Conditions: Healthy
Keywords: Dabigatran etexitlate Rosuvastatin Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs BCRP substrate P-gp substrate Anticoagulant Antihyperlipidemic
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 16
Healthy volunteers: yes

Brief summary:
The purpose of the study was to understand the effect of PF-07081532 on the movement of Dabigatran and Rosuvastatin into, though, and out of the body in healthy overweight or obese adult participants. This study also aims to collect data on safety and how tolerable the study medicine is.

The study is seeking for participants who are:

* Male or female who are 18 years of age or older.
* Healthy but are overweight or obese. Participants will receive dabigatran and rosuvastatin as single doses by mouth 3 times during the study. The amount of the study medicine PF-07081532 will be adjusted over time until any interactions are seen.

PF-07081532 is taken daily by mouth in 8 Study Periods while admitted into the study clinic over 53 days. Once discharged from the study clinic, participants will have a follow-up visit 7 to 10 days post last dose of study medicine. Then another follow-up via telephone contact, 28 to 35 days post last dose of study medicine.

Detailed description:

Arms:
arm 1: Participants will receive dabagatrin etexilate (DE) as a single dose arm 2: Participants will receive rosuvastatin as a single dose arm 3: Participants will receive PF-07081532 daily titrated arm 4: Participants will receive PF-07081532 daily and DE as a single dose arm 5: Participants will receive PF-07081532 daily and rosuvastatin as a single dose arm 6: Participants will receive PF-07081532 daily titrated arm 7: Participants will receive PF-07081532 daily and DE as a single dose arm 8: Participants will receive PF-07081532 daily and rosuvastatin as a single dose

Interventions: intervention 1: Dabigatran etexilate (DE) intervention 2: Rosuvastatin intervention 3: PF-07081532
Intervention descriptions: intervention 1: Dabigatran etexilate (DE) as oral capsule intervention 2: Rosuvastatin as oral tablet intervention 3: PF-07081532 as oral tablets

Protocol document:
Prot_000.pdf: 
PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
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Page 1
A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE STUDY TO ESTIMATE THE 
EFFECT OF PF-07081532 ADMINISTRATION ON THE SINGLE-DOSE
PHARMACOKINETICS OF DABIGATRAN AND ROSUVASTATIN IN 
OVERWEIGHT OR OBESE ADULT PARTICIPANTS
Study Intervention Number:
PF-07081532
Study Intervention Name:
NA
US IND Number:
160296 (PF-07081532)
[EudraCT/EU CT] Number:
NA
ClinicalTrials.gov ID:  
NA
Pediatric Investigational Plan Number:
NA
Protocol Number:
C3991047
Phase:
1
Brief Title: A Drug-Drug Interaction Study to Estimate the Effect of PF-07081532 on 
the Pharmacokinetics of Dabigatran and Rosuvastatin 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 C3991047
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Document History
Document
Version Date
Original protocol
31 January 2023


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................18
1.3. Schedule of Activities .............................................................................................19
2. INTRODUCTION ...............................................................................................................26
2.1. Study Rationale .......................................................................................................26
2.2. Background .............................................................................................................26
2.2.1. Nonclinical Pharmacology..........................................................................27
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................27
2.2.3. Nonclinical Safety ......................................................................................27
2.2.4. Clinical Overview.......................................................................................28
2.2.4.1. Clinical Pharmacokinetics.........................................................29
2.3. Benefit/Risk Assessment.........................................................................................29
2.3.1. Risk Assessment.........................................................................................30
2.3.2. Benefit Assessment.....................................................................................33
2.3.3. Overall Benefit/Risk Conclusion................................................................33
3. OBJECTIVES AND ENDPOINTS.....................................................................................34
4. STUDY DESIGN.................................................................................................................34
4.1. Overall Design.........................................................................................................34
4.2. Scientific Rationale for Study Design.....................................................................35
4.2.1. Choice of Contraception/Barrier Requirements .........................................36
4.2.2. Collection of Retained Research Samples..................................................37
4.3. Justification for Dose ..............................................................................................37
4.4. End of Study Definition ..........................................................................................39
5. STUDY POPULATION......................................................................................................39
5.1. Inclusion Criteria.....................................................................................................39
5.2. Exclusion Criteria....................................................................................................40
5.3. Lifestyle Considerations..........................................................................................44
5.3.1. Contraception..............................................................................................44
5.3.2. Meals and Dietary Restrictions...................................................................44


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5.3.3. Caffeine, Alcohol, and Tobacco .................................................................45
5.3.4. Activity .......................................................................................................45
5.4. Screen Failures ........................................................................................................45
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................45
6.1. Study Intervention(s) Administered........................................................................46
6.1.1. Administration............................................................................................49
6.2. Preparation, Handling, Storage, and Accountability...............................................50
6.2.1. Preparation and Dispensing........................................................................51
6.3. Assignment to Study Intervention...........................................................................51
6.4. Blinding...................................................................................................................52
6.4.1. Blinding of Participants..............................................................................52
6.4.2. Blinding of Site Personnel..........................................................................52
6.4.3. Blinding of the Sponsor..............................................................................52
6.4.4. Breaking the Blind......................................................................................52
6.5. Study Intervention Compliance...............................................................................52
6.6. Dose Modification...................................................................................................53
6.6.1. Dose Escalation and Stopping Rules..........................................................53
6.7. Continued Access to Study Intervention After the End of the Study......................53
6.8. Treatment of Overdose............................................................................................53
6.9. Prior and Concomitant Therapy..............................................................................54
6.9.1. Rescue Medicine.........................................................................................55
6.9.2. Management of Nausea and Vomiting .......................................................55
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................56
7.1. Discontinuation of Study Intervention ....................................................................56
7.1.1. Potential Cases of Acute Kidney Injury .....................................................56
7.1.2. Temporary Discontinuation........................................................................57
7.2. Participant Discontinuation/Withdrawal From the Study.......................................57
7.2.1. Withdrawal of Consent...............................................................................58
7.3. Lost to Follow-up....................................................................................................58
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................59
8.1. Administrative Procedures ......................................................................................59


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8.2. Efficacy Assessments..............................................................................................60
8.3. Safety Assessments .................................................................................................60
8.3.1. Physical Examinations................................................................................60
8.3.2. Vital Signs ..................................................................................................61
8.3.2.1. Blood Pressure and Pulse Rate..................................................61
8.3.2.2. Temperature ..............................................................................61
8.3.3. Electrocardiograms.....................................................................................61
8.3.4. Clinical Safety Laboratory Assessments ....................................................62
8.3.5. COVID-19 Specific Assessments...............................................................63
8.3.6. Management of Hypoglycemia...................................................................63
8.3.6.1. Definition and Severity of Categorization of 
Hypoglycemic Adverse Event (HAE)...............................................63
8.3.6.2. Glucometer Monitoring of Glucose ..........................................64
8.3.7. Pregnancy Testing ......................................................................................65
8.3.8. Suicidal Ideation and Behavior Risk Monitoring.......................................65
8.3.8.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................65
8.3.8.2. Patient Health Questionnaire-9 (PHQ-9) ..................................66
8.3.8.3. Referral to a Mental Health Professional ..................................66
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................66
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......67
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................67
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................68
8.4.2. Method of Detecting AEs and SAEs ..........................................................68
8.4.3. Follow-Up of AEs and SAEs......................................................................68
8.4.4. Regulatory Reporting Requirements for SAEs...........................................68
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................69
8.4.5.1. Exposure During Pregnancy......................................................69
8.4.5.2. Exposure During Breastfeeding ................................................71
8.4.5.3. Occupational Exposure .............................................................71
8.4.6. Cardiovascular and Death Events...............................................................71
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................71


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 6
8. 4. 8. A d verse E ve nts of S pecial I nterest............................................................. 7 1
8. 4. 8. 1. Lac k of Efficac y ........................................................................ 7 2
8. 4. 9. Me dical De vice Deficie ncies ......................................................................7 2
8. 4. 1 0. Me dicati o n Err ors ..................................................................................... 7 2
8. 5. P har mac o ki netics .................................................................................................... 7 3
8. 5. 1. P K of R os u vastati n ..................................................................................... 7 4
8. 5. 2. P K of Da bi gatra n ........................................................................................ 7 4
8. 5. 3. P K of P F -0 7 0 8 1 5 3 2 .................................................................................... 7 4
8. 6. Ge netics ................................................................................................................... 7 4
8. 6. 1. S pecifie d Ge netics ...................................................................................... 7 4
8. 6. 2. Retai ne d Researc h Sa m ples f or Ge netics................................................... 7 4
8. 7. Bi o mar kers .............................................................................................................. 7 4
...............................................................7 5
.................................................. 7 5
8. 7. 3. S pecifie d Ge ne E x pressi o n ( R N A) Researc h ............................................. 7 5
8. 7. 4. S pecifie d Pr otei n Researc h ......................................................................... 7 5
8. 7. 5. S pecifie d Meta b ol o mic Researc h ...............................................................7 5
8. 7. 6. Retai ne d Researc h Sa m ples f or Bi o mar kers ............................................... 7 5
8. 8. I m m u n o ge nicit y Assess me nts ................................................................................. 7 5
8. 9. Healt h Ec o n o mics ................................................................................................... 7 6
9. S T A TI S TI C A L C O N SI D E R A TI O N S ................................................................................ 7 6
9. 1. Statistical H y p ot hesis ..............................................................................................7 6
9. 2. A nal y sis Sets ........................................................................................................... 7 6
9. 3. Statistical A nal y ses ................................................................................................. 7 7
9. 3. 1. Ge neral C o nsi derati o ns ...............................................................................7 7
9. 3. 2. Deri vati o n of P har mac o ki netic Para meters ................................................ 7 7
9. 3. 3. Pri mar y  E n d p oi nt(s) A nalys is.....................................................................7 8
9. 3. 4. Ot her Safet y A nal yses ................................................................................ 7 9
9. 3. 4. 1. Electr ocar di o gra m A nal y ses...................................................... 7 9
9. 3. 5. Ot her A nal ys es ............................................................................................ 8 0
9. 4. I nteri m A nal ys es ..................................................................................................... 8 0
9. 5. Sa m ple Size Deter mi nati o n ..................................................................................... 8 0
C CI
C CI


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................82
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............82
10.1.1. Regulatory and Ethical Considerations ....................................................82
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................82
10.1.2. Financial Disclosure .................................................................................83
10.1.3. Informed Consent Process ........................................................................83
10.1.4. Data Protection .........................................................................................84
10.1.5. Committees Structure ...............................................................................84
10.1.5.1. Data Monitoring Committee ...................................................84
10.1.6. Dissemination of Clinical Study Data ......................................................84
10.1.7. Data Quality Assurance ............................................................................85
10.1.8. Source Documents....................................................................................87
10.1.9. Study and Site Start and Closure ..............................................................87
10.1.10. Publication Policy...................................................................................88
10.1.11. Sponsor’s Medically Qualified Individual..............................................89
10.2. Appendix 2: Clinical Laboratory Tests .................................................................90
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................93
10.3.1. Definition of AE .......................................................................................93
10.3.2. Definition of an SAE ................................................................................94
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................95
10.3.4. Reporting of SAEs....................................................................................99
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................100
10.4.1. Male Participant Reproductive Inclusion Criteria..................................100
10.4.2. Female Participant Reproductive Inclusion Criteria...............................100
10.4.3. Woman of Childbearing Potential ..........................................................100
10.4.4. Contraception Methods...........................................................................101
10.5. Appendix 5: Genetics..........................................................................................103
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .....104
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ..........................................106


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10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury............................................................................106
10.7.2. Age-Specific Kidney Function Calculation Recommendations.............106
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .........................................................................................106
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities.................................................................................................106
10.8. Appendix 8: ECG Findings of Potential Clinical Concern .................................107
10.9. Appendix 9: Abbreviations .................................................................................109
11. REFERENCES ................................................................................................................114
LIST OF TABLES
Table 1.
Overall Schedule of Activities Screening to Period 5 ..............................19
Table 2.
Overall Schedule of Activities Period 6 to ET .........................................22
Table 3.
Schedule of Activities – Period 1 (DE ONLY), Period 4 (DE + PF-
07081532 80 mg QD) and Period 7 (DE + PF-07081532 260 mg 
QD) ...........................................................................................................24
Table 4. 
Schedule of Activities –Period 2 (Rosuvastatin ONLY), Period 5 
(Rosuvastatin + PF07081532 80 mg QD), and Period 8 
(Rosuvastatin + PF-07081532 260 mg QD).............................................24
Table 5.
Schedule of Activities – Day 5 of Period 4 (DE + PF-07081532 
80 mg QD) and Period 7 (DE + PF-07081532 260 mg QD)....................25
Table 6.
Study Interventions...................................................................................47
Table 7.
Study Arms ...............................................................................................48
Table 8.
Study Interventions Administered............................................................49
Table 9.
PF-07081532 Dosing Regimens...............................................................52
Table 10.
Plasma PK Parameters for Rosuvastatin and Dabigatran.........................78
Table 11.
Plasma PK Parameters for PF-07081532 .................................................78
Table 12.
Safety QTcF Assessment..........................................................................80
Table 13.
Expected Widths of the 90% CIs (with 80% Coverage Probability) 
for Different Possible Estimated Effects and Parameters of Interest .......81
Table 14.
Protocol-Required Safety Laboratory Assessments .................................91


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Open-label, Fixed-sequence Study to Estimate the Effect of 
PF-07081532 Administration on the Single-Dose Pharmacokinetics of Dabigatran and 
Rosuvastatin in Overweight or Obese Adult Participants.
Brief Title: A Drug-Drug Interaction Study to Estimate the Effect of PF-07081532 on the 
Pharmacokinetics of Dabigatran and Rosuvastatin in Overweight or Obese Adult 
Participants.
Regulatory Agency Identification Number(s):
US IND Number:
160296 (PF-07081532)
EudraCT Number:
NA
ClinicalTrials.gov ID:  
NA
Pediatric Investigational Plan Number:
NA
Protocol Number:
C3991047
Phase:
1
Rationale: This is a Phase 1, open-label, fixed-sequence study to estimate the effect of 
PF-07081532 administration on the single-dose PK of dabigatran (total) and rosuvastatin in
otherwise healthy overweight or obese adult participants. The intent of this study is to 
generate PK, safety, and tolerability data for further clinical development.


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Objectives and Endpoints:
Objectives
Endpoints
Primary: 
Primary: 

To estimate the effect of PF-07081532 
administration on the single-dose PK of total 
dabigatran in otherwise healthy overweight or
obese participants.

Dabigatran (total) PK parameters: AUCinf (if data 
permit* otherwise AUClast) in Periods 1, 4, and 7.

To estimate the effect of MD PF-07081532 on 
the single-dose PK of rosuvastatin in otherwise 
healthy overweight or obese participants.

Rosuvastatin PK parameters: AUCinf (if data 
permit* otherwise AUClast) in Periods 2, 5, and 8.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
PF-07081532 administered separately and in 
combination with DE 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 safety and tolerability of 
PF-07081532 administered separately and in 
combination with rosuvastatin 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 PF-07081532 on 
additional PK parameters for total dabigatran.

Additional plasma PK parameters for total 
dabigatran: Cmax and Tmax; and CL/F, Vz/F, t½ as 
data permit, in Periods 1, 4, and 7.

To evaluate the effects of PF-07081532 on 
additional PK parameters for rosuvastatin.

Additional plasma PK parameters for rosuvastatin:  
Cmax and Tmax; and CL/F, Vz/F, t½ as data permit, 
in Periods 2, 5, and 8.

To evaluate the MD pharmacokinetics of 
PF-07081532 in healthy overweight or obese 
participants.

PF-07081532 plasma pharmacokinetic parameters: 
AUC24, Cmax, Tmax.
* Should it be deemed that too few AUCinf estimates (eg, less than 16 for a single treatment) are obtained 
from the evaluable participants, AUClast may be selected as the primary endpoint for CSR reporting. This will 
be considered for the dabigatran and rosuvastatin objectives separately.
Overall Design:
This is a Phase 1, open-label, 8-period, fixed-sequence study to evaluate the effect of 
PF-07081532 administration on the single-dose PK of dabigatran (total) and rosuvastatin in 
otherwise healthy, overweight or obese, adult female or male participants. The 8 periods will 
be conducted sequentially without any washout days between periods. 


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Number of Participants:
Approximately 24 participants will be enrolled in 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 
1. Participants aged 18 years or older (or the minimum age of consent in accordance 
with local regulations) at Screening.  

Women can be of child-bearing potential, but cannot be pregnant, breastfeeding, 
or planning to become pregnant while participating in the study and may not be 
taking either oral contraceptives or non-oral hormonal contraceptives (with the 
exception of implantable progestogen only hormone contraception or intrauterine 
hormone releasing system), and must avoid vaccination with live attenuated 
vaccines.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including detailed medical history, physical examination (including blood 
pressure and pulse rate measurement), standard 12-lead ECG, and clinical laboratory 
tests.
Other Inclusion Criteria:
3. BMI: ≥ 25 kg/m2 at Screening.  
4. 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 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 a GLP-1R agonist(s), rosuvastatin, or 
DE.
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. History of myocardial infarction, unstable angina, arterial revascularization, 
mechanical prosthetic heart valve, stroke, New York Association Functional Class 
II-IV heart failure, or transient ischemic attack within 6 months of Screening.
4. 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 cancer will be excluded, even if it was resected and they 
were considered ‘cured’.
5. Personal or family history of MTC or MEN2, or study participants with suspected 
MTC per the investigator’s judgment.
6. Acute pancreatitis, a history of repeated episodes of acute pancreatitis, or history of 
chronic pancreatitis. 
7. Symptomatic gallbladder disease.
8. Medical history or characteristics suggestive of genetic or syndromic obesity or 
obesity induced by other endocrinological disorders (eg, Cushing Syndrome).


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9. History of major depressive disorder or history of other severe psychiatric disorders 
(eg, schizophrenia or bipolar disorder) within the last 2 years from screening.
10. Any lifetime history of a suicide attempt. 
11. Known medical history of active liver disease (other than non-alcoholic hepatic 
steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, 
alcoholic liver disease, primary sclerosing cholangitis, autoimmune hepatitis, overlap 
syndrome, or prior known drug-induced liver injury.
12. History of HIV infection.
13. Recent history of bleeding, or risks of bleeding, including prior personal or familial 
history of abnormal bleeding, hereditary or acquired coagulation or platelet disorder, 
or abnormal coagulation test (INR >1.3) result at Screening. 
Prior/Concomitant Therapy
14. Use of any medications that are BCRP, OATP, P-gp and/or CYP3A4/5 inhibitors or 
inducers 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). 
Diagnostic Assessments (at Screening unless otherwise indicated)
15. 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.
16. Screening 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, ST-T interval changes suggestive of myocardial ischemia, second- or 
third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias).  
a.
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.
17. 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:


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
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.

