 
6.2.1. Preparation and Dispensing ........................................................................ 40 
6.3. Assignment to Study Intervention .......................................................................... 41 
6.4. Blinding .................................................................................................................. 41 
6.5. Study Intervention Compliance .............................................................................. 41 
6.6. Dose Modification .................................................................................................. 41 
6.7. Continued Access to Study Intervention After the End of the Study ..................... 41 
6.8. Treatment of Overdose ........................................................................................... 41 
6.9. Prior and Concomitant Therapy .............................................................................. 42 
6.9.1. Rescue Medicine ........................................................................................ 43 
6.9.1.1. Management of Nausea and Vomiting ..................................... 43 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 43 
7.1. Discontinuation of Study Intervention .................................................................... 43 
7.1.1. Potential Cases of Acute Kidney Injury ..................................................... 44 
7.2. Participant Discontinuation/Withdrawal From the Study ...................................... 45 
7.2.1. Withdrawal of Consent .............................................................................. 45 
7.3. Lost to Follow-up ................................................................................................... 45 
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 
8.3.2.2. Temperature .............................................................................. 48 


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Protocol C3991041 
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PFIZER CONFIDENTIAL 
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8.3.3. Electrocardiograms ...................................................................................... 48 
8.3.4. Clinical Safety Laboratory Assessments ..................................................... 49 
8.3.5. COVID-19 Specific Assessments ............................................................... 50 
8.3.6. Management of Hypoglycemia ................................................................... 50 
8.3.6.1. Definition and Severity of Categorization of 
Hypoglycemic Adverse Event ........................................................... 50 
8.3.6.2. Glucometer Monitoring of Glucose ........................................... 51 
8.3.7. Pregnancy Testing ....................................................................................... 52 
8.3.8. Suicidal Ideation and Behavior Risk Monitoring ........................................ 52 
8.3.8.1. Columbia Suicide Severity Rating Scale ................................... 52 
8.3.8.2. Patient Health Questionnaire-9 (PHQ-9) ................................... 52 
8.3.8.3. Referral to a Mental Health Professional ................................... 52 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 53 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information ....... 53 
8.4.1.1. Reporting SAEs to Pfizer Safety ............................................... 54 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 54 
8.4.2. Method of Detecting AEs and SAEs ........................................................... 55 
8.4.3. Follow-Up of AEs and SAEs ...................................................................... 55 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 55 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 55 
8.4.5.1. Exposure During Pregnancy ...................................................... 56 
8.4.5.2. Exposure During Breastfeeding ................................................. 57 
8.4.5.3. Occupational Exposure .............................................................. 58 
8.4.6. Cardiovascular and Death Events ................................................................ 58 
8.4.7. Disease -Related Events and/or Disease -Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 58 
8.4.8. Adverse Events of Special Interest ............................................................. 58 
8.4.8.1. Lack of Efficacy ........................................................................ 58 
8.4.9. Medical Device Deficiencies ...................................................................... 58 
8.4.10. Medication Errors ...................................................................................... 58 
8.5. Pharmacokinetics ..................................................................................................... 59 
8.6. Genetics ................................................................................................................... 60 


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8.7. Biomarkers .............................................................................................................. 60 
8.8. Immunogenicity Assessments ................................................................................ 61 
8.9. Health Economics ................................................................................................... 61 
9. STATISTICAL CONSIDERATIONS ................................................................................ 61 
9.1. Statistical Hypothesis ............................................................................................. 61 
9.2. Analysis Sets ........................................................................................................... 61 
9.3. Statistical Analyses ................................................................................................. 62 
9.3.1. Pharmacokinetic Analyses ......................................................................... 62 
9.3.1.1. Derivation of Pharmacokinetic Parameters .............................. 62 
9.3.1.2. Statistical Methods for PK Data ............................................... 63 
9.3.2. Safety Analyses .......................................................................................... 64 
9.3.2.1. Electrocardiogram Analyses ..................................................... 64 
9.3.2.2. Mental Health ........................................................................... 64 
9.4. Interim Analyses ..................................................................................................... 65 
9.5. Sample Size Determination .................................................................................... 65 
10. SUPPORTING  DOCUMENTATION  AND  OPERATIONAL 
CONSIDERATIONS.......................................................................................................... 66 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 66 
10.1.1. Regulatory and Ethical Considerations .................................................... 66 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 66 
10.1.2. Informed Consent Process ....................................................................... 67 
10.1.3. Data Protection ......................................................................................... 68 
10.1.4. Committees Structure ............................................................................... 68 
10.1.4.1. Data Monitoring Committee ................................................... 68 
10.1.5. Dissemination of Clinical Study Data ...................................................... 68 
10.1.6. Data Quality Assurance ............................................................................ 69 
10.1.7. Source Documents ................................................................................... 71 
10.1.8. Study and Site Start and Closure .............................................................. 71 
CCI 
CCI 
CCI 


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10.1.9. Publication Policy .................................................................................... 72 
10.1.10. Sponsor’s Medically Qualified Individual ............................................. 73 
10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 74 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ..................................................................... 75 
10.3.1. Definition of AE ....................................................................................... 75 
10.3.2. Definition of an SAE ................................................................................ 76 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ........................................................................... 77 
10.3.4. Reporting of SAEs ................................................................................... 81 
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................ 82 
10.4.1. Male Participant Reproductive Inclusion Criteria ................................... 82 
10.4.2. Female Participant Reproductive Inclusion Criteria ................................ 82 
10.4.3. Woman of Childbearing Potential ............................................................ 82 
10.4.4. Contraception Methods ............................................................................ 83 
CCI 
 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ....... 86 
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................ 88 
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury ............................................................................. 88 
10.7.2. Age-Specific Kidney Function Calculation Recommendations ............... 88 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .......................................................................................... 88 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities .................................................................................................. 88 
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ................................... 89 
10.9. Appendix 9: Abbreviations ................................................................................... 91 
11. REFERENCES .................................................................................................................. 95 


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LIST OF TABLES 
Table 1. 
Study Schedule of Assessment ................................................................. 16 
Table 2. 
PK Blood Sampling - Periods 1 and 2 ..................................................... 20 
Table 3. 
PK Blood Sampling – Period 3 ................................................................ 20 
Table 4. 
Plasma PK Parameters for PF-07081532 ................................................. 62 
Table 5. 
Protocol-Required Safety Laboratory Assessments ................................. 74 


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Protocol C3991041 
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Open-Label, Fixed-Sequence Study to Evaluate the Effect of 
Itraconazole and Cyclosporine on the Single-Dose Pharmacokinetics of PF-07081532 in 
Overweight or Obese Adult Participants. 
Brief Title: A Drug-Drug Interaction Study to Examine the Impact of Itraconazole and 
Cyclosporine on PF-07081532 Pharmacokinetics in Overweight or Obese Adult Participants. 
Regulatory Agency Identification Number(s): 
 
US IND Number: 
CCI  
EudraCT Number: 
NA 
ClinicalTrials.gov ID: 
NA 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C3991041 
Phase: 
1 
 
Rationale: This is a Phase 1, open-label, fixed-sequence study to evaluate the effect of 
multiple doses of itraconazole and a single dose of cyclosporine on the single-dose PK of 
PF-07081532 in otherwise healthy, overweight or obese adult participants and to generate 
safety, tolerability, and PK data for further clinical development. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To estimate the effect of MD itraconazole on the 
SD PK of PF-07081532 in otherwise healthy, 
overweight or obese participants. 
• 
PF-07081532 PK parameter: AUCinf (if data 
permita otherwise AUClast) 
• 
To estimate the effect of SD cyclosporine on the 
SD PK of PF-07081532 in otherwise healthy, 
overweight or obese participants. 
• 
PF-07081532 PK parameter: AUCinf (if data 
permita otherwise AUClast) 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of 
PF-07081532 administered separately and in 
combination with itraconazole or cyclosporine 
in otherwise healthy, overweight or obese 
participants. 
• 
Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and ECG 
parameters. 
• 
Assessment of mental health as determined by 
C-SSRS and PHQ-9. 
• 
To evaluate the effects of itraconazole or 
cyclosporine on additional PK parameters for 
PF-07081532. 
• 
Additional plasma PK parameters for 
PF-07081532: Cmax and Tmax; and CL/F, Vz/F, t½, 
as data permit. 
a. 
Should it be deemed that too few AUCinf estimates (eg, less than 12 for a single treatment) are obtained 
from the evaluable participants, AUClast may be selected as the primary endpoint for CSR reporting. 


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Protocol C3991041 
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Overall Design: 
This is a Phase 1, open-label, fixed-sequence, 3-period study to evaluate the effect of 
multiple doses of itraconazole and a SD of cyclosporine on the single-dose PK of 
PF-07081532 in otherwise healthy, overweight or obese, adult female and male participants. 
The 3 study periods will be conducted consecutively without a break. 
Number of Participants: 
Approximately 16 participants will be enrolled in the study such that approximately 
12 evaluable participants complete the study. 
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. 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: 
Inclusion Criteria 
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study: 
1. Otherwise healthy female and male participants must be at least 18 years of age at the 
time of signing the ICD (healthy is defined as no clinically relevant abnormalities 
identified by a detailed medical history, physical examination, including blood 
pressure and pulse rate measurement, standard 12-lead ECG and clinical laboratory 
tests). 
• Women can be of child-bearing potential, but cannot be pregnant, breastfeeding, 
or planning to become pregnant while participating in the study, may not be 
taking either oral contraceptives or non-oral hormonal contraceptives (with the 
exception of implantable progestogen only or intrauterine hormone releasing 
system), and must avoid vaccination with live attenuated vaccines. 
2. BMI: ≥25.0 kg/m2 at Screening. 
3. Stable body weight, defined as <5 kg change (per participant report) for 90 days 
before Screening. 


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Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded: 
Medical Conditions 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
• Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, cholecystectomy or any area of intestinal resection, active 
inflammatory bowel disease or pancreatic insufficiency). 
• Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the 
risk of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
• Known intolerance or hypersensitivity to GLP-1R agonists. 
• Known hypersensitivity to itraconazole or cyclosporine. 
2. Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at 
Screening. Note: women with prior diagnoses of gestational diabetes during 
pregnancy only are eligible if they meet the other eligibility criteria. 
3. Any malignancy not considered cured (except basal cell carcinoma and squamous cell 
carcinoma of the skin); a study participant is considered cured if there has been no 
evidence of cancer recurrence in the previous 5 years (from Screening). Anyone with 
any history of pancreatic CA will be excluded, even if it was resected and they were 
considered ‘cured’. 
4. Personal or family history of MTC or MEN2, or study participants with suspected 
MTC per the investigator’s judgment. 
5. Acute pancreatitis, a history of repeated episodes of acute pancreatitis, or history of 
chronic pancreatitis. 
6. Symptomatic gallbladder disease. 
7. Medical history or characteristics suggestive of genetic or syndromic obesity or 
obesity induced by other endocrinological disorders (eg, Cushing Syndrome). 
8. History of depressive disorder or history of other severe psychiatric disorders (eg, 
schizophrenia or bipolar disorder) within the last 2 years from screening. 


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9. Known medical history of active liver disease, including chronic hepatitis B or C, 
primary biliary cirrhosis, alcoholic liver disease, primary sclerosing cholangitis, 
autoimmune hepatitis, overlap syndrome, or prior known drug-induced liver injury. 
10. History of HIV infection. 
11. Any lifetime history of a suicide attempt. 
12. Use of any medications that are: 
• Moderate or strong CYP3A4/5 and/or CYP2C19 inhibitors within 14 days or 
5 half-lives (whichever is longer), 
• Moderate or strong CYP3A and/or CYP2C19 inducers within 14 days or 5 
half-lives (whichever is longer), or 
• Systemic therapy with inhibitors of OATP transporters within 14 days or 
5 half-lives (whichever is longer) prior to the first dose of study intervention. 
13. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. BP should be measured in triplicate and the average of 
the 3 BP values should be used to determine the participant’s eligibility. Note: At 
Screening, the participant’s arm circumference should be measured (eg, using a 
flexible anthropometric tape) at the midpoint of the length of the upper arm, and the 
appropriate cuff selected and used throughout the study. 
14. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF interval 
>450 msec, complete LBBB, signs of an acute or indeterminate age myocardial 
infarction (documented assessment), ST-T interval changes suggestive of myocardial 
ischemia, second- or third-degree AV block, or serious bradyarrhythmias or 
tachyarrhythmias). 
• If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be 
repeated 2 more times and the average of the 3 QTcF or QRS values should be 
used to determine the participant’s eligibility. Computer interpreted ECGs should 
be overread by a physician experienced in reading ECGs before excluding 
participants. 
15. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
• HbA1c ≥6.5%. 
• AST or ALT level ≥1.25 × ULN. 


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• Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ ULN. 
• TSH >1.5 × ULN or <LLN. 
• Serum calcitonin > ULN. 
• Amylase or lipase > ULN. 
• Fasting blood glucose ≥126 mg/dL. 
• Fasting C-peptide not within normal limit. 
• eGFR <75 mL/min/1.73 m2 as calculated by the CKD-EPI equation. 
Study Arms and Duration: 
The total duration of participation from the Screening Visit to the F/U telephone contact will 
be approximately 82 days or 12 weeks, approximately 3 weeks of which will be conducted 
on an inpatient basis. The 21-day inpatient portion of the study will be conducted as follows: 
Period 1: Days -1 to 5 (Study Days -1 to 5; participants are admitted to the CRU on Day -1), 
40 mg SD PF-07081532 on Day 1; 
Period 2: Days 1 to 5 (Study Days 6 to 10), 40 mg SD PF-07081532 plus 600 mg SD 
cyclosporine on Day 1; 
Period 3: Days 1 to 10 (Study Days 11 to 20; participants are discharged from the CRU on 
Study Day 20), 200 mg itraconazole QD ×9 days plus 40 mg SD PF-07081532 on Day 4. 
A telephone F/U contact will occur 28-35 days from the last dose of study intervention 
(Period 3, Day 9). 
 
Study Intervention(s) 
Intervention Name 
PF-07081532 
Itraconazole 
Cyclosporine 
Arm Name 
(group of participants 
receiving a specific 
treatment or no 
treatment) 
All participants 
All participants 
All participants 
Unit Dose Strength 
20 mg 
10 mg/mL 
100 mg 
Route of 
Administration 
Oral 
Oral 
Oral 


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Study Intervention(s) 
Use 
Substrate 
Perpetrator 
Perpetrator 
IMP or AxMP 
IMP 
AxMP 
AxMP 
 
 
Study Arm(s) 
Arm Title 
Period 1: PF-07081532 
single dose 
Period 2: Cyclosporine + 
PF-07081532 
Period 3: Itraconazole + 
PF-07081532 
Arm Type 
No intervention 
Experimental (DDI) 
Experimental (DDI) 
Arm 
Description 
Participants will 
receive PF-07081532 
as a single 40 mg dose 
on Day 1. 
Participants will receive a single 
40 mg dose of PF-07081532 and a 
single 600 mg dose of cyclosporine 
on Day 1. 
Participants will receive 
itraconazole 200 mg 
QD × 9 days plus a single 
40 mg dose of PF-07081532 
on Day 4. 
 