TSH >1.5x ULN or < LLN.

INR >1.3.

Serum calcitonin > ULN.

Amylase or lipase > ULN.

Fasting blood glucose ≥126 mg/dL. 

Fasting C-peptide not WNL.

eGFR <75 mL/min/1.73 m2 as calculated by the CKD-EPI equation.

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.

A positive SARS-CoV-2 test.
Study Arms and Duration:
The total duration of participation from the Screening Visit to the F/U outpatient telephone 
contact will be approximately 115 days or 16.5 weeks, approximately 8 weeks of which will 
be conducted on an inpatient basis. 
The 54-day inpatient portion of the study will be conducted as follows: 
Period 1: 3 days, includes CRU admission on Day -1 (DE 150 mg single dose); 
Period 2: 4 days (rosuvastatin 10 mg single dose); 
Period 3: 8 days (PF-07081532 titrated to 40 mg QD); 
Period 4: 5 days (DE 150 mg single dose + PF-07081532 80 mg QD); 
Period 5: 4 days (rosuvastatin 10 mg single dose + PF-07081532 80 mg QD); 
Period 6: 20 days (PF-07081532 titrated to 260 mg QD); 
Period 7: 5 days (DE 150 mg single dose + PF-07081532 260 mg QD); 


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
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Page 15
Period 8: 5 days, includes discharge day from CRU (rosuvastatin 10 mg single dose + 
PF-07081532 260 mg QD).
The onsite F/U visit/telephone F/U contact will occur 7-10 days from the last dose of study 
intervention (Period 8, Day 4) and an outpatient telephone F/U contact will occur 28-35 days 
from the last dose of study intervention (Period 8, Day 4). 
Study Interventions
Intervention Name
PF-07081532
Rosuvastatin
DE
Arm Name
(group of participants receiving a specific 
treatment or no treatment)
All participants
All participants
All participants
Unit Dose Strength
20 mg, 60 mg, 100 mg
10 mg
150 mg
Route of Administration
Oral
Oral
Oral
Use
Perpetrator
Substrate
Substrate
IMP or NIMP/AxMP
IMP
NIMP/AxMP
NIMP/AxMP


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
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Page 16
Study Arms
Arm Title
Period 1: 
single-dose
DE
Period 2: 
single-dose
rosuvastatin
Period 3: 
PF-07081532
titration
Period 4:
single-dose DE
+ PF-07081532  
Period 5: 
single-dose 
rosuvastatin + 
PF-07081532  
Period 6: 
PF-07081532 
titration
Period 7: 
single-dose DE
+ PF-07081532  
Period 8: 
single-dose 
rosuvastatin + 
PF-07081532  
Arm Type
Baseline
Baseline
IMP titration 
only 
Experimental 
(DDI)
Experimental 
(DDI)
IMP titration 
only
Experimental 
(DDI)
Experimental 
(DDI)
Arm 
Description
Participants 
will receive a 
single 150 
mg dose of 
DE.
Participants 
will receive a 
single 10 mg 
dose of
rosuvastatin.
Participants 
will receive 
PF-07081532
titrated from 
20 mg QD to 
40 mg QD
over a total of 
8 days.
Participants 
will receive a 
single 150 mg 
dose of DE
with 80 mg 
PF-07081532 
QD.
Participants 
will receive a 
single 10 mg 
dose of 
rosuvastatin on 
a background 
of 80 mg 
PF-07081532 
QD.
Participants will 
receive 
PF-07081532
titrated from 120 
mg QD to 260 
mg QD over a 
total of 20 days.
Participants will 
receive a single 
150 mg dose of 
DE with 260 mg 
QD 
PF-07081532.
Participants will 
receive a single 
10 mg dose of 
rosuvastatin on a 
background of 
260 mg QD 
PF-07081532.
Based on emerging data from other clinical studies that may become available during the conduct of this study, the titration rate, 
incremental increases in dose, and/or the PF-07081532 doses at which rosuvastatin and/or dabigatran PK interactions are evaluated 
may be adjusted. If participants are not able to tolerate titration to higher doses of PF-07081532 (eg, ≥180 mg QD), titration to the 
next dose level may be delayed temporarily or titration to a maximum tolerated dose may be permitted, with sponsor approval only.


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 17
Statistical Methods:
The PK data for PF-07081532, rosuvastatin, and dabigatran will be analyzed and reported 
separately.
Approximately 16 evaluable participants will complete the study.
Natural loge transformed AUCinf (as data permit), AUClast and Cmax of rosuvastatin 
administered without PF-07081532 or coadministered with PF-07081532 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 2 test treatments will be 
‘rosuvastatin and PF-07081532 80 mg QD’ (Period 5) and ‘rosuvastatin and PF-07081532 
260 mg QD’ (Period 8), which will be reported separately in comparison to the reference 
treatment of ‘rosuvastatin without PF-07081532’ (Period 2). 
Natural loge transformed AUCinf (as data permit), AUClast and Cmax of dabigatran
administered alone or coadministered with PF-07081532 will be analyzed and reported 
separately using the same mixed effect model as described above for rosuvastatin. For 
dabigatran, the 2 test treatments will be ‘dabigatran and PF-07081532 80 mg QD’ (Period 4) 
and ‘dabigatran and PF-07081532 260 mg QD’ (Period 7), which will be reported separately 
in comparison to the reference treatment of ‘dabigatran alone’ (Period 1). 
Ethical Considerations:
PF-07081532 is not expected to provide any long-term clinical benefit to the healthy obese 
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, diabetic retinopathy complications, 
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.


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
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Page 18
1.2. Schema


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 19
1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Table 1.
Overall Schedule of Activities Screening to Period 5
Visit Identifier
Abbreviations used in this table may be found in 
Appendix 9
Screening
Period 1
(DE only)
Period 2
(ROSU only)
Period 3 
(PF-07081532 only)
Period 4 
(PF-07081532 + DE)
Period 5 
(PF-07081532 
+ ROSU)
Day in Study Perioda
-28 to -2
-1
1-2
1-4
1
2-7
8
1-4
5
1-4
Days in Studyb
-28 to -2
-1
1-2
3-6
7
8-13
14
15-18
19
20-23
Informed consent and demography
X
Outpatient visit (after ≥10 h fast)
X
Medical history
X
Eligibility criteria
X
X
Physical examc (height at Screening only)
X
Review contraception use - WOCBP Only (Section 5.3.1)
X
X
Review drug, alcohol/tobacco use
X
X
COVID-19 screeningd
X
C-SSRS and PHQ-9
X
X
X
Review prior or concomitant treatments 
X
X







AE monitoring
X
X








Inpatient stay at CRU
X








Body weight
X
Xl
Xl
Xl
Xl
Supine 12-lead ECG
X
Xl
Xl
Single, supine vital signs assessmente
X
Xl
Xl
Xl
Xl


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 2 0
T a ble 1 .
O ver all Sc he d ule of Acti vities Scree ni n g t o Peri o d 5
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble ma y be f o u n d i n 
A p pe n di x 9
Scree ni n g
Peri o d 1
(D E o nl y)
Peri o d 2
(R O S U o nl y)
Peri o d 3 
( P F-0 7 0 8 1 5 3 2 o nl y)
Peri o d 4 
( P F-0 7 0 8 1 5 3 2 + D E )
Peri o d 5 
( P F-0 7 0 8 1 5 3 2 
+ R O S U )
D a y i n St u d y Peri o d a
-2 8 t o - 2
- 1
1- 2
1- 4
1
2- 7
8
1- 4
5
1- 4
D a ys i n St u d y b
-2 8 t o - 2
- 1
1- 2
3- 6
7
8- 1 3
1 4
1 5 -1 8
1 9
2 0 -2 3
R os u vastati n a d mi nistrati o n
Ta ble 4
Ta ble 4
D E a d mi nistrati o n
Ta ble 3
Ta ble 3
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n f
X  
X  
X
Ta ble 5
Ta ble 4
P F -0 7 0 8 1 5 3 2 P K
R os u vastati n P K
Ta ble 4
X g
Da bi gatra n P K
Ta ble 3
Ta ble 3
Bl o o d S a m pli n g f or: h
- C he mistr y
X  
X
X
- Calcit o ni n, a m ylase, li pase
X  
X
X
- Free T 4, T S H, li pi d pa nel, t otal bile aci ds
X  
X
- He mat ol o g y/ H b A 1c
X  
X
X
- F S H i, HI V, H Bs A g, H C V A b, H C V R N A, C -pe pti de 
X
- P T /I N R
X
- Ser u m pre g na nc y test i
X  
X
Uri ne S a m pli n g f or:
- Uri ne dr u g testk
X  
X
- Uri nal ysis (a n d micr osc o p y, as a p pr o priate)
X
C CI
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 2 1
T a ble 1 .
O ver all Sc he d ule of Acti vities Scree ni n g t o Peri o d 5
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble ma y be f o u n d i n 
A p pe n di x 9
Scree ni n g
Peri o d 1
(D E o nl y)
Peri o d 2
(R O S U o nl y)
Peri o d 3 
( P F-0 7 0 8 1 5 3 2 o nl y)
Peri o d 4 
( P F-0 7 0 8 1 5 3 2 + D E )
Peri o d 5 
( P F-0 7 0 8 1 5 3 2 
+ R O S U )
D a y i n St u d y Peri o d a
-2 8 t o - 2
- 1
1- 2
1- 4
1
2- 7
8
1- 4
5
1- 4
D a ys i n St u d y b
-2 8 t o - 2
- 1
1- 2
3- 6
7
8- 1 3
1 4
1 5 -1 8
1 9
2 0 -2 3
a.
Da y relati ve t o start of d osi n g Da y 1 of t hat Peri o d.
b.
Da y relati ve t o first d ose of i n vesti gati o nal pr o d uct ( D E) o n Da y 1 of Peri o d 1.
c.
C o m plete p h ysical e xa m at Scree ni n g; ot her wise, brief e xa m if fi n di n gs d uri n g pre vi o us e xa m or ne w/ o pe n A Es, if a p pr o priate, at i n vest i gat or discreti o n. 
d.
Partici pa nts will be scree ne d f or C O VI D -1 9 acc or di n g t o l ocal pr oce d ures pri or t o bei n g a d mitte d t o t he cli nic f or c o nfi ne me nt i n Peri o d 1. S u bse q ue nt testi n g will als o be 
d o ne acc or di n g t o l ocal pr oce d ure if partici pa nts de vel o p C O VI D -1 9 li ke s y m pt o ms. See als o Secti o n 8. 3. 5 (C O VI D - 1 9 Specific A ssess me nts). If a partici pa nt tests p ositi ve 
f or S A R S-C o V - 2 i nfecti o n, t he y will be disc har ge d fr o m t he st u d y.
e.
I ncl u des B P a n d P R pre d ose.
f.
D osi n g t o occ ur Q D wit h brea kfast as s pecifie d i n Secti o n 6. 1. 1 .
g.
T he r os u vastati n P K sa m ple is t o be c ollecte d pre d ose ( 0 hr) o n Da y 1 of Peri o d 3.
h.
C ollecti o n f oll o wi n g fasti n g d urati o n s pecifie d i n Secti o n 5. 3. 2 .
i.
F S H f or fe male partici pa nts t o c o nfir m P M stat us o nl y. Ser u m -h C G f or all W O C B P; test res ult s h o ul d c o nfir m n o pre g na nc y pri or t o d osi n g.
k.
Partici pa nts ma y u n der g o ra n d o m uri ne dr u g testi n g at t he discreti o n of t he i n vesti gat or.
l.
Assess me nts t o be d o ne o n Da y 1 of Peri o ds 1 , 3, a n d 5 a n d pri or t o I P a d mi nistrati o n o n all da ys i n dicate d.
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 2 2
T a ble 2 .  
O ver all Sc he d ule of Acti vities Peri o d 6 t o E T
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble ma y be f o u n d i n A p pe n di x 9
Peri o d 6
( P F-0 7 0 8 1 5 3 2 o nl y)
Peri o d 7
( P F-0 7 0 8 1 5 3 2 + 
D E )
Peri o d 8
( P F-0 7 0 8 1 5 3 2 + 
R O S U )
F/ U Visit q
F/ U C o nt act 
Tele p h o ne
E T
D a y i n St u d y Peri o d a
1- 5 
6- 1 0
1 1 -1 5
1 6 -2 0
1- 4
5
1- 4
5
7- 1 0
2 8 -3 5
-
D a ys i n St u d y b
2 4 -2 8
2 9 -3 3
3 4 -3 8
3 9 -4 3
4 4 - 4 7
4 8
4 9 -5 2
5 3 f
5 9 -6 2
8 0 -8 7
-
O ut patie nt visit (after ≥1 0 h r fast)
X
P h ysical e xa m 
X c
Re vie w c o ntrace pti o n use - W O C B P O nl y ( Secti o n 5. 3. 1 )
X
X
Re vie w dr u g, alc o h ol/t o bacc o use
X
C O VI D -1 9 scree ni n g d
C -S S R S a n d P H Q -9 e
X
X
X
X
X
Re vie w pri or or c o nc o mita nt treat me nts
 
 
 
 
 

X
X
X
A E m o nit ori n g
 
 
 
 
 

X
X
X
I n patie nt sta y at CR U
 
 
 
 
 

X i
B o d y wei g ht g
X
X
X
X i
X
X
S u pi ne 1 2 -lea d E C G
X h
X i
X
Si n gle, s u pi ne vital si g ns assess me nt j
X
X  
X
X i
X
X
Bl o o d S a m pli n g f or: k
- C he mistr y
X l
X l
X i
X
X
- Calcit o ni n, a m ylase, li pase
X l
X i
X
- Free T 4, T S H, li pi d pa nel, t otal bile aci ds
X i
X
- He mat ol o g y/ H b A 1c
X l
X i
X
X
- Ser u m pre g na nc y test m
X i
R os u vastati n a d mi nistrati o n
Ta ble 4
D E a d mi nistrati o n
Ta ble 3
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n n
 
 
 

Ta ble 5
Ta ble 4
P F -0 7 0 8 1 5 3 2 P K
X
R os u vastati n P K
X o
Ta ble 4
Da bi gatra n P K
Ta ble 3
Uri ne S a m pli n g f or:
- Uri ne dr u g test p
- Uri nal ysis (a n d micr osc o p y, as a p pr o priate)
X
a.
Da y relati ve t o start of d osi n g Da y 1 of t hat Peri o d.
b.
Da y relati ve t o first d ose of i n vesti gati o nal pr o d uct ( D E ) o n Da y 1 of Peri o d 1.
C CI


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
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Page 23
Table 2.
Overall Schedule of Activities Period 6 to ET
Visit Identifier
Abbreviations used in this table may be found in Appendix 9
Period 6
(PF-07081532 only)
Period 7
(PF-07081532 + 
DE)
Period 8
(PF-07081532 + 
ROSU)
F/U Visitq
F/U Contact 
Telephone
ET
Day in Study Perioda
1-5
6-10
11-15
16-20
1-4
5
1-4
5
7-10
28-35
-
Days in Studyb
24-28
29-33
34-38
39-43
44-47
48
49-52
53f
59-62
80-87
-
c.
Brief exam if findings during previous exam or new/open AEs, if appropriate, at investigator discretion.
d.
Participants will be screened for COVID-19 according to local practice prior to being admitted to the clinic for confinement in Period 1. A subsequent test will be done 
according to local procedure if participants develop COVID-19 like symptoms. See also Section 8.3.5 (COVID-19 Specific Assessments). If participants test positive for 
SARS-CoV-2 infection, they will be discharged from the study.
e.
C-SSRS and PHQ-9 will be administered in Period 6 on Days 5 and 19, and in Period 8 on Day 5 (discharge from CRU).
f.
Discharge from CRU.
g.
Body weight to be obtained on Days 5, 12 and 19 in Period 6.
h.
ECG to be obtained on Day 10 of Period 6.
i.
Assessments to be obtained on Day 5 of Period 8 prior to D/C from the CRU.
j.
Includes BP and PR predose; to be obtained on Days 5, 12 and 19 in Period 6.
k.
Collection following fasting duration specified in Section 5.3.2. 
l.
Chemistry to be obtained on Days 1 and 20 in Period 6; calcitonin, amylase, lipase and hematology to be obtained on Day 20 in Period 6.
m.
Serum -hCG for all WOCBP
n.
Dosing to occur QD with breakfast. Note that there is no PF-07081532 administration on Study Day 53 or anytime thereafter.
o.
The rosuvastatin PK sample is to be collected predose (0 hr) on Day 1 of Period 6.
p.
Participants may undergo random urine drug testing at the discretion of the investigator.
q.
The follow-up visit 7-10 days after the last dose of study intervention (Period 8, Day 4) can be on-site or via telephone call. Whether the follow-up visit is on-site or via 
telephone call is at the discretion of the Investigator. Regardless of location (ie, on site or telephone call), contraception use, drug, alcohol/tobacco use, concomitant 
medications and AEs must be reviewed/assessed as appropriate.