No dose adjustments or reductions will be permitted in this study. 
Statistical Methods: 
Approximately 12 evaluable participants will complete the study. 
Natural loge transformed AUCinf of PF-07081532 administered without cyclosporine or 
coadministered with cyclosporine will be analyzed using a mixed effect model with treatment 
as a fixed effect and participant as a random effect. Estimates of the adjusted mean 
differences (Test/Reference) and corresponding 90% CIs will be obtained from the models. 
The adjusted mean differences and 90% CIs for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for 
the ratios. The test treatment will be ‘PF-07081532 40 mg SD and cyclosporine’ (Period 2), 
which will be reported separately in comparison to the reference treatment of ‘PF-07081532 
40 mg SD without cyclosporine’ (Period 1). 
Natural loge transformed AUCinf of PF-07081532 administered without itraconazole or 
coadministered with itraconazole will be analyzed using a mixed effect model with treatment 
as a fixed effect and participant as a random effect. Estimates of the adjusted mean 
differences (Test/Reference) and corresponding 90% CIs will be obtained from the models. 
The adjusted mean differences and 90% CIs for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for 
the ratios. The test treatment will be ‘PF-07081532 40 mg SD and itraconazole’ (Period 3), 
which will be reported separately in comparison to the reference treatment of ‘PF-07081532 
40 mg SD without itraconazole’ (Period 1). 


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Ethical Considerations: 
PF-07081532 is not expected to provide any long-term clinical benefit to the healthy adult 
female and male participants in this study. This study is designed primarily to generate 
safety, tolerability, and PK data for further clinical development. 
Based on experience with PF-07081532 and other marketed GLP-1R agonists, the potential 
risks for PF-07081532 include thyroid C-cell tumors, pancreatitis, hypoglycemia, renal 
function impairment, gastrointestinal adverse reactions, suicidal ideation and behavior, 
changes in heart rate and blood pressure, weight loss, and/or acute gallbladder disease. 
Participants will be expected to commit time and may experience some discomfort while 
undergoing study assessments. In addition, participants of childbearing potential must agree 
to use appropriate contraception methods and avoid vaccination with live attenuated 
vaccines. 
1.2. Schema 
Not applicable. 


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1.3. Schedule of Activities 
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed infonnation 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 paiiicipant. 
 
Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this 
table may be fonnd in 
Annendix 9. 
Scr·een 
Period 1 
Period 2 
Period 3 
F/U (Phone 
Call) 
ET 
Notes 
Study Day 
-1 
lto5 
6to 10 
11 to 20 
47 to 54 
Days Relative to Day 1 
D-28 to D-2 
D-1 
Dl toD5 Dl to D5 Dl to DlO 28-35 Days 
1. 
All screening should be done '.S28 days before 
the first dose. 
2. 
 Day relative to start of study intervention 
(Day 1). 
3. 
 In this study, follow-up is to be conducted via 
phone contact 28 to 35 days after administration 
of the final dose of study intervention (Period 3 
Dav 9, Studv Dav 19). 
Info,med consent 
X 
• 
Info,med consent should be obtained prior to nndergoing 
any study-specific procedm·es. 
CRU confinement 
X 
➔ 
➔ 
X 
Inclusion/exclusion criteria 
X 
X 
Medical/medication histo,y 
X 
X 
X 
• 
Including histo,y collection of alcohol and tobacco use. 
Physical exam 
X 
X 
• 
Complete PE conducted at Screening or admission, and as 
required at PI' s discretion. 
Bodyweight 
X 
X 
X(D5) 
X(D5) 
X (DlO) 
X 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this 
table may be fonnd in 
Annendix 9. 
Scr·een 
Period 1 
Period 2 
Period 3 
F/U (Phone 
Call) 
ET 
Notes 
Study Day 
-1 
lto5 
6to 10 
11 to 20 
47 to 54 
Days Relative to Day 1 
D-28 to D-2
D-1 
Dl toD5 Dl to D5 Dl to DlO 28-35 Days 
1. 
All screening should be done '.S28 days before 
the first dose. 
2. 
 Day relative to start of study intervention 
(Day 1). 
3. 
In this study, follow-up is to be conducted via 
phone contact 28 to 35 days after administration 
of the final dose of study intervention (Period 3 
Dav 9. Studv Dav 19). 
Safety laborato,y (hematology, 
chemistiy, and UA) 
X 
X 
X(D5 
chemistiy 
only) 
X 
X • 
See Table 5 for a complete list of clinical lab tests. 
• 
Period 3 collection prior to discharge on Day 10. 
Calcitonin, amylase, lipase, 
HbAlC, TSH, C-Peptide 
X 
•  An ovemight fast is required prior to calcitonin sample 
collection. 
Demography 
X 
• 
Including height and weight. 
Serum and urine pregnancy 
test (WOCBP only) 
X 
X 
X (DlO) 
X 
•  Pregnancy tests will also be done whenever 1 menstmal 
cycle is missed during the active treatment period (or 
when potential pregnancy is otherwise suspected) and at 
the end of the studv nrior to discharoe on Period 3 Dav 10. 
Contraception check 
X 
X 
X 
X 
FSH 
X 
• 
For any female who has been ameno1Theic for at least 
12 consecutive months. 
Urine dmg testing 
X 
X 
• 
Participants may undergo random mine dmg testing at the 
discretion of the investigator. 
Single 12-Lead ECG 
X 
X 
X 
X 
X 
• 
Pre-dose Day 1 in each period, and prior to discharge on 
Period 3 Day 10. 
Blood pressure, pulse rate, and 
body temperature 
X 
X 
X 
X 
X 
• 
Pre-dose Day 1 in each period, and prior to discharge on 
Period 3 Day 10. 
• 
Bodv temoerattu·e will be taken at Sreenin  onlv. 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this 
table may be fonnd in 
A  endix 9. 
Scr·een 
Period 1 
-1 
lto5 
D-1 
Dl toD5 
Period 2 
Period 3 
F/U (Phone 
Call) 
ET 
Notes 
Study Day 
D-28 to D-2 
6to 10 
Dl to D5 
11 to 20 
Dl to DlO 
47 to 54 
28-35 Days 
1. All screening should be done '.S28 days before 
the first dose. 
2.  Day relative to start of study intervention 
(Day 1). 
3. In this study, follow-up is to be conducted via 
phone contact 28 to 35 days after administration 
of the final dose of study intervention (Period 3 
Da 9. Stud Da 19 . 
Days Relative to Day 1 
HIV, HBsAg, HBcAb, HCV 
RNA,HCVAb 
X 
X 
C-SSRS and PHQ-9 
X 
X 
X (Dl0) 
COVID-19 assessments 
X 
• 
See Section 8.3.5. 
• 
See Table 2 and Table 3 for specifics. 
• 
See Table 3. 
• 
See Table 2. 
• 
See blood sampling timepoints in Table 2 for Periods 1 
and 2 and Table 3 for Period 3. 
Study intervention 
administration PF-07081532 
X(D1) 
X(Dl) 
X(D4) 
Study intervention 
administration itra.conazole 
X (Dl-9) 
Study intervention 
administration cyclosporine 
X(Dl) 
Pha1macokinetic blood 
sampling: PF-07081532 
D1-5 
D1-5 
D4-10 
X 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this 
table may be fonnd in 
Aooendix 9. 
Scr·een 
Period 1 
Period 2 
Period 3 
F/U (Phone 
Call) 
ET 
Notes 
Study Day 
-1 
lto5 
6to 10 
11 to 20 
47 to 54 
Days Relative to Day 1 
D-28 to D-2 
D-1 
Dl toD5 Dl to D5 Dl to DlO 28-35 Days 
1. 
All screening should be done '.S28 days before 
the first dose. 
2. 
 Day relative to start of study intervention 
(Day 1). 
3. 
 In this study, follow-up is to be conducted via 
phone contact 28 to 35 days after administration 
of the final dose of study intervention (Period 3 
Dav 9. Studv Dav 19). 
CRU discharge 
X (DlO) 
Serious and nonserious AE 
monitoring 
X 
➔ 
➔ 
➔ 
➔ 
➔ 
➔ 
• 
See Section 8.4.3 for follow-up AE and SAE assessments. 


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Table 2. 
PK Blood Sampling - Periods 1 and 2 
 
Visit Identifier 
Periods 1 and 2 
Notes 
Period Day 
1 
2 
3 
4 
5 
Hours After Dose 
0 
0.5 
1 
2 
4 
6 
8 
10 
12 
14 
24 
36 
48 
72 
96 
120 • 
Hour 0 = predose sample 
collection. 
• 
The 120-hour PK samples 
in Periods 1 and 2 are the 
same as the 0-hour PK 
samples in Periods 2 and 3, 
respectively. 
Study intervention administration PF-07081532 
X 
Study intervention administration cyclosporine 
(Period 2 only) 
X 
PK blood sampling PF-07081532 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Table 3. 
PK Blood Sampling – Period 3 
 
Visit Identifier 
Period 3 
Notes 
Period Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Hours After Dose 
0 
0.5 
1 
2 
4 
6 
8 
10 12 14 
24 
36 
48 
72 
96 
120 
144 
Hour 0 = predose sample 
collection 
Study intervention administration 
PF-07081532 
X 
Study intervention administration 
itraconazole 
X X X 
X 
X 
X 
X 
X 
X 
PK blood sampling 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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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 GLP-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 an orally administered, potent and selective GLP-1R agonist in development 
as adjunct to diet and exercise, to improve glycemic control in T2DM, and for chronic weight 
management in a population that is overweight with co-morbidities or who have obesity. 
2.1. Study Rationale 
In vitro data indicate that PF-07081532 is a substrate for both CYP3A and OATP; therefore, 
an assessment of the impact of inhibition of these pathways is needed. This study will 
evaluate the impact of the strong CYP3A inhibitor, itraconazole, and the OATP inhibitor, 
cyclosporine, on the single-dose PK of PF-07081532. 
The purpose of this Phase 1, open-label, fixed-sequence study is to evaluate the effect of 
multiple doses of itraconazole and a single dose of cyclosporine on the SD PK of 
PF-07081532 in otherwise healthy, overweight or obese adult participants, and to generate 
safety, tolerability, and PK data for further clinical development. 
2.2. Background 
T2DM is estimated to affect more than 424 million people worldwide,5 and the prevalence of 
T2DM within the US is estimated to range from 12 to 14%.6 Patients with poorly controlled 
T2DM have an increased risk of developing complications associated with both 
microvascular and macrovascular disease, including nephropathy, neuropathy, retinopathy, 
cardiovascular disease and stroke; and are at 2 to 4 times increased risk of mortality than 
adults who do not have diabetes.7 While existing pharmacological options for the treatment 
of diabetes may provide satisfactory glycemic control for some patients, there remains a large 
number of patients who do not achieve target glycated HbA1c levels, suggesting a need for 
additional therapeutic options. 
Obesity is a chronic disease that is associated with serious co-morbidities, including T2DM, 
dyslipidemia, hypertension, atherosclerosis, obstructive sleep apnea and certain cancers,8 and 
is also associated with increased all-cause mortality.9 The global burden of obesity is high 
with more than 600 million adults estimated to have obesity worldwide. In addition, the 
prevalence of obesity has doubled in more than 70 countries since 1980 and poses a major 
public health challenge.10 First line treatment for obesity is lifestyle intervention including 
diet, exercise and behavioral therapy. While effective in many patients, lifestyle intervention 
is often not sustainable, and many patients regain weight after initial weight loss.11 
Pharmacotherapy has been approved for the long-term treatment of obesity and can be a 
useful adjunct to lifestyle intervention to augment and maintain weight loss. 
Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and cardiovascular safety, with more than one marketed agent demonstrating 


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cardiovascular benefit.12 Based on the clinical experience with injectable GLP-1R agonists, 
an oral, small molecule GLP-1R agonist is expected to improve glucose control and reduce 
HbA1c levels in patients with T2DM, and to decrease appetite and body weight, resulting in 
weight loss in patients with T2DM and obesity, while avoiding the subcutaneous injection 
required by currently available peptidic GLP-1R agonists. 
2.2.1. Nonclinical Pharmacology 
Refer to the IB for details on the nonclinical pharmacology of PF-07081532. 
2.2.2. Nonclinical Pharmacokinetics and Metabolism 
In rats and monkeys following single IV and oral dosing, PF-07081532 exhibited low CLp 
(13 and 0.6 mL/min/kg, respectively), with low to moderate steady-state Vss (0.76 and 
0.21 L/kg, respectively), leading to a t½ of 1.6 hours in rats and 8.8 hours in monkeys. Renal 
excretion was negligible in both species, and biliary excretion was minimal in rats. The 
systemic exposure (assessed by AUC and Cmax) of PF-07081532 following oral repeat doses 
generally increased in a dose-proportional manner. 
In vitro, PF-07081532 was a substrate for the hepatic uptake transporter, OATP1B3, but not 
for OATP1B1. Coadministration of an OATP inhibitor with PF-07081532 in monkeys 
resulted in a notable increase in the plasma AUC exposure of PF-07081532 and 
corresponding decrease in CL, suggesting a potential role for OATP transport in the uptake 
limited CL in monkeys. 
PF-07081532 was extensively metabolized via oxidative CYP and conjugation UGT 
pathways. CYP-mediated metabolism accounted for 67% of the hepatic metabolism, with 
CYP3A (31%) being the predominant CYP isoform. The contribution of non-CYP 
metabolism was estimated to be 33% of the hepatic metabolism, which was due to 
glucuronidation (24%) and chemical hydrolysis (9%). UGT1A1 and UGT1A3 were primarily 
responsible for the glucuronidation of PF-07081532, with possible minor contributions by the 
non-hepatic UGT isoforms, UGT1A7 and UGT1A8. 
Refer to the IB for more details on the nonclinical PK and metabolism of PF-07081532. 
2.2.3. Nonclinical Safety 
PF-07081532 has been evaluated in a comprehensive nonclinical safety package that includes 
toxicity studies up to 6 months (in rats) and 9 months (in monkeys), as well as reproductive 
and developmental toxicology studies in rats and rabbits. Based on the nonclinical studies 
conducted, the target organs and systems identified with PF-07081532 administration include 
the heart, stomach and liver. 
In the 6-month pivotal study with 1-month recovery phase in rats, oral gavage administration 
of PF-07081532 for 6 months did not result in any mortality or adverse effects in any of the 
study parameters or endpoints evaluated resulting in the high dose being the NOAEL. The 
exposure at this dose provided exposure margins of 40× and 29× (Cmax and AUC24, 
respectively) over the highest clinical dose planned (260 mg QD). 