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 2 4
T a ble 3 .
Sc he d ule of Acti vities – Peri o d 1 ( D E O N L Y), Peri o d 4 ( D E + P F -0 7 0 8 1 5 3 2 8 0 m g Q D) a n d Peri o d 7 ( D E + 
P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D)
St u d y D a y i n Peri o d
1
2
3 c
H o urs Rel ati ve t o D osi n g at 0 hr
0
0. 5
1
2
3
4
6
8
1 2
2 4
4 8 c
D E a d mi nistrati o n 
X a
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n ( Peri o ds 4 a n d 7 o nly)
X a
X
X
Bl o o d s a m pli n g f or: b
- Da bi gatra n (t otal) P K
X
X
X
X
X
X
X
X
X
X
X
a.
D osi n g t o occ ur wit h brea kfast as s pecifie d i n Secti o n 6. 1. 1 . 
b.
C ollecti o n f oll o wi n g fasti n g d urati o n as s pecifie d i n Secti o n 5. 3. 2 .
c.
T here is n o Da y 3 i n Peri o d 1 a n d t he 4 8- h o ur da bi gatra n P K sa m ple i n Peri o d 1 is t he sa me as t he 0-h o ur sa m ple i n Peri o d 2.
T a ble 4 . 
Sc he d ule of Acti vities – Peri o d 2 ( R os u v ast ati n O N L Y), Peri o d 5 ( R os u v ast ati n + P F 0 7 0 8 1 5 3 2 8 0 m g Q D), a n d 
Peri o d 8 ( R os u v ast ati n + P F- 0 7 0 8 1 5 3 2 2 6 0 m g Q D)
St u d y D a y i n Peri o d
1
2
3
4
5
H o urs Rel ati ve t o D osi n g at 0 hr
0
1
2
3
4
5
6
8
1 0
1 4
2 4
4 8
7 2
9 6 c
R os u vastati n a d mi nistrati o n 
X a
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n ( Peri o ds 5 a n d 8 o nly)
X a
X
X
X
Bl o o d s a m pli n g f or: b
- R os u vastati n P K
X
X
X
X
X
X
X
X
X
X
X
X
X
X
- Da bi gatra n (t otal) P K ( Peri o d 2 o nly)
X d
- P F -0 7 0 8 1 5 3 2 P K ( Peri o ds 5 a n d 8 o nly)
X e
a.
D osi n g t o occ ur wit h brea kfast as s pecifie d i n Secti o n 6. 1. 1 .
b.
C ollecti o n f oll o wi n g fasti n g d urati o n as s pecifie d i n Secti o n 5. 3. 2 . 
c.
T he 9 6 -h o ur P K r os u vastati n sa m ples i n Peri o ds 2 a n d 5 are t he sa me as t he 0 -h o ur P K sa m ples o n Da y 1 i n Peri o ds 3 a n d 6 , res pecti vel y.
d.
F or Peri o d 2 o nl y, t he 0- hr da bi gatra n P K sa m ple is t he sa me as t he 4 8- hr P K sa m ple fr o m Peri o d 1.
e.
T he 0 -hr P F -0 7 0 8 1 5 3 2 P K sa m ple s i n Peri o d s 5 a n d 8 are t he sa me as t he 2 4 -hr P K sa m ples fr o m D a y  5 of Peri o ds 4 a n d 7 , res pecti vel y.
C CI
C CI


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Table 5.
Schedule of Activities – Day 5 of Period 4 (DE + PF-07081532 80 mg QD) and Period 7 (DE + PF-07081532 260 mg 
QD)
Study Day in Period
5
Hours Relative to Dosing at 0 hr
0
0.5
1
2
4
6
8
10
14
24c
PF-07081532 administration 
Xa
Blood sampling for:b
- PF-07081532 PK
X
X
X
X
X
X
X
X
X
X
a.
Dosing to occur with breakfast as specified in Section 6.1.1. 
b.
Collection following fasting duration as specified in Section 5.3.2.
c.
Note: the 24-hour samples for Period 4 Day 5 and Period 7 Day 5 are the same as the 0-hour samples in Period 5 Day 1 and Period 8 Day 1, respectively.


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
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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 an 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 obese.  
2.1. Study Rationale 
In vitro data indicate the potential for PF-07081532 to inhibit both the BCRP and P-gp
transporters, therefore, this study will evaluate the impact of PF-07081532 administration on 
the PK of rosuvastatin, a sensitive BCRP substrate, and dabigatran, the active moiety of the
prodrug and P-gp substrate, DE. 
The purpose of this study is to evaluate the effect of 2 dose levels of PF-07081532 on the SD 
pharmacokinetics of rosuvastatin and dabigatran (total) 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 


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
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Page 27
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 examined for in vitro inhibition of the various efflux, hepatic uptake, and 
renal transporters. DDI risk was assessed according to the EMA13 and the Draft FDA14
Guidance documents for drug interactions intended to flag potential need for an in vivo DDI 
study. Based on these guidances, at a clinical dose of 260 mg QD, PF-07081532 may have 
the potential to inhibit BCRP, OATP1B1, OATP1B3, MATE1, MATE2K, and intestinal 
MDR1/P-gp.  
Further assessment was conducted using a more physiologically relevant static mechanistic 
model with the projected Cmax (reversible inhibition) or Cav (time-dependent inhibition) in 
plasma, intestinal lumen, enterocytes, liver, and portal inlet concentrations while 
incorporating a predicted liver-to-plasma unbound ratio (kpuu = 14.4) and ka, at a clinical 
dose of 260 mg. No clinically relevant transporter DDIs were predicted using this model.
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. 


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
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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). 
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 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.


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
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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 
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. Inter-participant 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 AUCτ) increased in 
an approximate 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 long-term clinical benefit to healthy obese 
participants. This study is designed primarily to generate safety, tolerability, and 
pharmacokinetic data for further clinical development.


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
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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 rosuvastatin and DE products are the corresponding USPIs.15,16
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.
Impairment in renal function
Potential risks are based on product 
labeling for injectable GLP-1R agonists, 
and predominantly occur in patients with 
Per exclusion criteria, potential 
participants with significant 


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
significant nausea, vomiting, and 
dehydration.
In the clinical trial program only one 
mild adverse event (Preferred Term 
Blood creatinine increased) has been 
observed.
renal impairment are not eligible 
for study entry.  
Renal function is monitored by 
lab assessments of serum BUN, 
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.  
During the study, PF-07081532 
will be titrated from a 20 mg QD 
dose to 40 mg QD over 8 days, 
and from 120 mg QD to 260 mg 
QD over 20 days, in an attempt 
to minimize gastrointestinal 
adverse reactions. 
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.


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
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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 
time points 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: Rosuvastatin
Skeletal muscle effects (eg, 
myopathy and 
rhabdomyolysis): Risks
increase with use of 40 mg 
dose, advanced age (≥65
years), hypothyroidism, renal 
impairment, and combination 
use with
cyclosporine, 
atazanavir/ritonavir, 
lopinavir/ritonavir, or 
simeprevir. Cases of 
myopathy and 
rhabdomyolysis with acute 
renal failure
secondary to myoglobinuria 
have been reported. These 
risks can occur at any dose 
level, but are increased at the 
highest dose (40 mg)
• Liver enzyme 
abnormalities: Persistent 
elevations in hepatic
transaminases can occur. 
Perform liver enzyme tests 
before initiating
therapy and as clinically 
indicated thereafter. 
Risk based on product labeling.
Participants will be monitored in 
an inpatient clinical research 
unit.
Liver enzyme levels will be 
monitored throughout the study.   
A single 10 mg dose is expected 
to pose minimal risk to the 
participants in this study. 
Study Intervention: DE
Risk of bleeding: serious and, 
sometimes, fatal bleeding. 
Promptly evaluate signs and 
symptoms of blood loss. 
Risk based on product labeling.
A single oral dose of 150 mg is 
administered in the study and 
poses minimal risk.  Participants 
will be monitored in an inpatient 
clinical research unit.
Other


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Risk of COVID-19 exposure 
during study
During the pandemic, 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 prior to 
admission to study site and 
according to the SoA.
2.3.2. Benefit Assessment
While PF-07081532 is not expected to provide any significant long-term clinical benefit to 
the healthy 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.


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 3 4
3. O B J E C TI V E S A N D E N D P O I N T S
O bjecti ves
E n d p oi nts
Pri m ar y: 
Pri m ar y: 

T o esti mate t he effect of P F -0 7 0 8 1 5 3 2 
a d mi nistrati o n o n t he si n gle -d ose P K of t otal 
da bi gatra n i n ot her wise healt h y o ver wei g ht or 
o bese partici pa nts.

Da bi gatra n (t otal) P K para meters: A U C i nf (if data 
per mit * ot her wise A U C last) i n Peri o ds 1, 4, a n d 7.

T o esti mate t he effect of M D P F -0 7 0 8 1 5 3 2 o n 
t he si n gle-d ose P K of r os u vastati n i n ot her wise 
healt h y o ver wei g ht or o bese partici pa nts.

R os u vastati n P K para meters: A U C i nf (if data 
per mit * ot her wise A U C last) i n Peri o ds 2, 5, a n d 8.
Sec o n d ar y: 
Sec o n d ar y: 

T o e val uate t he safet y a n d t olera bilit y of 
P F -0 7 0 8 1 5 3 2 a d mi nistere d se paratel y a n d i n 
c o m bi nati o n wit h D E i n ot her wise healt h y 
o ver w ei g ht or o bese partici pa nts.

Assess me nt of T E A Es, cli nical la b orat or y 
a b n or malities, vital si g ns, b o d y wei g ht, a n d E C G 
para meters. 

Assess me nt of me nta l healt h as deter mi ne d b y 
C -S S R S a n d P H Q -9.

T o e val uate t he safet y a n d t olera bilit y of 
P F -0 7 0 8 1 5 3 2 a d mi nistere d se paratel y a n d i n 
c o m bi nati o n wit h r os u vastati n i n ot her wise 
healt h y o ver wei g ht or o bese partici pa nts

Assess me nt of T E A Es, cli nical la b orat or y 
a b n or malities, vital si g ns, b o d y wei g ht, a n d E C G 
para meters. 

Assess me nt of me ntal healt h as deter mi ne d b y 
C -S S R S a n d P H Q -9.

T o e val uate t he effects of P F -0 7 0 8 1 5 3 2 o n 
a d diti o nal P K para meters f or t otal da bi gatra n.

A d diti o nal plas ma P K para meters f or t otal
da bi gatra n:  C ma x a n d T ma x ; a n d C L/ F, Vz/ F, t½ as 
data per mit, i n Peri o ds 1, 4, a n d 7.

T o e val uate t he effects of P F -0 7 0 8 1 5 3 2 o n 
a d diti o nal P K para meters f or r os u vastati n.

A d diti o nal plas ma P K para meters f or r os u vastati n:  
C m a x a n d T ma x; a n d C L/ F, Vz/ F, t½ as data 
per mit, i n Peri o ds 2, 5, a n d 8.

T o e val uate t he M D p har mac o ki netics of 
P F -0 7 0 8 1 5 3 2 i n healt h y o ver wei g ht or o bese 
partici pa nts.

P F -0 7 0 8 1 5 3 2 plas ma p har mac o ki netic para meters: 
A U C 2 4, Cma x , Tma x .
Terti ar y:
Terti ar y:
* S h o ul d it be dee me d t hat t o o fe w  A U Ci nf esti mates ( e g, less t ha n 1 6 f or a si n gle treat me nt) are o btai ne d 
fr o m t he e val ua ble partici pa nts, A U Clast ma y be selecte d as t he pri mar y e n d p oi nt f or C S R re p orti n g. T his will 
be c o nsi dere d f or t he r os u vastati n a n d da bi gatra n o bjecti ves se paratel y.
4. S T U D Y D E SI G N
4. 1. O ver all Desi g n
T his is a P hase 1, o pe n -la bel, fi xe d-se q ue nce, 8-peri o d st u d y t o e val uate t he effect of 
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n o n t he S D p har mac o ki netics of da bi gatra n (t otal) a n d 
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rosuvastatin in otherwise healthy overweight or obese adult participants. The 8 periods will 
be conducted sequentially without any washout days between periods. 
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 Day 1 of Period 1. Participants who discontinue from the study before 
completing all assessments may be replaced at the discretion of the investigator and sponsor.
Approximately 24 participants will be enrolled.
The total duration of participation from the Screening Visit to the F/U outpatient telephone 
contact will be approximately 115 days or 16.5 weeks, approximately 8 weeks of which will 
be conducted on an inpatient basis. 
The 54-day inpatient portion of the study will be conducted as follows:  
Period 1: 3 days, includes CRU admission on Day -1 (DE 150 mg single dose); 
Period 2: 4 days (rosuvastatin 10 mg single dose); 
Period 3: 8 days (PF-07081532 titrated to 40 mg QD); 
Period 4: 5 days (DE 150 mg single dose + PF-07081532 80 mg QD); 
Period 5: 4 days (rosuvastatin 10 mg single dose + PF-07081532 80 mg QD); 
Period 6: 20 days (PF-07081532 titrated to 260 mg QD); 
Period 7: 5 days (DE 150 mg single dose + PF-07081532 260 mg QD); 
Period 8: 5 days, includes discharge day from CRU (rosuvastatin 10 mg single dose + 
PF-07081532 260 mg QD).
The onsite F/U visit/telephone F/U contact will occur 7-10 days from the last dose of study 
intervention (Period 8, Day 4) and an outpatient telephone F/U contact will occur 28-35 days 
from the last dose of study intervention (Period 8, Day 4). 
4.2. Scientific Rationale for Study Design
This is a Phase 1, open-label, fixed-sequence, 8-period drug-drug interaction study to 
evaluate the effect of PF-07081532 administration on the single-dose pharmacokinetics of 
dabigatran (total) and rosuvastatin in otherwise healthy overweight or obese adult 
participants. The intent of this study is to generate safety, tolerability, and PK data for further 
clinical development.
PF-07081532 was examined for in vitro inhibition of the various efflux, hepatic uptake, and 
renal transporters. DDI risk was assessed according to the EMA13 and the Draft FDA14
Guidance documents for drug interactions, which are intended to flag potential need for an in 
vivo DDI study. Based on these guidances, at a clinical dose of 260 mg QD, PF-07081532 
may have the potential to inhibit BCRP, OATP1B1, OATP1B3, MATE1, MATE2K, and 
intestinal MDR1/P-gp. Further assessment was conducted using a more physiologically 
relevant static mechanistic model at a clinical dose of 260 mg QD; no clinically relevant


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transporter DDIs were predicted using this model. Given the inconsistent predictions
obtained using the 3 modeling approaches, and the strong likelihood that BCRP and P-gp 
substrates will be administered to the target populations, rosuvastatin will be evaluated as a 
BCRP substrate, and dabigatran, the active moiety of the prodrug and P-gp substrate DE, will 
be evaluated in this study to derisk the DDI potential with PF-07081532. Rosuvastatin is also 
a substrate for OATP; however, previous results using CP-I as a biomarker for OATP 
inhibition in C3991003 indicate relatively small changes (<13%) from baseline in CP-I 
AUC24 and Cmax across all PF-07081532 treatment groups that were not considered to be 
clinically relevant.  
The impact of PF-07081532 administration on inflammatory/cardiovascular risk biomarkers 
will be assessed in this study. CRP is a well-established biomarker of inflammation, and its 
elevation is a downstream manifestation of pro-inflammatory signaling by IL-6.17 Both CRP 
and IL-6 are elevated in obesity and in T2DM.18-20 Since elevated CRP is also associated 
with the development of cardiovascular disease, it has sometimes been used as a biomarker 
for cardiovascular risk.18,19 Indeed, trials have shown that targeted inhibition of this 
inflammatory pathway, as measured by changes in CRP concentrations, can reduce the rate 
of cardiovascular events.17,21,22 Likewise, fibrinogen is a biomarker for both thrombogenesis 
and inflammation, and elevated levels are significantly associated with an increased risk of 
CV and all-cause mortality in patients with CAD.23
Weight loss is associated with reductions in CRP and, therefore, inflammation, regardless of 
the modality used to promote weight loss.23,24 GLP-1RAs are known to improve glycemic 
control and reduce body weight, and have exhibited anti-inflammatory effects, including 
reduction of CRP.25,26 For example, in overweight and obese individuals with or without 
T2DM, once-weekly semaglutide 2.4 mg reduced CRP concentrations irrespective of 
baseline BMI/bodyweight/glycemic status compared with placebo.27
Since data suggest a potential anti-inflammatory role for GLP-1RAs in obesity and T2DM
(with the potential to reduce cardiovascular risk), and because PF-07081532 Phase 3 studies 
plan to enroll patients with increased CV risk, hs-CRP, IL-6, and fibrinogen will be collected 
in the current study as a preliminary assessment of the impact of PF-07081532 on the levels 
of these biomarkers. 
PF-07081532 will be titrated from 20 mg to 260 mg QD 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).


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 3 7
4. 2. 2. C ollecti o n of Ret ai ne d Rese arc h S a m ples
 
4. 3. J ustific ati o n f or D ose
P F -0 7 0 8 1 5 3 2 : T he dr u g -dr u g i nteracti o ns will be assesse d at 2 P F -0 7 0 8 1 5 3 2 d ose le vels, 
8 0 m g Q D a n d 2 6 0 m g Q D. T hese d oses re prese nt a p ote ntial t hera pe utic d ose f or T 2 D M, 
a n d t he hi g hest d ose bei n g assesse d i n t he P hase 2 st u d y  ( C 3 9 9 1 0 0 4) f or T 2 D M a n d o besit y, 
res pecti vely. E x p os ure mar gi ns f o r t he P F-0 7 0 8 1 5 3 2 2 6 0 m g Q D d ose are pr o vi de d i n 
Secti o n 2. 2. 3 . 
T he titrati o n t o P F -0 7 0 8 1 5 3 2 8 0 m g Q D is pla n ne d t o occ ur o ver a n 8- d a y  peri o d i n 
i ncre me nts of 2 0 m g t o 4 0 m g Q D e ver y  4 d a y s, a n d fr o m 1 2 0 m g Q D t o 2 6 0 m g Q D o ver 2 0
da y s, i n i ncre me nts of 2 0 m g t o 4 0 m g e ver y  4 d a y s (Secti o n 6. 1 , Ta ble 7 ). Titrati o n 
i ncre me nts as s h ort as 1 - 2 da y s ha ve bee n a d mi nistere d pre vi o usly i n St u d y C 3 9 9 1 0 0 2 a n d 
were s ufficie ntl y t olerate d.  
Base d o n e mer gi n g data fr o m ot her cli nical st u dies t hat ma y  bec o me a vaila ble d uri n g t he 
c o n d uct of t his st u d y, t he titrati o n rate, i ncre me ntal i ncreases i n d ose, a n d/ or t he 
P F - 0 7 0 8 1 5 3 2 d oses at w hic h r os u vastati n or t he da bi gatra n P K i nteracti o ns are e val uate d 
ma y  be a dj uste d. If partici pa nts are n ot a ble t o t olerate titrati o n t o hi g her d oses of 
P F - 0 7 0 8 1 5 3 2 (e g, ≥1 8 0 m g Q D ), titrati o n t o t he ne xt d ose le vel ma y  be dela ye d te m p oraril y 
or titrati o n t o a ma xi m u m t olerate d d ose ma y  be per mitte d, wit h sp o ns or a p pr o v al o nl y .
R os u v ast ati n: I n a si n gle d ose escalati o n st u d y, r os u vastati n was safe a n d well t olerate d at
d oses u p t o 8 0 m g. 2 8 T he m ost c o m m o n A Es re p orte d were hea dac he a n d ras h. T here was
n o e vi de nce of a relati o ns hi p bet wee n t he fre q ue nc y  of A Es a n d r os u vastati n d ose. N o
S A Es were re p orte d. 
After oral a d mi nistrati o n of r os u vastati n i n healt h y partici pa nts, C ma x occ ur re d at 3 t o 5 h o urs
p ost d ose. C o -a d mi nistrati o n of r os u vastati n wit h f o o d ha d n o i m pact o n its e x p os ure . B ot h 
C ma x a n d A U C i ncreased i n a n a p pr o xi matel y d ose-pr o p orti o nal ma n ner. T he eli mi nati o n 
half -life of r os u vastati n is a p pr o xi matel y 1 9 h o urs . R os u vastati n is a s u bstrate f or certai n 
tra ns p orter pr otei ns i ncl u di n g t he he patic u pta ke tra ns p orter, O A T P 1 B 1 , a n d t he effl u x 
tra ns p orter, B C R P. 1 5
M ost D DI  st u dies i n v ol vi n g r os u vastati n as a s u bstrate are c o n d ucte d at t he 1 0 m g or 2 0 m g 
d ose le vel. 2 9 -3 1 T he t hera pe utic d ose of r os u vastati n ma y be as hi g h as 4 0 m g. Si nce 
P F - 0 7 0 8 1 5 3 2 m a y  p ote ntiall y i ncrease r os u vastati n plas ma e x p os ure, 1 0 m g r os u vastati n was 
selecte d as a c o nser vati ve d ose i n t he c urre nt st u d y  a n d is e x pecte d t o be well-t olerate d.
R os u vastati n P K will be assesse d f oll o wi n g m ulti ple-d ose a d mi nistrati o n of 8 0 m g Q D a n d 
2 6 0 m g Q D P F -0 7 0 8 1 5 3 2 t o stea d y-state.
Resi d ual sa m ples f or a nalys is of ros u vastati n P K 
ma y  als o be utilize d f or p ote ntial a nal ysis of C P -I, a n e n d o ge n o us bi o mar ker of O A T P 
he patic u pta ke. I n vitr o data i n dicate l o w ris k f or P F-0 7 0 8 1 5 3 2 i n hi biti o n of O A T P , a n d o nl y 
mi n or i ncreases were o bser ve d f or C P -I e x p os ures i n t he C 3 9 9 1 0 0 2 st u d y. H o we ver, C P -I
C CI


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has only been evaluated up to a maximum PF-07081532 dose of 180 mg QD, therefore, data 
collected in this study are expected to further elucidate whether PF-07081532 affects OATP-
mediated uptake in humans at the highest dose (260 mg QD) being assessed in the Phase 2 
study (C3991004) for T2DM and obesity. These samples will be analyzed at the discretion of 
the sponsor. If analysis of these CP-I samples is judged to be useful, the highest dose cohort
(260 mg QD) may be assessed first and, if no meaningful effect of PF-07081532 is observed, 
the lower dose cohort (80 mg QD) may not be assayed.
Dabigatran: Dabigatran is the active moiety of the prodrug, dabigatran etexilate mesylate, 
and is an oral, direct thrombin inhibitor with antithrombotic effects.16 The recommended 
dose of dabigatran etexilate mesylate is 150 mg taken orally twice daily, with or without 
food, for patients with creatinine clearance >30 mL/min for most indications.
After oral administration of DE in healthy participants, Cmax occurred at 1 hour post 
administration in the fasted state. Co-administration of DE with a high fat meal delays the 
time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran. 
The half-life of dabigatran in healthy participants is 12 to 17 hours.16
Dabigatran was well tolerated after administration of single oral doses of 10–400 mg DE to
healthy participants.32 Seven of 40 participants reported an AE, all of which were mild to 
moderate in severity. The most frequently reported AE was headache, but in no case was this 
considered related to treatment with the study drug. There were no significant findings in 
vital signs and ECGs, in particular heart rate and PR interval, nor in safety laboratory 
assessments. There were no deaths, no SAEs, and no AEs leading to withdrawal during the 
study. 
In a drug interaction study with a single dose of verapamil 120 mg, a strong P-gp inhibitor, 
the AUC and Cmax of dabigatran (150 mg) increased by 143% and 179%, respectively.33 The 
treatments in this study were sufficiently well tolerated despite the increase in dabigatran 
exposures. The 150 mg dabigatran dose chosen for the current study is expected to be well 
tolerated.
DE is rapidly converted to dabigatran, which is the main moiety detected in the systemic 
circulation. Preclinical and clinical data suggest that DE, but not dabigatran, is a substrate of 
P-gp, therefore, changes in dabigatran exposure reflect an alteration in intestinal P-gp 
function.16 A single dose of the perpetrator is sufficient to assess changes in P-gp probe drug 
absorption, as intestinal P-gp appears to have the most significant impact on DDIs. 
Therefore, DE will be co-administered with the initial dose of 80 mg and 260 mg 
PF-07081532 in Periods 4 and 7. (PF-07081532 will continue to be dosed for an additional 4 
days in each of Periods 4 and 7 to allow steady-state exposures to be achieved prior to 
co-administration with single-dose rosuvastatin in Periods 5 and 8, respectively.)
Additionally, verapamil, a P-gp inhibitor, was shown to increase dabigatran exposures by a 
greater magnitude when dosed 1 hour prior to DE administration as compared to 
simultaneous dosing.33 Therefore, to assess near maximum intestinal exposures, and thus
maximal P-gp modulation by PF-07081532, DE will be administered ~60 min following 
administration of PF-07081532.


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4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all periods of 
the study, including the F/U telephone contact visit, approximately 28 to 35 days post last 
dose of study intervention in Period 8, Day 4. 
The end of the study is defined as the date of the last visit (F/U telephone contact) of the last 
participant in the study.
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. Participants aged 18 years or older (or the minimum age of consent in accordance 
with local regulations) at Screening.  

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 hormone 
contraception or intrauterine hormone releasing system), and must avoid 
vaccination with live attenuated vaccines.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including detailed medical history, physical examination (including blood 
pressure and pulse rate measurement), standard 12-lead ECG, and clinical laboratory 
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Other Inclusion Criteria:
3. BMI: ≥25 kg/m2 at Screening. 
4. Stable body weight, defined as <5 kg change (per participant report) for 90 days 
before Screening.
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 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 a GLP-1R agonists, rosuvastatin or 
DE.
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. History of myocardial infarction, unstable angina, arterial revascularization, 
mechanical prosthetic heart valve, stroke, New York Association Functional Class II-
IV heart failure, or transient ischemic attack within 6 months of Screening.
4. 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 cancer will be excluded, even if it was resected and they 
were considered ‘cured’.
5. Personal or family history of MTC or MEN2, or study participants with suspected 
MTC per the investigator’s judgment.


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6. Acute pancreatitis, history or repeated episodes of acute pancreatitis, or history of 
chronic pancreatitis. 
7. Symptomatic gallbladder disease.
8. Medical history or characteristics suggestive of genetic or syndromic obesity or
obesity induced by other endocrinological disorders (eg, Cushing Syndrome).
9. Known medical history of active liver disease (other than non-alcoholic hepatic
steatosis), including chronic active 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. History of major depressive disorder or history of other severe psychiatric disorders
(eg, schizophrenia or bipolar disorder) within the last 2 years from Screening.
12. Any lifetime history of a suicide attempt.
13. Other medical or psychiatric condition including recent 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.
14. Recent history of bleeding, or risk of bleeding, including prior personal or familial 
history of abnormal bleeding, hereditary or acquired coagulation or platelet disorder, 
or abnormal coagulation test (INR >1.3) result at Screening.
Prior/Concomitant Therapy:
15. 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 Prior and Concomitant Therapy for additional 
details.
16. Use of any medications that are BCRP, OATP, P-gp and/or CYP3A4/5 inhibitors or 
inducers 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.
17. Use of pH-altering drugs.
18. 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.


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Prior/Concurrent Clinical Study Experience:
19. 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).
20. Previous administration with a GLP-1R agonist within 90 days preceding the first 
dose of study intervention used in this study.  
Known prior participation in a trial involving PF-07081532 unless placebo treatment 
was received.
Diagnostic Assessments:
21. A PHQ-9 score ≥15 obtained at Screening or Day -1 in Study.
22. 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.
23. A positive urine drug test.
24. 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.
25. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF interval >450 ms,
complete LBBB, signs of an acute or indeterminate- age myocardial infarction, ST-T 
interval changes suggestive of myocardial ischemia, second- or third- degree AV
block, or serious bradyarrhythmias or tachyarrhythmias).
a.
If QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated 2 
more times and the average of the 3 QTcF or QRS values used to determine the 
participant’s eligibility. Computer-interpreted ECGs should be overread by a 
physician experienced in reading ECGs before excluding a participant.
26. 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.

INR >1.3.

Amylase or lipase > ULN.

Fasting blood glucose ≥126 mg/dL.

Fasting C-peptide not WNL.

eGFR <75 mL/min/1.73 m2 as calculated by the CKD-EPI equation.

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.

A positive SARS-CoV-2 test.
Other Exclusion Criteria:
27. Participation in a formal weight reduction program (eg, Weight Watchers) within 
90 days prior to Screening.
28. 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).
29. Current use of tobacco or nicotine containing products in excess of the equivalent of 
5 cigarettes per day.
30. Known or suspected illicit drug use.
31. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
32. History of sensitivity to heparin or heparin-induced thrombocytopenia. Unwilling or 
unable to comply with the criteria or procedures in the study.


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33. 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:
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 nonhormonal contraception (except for 
implantable progestogen only hormone contraception or intrauterine hormone releasing 
systems) for the individual participant from the permitted list of nonhormonal 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 SoA, the investigator 
or designee will inform the participant of the need to use highly effective nonhormonal
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 nonhormonal 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 nonhormonal 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) for at least 4 hours 
prior to any safety laboratory evaluations (at least 12 hours if lipids are to be 
evaluated) and 10 hours prior to the collection of a predose PK sample.  

Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. 

Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices—see 
below) may be consumed with meals and the evening snack.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample.  

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.


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
An evening snack may be permitted.

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 of each study period.  

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.
A participant who qualified for this protocol but did not enroll within the 28-day screening 
window may be re-screened. In this situation, all screening procedures must be repeated, and 
the participant assigned a new 8-digit SSID number. This criterion would also apply to 
participants who screened for this study more than 28 days prior to dosing.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and noninvestigational medicinal 
products/auxiliary medicinal products, medical devices, and other interventions (eg, surgical 
and behavioral) intended to be administered to the study participants during the study 
conduct.


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For the purposes of this protocol, study intervention refers to PF-07081532, rosuvastatin, and 
DE.
6.1. Study Intervention(s) Administered


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Table 6.
Study Interventions
Intervention Name
PF-07081532
Rosuvastatin
DE
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
Tablet
Capsule
Unit Dose Strength(s)
20 mg, 60 mg, 100 mg
10 mg
150 mg
Dosage Level(s)
PF-07081532 titrated from 20 mg QD to 
260 mg QD from Period 3 through 
Period 8
Single 10 mg doses in Periods 2, 5, 
and 8
Single 150 mg doses in Periods 1, 4, 
and 7
Route of Administration
Oral
Oral
Oral
Use
Perpetrator
Substrate
Substrate
IMP or NIMP/AxMP
IMP
NIMP/AxMP
NIMP/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 provided in a 
bottle. Each bottle will be labeled as 
required per country requirement.
Study intervention will be provided 
in commercial pack. Each 
commercial pack will be labeled as 
required per country requirement.
Study intervention will be provided 
in commercial pack. Each 
commercial pack will be labeled as 
required per country requirement.
Current/Former Name(s) or 
Alias(es)
PF-07081532
Rosuvastatin (Crestor®)
Dabigatran (Pradaxa®)


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Table 7.
Study Arms
Arm Title
Period 1: 
single-dose DE
Period 2: 
single-dose 
rosuvastatin
Period 3: 
PF-07081532
titration
Period 4:
single-dose 
DE + 
PF-07081532  
Period 5: single-dose 
rosuvastatin + 
PF-07081532  
Period 6: 
PF-07081532 
titration
Period 7: 
single-dose 
DE + 
PF-07081532  
Period 8:  
single-dose 
rosuvastatin + 
PF-07081532  
Arm Type
Baseline
Baseline
IMP titration 
only 
Experimental 
(DDI)
Experimental (DDI)
IMP titration 
only
Experimental 
(DDI)
Experimental 
(DDI)
Arm 
Description
Participants 
will receive a 
single 150 mg 
dose of DE.
Participants 
will receive 
a single 10 
mg dose of
rosuvastatin.
Participants 
will receive 
PF-07081532
titrated from 
20 mg QD to 
40 mg QD
over a total 
of 8 days.
Participants 
will receive a 
single 150 mg 
dose of DE
with 80 mg 
PF-07081532 
QD.
Participants will 
receive a single 10 mg 
dose of 
rosuvastatin on a 
background of 80 mg 
PF-07081532 QD.
Participants 
will receive 
PF-07081532
titrated from 
120 mg QD
to 260 mg 
QD over a 
total of 20
days.
Participants 
will receive a 
single 150 mg 
dose of DE
with 260 mg 
QD 
PF-07081532.
Participants 
will receive a 
single 10 mg 
dose of 
rosuvastatin 
on a 
background of 
260 mg QD 
PF-07081532.
Associated 
Intervention 
Labels
DE 
Rosuvastatin
PF-07081532
DE + 
PF-07081532
Rosuvastatin + 
PF-07081532
PF-07081532
DE + 
PF-07081532
Rosuvastatin + 
PF-07081532


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PF-07081532 will be provided by Pfizer as tablets at the CRU.
PF-07081532 will be presented to the participants in individual dosing containers.
PF-07081532 will be supplied to the CRU in bulk along with individual dosing containers for
unit dosing.
Rosuvastatin and dabigatran will be supplied by the CRU.
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive PF-07081532 with 
the breakfast meal at approximately 0800 hours (±2 hours). Investigator site personnel will 
administer PF-07081532, rosuvastatin, or DE during each period (as applicable per SoA) 
with ambient temperature water to a total volume of approximately 240 mL. Participants will 
swallow the study intervention whole and will not manipulate or chew the study intervention 
prior to swallowing. The study intervention will be administered according to the IP manual. 
PF-07081532 must be administered within approximately 10 minutes of completion of the 
morning meal (Periods 3 through 8). 
During the dabigatran DDI assessment periods (Periods 4 and 7), PF-07081532 will be 
administered first followed by administration of DE approximately 60 minutes later. When 
DE is administered alone (Period 1), it must be administered approximately 60 minutes after 
completion of the morning meal.
During the rosuvastatin DDI assessment periods (Periods 5 and 8), PF-07081532 will be 
administered first and rosuvastatin will be administered approximately 10 minutes later.
When rosuvastatin is administered alone (Period 2), it must be administered within 
approximately 10 minutes of completion of the morning meal.
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.  
Administration of study intervention will occur according to the study periods and dosing 
days listed in the SoA and Table 8.
Table 8.
Study Interventions Administered
Study Period
Study Day
Drug and Dosage
Period 1, Days 1-2
1-2
SD DE 150 mg
Period 2, Days 1-4
3-6
SD Rosuvastatin 10 mg
Period 3, Days 1-4
7-10
PF-07081532 20 mg QD
Period 3, Days 5-8
11-14
PF-07081532 40 mg QD
Period 4, Days 1-5
15-19
PF-07081532 80 mg QD + SD DE 150 mg
Period 5, Days 1-4
20-23
PF-07081532 80 mg QD + SD Rosuvastatin 10 mg


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Table 8.
Study Interventions Administered
Study Period
Study Day
Drug and Dosage
Period 6, Days 1-4
24-27
PF-07081532 120 mg QD
Period 6, Days 5-8
28-31
PF-07081532 160 mg QD
Period 6, Days 9-12
32-35
PF-07081532 200 mg QD
Period 6, Days 13-16
36-39
PF-07081532 220 mg QD
Period 6, Days 17-20
40-43
PF-07081532 240 mg QD
Period 7, Days 1-5
44-48
PF-07081532 260 mg QD + SD DE 150 mg
Period 8, Days 1-5*
49-53*
PF-07081532 260 mg QD + SD Rosuvastatin 10 mg
*No drug administration in Period 8, Day 5 (Study Day 53); participants discharged from the CRU. 
Modification of PF-07081532 dosing may be permitted upon sponsor approval only (see
Section 6.6).
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention.
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to 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 IP manual.
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.