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In the 9-month pivotal study in cynomolgus monkeys, PF-07081532 was administered by 
oral gavage with doses titrating up. There were no adverse findings in the endpoints 
evaluated in this study. The primary effects were consistent with the expected pharmacology 
of the test article which included decreased body weight associated with decreased food 
consumption, and secondary changes in clinical chemistry and hematology parameters. At 
the NOAEL dose, the exposure margins were 5.2× and 4.6× (Cmax and AUC24, respectively) 
over the highest clinical dose (260 mg QD) planned. 
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 of 768 ng/mL and unbound 
AUC24 of 8270 ng•h/mL in rats and unbound Cmax of 98.5 ng/mL and unbound AUC24 of 
1300 ng•h/mL in monkeys. 
PF-07081532 was not genotoxic in either in vitro or in vivo assays. In addition, PF-07081532 
was negative in the 3T3 Neutral Red uptake Phototoxicity Test, indicating that PF-07081532 
is not phototoxic. 
Refer to the IB for more details on the nonclinical safety of PF-07081532. 
2.2.4. Clinical Overview 
As of issuance of this protocol, 2 Phase 1 studies evaluating PF-07081532 (C3991001 and 
C3991002) have been completed. In total, 88 participants have been randomized, including 
22 healthy adult participants, 51 adult participants with T2DM, and 15 adult participants with 
obesity. A total of 74 unique participants have been exposed to at least 1 dose of 
PF-07081532. The safety profile of PF-07081532 was assessed in these 2 completed clinical 
studies and, to date, administration of PF-07081532 at single doses up to 200 mg and 
multiple doses up to 180 mg QD has been considered safe, with the majority of the TEAEs 
being mild in intensity. 
One Phase 1 study, C3991003, recently concluded. This inpatient study enrolled participants 
with T2DM inadequately controlled on metformin, and participants with obesity, to receive 
PF-07081532 or placebo QD for 42 days. The starting dose for the first cohort of this study 
was 20 mg QD of PF-07081532, with subsequent dose levels determined based on emerging 
data; the maximum dose administered was 80 mg QD. 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. 
Refer to the IB for more details on the clinical safety of PF-07081532. 
2.2.4.1. Clinical Pharmacokinetics 
The clinical PK of PF-07081532 in adult participants have been evaluated to date in 
2 completed studies (C3991001 and C3991002). The results of these completed studies are 
summarized in the PF-07081532 IB. 
In Study C3991001 following administration of single oral doses of PF-07081532 under 
fasted conditions to healthy participants, PF-07081532 was absorbed relatively rapidly with a 


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Protocol C3991041 
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median Tmax of 1.00 to 4.02 hours (individual Tmax values ranged between 0.5 and 6 hours). 
Based on the individual plasma concentration-time profiles, the absorption phase exhibited 
multiple peaks, especially at the higher dose levels. Mean t½ ranged from 18.03 to 
20.90 hours across all doses. Plasma Cmax increased less than proportionally across the entire 
investigated dose range (from 10 mg to 200 mg), while plasma AUCinf increased less than 
proportionally from 10 mg to 30 mg and approximately proportionally from 30 mg to 
200 mg. Inter-participant variability for PF-07081532 exposure was low to moderate and 
ranged from 9% to 36% CV for Cmax and 15% to 44% CV for AUCinf across all doses. 
Overall, the results indicate that PF-07081532 may be administered without regard to food. 
In Study C3991002 following administration of PF-07081532, Cmax was observed at 
1 to 2 hours on Day 1, and 2 to 8 hours following the last dose on Day 28 or 42. Across all 
dose groups, the mean t½ ranged from 20.70 to 26.50 hours. PF-07081532 exposure generally 
increased in an approximately dose-proportional manner across the dose range studied, and 
accumulation of less than 2.1-fold was observed. Urinary recovery of unchanged 
PF-07081532 was low, with less than 0.2% of the dose recovered in the 24-hour dosing 
interval following last dose administration. Interparticipant variability for PF-07081532 
exposure ranged from 17% to 51% CV for Cmax and 15% to 62% CV for AUCtau across all 
doses. No substantial differences in PF-07081532 exposure (Cmax and AUCtau) were observed 
between participants with T2DM and obesity either after single dose (Day 1, 10 mg) or 
multiple dose (Day 28, 120 mg and Day 42, 180 mg) administration. 
In Study C3991003 following single-dose (Day 1) and multiple-dose (Day 42) administration 
of PF-07081532, peak plasma PF-07081532 concentrations (Cmax) were observed at 
1 to 2 hours and 2 to 5 hours, respectively. Terminal t½ averaged 24.37 to 26.04 hours 
following multiple-dose administration (Day 42). PF-07081532 exposure (Cmax and AUCtau) 
increased in an approximately dose-proportional manner across the dose range studied. 
Accumulation with QD dosing was less than 2-fold. No substantial differences were 
observed in the achieved exposures (both Cmax and AUCtau) between participants with T2DM 
and obesity either after single-dose (Day 1, 20 mg) or multiple-dose (Day 42, 60 mg) 
administration. 
Refer to the IB for more details on the clinical PK of PF-07081532. 
2.3. Benefit/Risk Assessment 
PF-07081532 is not expected to provide any clinical benefit to healthy participants. This 
study is designed primarily to generate safety, tolerability, and pharmacokinetic data for 
further clinical development. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07081532 may be found in the IB, which is the SRSD for this study. The 
SRSD for the site sourced itraconazole and cyclosporine capsule products are the 
corresponding USPIs.13,14 


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2.3.1. Risk Assessment 
 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention: PF-07081532 
Thyroid C-cell tumors 
The potential risks are based on product 
labeling for injectable GLP-1R agonists 
(ie, liraglutide, dulaglutide, semaglutide, 
and exenatide) due to dose-dependent 
and treatment duration-dependent 
thyroid C-cell tumors in nonclinical 
studies in rats and mice at clinically 
relevant exposures. 
Of note, similar tumors were not seen in 
rodent studies with PF-07081532, likely 
as PF-07081532 does not stimulate 
rodent GLP-1 receptors. 
Potential participants with a 
personal or family history of 
medullary thyroid carcinoma or 
Multiple Endocrine Neoplasia 
syndrome type 2 are excluded from 
the clinical development program. 
Thyroid function tests are included 
in the clinical trial protocols to 
monitor participants’ thyroid 
function. 
Pancreatitis 
The potential risks are based on product 
labeling for injectable GLP-1R agonists 
(ie, liraglutide, exenatide, semaglutide 
and dulaglutide). 
One SAE of obstructive pancreatitis has 
been observed in the PF-07081532 
clinical trial program, which was 
considered to be treatment-related by the 
investigator, but unrelated by the 
sponsor. 
Per exclusion criteria, potential 
participants with acute pancreatitis 
or a history of chronic pancreatitis 
are not eligible for study entry. 
Serum amylase and lipase are 
monitored during clinical studies. 
Hypoglycemia 
Clinical trials with injectable GLP-1R 
agonists have not demonstrated an 
increased risk for hypoglycemia. But 
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. 
Participants with obesity who do not 
have co-existing T2DM would not be 
taking anti-diabetic agents and therefore 
would not be expected to have an 
increased risk for hypoglycemia. 
A low overall frequency of generally 
mild hypoglycemia has been reported in 
the PF-07081532 clinical development 
program to date. 
Anti-diabetic medications are 
prohibited in this study, and blood 
glucose is monitored as a part of the 
lab assessments during the study. 
Participants are informed about the 
signs and symptoms of 
hypoglycemia and are monitored 
for these symptoms during the 
study. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Impairment in renal 
function 
Potential risks are based on product 
labeling for injectable GLP-1R agonists, 
and predominantly occur in patients with 
significant nausea, vomiting, and 
dehydration. 
In the clinical trial program only one 
mild adverse event (Preferred Term 
Blood creatinine increased) has been 
observed. 
Per exclusion criteria, potential 
participants with significant renal 
impairment are not eligible for 
study entry. 
Renal function is monitored by lab 
assessments of serum urea, 
creatinine and eGFR. 
Hydration will be encouraged, and 
reduced fluid intake and evidence 
of dehydration, if detected, will be 
treated by close clinical follow-up. 
Gastrointestinal adverse 
reactions 
The potential risks are based on product 
labeling for injectable GLP-1R agonists 
(ie, liraglutide, exenatide, semaglutide 
and dulaglutide). 
Gastrointestinal AEs, the majority of 
which were mild in severity, have been 
observed in the clinical program with 
PF-07081532. In nonclinical studies with 
PF-07081532, gastrointestinal adverse 
effects were observed in rats and 
monkeys. 
Participants are monitored during 
the clinical studies to prevent 
potential sequelae of any severe 
gastrointestinal reactions, 
eg, dehydration. 
Hydration will be encouraged and 
concomitant medication for nausea 
is permitted in the study. 
Diabetic retinopathy 
complications 
The potential risk is based on the product 
labeling for the injectable GLP-1R 
agonist semaglutide and dulaglutide in 
patients with T2DM. 
There are no nonclinical or clinical data 
involving PF-07081532 to suggest an 
increased risk of diabetic retinopathy 
complications. 
Potential participants with diabetes 
mellitus are excluded from this 
clinical study. 
Suicidal ideation and 
behavior 
The potential risk is based on the product 
labeling for the injectable GLP-1R 
agonists liraglutide and semaglutide for 
obesity based on long-term studies. 
Suicidal ideation has not been observed 
in the PF-07081532 clinical studies to 
date. 
Suicidal ideation and behavior, 
along with symptoms of depression, 
will be monitored at specified 
intervals during the study using the 
C-SSRS and PHQ-9 questionnaires, 
with referral to a MHP for further 
evaluation if needed. 
Changes in heart rate 
Potential risk is based on the product 
labeling for the injectable GLP-1R 
agonists, liraglutide and semaglutide, for 
T2DM and obesity. 
Modest increases in HR have been noted 
in the early clinical studies with 
PF-07081532, with most values 
remaining within the normal range. 
HR is monitored during the clinical 
study. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Declines in body weight 
Decreased appetite and body weight loss 
have been reported for marketed 
GLP-1R agonists and declines in body 
weight have been noted at higher doses 
of PF-07081532. 
Weight is collected at multiple 
timepoints and will be monitored 
throughout the trial. 
Acute gallbladder disease 
Potential risk is based on the product 
labeling for the injectable GLP-1R 
agonists, semaglutide and liraglutide, for 
T2DM and obesity. 
Acute gallbladder disease has not been 
observed in the PF-07081532 clinical 
trial program to date. 
Participants with symptomatic 
gallbladder disease are excluded 
from this clinical study. 
Participants are monitored for AEs 
and laboratory tests that may 
suggest development of acute 
gallbladder disease. 
Study Intervention: Itraconazole 
Rare cases of serious 
hepatotoxicity, including 
liver failure and death. 
There have been reports 
of congestive heart 
failure. In post-marketing 
experience, heart failure 
was more frequently 
reported in patients 
receiving a total daily 
dose of 400 mg although 
there were also cases 
reported among those 
receiving lower total daily 
doses. Transient or 
permanent hearing loss 
has been reported in 
patients receiving 
treatment with 
itraconazole. 
Risk based on product labeling. 
Multiple oral doses of 200 mg QD 
for 9 days are administered in this 
study and pose minimal risk. 
Participants will be monitored in an 
inpatient clinical research unit. 
Study Intervention: Cyclosporine 
Systemic hypertension, 
hepatotoxicity and 
nephrotoxicity; the risk 
increases with increasing 
dose and duration of 
cyclosporine therapy. 
Renal dysfunction, 
including structural 
kidney damage, is a 
potential consequence of 
cyclosporine, and 
therefore, renal function 
must be monitored during 
therapy. 
Risk based on product labeling. 
A single oral dose of 600 mg is 
administered in the study and poses 
minimal risk. Participants will be 
monitored in an inpatient clinical 
research unit. 
Hydration will be encouraged and 
concomitant medication for nausea 
is permitted in the study. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Other 
Risk of COVID-19 
exposure during study 
Study participants could be infected with 
the SARS-CoV-2 virus during study 
participation. This could lead to 
increased health risk for this participant 
and others in the study. 
Participants undergo COVID-19 
specific assessments at admission to 
study site and when symptoms 
arise. 
2.3.2. Benefit Assessment 
While PF-07081532 is not expected to provide any significant long-term clinical benefit to 
the healthy, overweight or obese participants in this relatively short-term study, potential 
benefits may include weight loss, receiving medical evaluations/assessments associated with 
clinical study visits (eg, physical examinations, ECGs, labs), and contributing to the process 
of developing a potential new therapy for T2DM and obesity. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07081532 may be found in the IB, which is SRSD, for this study. 
2.3.3. Overall Benefit/Risk Conclusion 
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with PF-07081532 are justified by the anticipated benefits that may 
be afforded to participants who are overweight or obese. 
3. OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To estimate the effect of MD itraconazole on the 
single-dose PK of PF-07081532 in otherwise 
healthy, overweight or obese participants. 
• 
PF-07081532 PK parameter: AUCinf (if data 
permita otherwise AUClast) 
• 
To estimate the effect of SD cyclosporine on the 
single-dose PK of PF-07081532 in otherwise 
healthy, overweight or obese participants. 
• 
PF-07081532 PK parameter: AUCinf (if data 
permita otherwise AUClast) 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of 
PF-07081532 administered separately and in 
combination with itraconazole or cyclosporine 
in otherwise healthy, overweight or obese 
participants. 
• 
Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and ECG 
parameters. 
• 
Assessment of mental health as determined by 
C-SSRS and PHQ-9. 
• 
To evaluate the effects of itraconazole or 
cyclosporine on additional PK parameters for 
PF-07081532. 
• 
Additional plasma PK parameters for 
PF-07081532: Cmax and Tmax; and CL/F, Vz/F, t½, 
as data permit. 
a. 
Should it be deemed that too few AUCinf estimates (eg, less than 12 for a single treatment) are obtained 
from the evaluable participants, AUClast may be selected as the primary endpoint for CSR reporting. 