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7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
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 or
participant in accordance with this protocol. Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities.
Tablets or capsules will be prepared at the CRU in the individual dosing containers by 
2 operators, 1 of whom is an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist). The tablets or capsules will be provided in unit dose 
containers and labeled in accordance with Pfizer regulations and the clinical site’s labeling 
requirements. 
The commercially available products, rosuvastatin and dabigatran, provided by the CRU will 
be prepared as per the label and in accordance with the protocol by 2 operators, 1 of whom is 
an appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist). The 
rosuvastatin tablets and dabigatran capsules 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
This is a non-randomized, open-label study. 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 


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with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
Participants will receive the PF-07081532 doses as described in Table 9.
Table 9.
PF-07081532 Dosing Regimens
Period and QD
PF-07081532 Dose
Number of PF-07081532 Tablets
Total Number of 
Tablets
20 mg
60 mg
100 mg
Period 3: 20 mg
1
-
-
1
Period 3: 40 mg
2
-
-
2
Period 4: 80 mg
1
1
-
2
Period 5: 80 mg
1
1
-
2
Period 6: 120 mg
1
-
1
2
Period 6: 160 mg
-
1
1
2
Period 6: 200 mg
-
-
2
2
Period 6: 220 mg
1
-
2
3
Period 6: 240 mg
2
-
2
4
Period 7: 260 mg
-
1
2
3
Period 8: 260 mg
-
1
2
3
6.4. Blinding
This is an open-label study. 
6.4.1. Blinding of Participants
Participants will be unblinded to their assigned study intervention.
6.4.2. Blinding of Site Personnel
Investigators and other site staff will be unblinded to participants’ assigned study 
intervention. 
6.4.3. Blinding of the Sponsor
Sponsor staff will be unblinded to participants’ assigned study intervention. 
6.4.4. Breaking the Blind
Not applicable. 
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 


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administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
Study site personnel will examine each participant’s mouth to ensure that the study 
intervention was ingested; this is vitally important to ensure dosing compliance in light of 
the potential gastrointestinal AEs. Additionally, if vomiting occurs following oral dosing 
and up to 4 hours post-dose (twice the median Tmax of PF-07081532), site personnel will 
examine the emesis for evidence of drug product. 
A record of the number of PF-07081532 and rosuvastatin tablets and dabigatran capsules 
dispensed to and taken by each participant must be maintained and reconciled with study 
intervention and compliance records. Intervention start and stop dates, including dates for 
intervention delays and/or dose reductions, will also be recorded in the CRF.
6.6. Dose Modification
Based on emerging data from other clinical studies that may become available during the 
conduct of this study, the titration rate, incremental increases in dose, and/or the 
PF-07081532 doses at which rosuvastatin or the dabigatran PK interactions are evaluated 
may be adjusted. If participants are not able to tolerate titration to higher doses of 
PF-07081532 (eg, ≥180 mg QD), titration to the next dose level may be delayed temporarily 
or titration to a maximum tolerated dose may be permitted, with sponsor approval only.
6.6.1. Dose Escalation and Stopping Rules
Not applicable. 
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.  There is no specific 
treatment for an overdose of PF-07081532.
For this study, overdose for rosuvastatin will be as per the respective USPI label.15   
Any dose of DE greater than 2 × 150 mg capsules within a 24-hour time period (±12 hours) 
will be considered an overdose. A specific reversal agent (idarucizumab) is available for DE
when reversal of the anticoagulant effect is needed for emergency surgery/urgent procedures 


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or if AEs of life-threatening or uncontrolled bleeding should occur. Other procedures and 
agents are also available to remove dabigatran or affect the anticoagulant activity of 
dabigatran, but their clinical experience is limited. Please see the dabigatran USPI for 
specific information.16  
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 for at 
least 5 half-lives (approximately 5 days) after the overdose of study intervention, and 
as medically appropriate 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 sections of this protocol.
Use of prescription or nonprescription drugs and dietary and herbal supplements (eg, 
St. John’s wort) are prohibited within 7 days or 5 half-lives (whichever is longer) prior to the 
first dose of study intervention. 
Systemic therapy with any medications that are moderate or strong CYP3A4/5 inhibitors or
moderate or strong CYP3A4/5 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 or inducers of BCRP, OATP and P-gp transporters within 
14 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention are 
prohibited.
Use of pH altering drugs is prohibited; eg, proton-pump inhibitors, H2-blockers, etc.
Use of a GLP-1R agonist is prohibited within 90 days prior to the first dose of study 
intervention. 


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Hormonal contraceptives (including oral and non-oral) are prohibited in participants who are 
WOCBP (see Appendix 4). An exception is made for implantable progestogen only hormone 
contraception or intrauterine hormone releasing systems.
Females using hormonal contraceptives (including oral and non-oral) or 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.
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 (See 
Section 6.9.2).
Sites are encouraged to contact the sponsor should there be questions as to whether a 
medication is permitted or prohibited.
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).
6.9.2. Management of Nausea and Vomiting
Nausea and vomiting have been reported with administration of GLP-1R agonists and also 
with administration of PF-07081532. 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.


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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.  

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 8.3.8.3, should be 
discontinued from dosing at investigator discretion.

If the criteria for permanent discontinuation are met, the site should notify the sponsor 
Medical Monitor or sponsor Clinician.

Positive SARS-CoV-2 test (see Section 8.3.5).

Potential or confirmed AKI (see Section 7.1.1).
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 an ET visit. 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.


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If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants in a given treatment arm 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.
7.1.2. Temporary Discontinuation
If participants are not able to tolerate titration to higher doses of PF-07081532 (eg, ≥200 mg 
QD) titration to the next dose level may be delayed temporarily, with sponsor approval only. 
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:

Refused further study procedures.

Lost to follow-up.

Death.

Study terminated by sponsor.

Safety or behavioral reasons at the discretion of the investigator, including reasons 
related to mental health assessments.

Positive SARS-CoV-2 Test.
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. 


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The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.
If a participant withdraws from the study, 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.
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. 


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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.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
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.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
If 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 
535 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 
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To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.2. Efficacy Assessments
Not applicable.
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
8.3.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
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.
Complete physical examinations will be done at the time points specified in the SoA
otherwise, brief examinations if findings during a previous examination or new/open AEs, if 
appropriate at Investigator discretion.
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. Weight will be recorded using a calibrated scale (with the same scale used if 
possible, for the duration of the study) reporting weight in either pounds (lb) or kilograms 
(kg), and accuracy to the nearest 0.2 lb (or 0.1 kg); ie, the device must be able to distinguish 
a difference between 150.4 lb (68.4 kg) versus 150.2 lb (68.3 kg).
Weight measurement should be taken under the following conditions:

In the morning in a fasting state.

After void of urine.

After removal of shoes, bulky layers of clothing and jackets so that only light clothing 
remains.

After removal of pocket contents. 

While remaining still during the measurement.


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Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
8.3.2.1. Blood Pressure and Pulse Rate
Vital signes (systolic BP, diastolic BP and PR) will occur as specified in the SoA. 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. 
At Screening, the participant’s arm circumference should be measured (e.g., 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. 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 Sections 8.4.1 to 8.4.3.
8.3.2.2. Temperature
Body temperature will be measured at the timepoints listed in the SoA. Temperature will be 
measured orally. 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 section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) is not 
recommended given the potential risk of discrepancies with ECGs acquired using standard 
limb lead placement. All scheduled ECGs should be performed after the participant has 
rested quietly for at least 5 minutes in a supine position. 


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To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG. If either of these conditions occurs, 
then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to confirm the 
original measurement. If the QTcF values from these repeated ECGs remain above the 
threshold value, then a single ECG must be repeated at least hourly until QTc values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement.
If a) a postdose QTcF interval remains ≥30 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. 
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 28-35 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.


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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 screened for COVID-19 according to local procedures prior to being 
admitted to the clinic for confinement in Period 1. Subsequent testing will also be done 
according to local procedure, if participants develop symptoms suggestive of COVID-19. If a 
participant tests positive for SARS-CoV-2 infection, they will be discharged from the study. 
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 
(HAE)
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:34
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, 
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c.
Probable symptomatic hypoglycemia: An event during which symptoms of HAE are 
not accompanied by a glucose determination but was presumably caused by a glucose 
concentration of <70 mg/dL (3.9 mmol/L), and the clinical picture includes prompt 
resolution with food intake, subcutaneous glucagon, or IV glucose.
Each episode of HAE must be categorized with respect to severity. In order to characterize 
the event as severe, all 3 criteria below must be met:
1. The participant was unable to treat him/herself. Neurologic impairment, and not the 
age of the participant, is the explanation for why the participant could not treat 
him/herself and required the assistance of another person.
2. The participant exhibited at least 1 of the following neurological symptoms:

Memory loss.

Confusion.

Uncontrolled behavior.

Irrational behavior.

Unusual difficulty in awakening.

Suspected seizure.

Seizure.

Loss of consciousness.
3. Either:

If blood glucose was measured and was ≤54 mg/dL (2.7 mmol/L) using 
glucometer (or 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.


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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 
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. 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 (C-SSRS)
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behavior.35 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 screening or 
Day-1 will not be permitted in the study (see Section 5.2). 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.
8.3.8.1.1. Rater Qualifications
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
participants in this study. The minimum qualifications a rater must meet for each study rating 
assessment will be outlined in the guidance document provided to each participating site. The 
level of experience with the target population (or equivalent), specific scale experience (or 
equivalent), and certification required (if applicable) will be listed and used to determine 
whether a rater is approved for a given assessment. The rater must become certified to 
perform selected study assessments before he or she can participate in the conduct of the 
study. For specifically defined assessments, rater training and standardization exercises may 
be conducted, and written documentation will be provided by the site for each rater’s 
certification. In return, each site will be provided written and signed documentation outlining 
each rater’s certification for specific study assessments. Recertification may be required at 
periodic intervals during the study. The raters who administer specific study assessments will 


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be documented in a centralized location and all site staff who administer ratings will be 
verified in the site study documentation during the conduct of the study.
8.3.8.2. Patient Health Questionnaire-9 (PHQ-9)
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms.36 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 ≥15 on the PHQ-9.

In the investigator’s judgment a risk assessment or exclusion is required.
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 


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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, except as indicated 
below, after the last administration of the study intervention.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
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.


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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.
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.


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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention
inseminates a female partner. 

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 


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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after 
the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion 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 


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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 
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.


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8.4.8.1. Lack of Efficacy
Not applicable.
8.4.9. Medical Device Deficiencies
Not applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Other examples include, but are not limited to:

The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;

The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use.
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 


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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 will be collected for measurement of plasma concentrations of rosuvastatin, 
dabigatran, and PF-07081532 as specified in the SoA.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples collected for analyses of study intervention plasma concentrations may also be used
to evaluate safety or efficacy aspects related to concerns arising during or after the study, for 
metabolite identification and/or evaluation of the bioanalytical method, or for other internal 
exploratory purposes.
Genetic analyses will not be performed on these samples unless consent for this was included 
in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of study intervention will be 
analyzed using a validated analytical method in compliance with applicable SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
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 


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N F I D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 7 4
be i nf or me d of a n y safet y iss ues t hat re q uire alterati o n of t he safet y m o nit ori n g sc he me or 
a me n d me nt of t he I C D.
I nstr ucti o ns f or t he c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will be pr o vi de d i n t he 
la b orat or y ma n ual or b y t he s p o ns or. T he act ual date a n d ti me ( 2 4- h o ur cl oc k ti me) of eac h 
sa m ple will be rec or de d.
8. 5. 1. P K of R os u v ast ati n
Sa m ples will be use d t o e val uate t he P K of r os u vastati n. Bl o o d sa m ples of a p pr o xi matel y 6
m L , t o pr o vi de 2 ali q u ots of plas ma v ol u me of a p pr o xi matel y  1. 2 m L, will be c ollecte d i nt o 
a p pr o priatel y la bele d t u bes c o ntai ni n g K2E D T A f or meas ure me nt of plas ma c o nce ntrati o ns 
of r os u vastati n as s pecifie d i n t he S o A .
8. 5. 2. P K of D a bi g atr a n
Sa m ples will be use d t o e val uate t he P K of da bi gatra n. Bl o o d sa m ples of a p pr o xi matel y  
3 m L , t o pr o vi de 2 ali q u ots of plas ma v ol u me of a p pr o xi matel y  0. 6 m L  eac h, will be
c ollecte d i nt o a p pr o priatel y  la bele d t u bes c o ntai ni n g K2E D T A f or meas ure me nt of plas ma 
c o nce ntrati o ns of t otal da bi gatra n (s u m of u nc o nj u gate d da bi gatra n a n d c o nj u gate d 
da bi gatra n) as s pecifie d i n t he S o A .
8. 5. 3. P K of P F -0 7 0 8 1 5 3 2
Sa m ples will be use d t o e val uate t he P K of P F -0 7 0 8 1 5 3 2 . Bl o o d sa m ples of a p pr o xi matel y 
3 m L , t o pr o vi de 2 ali q u ots of plas ma v ol u me of a p pro xi matel y  0. 6 m L  eac h, will be 
c ollecte d i nt o a p pr o priatel y  la bele d t u bes c o ntai ni n g K2E D T A f or meas ure me nt of plas ma 
c o nce ntrati o ns of P F -0 7 0 8 1 5 3 2 as s pecifie d i n t he S o A .
8. 6. Ge netics
8. 6. 1. S pecifie d Ge netics
S pecifie d g e netic a nal ys es are n ot e val uate d i n t his st u d y .
8. 6. 2. Ret ai ne d Rese arc h S a m ples f or Ge netics
 
 
 
 
8. 7. Bi o m ar kers
 
C CI
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 7 5
 
 
 
8. 7. 3. S pecifie d Ge ne E x pressi o n ( R N A) Rese arc h
S pecifie d ge ne e x pressi o n ( R N A) researc h is n ot i ncl u de d i n t his st u d y .
8. 7. 4. S pecifie d Pr otei n Rese arc h
S pecifie d pr otei n researc h is n ot i ncl u de d i n t his st u d y .
8. 7. 5. S pecifie d Met a b ol o mic Rese arc h
S pecifie d meta b ol o mic researc h is n ot i ncl u de d i n t his st u d y .
8. 7. 6. Ret ai ne d Rese arc h S a m ples f or Bi o m ar kers
 
 
 
 
 
8. 8. I m m u n o ge nicit y Assess me nts
I m m u n o ge nicity assess me nts are n ot i ncl u de d i n t his st u d y .
C CI
C CI


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8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypothesis
No formal statistical hypothesis testing will be conducted in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
assignment to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Safety analysis set
Example: All participants randomly assigned to study 
intervention and who take at least 1 dose of study intervention.
PK Concentration Set
The PK concentration population is defined as all participants 
who receive at least 1 dose of rosuvastatin, dabigatran, and/or 
PF-07081532 and in whom at least 1 plasma concentration 
value is reported.
PK Parameter Set
The PK parameter analysis population is defined as all 
participants who receive at least 1 dose of rosuvastatin, 
dabigatran, and/or PF-07081532 and have at least 1 of the PK 
parameters of interest calculated. 
Should vomiting occur after coadministration of rosuvastatin 
or dabigatran with PF-07081532, the resulting PK parameters 


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Participant Analysis 
Set
Description
from that participant from the corresponding period may be 
excluded, where further details will be provided in the SAP.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. General Considerations
9.3.2. Derivation of Pharmacokinetic Parameters
The plasma PK parameters for rosuvastatin and dabigatran (total) following SD
administration (either alone or during coadministration with PF-07081532) will be derived 
from the concentration-time profiles as detailed in Table 10 below. The plasma PK 
parameters for PF-07081532 following MD administration will be derived from the 
concentration-time profiles as detailed in Table 11 below. 
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.


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Table 10.
Plasma PK Parameters for Rosuvastatin and Dabigatran
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.
AUCinf*
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.
t1/2*
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/F*
Apparent oral clearance.
Dose/AUCinf.
Vz/F*
Apparent volume of distribution.
Dose/ (AUCinf • kel). 
* as data permit
Table 11.
Plasma PK Parameters for PF-07081532
Parameter
Definition
Method of Determination
AUC24
Area under the plasma 
concentration-time profile from 
time zero to time 24 hours.
AUCt (area under the plasma 
concentration-time profile where 
t = 0 to 24 hours).
Cmax
Maximum plasma concentration 
observed from time zero to 
24 hours.
Observed directly from data.
Tmax
Time for Cmax.
Observed directly from data as time 
of first occurrence.
9.3.3. Primary Endpoint(s) Analysis.
The PK data for rosuvastatin, dabigatran (total), and PF-07081532 will be analyzed and 
reported separately.
Plasma concentrations will be listed and summarized descriptively by PK sampling time and 
treatment (dosing alone vs. coadministration, as applicable). Individual participant and 
median profiles of the concentration-time data will be plotted by treatment. For summary


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statistics and median plots by sampling time, the nominal PK sampling time will be used. For
individual participant plots by time, the actual PK sampling time for plasma samples will be 
used. Median profiles will be presented on both linear-linear and log-linear scales.
Natural loge transformed AUCinf (as data permit), AUClast and Cmax of dabigatran (total)
administered without PF-07081532 on Period 1 or coadministered with PF-07081532 in 
Period 4 and on Period 7 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 2 
test treatments will be ‘dabigatran and PF-07081532 80 mg QD’ (Period 4) and ‘dabigatran
and PF-07081532 260 mg QD’ (Period 7), which will be reported separately in comparison 
to the reference treatment of ‘dabigatran without PF-07081532’ (Period 1). 
Natural loge transformed AUCinf (as data permit), AUClast and Cmax of rosuvastatin
administered alone in Period 2 or coadministered with PF-07081532 on Period 5 and Period 
8 will be analyzed and reported separately using the same mixed effect model as described 
above for dabigatran. The 2 test treatments will be ‘rosuvastatin and PF-07081532 80 mg 
QD’ (Period 5) and ‘rosuvastatin and PF-07081532 260 mg QD’ (Period 8), which will be 
reported separately in comparison to the reference treatment of ‘rosuvastatin without 
PF-07081532’ (Period 2).
9.3.4. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, continuous cardiac monitoring, and safety laboratory data will be 
reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
participants. Any clinical laboratory, ECG, BP, and pulse rate abnormalities of potential 
clinical concern will be described. Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study, will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
9.3.4.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR
interval, and QRS complex will be summarized by treatment and time.


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The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment:
Table 12.
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
9.3.5. Other Analyses 
Tertiary/Exploratory analyses not included in the pharmacokinetic or safety analyses outlined 
above will be documented in the SAP. 
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR
9.4. Interim Analyses
No 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
A sample size of approximately 24 participants will be enrolled into the study, such that 
approximately 16 evaluable participants will complete the study. This number of evaluable 
participants has been selected to provide sufficient precision to detect a 1.5-fold and 
1.25-fold difference in AUCinf for dabigatran and rosuvastatin respectively, as described 
below.
For dabigatran AUCinf:

The co-administration of DE and PF-07081532 80 mg QD (Period 4) versus DE alone 
(Period 1, reference treatment).

The co-administration of DE and PF-07081532 260 mg QD (Period 7) versus DE
alone (Period 1, reference treatment).
For rosuvastatin AUCinf:

The co-administration of rosuvastatin and PF-07081532 80 mg QD (Period 5) versus 
rosuvastatin alone (Period 2, reference treatment).

The co-administration of rosuvastatin and PF-07081532 260 mg QD (Period 8) versus 
rosuvastatin alone (Period 2, reference treatment).


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 7
Fi nal Pr ot oc ol , 3 1 Ja n uar y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 A pril 2 0 2 2)
Pa ge 8 1
T he e x pecte d wi dt hs of t he 9 0 % CIs wit h 8 0 % c o vera ge pr o ba bilit y  f or t hese c o m paris o ns 
are s h o w n i n Ta ble 1 3 f or a ra n ge of p ossi ble effects base d o n a sa m ple size of 1 6
partici pa nts.
T a ble 1 3.
E x pecte d Wi dt hs of t he 9 0 % CIs ( wit h 8 0 % C o ver a ge Pr o b a bilit y) f or 
Differe nt P ossi ble Esti m ate d Effects a n d P ar a meters of I nterest
P a r a m eter
Es ti m ate d Effect
( Test/ Refere nce)
Pr o b a ble 9 0 % CI
Pr o b a ble CI Wi dt h
D a bi g atr a n: A U C i nf
( S D = 
)
7 5 %
1 0 0 %
1 2 5 %
1 5 0 %
2 0 0 %
R os u v ast ati n: A U C i nf
( S D = 
)
7 5 %
1 0 0 %
1 2 5 %
1 5 0 %
2 0 0 %
F or da bi gatra n, t hese esti mates are base d o n a c o nser vati ve sta n dar d de viati o n of  
 
(e q ui vale nt t o a ge o metric c oefficie nt of variati o n of  
%) i n l o geA U C i nf as o btai ne d fr o m 
i nter nal cli nical st u dies ( B 1 8 7 1 0 4 3 a n d B 7 4 5 1 0 2 6) a n d literat ure i n healt h y partici pa nts.3 7
F or r os u vastati n , these esti mates are base d o n a n ass u me d sta n dar d de viati o n of  
 
(e q ui vale nt t o a ge o metric c oefficie nt of variati o n of  
%) i n l o geA U C i nf as o bser ve d i n a 
pre vi o us i nter nal D DI st u d y i n t he sa me p o p ulati o n (C 3 4 2 1 0 0 7 ). 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data. 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about their
right to access and correct their personal data and to withdraw consent for the processing of 
their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
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.