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4. STUDY DESIGN 
4.1. Overall Design 
This is a Phase 1, open-label, fixed-sequence, 3-period study to evaluate the effect of 
multiple doses of itraconazole and a single dose of cyclosporine on the single-dose PK of 
PF-07081532 in otherwise healthy, overweight or obese adult participants. The 3 study 
periods will be conducted consecutively without a break. 
All participants will provide informed consent and undergo Screening evaluations to 
determine their eligibility. Screening will occur within 28 days of the first dose of study 
intervention on Period 1 Day 1. Participants who discontinue from the study before 
completing all assessments may be replaced at the discretion of the investigator and sponsor. 
Approximately 16 participants will be enrolled in the study such that approximately 
12 evaluable participants complete the study. 
The total duration of participation from the Screening Visit to the F/U telephone contact will 
be approximately 82 days or 12 weeks, approximately 3 weeks of which will be conducted 
on an inpatient basis. The 21-day inpatient portion of the study will be conducted as follows: 
Period 1: Days -1 to 5 (Study Days -1 to 5; participants are admitted to the CRU on Day -1), 
40 mg SD PF-07081532 on Day 1; 
Period 2: Days 1 to 5 (Study Days 6 to 10), 40 mg SD PF-07081532 plus 600 mg SD 
cyclosporine on Day 1; 
Period 3: Days 1 to 10 (Study Days 11 to 20; participants are discharged from the CRU on 
Study Day 20), 200 mg itraconazole QD ×9 days plus 40 mg SD PF-07081532 on Day 4. 
A telephone F/U contact will occur 28-35 days from the last dose of study intervention 
(Period 3, Day 9). 
4.2. Scientific Rationale for Study Design 
The purpose of this study is to characterize the effect of multiple doses of itraconazole and a 
single dose of cyclosporine on the SD PK of PF-07081532 in otherwise healthy, overweight 
or obese adult participants. 
In vitro data indicate that PF-07081532 is a substrate for the hepatic uptake transporter, 
OATP1B3. Likewise, an increase in the plasma AUC exposure of PF-07081532 was 
observed during coadministration of an OATP inhibitor in monkeys. Therefore, a single dose 
of cyclosporine will be coadministered with PF-07081532 in this study to assess the impact 
of an OATP inhibitor on the single-dose PK of PF-07081532. 
In vitro data also indicate that CYP3A is the predominant CYP isoform contributing to the 
metabolism of PF-07081532. Therefore, multiple doses of itraconazole will be 
co-administered with PF-07081532 in this study to assess the impact of a CYP3A strong 
inhibitor on the single-dose PK of PF-07081532. 


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PF-07081532 will be administered as a single 40 mg dose in all 3 study periods, and all 
dosing will be administered with food in order to minimize gastrointestinal related AEs. 
Participants will include overweight or obese males and females to represent the target 
population. Additionally, WOCBP will be permitted with the stipulation that they comply 
with the contraceptive guidelines provided in Appendix 4. 
4.2.1. Choice of Contraception/Barrier Requirements 
Human reproductive safety data are not available for PF-07081532, but there is no suspicion 
of human teratogenicity based on the intended pharmacology of the compound. Therefore, 
the use of a highly effective method of contraception is required (see Appendix 4). 
4.2.2. Collection of Retained Research Samples 
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention. 
4.3. Justification for Dose 
The 40 mg dose of PF-07081532 has been chosen based on safety and tolerability 
considerations during co-administration of either a CYP3A or OATP inhibitor. Because PF- 
07081532 was shown to be an OATP substrate in vitro, and because co-administration of an 
OATP inhibitor with PF-07081532 in monkeys resulted in a notable increase in PF-07081532 
plasma AUC exposure, a conservative dose of 40 mg has been chosen in the event 
cyclosporine co-administration results in significant increases in PF-07081532 exposure 
(refer to Section 2.2.2). 
Itraconazole is considered to be a strong inhibitor of CYP3A.15 The 200 mg QD itraconazole 
dosing regimen (3-day lead-in) has been chosen based on recommendations provided by the 
Innovation and Quality in Pharmaceutical Development’s Clinical Pharmacology Leadership 
Group16 and is expected to provide adequate inhibition of CYP3A. Multiple DDI studies 
using 100–200 mg/day of itraconazole with a 3-day lead-in have demonstrated that 
adequately strong CYP3A inhibition is observed with this strategy.17,18,19 Following the 
co-administration of itraconazole and PF-07081532 on Day 4 of Period 3, itraconazole 
administration will continue for an additional 5 days in order to maintain inhibition of 
CYP3A throughout the PK sampling duration of PF-07081532. 
Itraconazole is available as either capsules or solution for oral administration and either may 
be used when conducting DDI studies.16 The oral solution formulation will be administered 
in the current study as it provides higher systemic exposures, has less PK variability, and 
offers greater flexibility with respect to dosing (fed or fasted) compared to the capsule 
formulation.20,21 Finally, a total duration of 2 weeks of itraconazole dosing is a reasonable 
limit for minimizing unnecessary itraconazole exposure and potential safety risks associated 
with longer exposure,16 therefore, the 9-day dosing duration planned for the current study is 
expected to be safe and well-tolerated. 


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Cyclosporine is an FDA recommended inhibitor of OATP.15 The 600 mg single dose of 
cyclosporine has been chosen based on previous experience in clinical DDI studies and is 
expected to provide maximal inhibition of OATP, with adequate safety and tolerability.22,23 
4.4. End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit or the last scheduled procedure 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 
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: 
Age and Sex: 
1. Otherwise healthy female and male participants must be at least 18 years of age at the 
time of signing the ICD (healthy is defined as no clinically relevant abnormalities 
identified by a detailed medical history, physical examination, including blood 
pressure and pulse rate measurement, standard 12-lead ECG and clinical laboratory 
tests). 
• Women can be of child-bearing potential, but cannot be pregnant, breastfeeding, 
or planning to become pregnant while participating in the study, may not be 
taking either oral contraceptives or non-oral hormonal contraceptives (with the 
exception of implantable progestogen only or intrauterine hormone releasing 
system), and must avoid vaccination within live attenuated vaccines. Refer to 
Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
Other Inclusion Criteria: 
2. BMI: ≥25.0 kg/m2 at Screening. 


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3. Stable body weight, defined as <5 kg change (per participant report) for 90 days 
before Screening. 
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
5. Capable of giving signed informed consent as described in Appendix 1: Regulatory, 
Ethical, and Study Oversight Considerations, which includes compliance with the 
requirements and restrictions listed in the ICD and in this protocol. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
• Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, cholecystectomy or any area of intestinal resection, active 
inflammatory bowel disease or pancreatic insufficiency). 
• Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the 
risk of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
• Known intolerance or hypersensitivity to GLP-1R agonists. 
• Known hypersensitivity to itraconazole or cyclosporine. 
2. Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at 
Screening. Note: women with prior diagnoses of gestational diabetes during 
pregnancy only are eligible if they meet the other eligibility criteria. 
3. Any malignancy not considered cured (except basal cell carcinoma and squamous cell 
carcinoma of the skin); a study participant is considered cured if there has been no 
evidence of cancer recurrence in the previous 5 years (from Screening). Anyone with 
any history of pancreatic CA will be excluded, even if it was resected and they were 
considered ‘cured’. 
4. Personal or family history of MTC or MEN2, or study participants with suspected 
MTC per the investigator’s judgment. 


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5. Acute pancreatitis, history of repeated episodes of acute pancreatitis, or history of 
chronic pancreatitis. 
6. Symptomatic gallbladder disease. 
7. Medical history or characteristics suggestive of genetic or syndromic obesity or 
obesity induced by other endocrinological disorders (eg, Cushing Syndrome). 
8. History of major depressive disorder or history of other severe psychiatric disorders 
(eg, schizophrenia or bipolar disorder) within the last 2 years from screening. 
9. Known medical history of active liver disease, including chronic hepatitis B or C, 
primary biliary cirrhosis, alcoholic liver disease, primary sclerosing cholangitis, 
autoimmune hepatitis, overlap syndrome, or prior known drug-induced liver injury. 
10. History of HIV infection. 
11. Any lifetime history of a suicide attempt. 
Prior/Concomitant Therapy 
12. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention (Refer to Section 6.9 for additional details). 
13. Use of any medications that are: 
• Moderate or strong CYP3A4/5 and/or CYP2C19 inhibitors within 14 days or 5 
half-lives (whichever is longer), 
• Moderate or strong CYP3A and/or CYP2C19 inducers within 14 days or 5 half- 
lives (whichever is longer), 
• Systemic therapy with inhibitors of OATP transporters within 14 days or 5 half- 
lives (whichever is longer) prior to the first dose of study intervention (Refer to 
Section 6.9 for additional details). 
14. Current use of any prohibited concomitant medication(s) or those unwilling/unable to 
use a permitted concomitant medication(s) (Refer to Section 6.9 for additional 
details). 
15. Any vaccine (eg, COVID/influenza) within 7 days prior to the first dose of study 
intervention. 
Prior/Concurrent Clinical Study Experience: 
16. Previous administration with a GLP-1R agonist (other than PF-07081532) within 
90 days preceding the first dose of study intervention used in this study. Previous 


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administration with PF-07081532 within 30 days preceding the first dose of study 
intervention used in this study. 
17. 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). 
Diagnostic Assessments (at Screening unless otherwise indicated) 
18. A PHQ-9 score ≥15 obtained at Screening or Day -1 in Study. 
19. Response of “yes” to question 4 or 5, or on any suicidal behavioral question on the 
C-SSRS at Screening or Day -1 in Study. 
20. A positive urine drug test. 
21. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. BP should be measured in triplicate and the average of 
the 3 BP values should be used to determine the participant’s eligibility. Note: At 
Screening, the participant’s arm circumference should be measured (eg, using a 
flexible anthropometric tape) at the midpoint of the length of the upper arm, and the 
appropriate cuff selected and used throughout the study. 
22. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF interval 
>450 msec, complete LBBB, signs of an acute or indeterminate age myocardial 
infarction (documented assessment), ST-T interval changes suggestive of myocardial 
ischemia, second- or third-degree AV block, or serious bradyarrhythmias or 
tachyarrhythmias). 
• If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be 
repeated 2 more times and the average of the 3 QTcF or QRS values should be 
used to determine the participant’s eligibility. Computer interpreted ECGs should 
be overread by a physician experienced in reading ECGs before excluding 
participants. 
23. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
• HbA1c ≥6.5%. 
• AST or ALT level ≥1.25 × ULN. 
• Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ ULN. 


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• TSH >1.5x ULN or <LLN. 
• Serum calcitonin >ULN. 
• Amylase or lipase >ULN. 
• Fasting blood glucose ≥126 mg/dL. 
• Fasting C-peptide not within normal limit. 
• eGFR <75 mL/min/1.73 m2 as calculated by the CKD-EPI equation. 
24. Positive testing for HIV, HBsAg, HBcAb, or HCVAb. Study participants positive for 
HCVAb are to be excluded unless known to have been treated with a known curative 
therapy and negative for HCV RNA. Anyone who has a history of HBV that is 
treated/cleared is excluded. Hepatitis B vaccination is allowed. 
25. A positive SARS-CoV-2 test. 
Other Exclusions: at Screening unless indicated 
26. 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). 
27. Current use of tobacco or nicotine containing products in excess of the equivalent of 
5 cigarettes per day. 
28. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
29. History of sensitivity to heparin or heparin induced thrombocytopenia. 
30. Unwilling or unable to comply with the criteria or procedures in the study. 
31. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
5.3. Lifestyle Considerations 
The following guidelines are provided: 


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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 
and their partner(s) from the permitted list of contraception methods (see Appendix 4, 
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. At time points indicated in the SoA the investigator or designee will inform the 
participant of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the participant’s chart. 
Participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception, considering that their risk for pregnancy may have changed since 
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 any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample. The predose PK sample should be taken prior to consumption of the 
breakfast meal on Day 1 in Periods 1 and 2, and on Day 4 in Period 3. 
• Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices—see below) may be 
consumed with meals and the evening snack. 
• During CRU confinement, participants should begin consumption of a standard 
breakfast (morning) approximately 30 minutes prior to dosing. The breakfast meal 
will be consumed over approximately a 20-minute period, with the study intervention 
administered within approximately 10 minutes of completion of the meal. Participants 
will be encouraged to consume the entire meal. 
• Lunch will be provided approximately 4 hours after dosing. 
• Dinner will be provided approximately 9 to 10 hours after dosing. 
• An evening snack may be permitted. 
• Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 14 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 


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• While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal. 
5.3.3. Caffeine, Alcohol, and Tobacco 
• Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample. 
• Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample. Participants may undergo an alcohol breath test or blood 
alcohol test at the discretion of the investigator. 
• Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU. 
5.3.4. Activity 
• Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted; 
• In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing. 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study interventions are all prespecified investigational and auxiliary medicinal 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, itraconazole, and 
cyclosporine. 


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6.1. Study Intervention(s) Administered 
 
Study Intervention(s) 
Intervention Name 
PF-07081532 
Itraconazole 
Cyclosporine 
Arm Name 
(group of participants 
receiving a specific 
treatment or no 
treatment) 
All participants 
All participants 
All participants 
Type 
Drug 
Drug 
Drug 
Dose Formulation 
Tablet 
Solution 
Capsule 
Unit Dose Strength(s) 
20 mg 
10 mg/mL 
100 mg 
Dosage Level(s) 
40 mg 
200 mg (20 mL) 
600 mg (6 × 100 mg) 
Route of 
Administration 
Oral 
Oral 
Oral 
Use 
Substrate 
Perpetrator 
Perpetrator 
IMP or AxMP 
IMP 
AxMP 
AxMP 
Sourcing 
Provided centrally by the 
sponsor 
Provided locally by the 
trial site 
Provided locally by the 
trial site 
Packaging and 
Labeling 
Study intervention will 
be supplied by Pfizer to 
the CRU in bulk along 
with individual dosing 
containers, as necessary, 
for unit dosing. 
Commercially available 
itraconazole will be 
supplied by the CRU. 
Commercially available 
cyclosporine will be 
supplied by the CRU. 
[Current/Former 
Name(s) or Alias(es)] 
N/A 
SPORANOX® 
NEORAL® 
 
Study Arm(s) 
Arm Title 
Period 1: PF-07081532 
Period 2: Cyclosporine + 
PF-07081532 
Period 3: Itraconazole + 
PF-07081532 
Arm Type 
No intervention 
Experimental (DDI) 
Experimental (DDI) 
Arm 
Description 
Participants will 
receive PF-07081532 
as a single 40 mg dose 
on Day 1. 
Participants will receive a single 
40 mg dose of PF-07081532 and a 
single 600 mg dose of cyclosporine on 
Day 1. 
Participants will receive 
itraconazole 200 mg 
QD × 9 days plus a 
single 40 mg dose of 
PF-07081532 on Day 4. 


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Study Arm(s) 
Associated 
Intervention 
Labels 
20 mg PF-07081532 
oral tablets 
20 mg PF-07081532 oral tablets; 
Commercially available cyclosporine 
100 mg capsules 
20 mg PF-07081532 oral 
tablets; 
Commercially available 
itraconazole solution 
(10 mg/mL) 
 
PF-07081532 20 mg oral tablets will be provided by Pfizer to the CRU in bulk along with 
individual dosing containers, as necessary, for unit dosing. 
Commercially available itraconazole will be supplied by the CRU. 
Commercially available cyclosporine will be supplied by the CRU. 
6.1.1. Administration 
Following an overnight fast of at least 10 hours, participants will receive study intervention 
with the breakfast meal at approximately 0800 hours (±2 hours). Investigator site personnel 
will administer PF-07081532, itraconazole, or cyclosporine during each period (as applicable 
per SoA) with ambient temperature water to a total volume of approximately 240 mL. On 
coadministration day, participants may receive additional ambient temperature water up to 
100 mL, if needed. Details regarding meals on dosing days are provided in Section 5.3.2. 
Participants will swallow the study intervention whole and will not manipulate or chew (as 
relevant) the study intervention prior to swallowing. 
PF-07081532 must be administered within approximately 10 minutes of completion of the 
morning meal. PF-07081532 will be administered first and itraconazole or cyclosporine will 
be administered within 5 minutes of PF-07081532 during the DDI assessment periods. 
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing. 
6.2. Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm 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 


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a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business. 
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to 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 PCRU local/site 
procedures. 
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 PCRU’s local/site procedures. 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. 
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/capsules/solution 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 


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staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist). The tablets, capsules, or solution will be provided in unit 
dose containers and labeled in accordance with Pfizer regulations and the clinical site’s 
labeling requirements. 
6.3. Assignment to Study Intervention 
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled. 
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number. 
6.4. Blinding 
This is an open label study. 
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. 
Study site personnel will examine each participant’s mouth to ensure that the study 
intervention was ingested. 
6.6. Dose Modification 
Dose modification will not be permitted in this study for any study intervention. 
6.7. Continued Access to Study Intervention After the End of the Study 
No study intervention will be provided to participants at the end of their study participation. 
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician. 
6.8. Treatment of Overdose 
For this study, any dose of PF-07081532 greater than 1.6 g within a 24-hour time period will 
be considered an overdose. A single dose of 1.6 g 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. 
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There is no specific treatment for an overdose of PF-07081532. Treatment of overdose 
should consist of general supportive measures. 
In the event of an overdose, the investigator 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 1 day from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a case- 
by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant. 
6.9. Prior and Concomitant Therapy 
Study participants will abstain from all concomitant treatments, except for the treatment of 
AEs, as described in the Exclusion Criteria section of this protocol. 
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. 
Sytemic therapy with moderate or strong CYP3A4/5 and/or CYP2C19 inhibitors or inducers 
within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention are prohibited. Systemic therapy with inhibitors of OATP transporters within 
14 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention are 
prohibited. 
Use of a GLP-1R agonist is prohibited within 90 days prior to the first dose of study 
intervention, with the exception of PF-07081532, which is prohibited within 30 days prior to 
the first dose of study drug. 
Limited use of nonprescription medications that are not believed to affect participant safety 
or the overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor. Acetaminophen/paracetamol may be used at doses of ≤1 g/day. 
Anti-emetics (eg, prochlorperazine, promethazine, ondansetron) may be administered at the 
investigator’s discretion with notification to the sponsor and entry in the CRF. 


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Sites are encouraged to contact the sponsor should there be questions as to whether a 
medication is permitted or prohibited. 
Implantable progestogen or intrauterine hormone releasing system only are allowed to be 
used in participants who are WOCBP (see Appendix 4). 
Females using hormonal contraceptives that do not meet the requirements of this study or 
who are taking hormone replacement therapy may be eligible to participate in this study if 
they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study. Depo-Provera® must 
be discontinued at least 6 months prior to the first dose of study treatment. 
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 the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments. 
6.9.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with PF-07081532; standard medical 
supportive care must be provided to manage the AEs, including administration of 
carbohydrates to treat HAEs (see Section 8.3.6). 
6.9.1.1. Management of Nausea and Vomiting 
Nausea and vomiting have been reported with administration of GLP-1R agonists and also 
with administration of PF-07081532 (see Section 2.2.4). Study participants complaining of 
nausea may be managed conservatively with bed rest and/or fluid management at the 
discretion of the investigator. If nausea and vomiting are not amenable to conservative 
management, anti-emetics (eg, prochlorperazine, promethazine, ondansetron) may be 
administered at the investigator’s discretion with notification to the sponsor and entry in the 
CRF. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: 
• Criteria for a potential Hy’s law case are met (see Appendix 6). 
• Intent to become pregnant or pregnancy confirmed by serum -hCG testing. 


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• Safety or tolerability concern arises, in particular, if not responsive to symptomatic 
management, dosing with study intervention may be stopped in an individual 
participant at investigator discretion. 
• Based on mental health assessment as outlined in Section 8.3.8, should be 
discontinued from dosing at investigator discretion. 
• Positive SARS-CoV-2 Test. 
If the criteria for permanent discontinuation are met, the site should notify the sponsor 
Medical Monitor or sponsor Clinician. 
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is permanently discontinued, the participant should remain in the study 
to be evaluated for safety. See the SoA for data to be collected at the time of discontinuation 
of study intervention and follow-up for any further evaluations that need to be completed. 
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, post-treatment study follow-up, 
and/or future collection of additional information. 
7.1.1. Potential Cases of Acute Kidney Injury 
Abnormal values in Scr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in Scr level relative to the participant’s own 
baseline measurement should trigger another assessment of Scr as soon as practically 
feasible, preferably within 48 hours from awareness. 
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in Scr 
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury. 
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
Scr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating Scr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 


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abnormal Scr. If ≥2 healthy participants in a given period are noted to have 2 consecutive Scr 
results of ≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the finding may be 
considered an adverse drug reaction should be undertaken. 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following: safety, behavioral, compliance, 
administrative reasons, and/or if the study is terminated by the 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/randomized 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. 
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. 


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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 do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria. 
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may be used without repeat collection, as appropriate. 
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 


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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 an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the 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 
200 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 Prior and Concomitant Therapy sections of the protocol. 
8.2. Efficacy Assessments 
Efficacy is not evaluated in this study. 
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, 
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. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 


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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 
Section 8.4.1 to Section 8.4.3. 
8.3.2. Vital Signs 
8.3.2.1. Blood Pressure and Pulse Rate 
Supine BP will be measured with the participant’s arm supported at the level of the heart and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements. If triplicate measurements are obtained, they 
should be collected approximately 2 minutes apart. 
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 Section 8.4.3. 
8.3.2.2. Temperature 
Temperature will be measured orally at Screening. No eating, drinking, or smoking is 
allowed for 15 minutes prior to the measurement. 
8.3.3. Electrocardiograms 
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA of this protocol using an ECG methodology that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. 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, 


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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. 
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 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or 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 
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See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities. 
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Specific Assessments 
Participants will be tested for COVID-19 infection by PCR at admission to the clinic for 
confinement, and if they develop COVID-19 -like symptoms. Additional testing may be 
required by local regulations or by the PI. 
8.3.6. Management of Hypoglycemia 
While hypoglycemia is not expected in the study participants, fasting blood glucose will be 
measured as part of laboratory assessment per the SoA. In addition, as a precaution, 
participants will be monitored for the signs and symptoms associated with hypoglycemia. 
Any episode of hypoglycemia must be captured on the HAE CRF with specific details 
captured on the HAE Form CRF. For the definition of a hypoglycemic episode and severity 
categorization see Section 8.3.6.1 below. 
For medical management of hypoglycemia, the investigator may administer oral 
carbohydrate, glucagon, or IV glucose according to his or her medical judgment. 
8.3.6.1. Definition and Severity of Categorization of Hypoglycemic Adverse Event 
The investigator must assess the glucose values reported by the central/local laboratory, as 
well as any signs or symptoms reported by the study participant. 
HAE is defined as one of the following:24 
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-identified central/local 
laboratory (blood glucose). 
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 at the study site or sponsor identified central/local laboratory, 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. 


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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 central/local 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. 
8.3.6.2. Glucometer Monitoring of Glucose 
Monitoring of FSBG using glucometer measurements is not required per protocol but may be 
obtained if the investigator or participant notes symptoms of hypoglycemia. 
If obtained, FSBG readings will be maintained at the CRU in source documents, and only the 
glucose results from the laboratory will be reported in the study database. 
If an FSBG result is ≤70 mg/dL, a second FSBG should be obtained to confirm the glucose 
value, in addition to a venous sample that will be sent to the clinical laboratory for 
confirmation. If the value from this second FSBG is also ≤70 mg/dL, the second value will 
be recorded as a hypoglycemic AE. FSBG will continue to be monitored until the glucose 


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value returns to >70 mg/dL. Samples may be taken more frequently if deemed necessary by 
the investigator. 
8.3.7. Pregnancy Testing 
A serum pregnancy test is required 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. Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and a second negative 
pregnancy test result will be required at the baseline visit prior to the participant’s receiving 
the study intervention. Pregnancy tests will also be done whenever 1 menstrual cycle is 
missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the study prior to discharge on Period 3 Day 10. 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. 
8.3.8. Suicidal Ideation and Behavior Risk Monitoring 
8.3.8.1. Columbia Suicide Severity Rating Scale 
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behavior.25 The “baseline/screening” version of the C-SSRS26 will be administered at 
Screening and Day -1 in study. Participants who respond “yes” to Question 4 or 5 (indicating 
suicidal ideation), or to any suicidal behavioral question on the C-SSRS at screening or 
Day -1 will not be permitted in the study (see Section 5.2). The “since last visit” version of 
the C-SSRS27 will be administered at the time points specified in the SoA. The C-SSRS will 
be administered by study site staff who have completed training in its administration. 
8.3.8.2. Patient Health Questionnaire-9 (PHQ-9) 
The PHQ9-9 is a 9 item self-report scale for the assessment of depressive symptoms.28 The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in the SoA. A PHQ-9 score of ≥15 at Screening or Day -1 indicates clinically 
significant depression and serves as an exclusion criterion for this study (see Section 5.2). 
8.3.8.3. Referral to a Mental Health Professional 
A participant should be referred to a MHP for the following reasons: 
• Response of “yes” to question 4 or 5, or on any suicidal behavioral question on the 
C-SSRS. 
• A score of ≥10 on the PHQ-9. 
• In the investigator’s judgment a risk assessment or exclusion is required. 


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A clinically qualified MHP is an MHP with appropriate training in the assessment of suicide 
risk, according to local clinical practice standards and regulations, who would normally 
evaluate the risk for suicidal ideation and behavior in a patient. 
Participants who have recurrent suicidal ideation or behavior during the study should be 
discontinued from the study and treated appropriately. If a study participant endorses a 4 or 5 
on the ideation subscale or any behavioral item of the C-SSRS on 2 or more occasions and is 
confirmed to have active suicidal ideation or behavior on both occasions by a risk assessment 
conducted by a qualified MHP, then the participant should be discontinued from the study 
and treated appropriately. 
Participants who meet criteria for referral to a MHP but refuse evaluation and/or treatment by 
a MHP, must be assessed by the investigator to determine if the participant should be 
discontinued from dosing or from the study. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Appendix 3. 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days 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. 


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When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form. 
8.4.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available. 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4. 


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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. 
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 


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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. 
• A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then inseminates his female partner prior to or around 
the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
• If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental 
Form, regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until 28 days after the last dose. 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
followup to the initial EDP Supplemental Form. In the case of a live birth, the structural 


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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 
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 


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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. 
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. 


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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 
Blood samples of approximately 3 mL, to provide approximately 1 mL of plasma, will be 
collected 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. 
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. 
Samples will be used to evaluate the PK of PF-07081532. Each plasma sample will be 
divided into 2 aliquots (1 each for primary and backup). Samples collected for analyses of 
PF-07081532 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 CCI 
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Genetic analyses will not be perfo1med on these plasma samples. 
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 explorato1y 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 detennination as to whether sample 
integrity has been compromised. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be infonned of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
8.6. Genetics 
8.6.1. Specified Genetics 
Specified genetic analyses are not evaluated in this study. 
 
 
 
8.7. Biomarkers 
Biomarkers are not evaluated in this study. 
 
I  
 
I 
 


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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 summaiy 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 primaiy endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 
9.1. Statistical Hypothesis 
No fonnal statistical hypothesis testing will be perfonned in this study. 
9.2. Analysis Sets 
For pmposes of analysis, the following analysis sets are defined: 
 
Participant Analysis 
Set 
Description 
Enrolled 
"Enrolled" means a paiticipant's, or their legally authorized 
representative's, agreement to paiticipate in a clinical study 
following completion of the info1med consent process and 
assignment to study intervention. A paiticipant will be 
considered enrolled if the info1med consent is not withdrawn 
prior to paiticipating in any study activity after screening. 
Potential paiticipants who ai·e screened for the pmpose of 
dete1mining eligibility for the study, but do not paiticipate in 
the study, are not considered enrolled, unless othe1wise 
specified by the protocol. 


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Participant Analysis 
Set 
Description 
Safety analysis set 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the product they actually received. 
PK concentration set 
All participants who take at least 1 dose of study intervention 
and in whom at least 1 concentration value is reported. 
PK parameter set 
All participants who take at least 1 dose of study intervention 
and in whom at least 1 of the PK parameters of primary 
interest are reported. 
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. Pharmacokinetic Analyses 
9.3.1.1. Derivation of Pharmacokinetic Parameters 
Plasma PK parameters of PF-07081532 will be derived (as data permits) from the 
concentration-time data using standard noncompartmental methods as outlined in Table 4. 
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. 
 
Table 4. 
Plasma PK Parameters for PF-07081532 
 
Parameter 
Definition 
Method of Determination 
AUClast 
Area under the plasma 
concentration-time profile from 
time zero to the time of the last 
quantifiable concentration (Clast). 
Linear/Log trapezoidal method. 
AUCinfa 
Area under the plasma 
concentration-time profile from 
time zero extrapolated to infinite 
time. 
AUClast + (Clast*/kel), where Clast* is 
the predicted plasma concentration 
at the last quantifiable time point 
estimated from the log-linear 
regression analysis. 
Cmax 
Maximum plasma concentration. 
Observed directly from data. 
Tmax 
Time for Cmax. 
Observed directly from data as time 
of first occurrence. 


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Table 4. 
Plasma PK Parameters for PF-07081532 
 
Parameter 
Definition 
Method of Determination 
t½a 
Terminal half-life. 
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a 
linear regression of the log-linear 
concentration-time curve. Only 
those data points judged to describe 
the terminal log-linear decline will 
be used in the regression. 
CL/Fa 
Apparent oral clearance. 
Dose/AUCinf. 
Vz/F 
Apparent volume of distribution. 
Dose/ (AUCinf • kel). 
a. 
as data permit 
 
9.3.1.2. Statistical Methods for PK Data 
Natural loge transformed AUCinf of PF-07081532 administered without cyclosporine or 
coadministered with cyclosporine will be analyzed using a mixed effect model with treatment 
as a fixed effect and participant as a random effect. Estimates of the adjusted mean 
differences (Test/Reference) and corresponding 90% CIs will be obtained from the models. 
The adjusted mean differences and 90% CIs for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for 
the ratios. The test treatment will be ‘PF-07081532 40 mg singe dose and cyclosporine’ 
(Period 2), which will be reported separately in comparison to the reference treatment of 
‘PF-07081532 40 mg singe dose without cyclosporine’ (Period 1). 
Natural loge transformed AUCinf of PF-07081532 administered without itraconazole or 
coadministered with itraconazole will be analyzed using a mixed effect model with treatment 
as a fixed effect and participant as a random effect. Estimates of the adjusted mean 
differences (Test/Reference) and corresponding 90% CIs will be obtained from the models. 
The adjusted mean differences and 90% CIs for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for 
the ratios. The test treatment will be ‘PF-07081532 40 mg singe dose and itraconazole’ 
(Period 3), which will be reported separately in comparison to the reference treatment of 
‘PF-07081532 40 mg singe dose without itraconazole’ (Period 1). 
PK parameters, including plasma AUCinf, AUClast, Cmax, Tmax, and CL/F, Vz/F, t½, as data 
permit, of PF-07081532 will be summarized descriptively by treatment. For AUCinf, a listing 
of the individual participant ratios (Test/Reference) will be provided. Box and whisker plots 
for AUCinf will be plotted by treatment. 
The plasma concentrations of PF-07081532 will be listed and descriptively summarized by 
nominal PK sampling time and treatment. Individual participant, as well as mean and median 
profiles, of the plasma concentration-time data will be plotted by treatment using actual (for 
individual) and nominal (for mean and median) times, respectively. Mean and median 
profiles will be presented on both linear and semi-log scales. 