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A copy of the ICD(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use a DMC. 
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 


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responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality, such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
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 


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submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.


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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.
10.1.10. Publication Policy
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.
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 


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access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.11. Sponsor’s Medically Qualified Individual
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the SToD system.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, participants are provided with 
an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol and 
study intervention identifiers, (b) participant’s study identification number, (c) site 
emergency phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center 
number.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.


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Table 14.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
CystatinC and eGFR
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Direct bilirubin
Indirect bilrubin
GGT
Alkaline phosphatase
Uric acid
Albumin
Total protein
Local dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Laboratory:
Microscopy and 
culturea
HbA1c
Pregnancy test (β-hCG)b
Lipid panel:

Total cholesterol

Direct LDL-C

HDL-C

Triglycerides
TSH
Free T4
Calcitonin
Amylase
Lipase
Serum TBA
Fibrinogen
Urine drug screeningd
At screening only:
FSHc
C-peptide (fasting)
HIV
Hepatitis B surface antigen
Hepatitis C antibody
HCV RNA
SARS-CoV-2
PT/INR
Additional Tests (Needed 
for Potential DILI):
AST/ALT (all repeat)
T bili, direct and indirect 
bili (all repeat)
Total bile acids, (repeat)
GGT (repeat)
Total protein, albumin 
(repeat), alkaline 
phosphatase (repeat)
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.
Serum testing will be standard for female participants of childbearing potential.
c.
For confirmation of postmenopausal status only.
d.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific). At screening, Period 1 Day-1 and at the discretion 
of the investigator.
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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Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.


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d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic 
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 


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nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/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***
*
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.


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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention.  The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.


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
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for 
marketed products, in their assessment.

For each AE or SAE, the investigator must document in the medical notes that 
they have reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.

The investigator may change theiropinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.


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


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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants.  Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she 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.
6. Sexual Abstinence


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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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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 Equations
2021 CKD-
EPI          
Scr-Scys 
Combined
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
if ≤ 0.8
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.323  × (0.9961)Age
Female
if ≤ 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.778  × (0.9961)Age
Female
if > 0.7
if ≤ 0.8
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.323  × (0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.778  × (0.9961)Age
Male
if ≤ 0.9
if ≤ 0.8
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.323  × (0.9961)Age
Male
if ≤ 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.778  × (0.9961)Age
Male
if > 0.9
if ≤ 0.8
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.323  × (0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.778  × (0.9961)Age
Inker LA et al. N Engl J Med. 2021;385:1737-49.
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO
criteria.


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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB (QRS complex>120 ms).

New-onset right bundle branch block (QRS complex>120 ms).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with 
an escape rhythm that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and 
bradycardia with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid 
= rate >120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 


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


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10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
Abs
absolute
ADL
activity/activities of daily living
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
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
AUCtau (AUCτ)
area under the plasma concentration-time profile over the dosing 
interval, tau
AV
atrioventricular
AxMP
auxiliary medicinal product
BBS
Biospecimen Banking System
BCRP
breast cancer resistant protein
-hCG
b-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CAD
coronary artery disease
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
Clast
predicted plasma concentration at the last quantifiable time point 
estimated from the log-linear regression analysis
CL/F
apparent oral clearance
CLp
plasma clearance
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CP-I
coproporphyrin I
COVID-19
coronavirus disease 2019
CRF
case report form


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Abbreviation
Term
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CT
clinical trial
CTIS
Clinical Trial Information System
%CV
percent coefficient of variation
CV
cardiovascular
CYP
cytochrome P450
D
day
D/C
discontinue
DABI
dabigatran
DCT
data collection tool
DDI
drug-drug interaction 
DE
dabigatran etexilate
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DRE
disease-related event
DU
dispensable unit
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
eSAE
electronic serious adverse event
ET
end-of-treatment
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FDA
Food and Drug Administration
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
HBcAb
hepatitis B core antibody


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Abbreviation
Term
HbA1c
hemoglobin A1c
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
hr
hour(s)
HR
heart rate
HRT
hormone replacement therapy
hs-CRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ID
identification
IL-6
interleukin-6
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IP
Investigational Product
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IRC
internal review committee
IRT
Interactive Response Technology
IV
intravenous(ly)
kel
first-order elimination rate constant
K2EDTA
dipotassium ethylenediaminetetraacetic acid
KDIGO
Kidney Disease Improving Global Outcomes
LBBB
left bundle branch block
LDL
low-density lipoprotein
LFT
liver function test
LLN
lower limit of normal
MATE
multidrug and toxic compound extrusion
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MD
multiple dose
MEN2
multiple endocrine neoplasia syndrome type 2
MDR
medical device regulation
MHP
mental health professional
MQI
medically qualified individual
MTC
medullary thyroid carcinoma
NA
not applicable


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Abbreviation
Term
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
OATP
organic anion transporting polypeptides
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
P-gP
P-glycoprotein
PHQ-9
Patient Health Questionnaire-9
PI
principal investigator
PK
pharmacokinetic(s)
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
once daily
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
QTL
quality tolerance limit
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
ROSU
rosuvastatin
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
Scr
serum creatinine
Scys
serum cystatin C
SD
single dose; standard deviation
SoA
schedule of activities
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SSID
single subject identifier
ST-T
ST segment to T wave changes on 12-lead ECG
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal half-life.
T2DM
type 2 diabetes mellitus
TB
tuberculosis 
TBA
total bile acids
T bili
total bilirubin
TEAE
treatment emergent adverse event 
THC
tetrahydrocannabinol
Tmax
time for Cmax
TOC
table of contents


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Abbreviation
Term
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information
UTI
urinary tract infection
Vss
volume of distribution at steady state
Vz/F
apparent volume of distribution
WBC
white blood cell
WNL
within normal limits
WOCBP
woman/women of childbearing potential


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11. REFERENCES
1.
Ørskov C, Holst JJ, Knuhtsen S,et al. Glucagon-like peptides GLP-1 and GLP-2, 
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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.
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Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
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Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
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IDF Diabetes Atlas; 9th Edition. Available from: IDF Diabetes Atlas. Accessed 
05 Nov 2022.  
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Menke A, Casagrande S, Geiss L,et al. Prevalence of and trends in diabetes among
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Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and 
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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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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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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.
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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.
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Drucker DJ. The ascending GLP-1 road from clinical safety to reduction of 
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CHMP. Guideline on the investigation of drug interactions. CPMP/EWP/560/95/Rev. 1 
Corr. 2. 2012. Available from: Guideline on the investigation of drug interactions 
(europa.eu). Accessed: 29 Jan 2023.


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14.
US Department of Health and Human Services, Food and Drug Administration, Center
for Drug Evaluation and Research (CDER). In vitro metabolism and transporter
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15.
Rosuvastatin. US Prescribing Information (USPI). Parsippany, NJ: Actavis Pharma, Inc.
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16.
Pradaxa. Highlights of Prescribing Information. Ridgefield, CT: Boehringer Ingelheim 
Pharmaceuticals, Inc. Available from: PRADAXA (dabigatran etexilate mesylate) 
capsules for oral use Label (fda.gov). Accessed 27 Dec 2022.  
17.
Ridker PM. From CANTOS to CIRT to COLCOT to clinic: will all atherosclerosis 
patients soon be treated with combination lipid-lowering and inflammation-inhibiting 
agents? Circulation. 2020;141(10):787–789.
18.
Avan A, Tavakoly SB, Ghayour-Mobarhan M, et al. Serum C-reactive protein in the 
prediction of cardiovascular diseases: overview of the latest clinical studies and public 
health practice. J Cell Physiol. 2018;233(11):8508–8525. 
19.
Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream 
to identify novel targets for atheroprotection. Circ Res. 2016;118(1):145–156. 
20.
Szmitko PE, Wang CH, Weisel RD, et al. New markers of inflammation and endothelial 
cell activation: part I. Circulation. 2003;108(16):1917–1923.
21.
Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with canakinumab 
for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–1131. 
22.
Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after 
myocardial infarction. N Engl J Med. 2019;381(26):2497–2505.
23.
Cui Z, Ma M, Zhao G, et al. Blood fibrinogen level as a biomarker of adverse outcomes 
in patients with coronary artery disease: A systematic review and meta-analysis.  
Medicine 2022;101:33(e30117).
24.
Askarpour M, Khani D, Sheikhi A, et al. Effect of bariatric surgery on serum 
inflammatory factors of obese patients: a systematic review and meta-analysis. Obes 
Surg. 2019;29(8):2631– 2647.
25.
Mazidi M, Karimi E, Rezaie P, et al. Treatment with GLP1 receptor agonists reduce 
serum CRP concentrations in patients with type 2 diabetes mellitus: a systematic review 
and meta-analysis of randomized controlled trials. J Diabet Complicat. 2017;31(7): 
1237–1242. 


PF-07081532
Protocol C3991047
Final Protocol, 31 January 2023
PFIZER CONFIDENTIAL
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26.
Katsiki N, Ferrannini E. Anti-inflammatory properties of antidiabetic drugs: a 
“promised land” in the COVID-19 era? J Diabet Complicat. 2020;34(12):107723.
27.
Verma S, Bhatta M, Davies M, et.al.  Effects of once-weekly semaglutide 2.4 mg on C-
reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): Exploratory 
analyses of three randomised, double-blind, placebo-controlled, phase 3 trials. 
eClinicalMedicine 2023;55: 101737.
28.
Martin, PD, Warwick MJ, Dane AL, et al. A double-blind, randomized, incomplete 
crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers. 
Clin Ther 2003;25(8):2215-24.
29.
Martin P, Gillen M, Ritter J, et al. Effects of fostamatinib on the pharmacokinetics of 
oral contraceptive, warfarin, and the statins rosuvastatin and simvastatin: results from 
Phase I clinical studies. Drugs RD 2016;16(1):93-107.
30.
Cooper KJ, Martin PD, Dane AL, et al. Effect of itraconazole on the pharmacokinetics 
of rosuvastatin. Clin Pharmacol Ther 2003;73(4):322-9.
31.
Stopfer P, Giessmann T, Holh K, et al. Effects of metformin and furosemide on 
rosuvastatin pharmacokinetics in healthy volunteers: implications for their use as probe 
drugs in a transporter cocktail. Eur J Drug Metab Pharmacokinet 2018;43(1): 69-80.
32.
Stangier J, Rathgen K, Stähle H, et al. The pharmacokinetics, pharmacodynamics and 
tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male 
participants. Br J Clin Pharmacology 2007;64:292-303.
33.
Hartter S, Sennewald R, Nehmiz G, et al. Oral bioavailability of dabigatran etexilate 
(Pradaxa®) after co-medication with verapamil in healthy participants. Br J Clin 
Pharmacology 2012;75(4):1053-1062.
34.
American Diabetes Association. Standards of medical care in diabetes-2019. Diabetes 
Care. 2019;42(Suppl 1): S13-S28.
35.
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.
36.
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.
37.
Hartter S, Sennewald R, Nehmiz G, et al. Oral bioavailability of dabigatran etexilate 
(Pradaxa®) after co-medication with verapamil in healthy subjects. British Journal of 
Clinical Pharmacology 2013;75(4)(Apr):1053-62.

SAP_001.pdf: 
Protocol C3991047 (PF-07081532) 
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022 
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Page 1 of 30 
 
 
Protocol  C3991047 
 
 
 
 
A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE STUDY TO ESTIMATE THE 
EFFECT OF PF-07081532 ADMINISTRATION ON THE SINGLE-DOSE 
PHARMACOKINETICS OF DABIGATRAN AND ROSUVASTATIN IN 
OVERWEIGHT OR OBESE ADULT PARTICIPANTS 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
2 
 
 
Date:  
04 Jul 2023   


Protocol C3991047 (PF-07081532) 
Statistical Analysis Plan 
 
 
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TABLE OF CONTENTS 
LIST OF TABLES ................................................................................................................ 4 
LIST OF FIGURES ............................................................................................................... 4 
APPENDICES ...................................................................................................................... 4 
1. VERSION HISTORY........................................................................................................ 6 
2. INTRODUCTION ............................................................................................................. 6 
2.1. Modifications to the Analysis Plan Described in the Protocol ................................ 6 
2.2. Study Objectives, Endpoints, and Estimands ......................................................... 7 
2.3. Study Design ......................................................................................................... 8 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS .............................................................................................................. 9 
3.1. Primary Endpoint(s) .............................................................................................. 9 
3.2. Secondary Endpoint(s) .......................................................................................... 9 
3.2.1. Safety Endpoints ....................................................................................... 9 
3.2.1.1. Additional Safety Endpoints of Interest .................................. 10 
3.2.1.2. Laboratory Parameters of Interest – Liver Function Tests ....... 11 
3.2.2. Assessment of Mental Health .................................................................. 11 
3.2.2.1. Columbia Suicide Severity Rating Scale (C-SSRS) ................. 11 
3.2.2.2. Patient Health Questionnaire (PHQ-9) .................................... 11 
3.2.3. Additional plasma PK Parameters for total Dabigatran and 
Rosuvastatin ................................................................................................. 12 
3.2.4. Plasma PK Parameters for PF-07081532 ................................................. 12 
3.3. Other Endpoint(s) ................................................................................................ 13 
.................................. 13 
.................................. 13 
.................................. 13 
3.4. Baseline Variables ............................................................................................... 13 
3.5. Safety Endpoints ................................................................................................. 13 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ................................................. 14 
5. GENERAL METHODOLOGY AND CONVENTIONS ................................................. 15 
5.1. Hypotheses and Decision Rules ........................................................................... 15 
5.2. General Methods ................................................................................................. 15 
5.2.1. Analyses for Continuous Endpoints ......................................................... 15 
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5.2.2. Analyses for Categorical Endpoints ......................................................... 15 
5.2.3. Mixed effects model ................................................................................ 15 
5.3. Methods to Manage Missing Data ....................................................................... 16 
5.3.1. Plasma Pharmacokinetic Parameters ........................................................ 16 
6. ANALYSES AND SUMMARIES ................................................................................... 17 
6.1. Primary Endpoint(s) ............................................................................................ 17 
6.1.1. AUCinf and AUClast for Total Dabigatran and Rosuvastatin...................... 17 
6.2. Secondary Endpoint(s) ........................................................................................ 19 
6.2.1. Safety Endpoints ..................................................................................... 19 
6.2.1.1. Adverse Events ....................................................................... 19 
6.2.1.2. Laboratory Data ...................................................................... 19 
6.2.1.3. Vital Signs .............................................................................. 20 
6.2.1.4. Electrocardiogram (ECG) ....................................................... 20 
6.2.1.5. Additional Safety Endpoints of Interest .................................. 21 
6.2.1.6. C-SSRS .................................................................................. 21 
6.2.1.7. PHQ-9 .................................................................................... 21 
6.2.1.8. Mental Health Risk Assessment .............................................. 21 
6.2.2. Additional Plasma PK Parameters ........................................................... 21 
6.2.2.1. Additional Plasma PK Parameters for Total Dabigatran 
and Rosuvastatin ............................................................................ 21 
6.2.2.2. Plasma PK Parameters for PF-07081532................................. 22 
6.3. Other Endpoint(s) ................................................................................................ 23 
................................. 23 
................................. 23 
................................. 24 
6.4. Subset Analyses .................................................................................................. 24 
6.5. Baseline and Other Summaries and Analyses ...................................................... 24 
6.5.1. Baseline Summaries ................................................................................ 24 
6.5.2. Study Conduct and Participant Disposition .............................................. 25 
6.5.3. Study Treatment Exposure ...................................................................... 25 
6.5.4. Concomitant Medications and Nondrug Treatments ................................ 25 
6.6. Safety Summaries and Analyses .......................................................................... 25 
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7. INTERIM ANALYSES ................................................................................................... 25 
7.1. Introduction ......................................................................................................... 25 
7.2. Interim Analyses and Summaries......................................................................... 25 
8. REFERENCES ................................................................................................................ 25 
APPENDICES .................................................................................................................... 26 
 
LIST OF TABLES 
Table 1. Summary of Changes ............................................................................................... 6 
Table 2. Summary of primary total dabigatran and rosuvastatin plasma PK parameters 
to be calculated. ....................................................................................... 9 
Table 3. Liver Function Tests of Interest ............................................................................. 11 
Table 4. Summary of additional total dabigatran and rosuvastatin plasma PK 
Parameters to be calculated.................................................................... 12 
Table 5. Summary of PF-07081532 plasma PK Parameters to be calculated ........................ 12 
 ............................................ 13 
Table 7. Summary statistics to be produced for plasma PK Parameters of total 
dabigatran and rosuvastatin ................................................................... 18 
Table 8. Summary statistics to be produced for additional plasma PK Parameters for 
total dabigatran and rosuvastatin ............................................................ 22 
Table 9. Summary statistics to be produced for plasma PK Parameters for PF-
07081532 .............................................................................................. 22 
 ........................... 24 
 
LIST OF FIGURES 
Figure 1. Study Design .......................................................................................................... 8 
 
APPENDICES 
Appendix 1. PK Analyses – Example of SAS Code for mixed effects model ....................... 26 
Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern ..... 27 
Appendix 3. List of Abbreviations ....................................................................................... 28 
Appendix 4. C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events and 
Codes .................................................................................................... 30 
 
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NOTE:  Italicized text within this document has been taken verbatim from the Protocol. 


Protocol C3991047 (PF-07081532) 
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1. VERSION HISTORY 
Table 1. 
Summary of Changes  
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1 
24 Mar 2023 
Original  
31 Jan 2023 
N/A 
N/A 
2 
04 Jul 2023 
N/A 
In order to be 
consistent with 
C3991004 IRC Charter 
(01-May-2023) 
inclusion of LFTs 
outputs. 
 