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Additional specifications regarding the tables, listings, and figures will be outlined in the 
SAP. 
9.3.2. Safety Analyses 
All safety analyses will be perfo1med on the safety population. 
AEs, ECGs, BP, pulse rate, body weight, and safety laborato1y data will be reviewed and 
summarized on an ongoing basis dming the study to evaluate the safety of paiiicipants. Body 
weight will be summarized descriptively by period. Any clinical laborato1y, ECG, BP, and 
pulse rate abnonnalities of potential clinical concern will be described. Safety data will be 
presented in tabulai·and/or graphical fo1mat and smnmai·ized descriptively, where 
appropriate. 
Medical histo1y and physical exainination and neurological examination infonnation, as 
applicable, collected during the course of the study, will be considered source data and will 
not be required to be repo1ied, unless othe1wise noted. However, any untowai·d 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 ai·e used for inclusion/exclusion criteria, such as laborato1y 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
repo1ied, unless othe1wise noted. Demographic data collected at screening will be repo1ied. 
9.3.2.1. Electrocardiogram Analyses 
Changes from baseline for the ECG pai·ameters HR, QTcF, PR interval, and QRS complex 
will be summarized by period and time. The frequency of uncoITected QT values above 
500 ms will be tabulated. 
The number (%) of pa1iicipants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by period: 
 
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 
Baseline will be pre-dose on Day I. 
 
9.3.2.2. Mental Health 
Assessment of mental health as dete1mined by C-SSRS and PHQ-9. Details will be provided 
in the SAP. 
 


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9.4. Interim Analyses 
No 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 and PK assessments. 
9.5. Sample Size Determination 
Approximately 16 participants will be enrolled in the study such that approximately 
12 evaluable participants complete the study. 
A sample size of 12 participants will provide adequate precision to estimate the relative 
bioavailability of PF-07081532. The following table presents the width of 90% CI for 
different estimated effects, with 80% coverage probability. 
 
Parameter 
Estimated Effect 
(100*Test/Reference) 
90% CI 
CI Width 
AUCinf 
85% 
66.46% 
108.71% 
42.25% 
90% 
70.37% 
115.11% 
44.74% 
95% 
74.28% 
121.50% 
47.22% 
100% 
78.19% 
127.90% 
49.71% 
105% 
82.10% 
134.29% 
52.20% 
110% 
86.01% 
140.69% 
54.68% 
115% 
89.92% 
147.08% 
57.17% 
These estimates are based on the assumption that within-participant standard deviation is 
0.291 for lnAUCinf as obtained from study C3991001. 
Participants who withdraw from the study or discontinue treatment, or whose PK samples are 
considered to be non-evaluable with respect to the primary PK objective may be replaced at 
the discretion of the investigator upon consultation with the sponsor. For participants who 
remain in the study, the SAP will address PK data associated with episodes of vomiting 
following administration of study intervention and/or missed doses for any of the study 
interventions. 


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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. Informed Consent Process 
The investigator or the investigator’srepresentative 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 theirmedical 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 
theirright to access and correct theirpersonal data and to withdraw consent for the processing 
of theirpersonal 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. 
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. 


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10.1.3. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site 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. 
10.1.4. Committees Structure 
10.1.4.1. Data Monitoring Committee 
This study will not use an E-DMC. 
10.1.5. 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. 


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www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
EudraCT/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. 
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. 
10.1.6. 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. 


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Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document. 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties. 
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source 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 IQMP 
maintained and utilized by the sponsor or designee. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained. 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
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. 


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10.1.7. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document. 
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor or sponsor’s designee (Pfizer CRU). 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor or sponsor’s designee (Pfizer CRU). 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The sponsor or designee will perform mornitoring 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. 
10.1.8. 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 
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 if requested to do so by the responsible IRB/EC or if such termination is required 
to protect the health of study participants. 


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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. 
10.1.9. 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 
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. 


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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. 
10.1.10. 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/CTMS. 
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, and (c) site 
emergency phone number active 24 hours/day, 7 days per week. 
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. 


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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 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Urea and creatinine 
Cystatin C and eGFR 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
TBili 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
Local dipstick: 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Laboratory: 
Microscopy and 
culturea 
• Urine drug screeningb 
• Pregnancy test (β-hCG)c 
• COVID-19 testing 
At Screening: 
• FSHd 
• HIV, HbsAg, HCVAb, 
HbcAb, HCV RNAe 
• HbA1C 
• TSH 
• Calcitonin 
• C-peptide 
• Amylase and lipase 
Required: 
For suspected DILI: 
AST/ALT 
TBili, direct and indirect bili 
Total bile acids, GGT 
Total protein, albumin 
CK 
PT, INR 
Acetaminophen/paracetamol 
or 
protein adduct levels 
Hepatitis serology (even if 
screening negative) 
a. 
Only if UTI is suspected and urine dipstick is positive for nitrites or leukocyte esterase or both. 
b. The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific). 
c. 
Serum or urine β-hCG for female participants of childbearing potential. 
d. For confirmation of postmenopausal status only. 
e. 
The test will be performed if HCV is positive. 
 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• 
 An AE is any untoward medical occmTence in a patient or clinical study 
paiiicipant, 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 
abno1mal laborato1y finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• 
 Any abno1mal laborato1y test results (hematology, clinical chemistiy, 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 abnonnal laborato1y 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 medicaVsurgical intervention; 
• 
 Leads to a change in study dosing (outside of any protocol-specified dose 
adjustinents) or discontinuation from the study, significant additional 
conc01nitant drng ti·eatinent, or other therapy. 
• 
Exacerbation of a chronic or inte1mittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention administl'ation, even 
though it may have been present before the staii of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drng-drng 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 repo1ied as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidaVself-haiming intent. Such overdoses should be repo1ied regardless of 
sequelae. 


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Events Meeting the AE Definition 
• 
Any clinically significant abno1mal laborato1y findings or other abno1mal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the paiiicipant'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 
paiiicipant's condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
 Situations in which an untowai·d medical occmTence 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 staii 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 te1m "life-threatening" in the definition of "serious" refers to an event in which the 
paiiicipant 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 wai·d 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" occmTed or was necessaiy, 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 te1m disability means a substantial dismption of a person's ability to conduct 
nonnal life functions. 
•  This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diaiThea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent eve1yday life functions but do not constitute a substantial dismption. 
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 laborato1y findings indicating 
an infection in a pa1ticipant exposed to a Pfizer product. The tenns "suspected 
transmission" and "transmission" are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by phaimacovigilance 
personnel. Such cases ai·e also considered for repo1ting as product defects, if 
appropriate. 
g. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE repo1ting is appropriate in other situations, such as significant medical 
events that may jeopai·dize the paiticipant 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 diug 
dependency or diug 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 
repo1ting SAEs on the CT SAE Repo1t Fo1m 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. 
• 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. 
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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• 
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 paiiicipant 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 info1mation. 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 repo1ied 
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 discomfo1i, 
but poses no significant or pennanent risk of haim to the research paiiicipant. 
• 
 Severe: A type of AE that intenupts 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 occmTence of each AE or SAE. The investigator will use clinical 
judgment to dete1mine 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 rnled out. 
• 
Alternative causes, such as underlying disease(s), concoinitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
adininistration, will be considered and investigated. 
• 
The investigator will also consult the IB and/or product info1mation, for mai·keted 
products, in their assessment. 


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• 
For each AE or SAE, the investigator !!!!!.U 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 occmTed and the investigator has 
minimal info1mation to include in the initial repo1i 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 theiropinion of causality in light of follow-up 
info1mation and send an SAE follow-up repo1i with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when dete1mining regulato1y 
repo1iing 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 repo1iing 
pmposes, as defined by the sponsor. In addition, if the investigator dete1mines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and repo1i such an 
assessment in the dedicated section of the CT SAE Repo1i Fo1m and in accordance 
with the SAE reporting requirements. 
 
 
Follow-Up of AEs and SAEs 
• 
 The investigator is obligated to perfonn or aiTange 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 laborato1y tests or investigations, 
histopathological exaininations, or consultation with other healthcai·e providers. 
• 
If a paiiicipant dies during paiiicipation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmo1iem findings, including histopathology. 
• 
New or updated infonnation will be recorded in the originally submitted 
documents. 
• 
The investigator will subinit any updated SAE data to the sponsor within 24 hours 
of receipt of the info1mation. 


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10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via an Electronic DCT 
• 
The primaiy 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 repo1t the event within 24 hours. 
• 
The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper f01m (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 entiy of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study paiticipant or receives updated 
data on a previously repo1ted SAE after the electi·onic DCT has been taken off-line, 
then the site can repo1t this infonnation on a paper SAE f01m (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 Repo1t Fo1m is the prefeITed method to 
ti·ansmit this infonnation to Pfizer Safety. 
• 
 In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transpo1t 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 Repo1t Fo1m 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 Repo1t Fo1m pages within the designated repo1ting 
time frames. 


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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies. 
10.4.2. Female Participant Reproductive Inclusion Criteria 
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 of the following conditions applies: 
• Is not a WOCBP (see definition in Section 10.4.3). 
OR 
• Is a WOCBP and agrees to use a highly effective contraceptive method (failure rate of 
<1% per year) during the intervention period and for at least 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). If a highly effective, 
user-dependent method is chosen, she agrees to concurrently use an effective barrier 
method of contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
The investigator is responsible for 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). 
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; 


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• 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. 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
The following contraceptive methods are appropriate for this study: 
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen only hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device. 
3. Intrauterine hormone releasing system. 
4. Bilateral tubal occlusion. 
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. 


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6. 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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I 
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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). 
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. 


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


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10.7. Appendix 7: Kidney Safety: Monitoring Guidelines 
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury 
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr measurement to estimate glomerular filtration rate [Scr-based eGFR] or 
creatinine clearance [eCrCl]). Baseline and postbaseline serum Scys makes it feasible to 
distinguish AKI from other causes of Scr increase. If Scr increase is confirmed after baseline, 
then reflex measurement of Scys is indicated to estimate the combined Scr-Scys eGFR 
calculation (for adults only). 
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care. 
10.7.2. Age-Specific Kidney Function Calculation Recommendations 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations29 
 
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.29 


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10.8. Appendix 8: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
1. Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
1. New PR interval prolongation >280 ms. 
2. New prolongation of QTcF to >480 ms (absolute) or by60 ms from baseline. 
3. New-onset atrial flutter or fibrillation, with controlled venti·icular response rate: ie, 
rate <120 bpm. 
4. New-onset type I second-degree (Wenckebach) AV block of>30 seconds' 
duration. 
5.  Frequent PVCs, triplets, or sho1i inte1vals (<30 seconds) of consecutive venti·icular 
complexes. 
ECG Findings That May Qualify as SAEs 
6. QTcF prolongation >500 ms. 
7. New ST-T changes suggestive of myocardial ischemia. 
8. New-onset LBBB (QRS complex>120 ms). 
9. New-onset right bundle branch block (QRS complex>120 ms). 
10. Symptomatic bradycardia. 
11. Asystole: 
• 
In awake, symptom-free paiiicipants in sinus rhythm, with documented periods 
of asystole3.0
seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 
• 
In awake, symptom-free paiiicipants with atrial fibrillation and bradycai·dia 
with 1 or more pauses of at least 5 seconds or longer. 
• 
Atrial flutter or fibrillation, with rapid venti·icular response rate: rapid = rate 
>120 bpm. 
12. Sustained supraventriculai·tachycai·dia (rate>120 bpm) ("sustained"= short 
duration with relevant symptoms or lasting>1 minute). 
13. Ventriculai·rhythms >30 seconds' duration, including idioventi·icular rhythm (HR 
<40 bpm), accelerated idioventriculai·rhythm (HR >40 bpm to <100 bpm), and 


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monomo1phic/polymorphic ventricular tachycardia (HR >100 bpm [such as 
torsades de pointes]). 
14. Type II second-degree (Mobitz II) AV block. 
15. Complete (third-degree) heait block. 
ECG Findings That Qualify as SAEs 
16. Change in pattern suggestive of new myocai·dial infai·ction. 
17. Sustained ventriculai·tachyaiThythmias (>30 seconds' duration). 
18. Second- or third-degree AV block requiring pacemaker placement. 
19. Asystolic pauses requiring pacemaker placement. 
20. Atrial flutter or fibrillation with rapid ventriculai·response requiring cardioversion. 
21. Ventriculai·fibrillation/flutter. 
22. At the discretion of the investigator, any aiThythmia classified as an adverse 
expenence. 
The enumerated list of major events of potential clinical concem 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 repo1ted as AEs/SAEs. 


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10.9. Appendix 9: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
Abs 
absolute 
ADL 
activities of daily living 
AE 
adverse event 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
AM 
before noon 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCinf 
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time 
AUCtau 
area under the plasma concentration-time profile over the dosing 
interval, tau 
AUC24 
area under the plasma concentration-time profile from time zero to 
time 24 hours 
AV 
atrioventricular 
AxMP 
auxiliary medicinal products 
-hCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
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 Collaboration 
CL 
clearance 
CL/F 
apparent oral clearance 
Clast 
predicted plasma concentration at the last quantifiable time point 
estimated from the log-linear regression analysis 
CLp 
plasma clearance 
Cmax 
maximum plasma concentration 
CO2 
carbon dioxide (bicarbonate) 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
clinical trial 


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Abbreviation 
Term 
CTIS 
Clinical Trials Information System 
CTMS 
Clinical Trial Management System 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
EC 
ethics committee 
ECC 
Emergency Contact Card 
eCrCl 
estimated creatinine clearance 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
E-DMC 
External Data Monitoring Committee 
EDP 
exposure during pregnancy 
EE 
ethinyl estradiol 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
EV 
extracellular vesicles 
FSBG 
fingerstick blood glucose 
FSH 
follicle-stimulating hormone 
F/U 
follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP-1 
glucagon-like peptide 1 
GLP-1R 
glucagon-like peptide 1 receptor 
HAE 
hypoglycemic adverse event 
HbA1c 
hemoglobin A1c 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
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 
IL 
Interleukin 
IMP 
investigational medicinal product 


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Abbreviation 
Term 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IP 
investigational product 
IPAL 
Investigational Product Accountability Log 
IQMP 
Integrated Quality Management Plan 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
KDIGO 
Kidney Disease: Improving Global Outcomes 
kel 
first-order elimination rate constant 
LBBB 
left bundle branch block 
LE 
levonorgestrel 
LFT 
liver function test 
LLN 
Lower limit of normal 
MD 
multiple dose 
MEN2 
multiple endocrine neoplasia syndrome type 2 
MHP 
mental health professional 
MQI 
medically qualified individual 
MTC 
medullary thyroid carcinoma 
NA 
not applicable 
NOAEL 
no observed adverse effect level 
OATP 
organic anion transporting polypeptides 
PCR 
polymerase chain reaction 
PCRU 
Pfizer Clinical Research Unit 
PE 
physical examination 
pH 
potential of hydrogen 
PHQ-9 
Patient Health Questionnaire-9 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
PT 
prothrombin time 
PVC 
premature ventricular contraction/complex 
QD 
once daily 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
qual 
qualitative 
QTL 
quality tolerance limits 
RA 
rheumatoid arthritis 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
Scr 
serum creatinine 
Scys 
serum cystatin C 


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Abbreviation 
Term 
SD 
single dose; standard deviation 
SIB 
Suicidal Ideation and Behavior 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
ST-T 
ST segment to T wave changes on 12-lead ECG 
SSID 
study-specific subject identification number 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
terminal elimination half-life 
T2DM 
type 2 diabetes mellitus 
T4 
thyroxine 
TBA 
total bile acids 
TBili 
total bilirubin 
TEAE 
treatment emergent adverse event 
THC 
tetrahydrocannabinol 
Tmax 
time to Cmax 
TNF- 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
UA 
urine analysis 
UGT 
uridine 5'-diphospho glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Package Insert 
UTI 
urinary tract infection 
Vss 
volume of distribution at steady state 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 


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11. REFERENCES 
 
 
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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. 
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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 
IDF Diabetes Atlas; 9th Edition. Available from: IDF Diabetes Atlas. Accessed on 
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6 
Menke A, Casagrande S, Geiss L,et al. Prevalence of and trends in diabetes among 
adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-9. 
7 
Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular 
and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational 
study. BMJ. 2000;321:405-12. 
8 
Guh DP, Zhang W, Bansback N, et al. The incidence of co-morbidities related to 
obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 
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9 
Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with 
overweight and obesity using standard body mass index categories: a systematic review and 
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10 
The GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 
195 countries over 25 years. N Engl J Med. 2017;377(1):13-27. 
11  Anderson JW, Konz EC, Frederich RC, et al. Long-term weight-loss maintenance: a 
meta-analysis of US studies. Am J Clin Nutr. 2001;74(5):579-84. 
12 
Drucker DJ. The ascending GLP-1 road from clinical safety to reduction of 
cardiovascular complications. Diabetes. 2018;67:1710-9. 


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13 
Sporanox® (itraconazole) Solution USP. United States Prescribing Information, 
2003. Available at label (fda.gov). Accessed on 15 Jan 2022. 
14 
Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) Modified. Revised Sept 
2009. Available at label (fda.gov). Accessed on 12 Dec 2022. 
15 
Drug Development and Drug Interactions | Table of Substrates, Inhibitors and 
Inducers | FDA 
16 
Liu L, Bello A, Dresser MJ, et.al. Best Practices for the Use of Itraconazole as a 
Replacement for Ketoconazole in Drug–Drug Interaction Studies. J Clin Pharmac. 2016, 
56(2) 143–151. 
17 
Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the plasma 
concentration-time curve for oral midazolam is 400-fold larger during treatment with 
itraconazole than with rifampicin. Eur J Clin Pharmacol. 1998;54(1):53–58. 
18 
Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the 
pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol. 1998;46(1):49–53. 
19 
Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma 
concentrations and effects of felodipine. Clin Pharmacol Ther. 1997;61(4):410–415 
20 
Barone JA, Koh JG, Bierman RH, et al. Food interaction and steady state 
pharmacokinetics of itraconazole capsules in healthy male volunteers. Antimicrob Agents 
Chemother. 1993;37(4):778–784. 
21 
Barone JA, Moskovitz BL, Guarnieri J, et al. Food interaction and steady-state 
pharmacokinetics of itraconazole oral solution in healthy volunteers. Pharmacotherapy. 
1998;18(2):295–301. 
22 
J. Michael Davenport, Paul Covington, Laura Bonifacio, et al. Effect of Uptake 
Transporters OAT3 and OATP1B1 and Efflux Transporter MRP2 on the Pharmacokinetics 
of Eluxadoline. The Journal of Clinical Pharmacology. 2015, 55(5) 534–542. 
23 
Sam Rebello, Séverine Compain, Aimin Feng, et al. Effect of Cyclosporine on the 
Pharmacokinetics of Aliskiren in Healthy Subjects. Journal of Clinical Pharmacology. 
2011;51:1549-1560. 
24 
American Diabetes Association. Standards of medical care in diabetes-2019. Diabetes 
Care. 2019;42(Suppl 1): S1-S193. 


PF-07081532 
Protocol C3991041 
Final Protocol 31 January 2023 
PFIZER CONFIDENTIAL 
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Page 97 
 
 
 
 
 
25  Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with adolescents 
and adults. Am J Psychiatry. 2011;168(12):1266-77. 
26    C-SSRS-Full-Lifetime-Recent-1.doc (live.com). 
27    C-SSRS-Full-Since-Last-Contact-1.doc (live.com). 
28 
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression 
severity measure. J Gen Intern Med. 2001;16(9):606-13. 
29 
Inker LA et al. KDIGO 2012 Clinical Practice Guideline for the Evaluation and 
Management of Chronic Kidney Disease. N Engl J Med. 2021;385:1737-49. 

SAP_001.pdf: 
Protocol C3991041 (PF-07081532) Statistical Analysis Plan 
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Page 1 of 17 
 
 
 
 
 
 
 
Protocol C3991041 
 
 
 
 
A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE STUDY TO EVALUATE THE 
EFFECT OF ITRACONAZOLE AND CYCLOSPORINE ON THE SINGLE-DOSE 
PHARMACOKINETICS OF PF-07081532 IN OVERWEIGHT OR OBESE ADULT 
PARTICIPANTS 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
Version: 
1.0 
 
Date: 
22 Mar 2023 


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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 3 
APPENDICES ............................................................................................................................ 3 
1. VERSION HISTORY ............................................................................................................ 4 
2. INTRODUCTION .................................................................................................................. 4 
2.1. Modifications to the Analysis Plan Described in the Protocol .................................. 4 
2.2. Study Objectives and Endpoints ................................................................................ 5 
2.3. Study Design .............................................................................................................. 5 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................... 6 
3.1. Primary Endpoint(s) ................................................................................................... 6 
3.2. Secondary Endpoint(s) ............................................................................................... 6 
3.3. Other Endpoint(s) ...................................................................................................... 6 
3.4. Baseline Variables ..................................................................................................... 6 
3.5. Safety Endpoints ........................................................................................................ 6 
3.5.1. Adverse Events ............................................................................................. 7 
3.5.2. Laboratory Data ............................................................................................ 7 
3.5.3. Body Weight ................................................................................................. 7 
3.5.4. Vital Signs ..................................................................................................... 7 
3.5.5. Electrocardiograms ........................................................................................ 7 
3.5.6. Mental health................................................................................................. 7 
3.5.6.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................... 7 
3.5.6.2. Patient Health Questionnaire-9 (PHQ-9) ..................................... 8 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ...................................................... 8 
5. GENERAL METHODOLOGY AND CONVENTIONS ...................................................... 9 
5.1. Hypotheses and Decision Rules ................................................................................ 9 
5.2. General Methods ........................................................................................................ 9 
5.2.1. Analyses for Binary/Categorical Endpoints .................................................. 9 
5.2.2. Analyses for Continuous Endpoints .............................................................. 9 
5.3. Methods to Manage Missing Data ............................................................................. 9 
5.3.1. Pharmacokinetic Data ................................................................................... 9 
6. ANALYSES AND SUMMARIES ....................................................................................... 10 


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6.1. Primary Endpoints ................................................................................................... 10 
6.2. Subset Analyses ....................................................................................................... 13 
6.3. Baseline and Other Summaries and Analyses .......................................................... 13 
6.3.1. Demographic Summaries ............................................................................ 13 
6.3.2. Study Conduct and Participant Disposition ................................................ 13 
6.3.3. Study Treatment Exposure .......................................................................... 13 
6.3.4. Concomitant Medications and Nondrug Treatments .................................. 13 
6.4. Safety Summaries and Analyses .............................................................................. 13 
6.4.1. Adverse Events ........................................................................................... 13 
6.4.2. Laboratory Data .......................................................................................... 14 
6.4.3. Body Weight ............................................................................................... 14 
6.4.4. Vital Signs ................................................................................................... 14 
6.4.5. Electrocardiograms ...................................................................................... 14 
6.4.6. Mental Health .............................................................................................. 14 
7. INTERIM ANALYSES ....................................................................................................... 14 
APPENDICES .......................................................................................................................... 15 
LIST OF TABLES 
Table 1. 
Summary of Changes ................................................................................. 4 
APPENDICES 
Appendix 1. SAS Code for Analyses ....................................................................................... 15 
Appendix 2. List of Abbreviations ........................................................................................... 16 


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1. VERSION HISTORY 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1.0 / 
22 Mar 2023 
Original 
31 Jan 2023 
N/A 
N/A 
 
2. INTRODUCTION 
GLP-1 is a neuroendocrine hormone that is predominantly released from the small intestine 
in response to food intake. GLP-1 activation of the GLP-1R stimulates insulin release, 
inhibits glucagon secretion in a glucose-dependent manner, and delays gastric emptying. In 
addition, GLP-1 has been shown to increase satiety and suppress food intake. 
PF-07081532 is an orally administered, potent and selective GLP-1R agonist in development 
as adjunct to diet and exercise, to improve glycemic control in T2DM, and for chronic weight 
management in a population that is overweight with co-morbidities or who have obesity. 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3991041. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
None. 


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2.2. Study Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To estimate the effect of MD itraconazole on the 
single-dose PK of PF-07081532 in otherwise 
healthy, overweight or obese participants. 
• 
PF-07081532 PK parameter: AUCinf (if data 
permita otherwise AUClast) 
• 
To estimate the effect of SD cyclosporine on the 
single-dose PK of PF-07081532 in otherwise 
healthy, overweight or obese participants. 
• 
PF-07081532 PK parameter: AUCinf (if data 
permita otherwise AUClast) 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of 
PF-07081532 administered separately and in 
combination with itraconazole or cyclosporine 
in otherwise healthy, overweight or obese 
participants. 
• 
Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and ECG 
parameters. 
• 
Assessment of mental health as determined by 
C-SSRS and PHQ-9. 
• 
To evaluate the effects of itraconazole or 
cyclosporine on additional PK parameters for 
PF-07081532. 
• 
Additional plasma PK parameters for 
PF-07081532: Cmax and Tmax; and CL/F, Vz/F, t½, 
as data permit. 
a. Should it be deemed that too few AUCinf estimates (eg, less than 12 for a single treatment) are obtained 
from the evaluable participants, AUClast may be selected as the primary endpoint for CSR reporting. 
2.3. Study Design 
This is a Phase 1, open-label, fixed-sequence, 3-period study to evaluate the effect of multiple 
doses of itraconazole and a single dose of cyclosporine on the single-dose PK of 
PF-07081532 in otherwise healthy, overweight or obese adult participants. The 3 study 
periods will be conducted consecutively without a break. 
All participants will provide informed consent and undergo Screening evaluations to 
determine their eligibility. Screening will occur within 28 days of the first dose of study 
intervention on Period 1 Day 1. Participants who discontinue from the study before 
completing all assessments may be replaced at the discretion of the investigator and sponsor. 
Approximately 16 participants will be enrolled in the study such that approximately 
12 evaluable participants complete the study. 
The total duration of participation from the Screening Visit to the F/U telephone contact will 
be approximately 82 days or 12 weeks, approximately 3 weeks of which will be conducted on 
an inpatient basis. The 21-day inpatient portion of the study will be conducted as follows: 
Period 1: Days -1 to 5 (Study Days -1 to 5; participants are admitted to the CRU on Day -1), 
40 mg SD PF-07081532 on Day 1; 
Period 2: Days 1 to 5 (Study Days 6 to 10), 40 mg SD PF-07081532 plus 600 mg SD 
cyclosporine on Day 1; 


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Period 3: Days 1 to 10 (Study Days 11 to 20; participants are discharged from the CRU on 
Study Day 20), 200 mg itraconazole QD ×9 days plus 40 mg SD PF-07081532 on Day 4. 
A telephone F/U contact will occur 28-35 days from the last dose of study intervention 
(Period 3, Day 9). 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
The primary endpoints are plasma PF-07081532 AUCinf (if data permit, otherwise AUClast) 
when administered with MD itraconazole and with SD cyclosporine. 
3.2. Secondary Endpoint(s) 
The secondary endpoints are the following: 
• Safety and tolerability data, discussed in Section 0. 
• Assessment of mental health as determined by C-SSRS and PHQ-9. 
• Additional plasma PK parameters (Cmax and Tmax; and CL/F, Vz/F, t½, as data permit) 
for PF-07081532. 
3.3. Other Endpoint(s) 
None. 
3.4. Baseline Variables 
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol. 
3.5. Safety Endpoints 
The following data are considered in standard safety summaries (see protocol for collection 
days, baseline assessment, and list of parameters): 
• adverse events (AE) 
• laboratory data 
• body weight 
• mental health 
• vital signs data 
• electrocardiogram (ECG) results 