Dosing of PF-
07081532 was capped 
at 240mg QD. 
 
Changes to vital signs 
thresholds to include a 
maximum threshold for 
SBP and DBP  
 
These definitions of 
baseline were not being 
used in any analyses 
 
Analyses are not 
needed as sufficient 
participants got to 
240mg QD 
Addition of Sections 3.2.1.2 and 
6.2.1.2.1 describing additional 
outputs related to LFTs to be 
reported and the expected outputs. 
 
 
 
Addition of text to Section 2.1 to 
explain the change of design from 
the protocol. 
 
Changes to Appendix 2 – Categories 
for Vital Signs 
 
 
 
Removal of the definitions of 
baseline for C-SSRS and PHQ-9 
 
 
Removed sensitivity analysis for 
Section 6.1.1 
 
2. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3991047. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
Due to the dosing of  PF-07081532 being capped at 240mg QD, the titration of PF-07081532 
stopped at the end of Period 6 and the study was shortened by 6 days. Therefore, the study 
design presented in Section 2.3 is accurate according to study protocol but not the most up to 
date study design for C3991047, in terms of dose and execution day. 
 


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2.2. Study Objectives, Endpoints, and Estimands 
Type 
Objective 
Endpoint 
 
Primary:  
Primary:  
PK 
Section 6.1 
• 
To estimate the effect of PF-07081532 
administration on the single-dose PK of 
total dabigatran in otherwise healthy 
overweight or obese participants. 
• 
Dabigatran (total) PK parameters: 
AUCinf  (if data permit* otherwise 
AUClast ) in Periods 1, 4, and 7. 
PK 
Section 6.1 
• 
To estimate the effect of MD PF-
07081532 on the single-dose PK of 
rosuvastatin in otherwise healthy 
overweight or obese participants. 
• 
Rosuvastatin PK parameters: AUCinf  
(if data permit* otherwise AUClast ) in 
Periods 2, 5, and 8. 
 
Secondary:  
Secondary:  
Safety 
Section 6.2 
• 
To evaluate the safety and tolerability of 
PF-07081532 administered separately 
and in combination with DE 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. 
Safety 
Section 6.2 
• 
To evaluate the safety and tolerability of 
PF-07081532 administered separately 
and in combination with rosuvastatin 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. 
PK 
Section 6.2.2.1 
• 
To evaluate the effects of PF-07081532 
on additional PK parameters for total 
dabigatran. 
• 
Additional plasma PK parameters for 
total dabigatran: Cmax  and Tmax; and 
CL/F, Vz/F, t½ as data permit, in 
Periods 1, 4, and 7. 
PK 
Section 6.2.2.1 
• 
To evaluate the effects of PF-07081532 
on additional PK parameters for 
rosuvastatin. 
• 
Additional plasma PK parameters for 
rosuvastatin:  Cmax  and Tmax; and 
CL/F , Vz/F, t½ as data permit, in 
Periods 2, 5, and 8. 
PK 
Section 6.2.2.2 
• 
To evaluate the MD pharmacokinetics 
of PF-07081532 in healthy overweight 
or obese participants. 
• 
PF-07081532 plasma 
pharmacokinetic parameters: AUC24, 
Cmax, Tmax. 
 
Tertiary: 
Tertiary: 
*Should it be deemed that too few AUCinf estimates (e.g. less than 16 for a single treatment) are obtained from 
the evaluable participants, AUClast may be selected as the primary endpoint for CSR reporting. This will be 
considered for the rosuvastatin and dabigatran objectives separately. 
 
There are no estimands for this study. 
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2.3. Study Design 
This study is a Phase 1, open-label, fixed-sequence, 8-period study to evaluate the effect of 
PF-07081532 administration on the SD pharmacokinetics of total dabigatran and 
rosuvastatin in otherwise healthy overweight or obese adult participants. The 8 periods will 
be conducted sequentially without any washout days between periods.  
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 Day 1 of Period 1. Participants who discontinue from the study before 
completing all assessments may be replaced at the discretion of the investigator and sponsor. 
Approximately 24 participants will be enrolled such that approximately 16 evaluable 
participants complete the study. 
Figure 1. Study Design 
 
The total duration of participation from the Screening Visit to the F/U outpatient telephone 
contact will be approximately 115 days or 16.5 weeks, approximately 8 weeks of which will 
be conducted on an inpatient basis.  
The 54-day inpatient portion of the study will be conducted as follows:   
Period 1: 3 days, includes CRU admission on Day -1 (DE 150 mg single dose);  
Period 2: 4 days (rosuvastatin 10 mg single dose);  
Period 3: 8 days (PF-07081532 titrated to 40 mg QD);  
Period 4: 5 days (DE 150 mg single dose + PF-07081532 80 mg QD);  
Period 5: 4 days (rosuvastatin 10 mg single dose + PF-07081532 80 mg QD);  
Period 6: 20 days (PF-07081532 titrated to 240 mg QD);  
Period 7: 5 days (DE 150 mg single dose + PF-07081532 240 mg QD);  
Period 8: 5 days, includes discharge day from CRU (rosuvastatin 10 mg single dose + 
PF-07081532 240 mg QD). 


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The onsite F/U visit/telephone F/U contact will occur 7-10 days from the last dose of study 
intervention (Period 8, Day 4) and an outpatient telephone F/U contact will occur 28-
35 days from the last dose of study intervention (Period 8, Day 4).  
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
Blood samples for PK analysis of total dabigatran, rosuvastatin, and PF-07081532 will be 
collected according to the Schedule of Activities given in the protocol. 
PK parameters and 
 will be calculated (if possible) from the concentration-
time data using standard noncompartmental methods. 
3.1. Primary Endpoint(s) 
• Dabigatran (total) plasma PK parameters: AUCinf (if data permit* otherwise AUClast ) in 
Periods 1, 4, and 7. 
• Rosuvastatin plasma PK parameters: AUCinf (if data permit* otherwise AUClast ) in 
Periods 2, 5, and 8 
*Should it be deemed that too few AUCinf estimates (e.g. less than 16 for a single treatment) 
are obtained from the evaluable participants, AUClast may be selected as the primary 
endpoint for CSR reporting. This will be considered for the rosuvastatin and total dabigatran 
objectives separately. 
AUClast will be calculated and reported regardless of whether AUCinf is the primary endpoint 
for CSR reporting or not. The plasma PK parameters in Table 2 will be determined: 
Table 2. Summary of primary total dabigatran and rosuvastatin plasma PK parameters 
to be calculated. 
Parameter 
Analysis 
Scale 
Dabigatran Etexilate 150mg 
(Periods 1, 4 and 7) 
Rosuvastatin 10mg 
(Periods 2, 5 and 8) 
AUCinf* 
ln 
A, D 
A, D 
AUClast 
ln 
A, D 
A, D 
*=if data permits. Abbreviations: A=analyzed using a statistical model; D=displayed with 
descriptive statistics as outlined in Table 7 in Section 6.1.1 ; ln=natural-log transformed. 
3.2. Secondary Endpoint(s) 
3.2.1. Safety Endpoints 
• Assessment of treatment-emergent adverse events (TEAEs), clinical laboratory 
abnormalities, vital signs, body weight, and ECG parameters during the entire study, by 
period.  
 
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Any events occurring following start of study intervention (i.e. treatment) will be counted as 
treatment emergent.  
Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the most recent treatment taken. 
A 3-tier approach for summarizing adverse events (AEs) will not be used due to the low 
number of participants planned to be recruited.  
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters): 
• adverse events, 
• laboratory data (except data from screening visit), 
• vital signs data, 
• body weight 
• ECG results. 
For laboratory, vital signs, ECG data, laboratory data and body weight, baseline is defined as 
the last pre-dose measurement in Period 1. 
3.2.1.1. Additional Safety Endpoints of Interest 
• Change from baseline in body weight at all post-dose time points as outlined in the 
SoA  
• Percent change from baseline in body weight at all post-dose time points as outlined 
in the SoA 
• Change from baseline in fasting plasma glucose at all post-dose time points as 
outlined in the SoA  
• Change from baseline in HbA1c at all post-dose time points as outlined in the SoA 
For these additional endpoints, baseline is defined as the last pre-dose measurement in Period 
1 (i.e. Day -1). 


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3.2.1.2. Laboratory Parameters of Interest – Liver Function Tests 
Normalized values for liver function tests as described in Table 3 will be derived and a flag 
for each level of abnormality (ie “Flag Level” or “Alert Level”) will be included in the 
derived dataset. If abnormalities persist across periods for the same participant these should 
be reported across the multiple periods. 
Table 3. Liver Function Tests of Interest 
Parameter  
Flag Level 
Alert Level 
Conventional Units 
Alanine 
aminotransferase  
> ULN  
-  
U/L  
> 2x ULN  
-  
U/L  
> 3x ULN  
-  
U/L  
> 5x ULN  
> 8x ULN  
U/L  
> 5x ULN  
> 10x ULN  
U/L  
> 5x ULN  
> 20x ULN  
U/L  
Aspartate 
aminotransferase  
> ULN  
-  
U/L  
> 2x ULN  
-  
U/L  
> 3x ULN  
-  
U/L  
> 5x ULN  
> 8x ULN  
U/L  
> 5x ULN  
> 10x ULN  
U/L  
> 5x ULN  
> 20x ULN  
U/L  
Alkaline 
Phosphatase  
> 2x ULN  
-  
U/L  
> 3x ULN  
-  
U/L  
> 5x ULN  
-  
U/L  
Total Bilirubin  
> 2x ULN  
> 3x ULN  
mg/dL  
Direct and Indirect 
Bilirubin  
> ULN  
-  
mg/dL  
   ULN – Upper Limit of Normal as determined by the central laboratory  
3.2.2. Assessment of Mental Health 
• Assessment of mental health as determined by C-SSRS and PHQ-9 during the entire 
study. 
3.2.2.1. Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behaviour.   
Data relevant to the assessment of suicidality will be mapped to the Columbia-Classification 
Algorithm of Suicide Assessment (C-CASA) codes as given in Appendix 4. 
3.2.2.2.  
Patient Health Questionnaire (PHQ-9) 
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 schedule of activities (SoA). 


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The PHQ-9 total score will be derived for each time point separately by summing the 
responses to the 9 questions. 
3.2.3. Additional plasma PK Parameters for total Dabigatran and Rosuvastatin  
• Additional plasma pharmacokinetic (PK) parameters for total dabigatran (Periods 1, 
4 and 7: Cmax, Tmax , and CL/F, Vz/F, t½ , as data permit 
• Additional plasma pharmacokinetic (PK) parameters for rosuvastatin (Periods 2, 5 
and 8): Cmax , Tmax , and CL/F, Vz/F, t½ , as data permit 
The additional plasma PK parameters for total dabigatran and rosuvastatin in Table 4 will be 
determined: 
Table 4. Summary of additional total dabigatran and rosuvastatin plasma PK 
Parameters to be calculated 
Parameter 
Analysis 
Scale 
Dabigatran Etexilate 150mg 
(Periods 1, 4 and 7) 
Rosuvastatin 10mg 
(Periods 2, 5 and 8) 
Cmax 
Ln 
A, D 
A, D 
Tmax 
R 
D 
D 
t½* 
R 
D 
D 
CL/F* 
Ln 
D 
D 
Vz/F* 
Ln 
D 
D 
*=if data permits. Abbreviations: A=analyzed using a statistical model; D=displayed with 
descriptive statistics as outlined in Table 8 in Section 6.2.2.1; ln=natural-log transformed; 
R=raw (untransformed). 
3.2.4. Plasma PK Parameters for PF-07081532 
• PF-07081532 plasma pharmacokinetic parameters at Study Days 19 and 48: AUC24,  
Cmax, Tmax. 
The plasma PK parameters for PF-07081532 in Table 5 will be determined: 
Table 5. Summary of PF-07081532 plasma PK Parameters to be calculated  
Parameter 
Analysis 
Scale 
PF-07081532 80mg QD 
(Day 19) 
PF-07081532 240mg QD 
(Day 48) 
AUC24  
Ln 
D 
D 
Cmax  
Ln 
D 
D 
Tmax  
R 
D 
D 
Abbreviations: D=displayed with descriptive statistics as outlined in Table 9 in Section 
6.2.2.2; ln=natural-log transformed; R=raw (untransformed). 


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3.3. Other Endpoint(s) 
3.4. Baseline Variables 
Not applicable. 
3.5. Safety Endpoints 
See Section 3.2 for details. 
 
 
CCI


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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures. 
Participant Analysis Set Description 
Enrolled  
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
assignment to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol.  
Evaluable 
All participants assigned to study intervention and who take 
at least 1 dose of study intervention. 
Safety analysis set 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. 
PK Concentration Set 
The PK concentration population is defined as all 
participants who receive at least 1 dose of rosuvastatin, 
dabigatran etexilate, and/or PF-07081532 and in whom at 
least 1 plasma concentration value is reported 
PK Parameter Set 
The PK parameter analysis population is defined as all 
participants who receive at least 1 dose of rosuvastatin, 
dabigatran etexilate, and/or PF-07081532 and have at least 
1 of the PK parameters of interest calculated.  
Should vomiting occur after co-administration of 
rosuvastatin or dabigatran etexilate with PF-07081532, the 
resulting PK parameters from that participant from the 
corresponding period may be excluded, where further details 
are provided in Section 5.3. 
 
 
 


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5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
There is no statistical hypothesis testing planned for this study and no statistical decision 
rules will be applied. 
5.2. General Methods 
Unless otherwise stated, all summaries and plots will be presented by treatment group 
(equivalent to ‘by Period’). The following treatment labels (or similar) will be used, which 
represent Periods 1 to 8 as: 
Period 
Treatment Label 
1 
Dabigatran etexilate 150 mg (Period 1) 
2 
Rosuvastatin 10 mg (Period 2) 
3 
PF-07081532 titration up to 40 mg QD (Period 3) 
4 
PF-07081532 80 mg QD + dabigatran etexilate 150 mg (Period 4) 
5 
PF-07081532 80 mg QD + rosuvastatin 10 mg (Period 5) 
6 
PF-07081532 titration up to 240 mg QD (Period 6) 
7 
PF-07081532 240 mg QD + dabigatran etexilate 150 mg (Period 7) 
8 
PF-07081532 240 mg QD + rosuvastatin 10 mg (Period 8) 
 
5.2.1. Analyses for Continuous Endpoints 
Unless otherwise stated, continuous variables will be presented using summary statistics: 
number of observations, arithmetic mean, standard deviation, median, minimum and 
maximum values.  
5.2.2. Analyses for Categorical Endpoints 
Categorical variables will be presented using summary statistics: number of observations and 
percentages.  
5.2.3. Mixed effects model 
A mixed effects model with treatment as a fixed effect and participant as a random effect will 
be used. Estimates of the adjusted (least squares) mean differences (Test-reference) and 
corresponding 90% CIs will be obtained from the model. 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. 


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The mixed effects model will be implemented using SAS Proc Mixed, with REML 
estimation method and the Kenward-Roger degrees of freedom algorithm.  
 
Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report.  If there are major 
deviations from normality or outliers (where studentized [conditional] residuals are greater 
than 3 or less than -3) then the effect of these on the conclusions may be investigated through 
alternative transformations and/or analyses excluding outliers. Justification for any 
alternative to the planned analysis will be given in the report of the study if applicable. 
Example code is shown in Appendix 1. 
 
5.3. Methods to Manage Missing Data 
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.  
In all exploratory safety data presentations (except listings), concentrations below the limit of 
quantification (BLQ) will be set to the lower limit of quantification (LLOQ). 
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. In listings BLQ values will be reported as “<LLOQ”, where LLOQ 
will be replaced with the value for the LLOQ.  
In PK summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if one of the following cases is true:  
1. A concentration has been collected as ND (i.e. not done) or NS (i.e. no sample),  
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist/statistician.  
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
Participants who experience events that may affect their PK profile (e.g., lack of compliance 
with dosing or vomiting) may be excluded from the PK analysis. At the discretion of the 
pharmacokineticist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason. 
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure. 
5.3.1. Plasma Pharmacokinetic Parameters 
Actual PK sampling times will be used in the derivation of plasma PK parameters. 


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If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (i.e., not calculated). (Note that NC values will not be generated beyond 
the day that a participant discontinues.) 
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular treatment group/analyte with ≥3 evaluable measurements. 
For statistical analyses (i.e., mixed effects model), PK parameters coded as NC will also be 
set to missing; and analyses will not be performed for a particular parameter if more than 
50% of the data are NC. 
If an individual participant has a known biased estimate of a plasma PK parameter (due, for 
example, to an unexpected event such as vomiting before all the compound is adequately 
absorbed in the body, e.g., within 2 times the median Tmax after the last dose for the 
respective treatment1), this will be footnoted in summary tables and will not be included in 
the calculation of summary statistics or statistical analyses. 
6. ANALYSES AND SUMMARIES 
For all presentations, study day will refer to the day within a particular treatment period, 
unless otherwise specified. 
6.1. Primary Endpoint(s) 
6.1.1. AUCinf and AUClast for Total Dabigatran and Rosuvastatin 
The PK data for rosuvastatin, total dabigatran, and PF-07081532 will be analyzed and 
reported separately. 
AUCinf and AUClast for total dabigatran and rosuvastatin alone and co-administered with  
PF-07081532 will be listed, summarized descriptively and analyzed by treatment for 
participants in the PK Parameter Set (as defined in Section 4). Missing values will be handled 
as detailed in Section 5.3. 
Natural loge transformed AUCinf (as data permit), and AUClast of total dabigatran 
administered without PF-07081532 on Period 1 or coadministered with PF-07081532 in 
Period 4 and on Period 7 will be analyzed using a mixed effect model as described in Section 
5.2.3. 
 The 2 test treatments will be ‘dabigatran and PF-07081532 80 mg QD’ (Period 4) and 
‘dabigatran and PF-07081532 240 mg QD’ (Period 7), which will be reported separately in 
comparison to the reference treatment of ‘dabigatran without PF-07081532’ (Period 1).  
Natural loge transformed AUCinf (as data permit), and AUClast of rosuvastatin administered 
alone in Period 2 or coadministered with PF-07081532 on Period 5 and Period 8 will be 
analyzed and reported separately using the same mixed effect model as described above for 
total dabigatran. The 2 test treatments will be ‘rosuvastatin and PF-07081532 80 mg QD’ 
(Period 5) and ‘rosuvastatin and PF-07081532 240 mg QD’ (Period 8), which will be 


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reported separately in comparison to the reference treatment of ‘rosuvastatin without 
PF-07081532’ (Period 2). 
In the event that participants do not successfully titrate to the target PF-07081532 doses by 
the end of Periods 3 and/or 6, the related PK parameters for total dabigatran and rosuvastatin 
in the subsequent periods would not be included in the above models (but may be included in 
sensitivity analyses described below). Note this implies that evaluable PK parameters for the 
same participants from at least Period 1 (for total dabigatran) and 2 (for rosuvastatin) would 
be included in the models. 
AUCinf and AUClast will be listed, summarized for each treatment (total dabigatran and 
rosuvastatin will be reported in separate tables) as specified in the table below: 
Table 7. Summary statistics to be produced for plasma PK Parameters of total 
dabigatran and rosuvastatin 
Parameter 
Summary Statistics 
AUClast & AUCinf  
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%. 
Supporting data from the estimation of AUCinf will be listed by treatment: 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. 
As a sensitivity analysis an additional physiologically-based PK or other related model may 
be explored if fewer than 16 participants have PK parameters as above to further characterize 
the relationship between PK of PF-07081532 and PK of total dabigatran and/or rosuvastatin, 
which would be reported outside of the CSR. 
The following plots will be presented: 
− Box and whisker plots for individual PK parameters (AUCinf and AUClast) will be 
presented by treatment and overlaid with geometric means. These will be produced 
for total dabigatran and rosuvastatin PK parameters separately. 
The following will additionally be presented for the plasma concentration data of total 
dabigatran and rosuvastatin (reported in separate tables) using the PK Concentration Set (as 
defined in Section 4):  
- 
a listing of all concentrations sorted by participant ID and nominal time post-dose for 
each treatment (i.e. total dabigatran and rosuvastatin dosed alone or co-administered, as 
applicable) separately. 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 each nominal time post-dose (produced separately for 
each treatment), where the set of statistics will include n, mean, median, standard 
deviation, coefficient of variation (cv), minimum, maximum and the number of 
concentrations above the lower limit of quantification.  