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3.5.1. Adverse Events 
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of 
up to 35 days after the last dose of study intervention will be counted as treatment emergent 
and attributed to the last treatment taken. The time period for collecting AEs (“active 
collection period”) for each participant begins from the time the participant provides 
informed consent. 
3.5.2. Laboratory Data 
Safety laboratory tests will be performed as described in the protocol. To determine if there 
are any clinically significant laboratory abnormalities, the hematological, clinical chemistry 
(serum) and urinalysis safety tests will be assessed against the criteria specified in the 
sponsor’s reporting standards. The assessment will not take into account whether each 
participants’s baseline test result is within or outside the laboratory reference range for the 
particular laboratory parameter. 
The baseline measurement is the latest predose measurement on Day 1 of Period 1. 
3.5.3. Body Weight 
Body weight will be measured at times specified in the SoA given in the protocol. 
The baseline measurement is the predose measurement on Day 1 of Period 1. 
3.5.4. Vital Signs 
Supine blood pressure (BP), pulse rate (PR) and temperature will be measured at times 
specified in the SoA given in the protocol. 
The baseline measurement is the latest predose measurement on Day 1 of Period 1. 
3.5.5. Electrocardiograms 
QT interval, QTcF, PR, QRS and heart rate (HR) will be recorded at each assessment time 
indicated in the SoA given in the protocol. QTcF will be derived using Fridericia’s heart rate 
correction formula: 
QTcF = QT / (RR)^(1/3) where RR = 60/HR (if not provided) 
The baseline measurement is the latest measurement on Day 1 of Period 1. 
3.5.6. Mental health 
3.5.6.1. Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behavior. The “baseline/screening” version of the C-SSRS will be administered at 
Screening and Day -1 in study. Participants who respond “yes” to Question 4 or 
5 (indicating suicidal ideation), or to any suicidal behavioral question on the C-SSRS at 


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screening or Day -1 will not be permitted in the study (see CCI 
 The “since last visit” 
version of the C-SSRS will be administered at the time points specified in the SoA. The 
C-SSRS will be administered by study site staff who have completed training in its 
administration. Participants who have recurrent suicidal ideation or behavior during the 
study should be discontinued from the study and treated appropriately. If a study participant 
endorses a 4 or 5 on the ideation subscale or any behavioral item of the C-SSRS on 2 or 
more occasions and is confirmed to have active suicidal ideation or behavior on both 
occasions by a risk assessment conducted by a qualified MHP, then the participant should be 
discontinued from the study and treated appropriately. 
3.5.6.2. Patient Health Questionnaire-9 (PHQ-9) 
The PHQ9-9 is a 9 item self-report scale for the assessment of depressive symptoms. The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in the SoA. A PHQ-9 score of ≥15 at Screening or Day -1 indicates clinically 
significant depression and serves as an exclusion criterion for this study (see section 5.2 of 
the protocol). 
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in the SoA. The total score will be derived by adding the corresponding values 
of responses to each item. The total score ranges from 0 to 27, with the following 
interpretation: 
 
Total Score 
Depression Severity 
1-4 
Minimal depression 
5-9 
Mild depression 
10-14 
Moderate depression 
15-19 
Moderately severe depression 
20-27 
Severe depression 
 
A participant with a postbaseline assessment with a score of > 15 should be referred to a 
MHP. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
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 


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Participant Analysis Set 
Description 
the study, are not considered enrolled, unless otherwise 
specified by the protocol. 
Safety analysis set 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the product they actually received. 
PK concentration set 
All participants who take at least 1 dose of study intervention 
and in whom at least 1 concentration value is reported. 
PK parameter set 
All participants who take at least 1 dose of study intervention 
and in whom at least 1 of the PK parameters of primary 
interest are reported. 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
Final analysis will be performed after study participant data set release following last 
participant last visit. 
5.1. Hypotheses and Decision Rules 
No statistical hypothesis will be tested in this study. 
5.2. General Methods 
5.2.1. Analyses for Binary/Categorical Endpoints 
For binary or categorical variables, number of participants, and numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the Clinical 
Data Interchange Standards Consortium and Pfizer Standards (CaPS). 
5.2.2. Analyses for Continuous Endpoints 
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
CaPS. For appropriate PK parameters, geometric mean and geometric coefficient of variation 
(%CV) will also be summarized. 
5.3. Methods to Manage Missing Data 
5.3.1. Pharmacokinetic Data 
Methods to handle missing PK data are described below. 
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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Deviations, Missing Concentrations and Anomalous Values: 
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true: 
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample). 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
participants. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst. 
PK 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 summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC. For statistical analyses, PK parameters coded as NC will also 
be set to missing. 
If an individual participant has a known biased estimate of a PK parameter (due for example 
to dosing error or an unexpected event, such as vomiting, before all the compound is 
adequately absorbed from the gastrointestinal tract), this will be footnoted in summary tables 
and will not be included in the calculation of summary statistics or statistical analyses. For 
instance, if a participant has a vomiting event post dose that is within a duration of time that 
is 2-times the derived median Tmax for the population for the administered treatment, then the 
pharmacokineticist should consider the exclusion of the PK concentration data collected 
following the initial vomiting event in that treatment period and the PK parameter data 
reported for that treatment period from the datasets used to calculate summary statistics or 
statistical analyses. 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoints 
Natural loge transformed AUCinf (if data permit, otherwise AUClast) of PF-07081532 
administered without cyclosporine or coadministered with cyclosporine will be analyzed 
using a mixed effect model with treatment as a fixed effect and participant as a random 


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effect. Estimates of the adjusted mean differences (Test/Reference) and corresponding 90% 
CIs will be obtained from the models. The adjusted mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% CIs for the ratios. The test treatment will be ‘PF-07081532 
40 mg singe dose and cyclosporine’ (Period 2), which will be reported separately in 
comparison to the reference treatment of ‘PF-07081532 40 mg singe dose without 
cyclosporine’ (Period 1). 
Natural loge transformed AUCinf (if data permit, otherwise AUClast) of PF-07081532 
administered without itraconazole or coadministered with itraconazole will be analyzed 
using a mixed effect model with treatment as a fixed effect and participant as a random 
effect. Estimates of the adjusted mean differences (Test/Reference) and corresponding 90% 
CIs will be obtained from the models. The adjusted mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% CIs for the ratios. The test treatment will be ‘PF-07081532 
40 mg singe dose and itraconazole’ (Period 3), which will be reported separately in 
comparison to the reference treatment of ‘PF-07081532 40 mg singe dose without 
itraconazole’ (Period 1). 
6.2. Secondary Endpoints 
Natural loge transformed CCI 
 of PF-07081532 administered without 
cyclosporine or coadministered with cyclosporine will be analyzed using a mixed effect 
model with treatment as a fixed effect and participant as a random effect. Estimates of the 
adjusted mean differences (Test/Reference) and corresponding 90% CIs will be obtained 
from the models. The adjusted mean differences and 90% CIs for the differences will be 
exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) 
and 90% CIs for the ratios. The test treatment will be ‘PF-07081532 40 mg singe dose and 
cyclosporine’ (Period 2), which will be reported separately in comparison to the reference 
treatment of ‘PF-07081532 40 mg singe dose without cyclosporine’ (Period 1). 
Natural loge transformed CCI 
 of PF-07081532 administered without 
itraconazole or coadministered with itraconazole will be analyzed using a mixed effect model 
with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted 
mean differences (Test/Reference) and corresponding 90% CIs will be obtained from the 
models. The adjusted mean differences and 90% CIs for the differences will be exponentiated 
to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs 
for the ratios. The test treatment will be ‘PF-07081532 40 mg singe dose and itraconazole’ 
(Period 3), which will be reported separately in comparison to the reference treatment of 
‘PF-07081532 40 mg singe dose without itraconazole’ (Period 1). 
 
 
6.2.1. PK Concentrations 
The plasma concentrations of PF-07081532 will be listed and descriptively summarized by 
nominal PK sampling time and treatment. Individual participant, as well as mean and 
median profiles, of the plasma concentration-time data will be plotted by treatment using 


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actual (for individual) and nominal (for mean and median) times, respectively. Mean and 
median profiles will be presented on both linear and semi-log scales. 
Presentations of concentrations will include: 
• A listing of all concentrations sorted by participant ID, treatment and nominal time 
postdose. The concentration listing will also include the actual times. Deviations from the 
nominal time will be given in a separate listing. 
• A summary of concentrations by treatment and nominal time postdose, where the set of 
statistics will include n, mean, median, SD, %CV, minimum, maximum and the number 
of concentrations above the LLQ. 
• Median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose). 
• Mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by treatment (all treatments on the same plot per scale, based on the summary of 
concentrations by treatment and time postdose). 
• Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment per 
scale). 
Individual concentration time plots by participant (on both linear and semi-log scales) against 
actual time postdose [there will be separate plots for each participant (containing all 
treatments) per scale]. 
6.2.2. PK Parameters 
The PK parameters will be summarized descriptively by treatment group in accordance with 
Pfizer data standards on the PK Parameter Analysis Set, as data permit. PK parameters, 
including plasma AUCinf, AUClast, Cmax, Tmax, and CL/F, Vz/F, t½, as data permit, of PF- 
07081532 will be summarized descriptively by treatment. For AUCinf, a listing of the 
individual participant ratios (Test/Reference) will be provided. Box and whisker plots for 
AUCinf will be plotted by treatment. Missing values will be handled as detailed in Section 
5.3.1. Each PK parameter will be summarized by treatment group and will include the set of 
summary statistics as specified in Table . 


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Table 2. PK Parameters to be Summarized Descriptively by Treatment 
 
Parameter 
Summary Statistics 
AUCinf, AUClast, Cmax, 
CL/F, Vz/F 
N, arithmetic mean, median, SD, %CV, minimum, maximum, 
geometric mean and geometric %CV 
Tmax 
N, median, minimum, maximum 
t½ 
N, arithmetic mean, median, SD, %CV, minimum, maximum 
 
Supporting data from the estimation of t½ and AUCinf will be listed by analyte and group: 
terminal phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); 
the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of 
time points used in the estimation of kel. This data may be included in the clinical study 
report. 
6.3. Subset Analyses 
There are no planned subset analyses. 
6.4. Baseline and Other Summaries and Analyses 
6.4.1. Demographic Summaries 
Demographic characteristics will be summarized for the enrolled population in accordance 
with the CaPS. 
6.4.2. Study Conduct and Participant Disposition 
Participant evaluation groups will show end of study participant disposition. Frequency 
counts will be supplied for participant discontinuation(s) by treatment. Data will be reported 
in accordance with the CaPS. 
6.4.3. Study Treatment Exposure 
Study treatment exposure will be listed. 
6.4.4. Concomitant Medications and Nondrug Treatments 
All concomitant medication(s) as well as non-drug treatment(s) will be reported in the 
listings. 
6.5. Safety Summaries and Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
6.5.1. Adverse Events 
Adverse events will be reported in accordance with the CaPS. 


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Participant discontinuations due to adverse events will be detailed by treatment. Data will be 
reported in accordance with the CaPS. 
6.5.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the CaPS. 
6.5.3. Body Weight 
Observed value and change from baseline in body weight will be summarized descriptively 
by treatment. 
6.5.4. Vital Signs 
Vital signs data will be listed and summarized by treatment in accordance with the CaPS. 
6.5.5. Electrocardiograms 
Changes from baseline for the ECG parameters HR, QTcF, PR interval, and QRS complex 
will be summarized by period 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 period: 
 
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 
Baseline will be pre-dose on Day 1. 
6.5.6. Mental Health 
C-SSRS and PHQ-9 data will be listed. 
7. 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. 
Final analysis will follow the official database release. As this will be an open-label study, 
there is no formal unblinding of the randomization code. 


Protocol C3991041 (PF-07081532) Statistical Analysis Plan 
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022 
PFIZER CONFIDENTIAL 
TMF Doc ID: 98.03 
Page 15 of 17 
 
 
APPENDICES 
Appendix 1. SAS Code for Analyses 
An example of the PROC MIXED code is provided below: 
For the primary objective: 
Treatment B (Test) vs Treatment A (Reference) 
 
proc mixed data=tab.pk; 
where trt in (“A”,”B”); 
class trt participant; 
model l&var=trt / ddfm=KR; 
random participant / subject=participant; 
lsmeans trt; 
estimate 'B vs A' trt -1 1 /cl alpha=0.1; 
ods 'Estimates' out=est&var; 
ods 'lsmeans' out=ls&var; 
ods 'covparms' out=cov&var; 
ods 'tests3' out=tst&var; 
run; 
Treatment C (Test) vs Treatment A (Reference) 
 
proc mixed data=tab.pk; 
where trt in (“A”,”C”); 
class trt participant; 
model l&var=trt / ddfm=KR; 
random participant / subject=participant; 
lsmeans trt; 
estimate 'C vs A' trt -1 1 /cl alpha=0.1; 
 
ods 'Estimates' out=est&var; 
ods 'lsmeans' out=ls&var; 
ods 'covparms' out=cov&var; 
ods 'tests3' out=tst&var; 
run; 
 
/* Letter assignments for treatments (trt) within the estimate statement above are as follows 
A: 40 mg SD PF-07081532 
B: 40 mg SD PF-07081532 plus 600 mg SD cyclosporine 
C: 200 mg itraconazole QD ×9 days plus 40 mg SD PF-07081532 
*/ 


Protocol C3991041 (PF-07081532) Statistical Analysis Plan 
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022 
PFIZER CONFIDENTIAL 
TMF Doc ID: 98.03 
Page 16 of 17 
 
 
 
Appendix 2. List of Abbreviations 
 
Abbrevia 
tion 
Term 
%CV 
coefficient of variation 
AE 
adverse event 
AUC24 
area under the plasma concentration-time profile from time zero to time 24 
hours 
AUCinf 
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 (Clast) 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
BP 
blood pressure 
CaPS 
Clinical Data Interchange Standards Consortium and Pfizer Standards 
CI 
confidence interval 
Clast 
predicted plasma concentration at the last quantifiable time point estimated 
from the log-linear regression analysis 
CL/F 
apparent oral clearance 
Cmax 
maximum plasma concentration 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSR 
clinical study report 
ECG 
electrocardiogram 
EE 
ethinyl estradiol 
HR 
heart rate 
kel 
the terminal phase rate constant calculated by a linear regression of the 
loglinear concentration-time curve 
LE 
levonorgestrel 
LLQ 
lower limit of quantitation 
MD 
multiple dose 
mg 
milligram 
MHP 
mental health professional 
MR 
metabolite to parent ratio 
MRAUCi 
nf 
1-hydroxymidazolam AUCinf/midazolam AUCinf; 5-hydroxyomeprazole 
AUCinf/omeprazole AUCinf 
N/A 
not applicable 
NC 
not calculated 
ND 
not done 
NS 
no sample 
OC 
oral contraceptive 
PHQ-9 
Patient Health Questionnaire-9 
PK 
pharmacokinetic(s) 
PR 
pulse rate 


Protocol C3991041 (PF-07081532) Statistical Analysis Plan 
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022 
PFIZER CONFIDENTIAL 
TMF Doc ID: 98.03 
Page 17 of 17 
 
 
 
Abbrevia 
tion 
Term 
QD 
once daily 
QRS 
Combination of Q-, R- and S- wave on an electrocardiogram representing 
ventricular depolarization 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
RR 
R-R interval from ECG 
SAP 
statistical analysis plan 
SD 
single dose; standard deviation 
SoA 
schedule of activities 
t1/2 
terminal elimination half-life 
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment emergent adverse event 
Tmax 
time to Cmax 
Vz/F 
apparent volume of distribution