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- 
median concentration time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment. Two plots will be presented for each scale: one for the three 
treatments with total dabigatran and another for the three treatments with rosuvastatin.  
- 
individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time post-dose (there will be separate spaghetti plots for each treatment, 
with a line for each participant per scale). Plots for total dabigatran and rosuvastatin will 
be produced separately.  
- 
individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time post-dose. Two plots for each participant and scale will be presented: 
one for the three treatments with total dabigatran and one for the three treatments with 
rosuvastatin.  
 
The nominal PK sampling time will be used for summary statistics and relevant median plots, 
whereas for individual participant plots by time, the actual PK sampling time will be used. 
6.2. Secondary Endpoint(s) 
6.2.1. Safety Endpoints 
6.2.1.1. Adverse Events  
Adverse events will be summarized by treatment and overall and in accordance with sponsor 
reporting standards using the safety population defined in Section 4.   
Incidence and severity of treatment emergent adverse event (TEAE) tables will additionally be 
produced (‘All causality’ and ‘Treatment related’, separately) to summarize the total number of 
adverse events by preferred term, which will be reported by treatment and overall in accordance 
with sponsor reporting standards using the safety analysis set defined in Section 4. 
The AEs will be presented sorted in descending frequency based on the overall number of 
AEs (by preferred term or system order class as appropriate) across treatments. 
6.2.1.2. Laboratory Data   
Laboratory data will be listed and summarized by treatment and overall, in accordance with 
the sponsor reporting standards using the safety population defined in Section 4. Change from 
baseline (as defined in Section 3.2.1) summaries will be presented. In summary and listing 
tables, laboratory abnormalities occurring pre-dose on Day 1 during Periods 2-8, will be 
attributed to the treatment from the previous Period (e.g., an occurrence pre-dose at Period 3 
Day 1, will be attributed to the Period 2 treatment).  
6.2.1.2.1. Additional Summaries for Liver Function Tests 
Using the safety population defined in Section 4, the number of participants with values 
meeting the flag or alert boundaries as defined in Table 3 for each of the parameters will be 
summarized (as specified in Section 5.2.2), by period/treatment and overall. All planned and 
unplanned post baseline time points will be counted in these categorical summaries. 
Figure: 


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For ALT, AST, ALP, Total Bilirubin and Direct Bilirubin, individual normalized values 
(i.e. raw value divided by the upper limit of normal) over time (i.e. spaghetti plot) will be 
reported. Reference lines for flag and alert levels crossing Y-axis will be displayed. 
Screening and unplanned collections before Day 1 will not be included in individual 
plots. All other unplanned visits will be included. If two or more values are collected on 
the same day, all collections will be included in the plot. A reference median line will 
also be included in the plots. Screening, unplanned and early termination collections will 
not be included in the median calculation. For any value over 3xULN the subject ID will 
be displayed in the plot. 
 
6.2.1.3. Vital Signs  
Absolute values and changes from baseline (as defined in Section 3.2.1) in supine systolic 
and diastolic blood pressure and pulse rate will be listed, and summarized by treatment and 
time point, according to sponsor reporting standards using the safety population defined in 
Section 4. 
Mean absolute values and mean changes from baseline for systolic and diastolic blood 
pressure and pulse rate will be plotted against time point i.e., analysis visit. Corresponding 
individual plots of changes from baseline will also be produced for each treatment. 
Maximum and minimum absolute values and changes from baseline (as defined in Section 
3.2.1) for supine vital signs will also be summarized descriptively by treatment using 
categories as defined in Appendix 2. Numbers and percentages of participants meeting the 
categorical criteria will be provided. All planned and unplanned post dose time points will be 
counted in these categorical summaries. All values meeting the criteria of potential clinical 
concern will be listed. Values meeting the categorical criteria occurring pre-dose on Day 1 
during Periods 2-8, will be attributed to the treatment from the previous Period (e.g., an 
occurrence pre-dose at Period 3 Day 1, will be attributed to the Period 2 treatment).  
6.2.1.4. Electrocardiogram (ECG)  
Absolute values and changes from baseline (as defined in Section 3.2.1) in QT interval, heart 
rate, QTcF interval, PR interval and QRS interval will be listed, and summarized by 
treatment and time point using sponsor reporting standards using the safety population 
defined in Section 4. Tables will be paged by parameter. 
Mean changes from baseline for QT interval, heart rate and QTcF interval will be plotted 
against time point i.e., analysis visit. Corresponding individual plots of changes from 
baseline will also be produced for each treatment. 
Maximum absolute values and changes from baseline for QTcF, PR and QRS will also be 
summarized descriptively by treatment using categories as defined in Appendix 2. Numbers 
and percentages of participants meeting the categorical criteria will be provided. All planned 
and unplanned post dose timepoints will be counted in these categorical summaries. All 
values meeting the criteria of potential clinical concern will be listed. Values meeting the 
categorical criteria occurring pre-dose on Day 1 during Periods 2-8, will be attributed to the 


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treatment from the previous Period (e.g., an occurrence pre-dose at Period 3 Day 1, will be 
attributed to the Period 2 treatment). 
6.2.1.5. Additional Safety Endpoints of Interest 
Absolute values and changes from baseline for body weight (both absolute and percent 
change, separately), fasting glucose and HbA1c will summarized by treatment and time point 
as outlined in Section 5.2.1 for participants in the safety population (as defined in Section 4). 
6.2.1.6. C-SSRS 
Baseline and post-baseline C-SSRS data (mapped to C-CASA scores as described in Section 
3.2.2.1) using the safety population defined in Section 4 will be summarized categorically by 
treatment and time point as outlined in Section 5.2.2.   
6.2.1.7. PHQ-9 
Baseline and post-baseline PHQ-9 data (responses to each of the 9 items) using the safety 
population defined in Section 4, will be summarized categorically for each question 
separately by treatment and time point as outlined in Section 5.2.2. 
The PHQ-9 total score as defined in Section 3.2.2.2 will additionally be summarized 
descriptively by treatment group and time point as outlined in Section 5.2.1. 
6.2.1.8. Mental Health Risk Assessment 
The number of participants who met the criteria for referral to a mental health professional 
will be listed and summarized by treatment group and time point as outlined in Section 5.2.2. 
6.2.2. Additional Plasma PK Parameters 
6.2.2.1. Additional Plasma PK Parameters for Total Dabigatran and Rosuvastatin 
Cmax, Tmax, CL/F, Vz/F, t½ for total dabigatran and rosuvastatin alone and co-administered 
with PF-07081532 will be listed, summarized descriptively and analyzed by treatment for 
participants in the PK Parameter Set (as defined in Section 4). Missing values will be handled 
as detailed in Section 5.3. 
Cmax, Tmax, CL/F, Vz/F, t½ will be summarized for each treatment (total dabigatran and 
rosuvastatin will be reported in separate tables) as specified in the table below: 


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Table 8. Summary statistics to be produced for additional plasma PK Parameters for 
total dabigatran and rosuvastatin 
Parameter 
Summary Statistics 
Cmax, CL/F, Vz/F  
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%. 
Tmax  
N, median, minimum, maximum.  
t½  
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum.  
 
Natural loge transformed Cmax of total dabigatran administered without PF-07081532 on 
Period 1 or coadministered with PF-07081532 in Period 4 and on Period 7 will be analyzed 
using a mixed effect model as described in Section 5.2.3. 
The 2 test treatments will be ‘dabigatran and PF-07081532 80 mg QD’ (Period 4) and 
‘dabigatran and PF-07081532 240 mg QD’ (Period 7), which will be reported separately in 
comparison to the reference treatment of ‘dabigatran without PF-07081532’ (Period 1).  
Natural loge transformed Cmax of rosuvastatin administered alone in Period 2 or 
coadministered with PF-07081532 on Period 5 and Period 8 will be analyzed and reported 
separately using the same mixed effect model as described above for total dabigatran. The 2 
test treatments will be ‘rosuvastatin and PF-07081532 80 mg QD’ (Period 5) and 
‘rosuvastatin and PF-07081532 240 mg QD’ (Period 8), which will be reported separately in 
comparison to the reference treatment of ‘rosuvastatin without PF-07081532’ (Period 2). 
The following plots will be presented: 
− Box and whisker plots for individual Cmax will be presented by treatment and overlaid 
with geometric means. These will be produced for total dabigatran and rosuvastatin 
Cmax separately. 
6.2.2.2. Plasma PK Parameters for PF-07081532  
Plasma PK parameters for PF-07081532 as described in Section 3.2.4 will be listed and 
summarized descriptively for participants in the PK Parameter Set (as defined in Section 4). 
Missing values will be handled as detailed in Section 5.3.  
AUC24, Cmax, Tmax will be summarized for each treatment period of PF-07081532  as 
required in the table below: 
Table 9. Summary statistics to be produced for plasma PK Parameters for PF-07081532  
Parameter 
Summary Statistics 
AUC24, Cmax  
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%. 
Tmax  
N, median, minimum, maximum.  


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The following plots will be presented: 
− Box and whisker plots for individual PK parameters of PF-07081532 (AUC24 and 
Cmax) will be presented by treatment and overlaid with geometric means. 
The following summaries will additionally be presented for the plasma concentration data of 
PF-07081532 using the PK Concentration Set (as defined in Section 4): 
− a listing of all concentrations sorted by participant ID and nominal time post-dose for 
each PF-07081532 treatment period separately. 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 each nominal time post-dose (produced separately 
for each treatment period), where the set of statistics will include n, mean, median, 
standard deviation, coefficient of variation (CV), minimum, maximum and the 
number of concentrations above the lower limit of quantification. 
− median concentration time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment period. One plot for each scale will be presented which 
will include both PF-07081532 treatment periods in the same plot. 
− individual concentration time plots by treatment period (on both linear and semi-log 
scales) against actual time post-dose (there will be separate spaghetti plots for each 
treatment period, with a line for each participant per scale).  
− individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time post-dose. One plot for each participant and scale will be 
presented, which will include both PF-07081532  treatment periods in the same plot.  
For summary statistics and median plots by sampling time, the nominal PK sampling time 
will be used. For individual participant plots by time, the actual PK sampling time will be 
used. Median profiles will be presented on both linear-linear and log-linear scales. 
6.3. Other Endpoint(s) 
CCI


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6.4. Subset Analyses 
No subset analyses will be performed. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
Demographics data (age, biological sex, race, ethnicity, body weight, body mass index and 
height) will be summarized across all participants in the safety population (as defined in 
Section 4) as described in Section 5.2.1 or Section 5.2.2 (as appropriate). 
CCI


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6.5.2. Study Conduct and Participant Disposition 
Participant evaluation groups will show end of study participant disposition by treatment and 
overall and will show which participants were analyzed for PK and safety, which may not be 
produced in one table. Frequency counts and percentages will be supplied for participant 
discontinuation(s) by treatment.   
6.5.3. Study Treatment Exposure 
Not applicable. 
6.5.4. Concomitant Medications and Nondrug Treatments 
All prior and concomitant medication(s) as well as non-drug treatment(s) will be provided in 
listings.   
6.6. Safety Summaries and Analyses 
See Section 6.2. 
7. INTERIM ANALYSES 
7.1. Introduction 
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 assessment, facilitating PK/PD modeling, and/or supporting clinical 
development.  
7.2. Interim Analyses and Summaries 
Not applicable. 
8. REFERENCES 
1) Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs – General 
Considerations. Draft Guidance from the FDA. March 2014. 


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APPENDICES 
 
Appendix 1. PK Analyses – Example of SAS Code for mixed effects model 
An example of the PROC MIXED code:  
 
proc mixed data=tab.pk;   
 
class trt subject;   
 
model &var = trt / ddfm=KR;   
 
random subject /subject=subject;   
 
lsmeans trt/ diff cl alpha=0.1;   
run; 
 
 
 


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Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern 
Categories for QTcF  
 
Degree of Prolongation 
Mild (ms)  
Moderate (ms)  
Severe (ms)  
Absolute value of QTcF  
>450 and ≤480  
>480 and ≤500  
>500  
Increase from baseline in 
QTcF  
>30 and ≤60  
>60  
  
  
Categories for PR and QRS  
 
PR (ms)  
max. ≥300  
  
PR (ms) increase 
from baseline  
Baseline >200 and 
max. ≥25% increase  
Baseline ≤200 and 
max. ≥50% increase  
QRS (ms)  
max. ≥140  
  
QRS (ms) increase 
from baseline  
≥50% increase  
  
  
Categories for Vital Signs  
 
Systolic BP (mm Hg)  
min. <90  
 max. >200 
Systolic BP (mm Hg) change from baseline  
max. decrease ≥30  
max. increase ≥30  
Diastolic BP (mm Hg)  
min. <50  
 max. >100 
Diastolic BP (mm Hg) change from baseline  
max. decrease ≥20  
max. increase ≥20  
Supine pulse rate (bpm)  
min. <40  
max. >120  
  
Measurements that fulfill these criteria are to be listed in the report.  
 
 


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Appendix 3. List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUCinf  
Area Under the Concentration-Time Curve from time zero 
extrapolated to infinity 
AUClast  
Area Under the Concentration-Time Curve from time zero to the last 
measurable concentration 
AUC24  
Area Under the Concentration-Time Curve from time zero to time 24 
hours 
BLQ 
Below the Limit of Quantitation 
bpm 
Beats per minute 
CL  
Clearance 
CL/F  
Apparent total body clearance 
Cmax  
Maximum observed concentration 
C-CASA 
Columbia-Classification Algorithm of Suicide Assessment 
 
 
CRU 
Clinical Research Unit 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DE 
Dabigatran etexilate 
dL 
Deciliter 
ECG 
Electrocardiogram 
F/U 
Follow Up 
HbA1c 
Haemoglobin A1c 
 
 
ID 
Identification 
 
 
IRC 
Internal Review Committee 
LFT 
Liver Function Test 
LLOQ 
Lower Limit of Quantitation 
ln 
Natural log 
MD 
Multiple dose 
mg 
milligram 
mmHg 
Millimetres of Mercury 
ms 
Millisecond 
N 
Sample Size 
CCI
CCI
CCI


Protocol C3991047 (PF-07081532) 
Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022 
PFIZER  CONFIDENTIAL  
TMF Doc ID: 98.03 
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Abbreviation 
Term 
N/A 
Not Applicable 
NC 
Not Calculated 
ND 
Not Done 
NS 
No Sample 
 
 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PHQ-9 
Patient Healthy Questionnaire 9 
QD 
Once a Day 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
REML 
Restricted Maximum Likelihood 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Single Dose 
SoA 
Schedule of Activities 
TEAEs 
Treatment Emergent Adverse Events 
Tmax  
Time to maximum observed concentration 
t½  
Half life 
U/L 
Units per Litre 
ULN 
Upper Limit of Normal 
Vz/F  
Apparent volume of distribution 
 
 
 
CCI


Protocol C3991047 (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 30 of 30 
 
Appendix 4.  C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events and 
Codes 
SSRS Mapped to C-CASA (Suicidality Events and Codes) 
Event Code 
C-CASA Event 
C-SSRS Response 
Suicidal Ideation 
1 
Passive 
“Yes” on “Wish to be dead” 
2 
Active: Nonspecific (no method, 
intent, or plan) 
“Yes” on “Non-Specific Active 
Suicidal Thoughts” 
3 
Active: Method, but no intent or plan 
“Yes” on “Active Suicidal Ideation 
with Any Methods (Not Plan) without 
Intent to Act” 
4 
Active: Method and intent, but no 
plan 
“Yes” on “Active Suicidal Ideation 
with Some Intent to Act, without 
Specific Plan” 
5 
Active: Method, intent, and plan* 
“Yes” on “Active Suicidal Ideation 
with Specific Plan and Intent” 
Suicidal Behavior 
1 
Completed suicide 
“Yes” on “Completed Suicide” 
2 
Suicide attempt 
“Yes” on “Actual Attempt” 
3 
Interrupted attempt  
“Yes” on “Interrupted attempt” 
4 
Aborted attempt 
“Yes” on “Aborted attempt” 
5 
Preparatory actions toward imminent 
suicidal behaviors 
“Yes” on “Preparatory Acts or 
Behavior” 
Self-injurious behavior, no suicidal intent 
 
Self-injurious behavior, no suicidal 
intent 
“Yes” on “Has subject engaged in 
Non-suicidal Self-Injurious 
Behavior?” 
*According to C-SSRS, the definition of plan includes intent (i.e., intent to complete the suicide is implicit with 
the concept of plan). Thus, there is no need for the category method and plan, but no intent.