Clinical trial NCT05093205
Conditions: Healthy Adults
Sponsor: Pfizer
Start date: 2021-10-25; Completion date: 2022-07-06
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to characterize the effect of PF-06882961, administered at 2 steady-state dose levels, on the PK of single doses of atorvastatin (20 mg) or midazolam (5 mg), administered separately, in healthy adult male and female participants (Part A), or an OC in healthy PM female participants (Part B).

Detailed description:

Arms: arm 1: To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of atorvastatin (20 mg tablet) and midazolam (5 mg syrup). arm 2: To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of an Oral Contraceptive (Levonorgestrel 0.15 mg and Ethinyl Estradiol 0.03 mg tablet).
Interventions: intervention 1: PF-06882961 intervention 2: Atorvastatin intervention 3: Midazolam intervention 4: Levonorgestrel & Ethinyl Estradiol
Intervention descriptions: intervention 1: Tablets intervention 2: Tablets intervention 3: Syrup intervention 4: Tablet

Protocol documents:
Prot_000.pdf: 
PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, OPEN-LABEL, TWO-PART STUDY TO EVALUATE THE EFFECT OF 
TWO STEADY-STATE DOSE LEVELS OF PF-06882961 ON THE 
PHARMACOKINETICS OF SINGLE ORAL DOSES OF ATORVASTATIN AND
MIDAZOLAM IN HEALTHY ADULTS AND AN ORAL CONTRACEPTIVE IN 
HEALTHY POST-MENOPAUSAL FEMALES
Study Intervention Number:
PF-06882961
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
N/A
ClinicalTrials.gov ID:  
N/A
Protocol Number:
C3421047
Phase:
1
Brief Title: A Phase 1, 2-Part Study to Evaluate the Effect of 2 Steady-State Doses of 
PF-06882961 on Single-Dose Atorvastatin, Midazolam and Oral Contraceptive 
Pharmacokinetics in Healthy 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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Document History
Document
Version Date
Original Protocol
30 August 2021


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Final Protocol, 30 August 2021
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................13
1.3. Schedule of Activities .............................................................................................13
2. INTRODUCTION ...............................................................................................................30
2.1. Study Rationale .......................................................................................................30
2.2. Background .............................................................................................................30
2.2.1. Nonclinical Pharmacology..........................................................................31
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................31
2.2.3. Nonclinical Safety ......................................................................................32
2.2.4. Clinical Overview and Safety.....................................................................33
2.2.4.1. Clinical Pharmacokinetics.........................................................34
2.3. Benefit/Risk Assessment.........................................................................................35
2.3.1. Risk Assessment.........................................................................................36
2.3.2. Benefit Assessment.....................................................................................38
2.3.3. Overall Benefit/Risk Conclusion................................................................39
3. OBJECTIVES AND ENDPOINTS.....................................................................................39
4. STUDY DESIGN.................................................................................................................40
4.1. Overall Design.........................................................................................................40
4.1.1. Part A..........................................................................................................41
4.1.2. Part B ..........................................................................................................41
4.2. Scientific Rationale for Study Design.....................................................................42
4.2.1. Part A..........................................................................................................42
4.2.1.1. Midazolam Administration .......................................................42
4.2.1.2. Atorvastatin Administration......................................................43
4.2.1.3. PF-06882961 Administration....................................................44
4.2.2. Part B ..........................................................................................................45
4.2.2.1. Oral Contraceptive Administration ...........................................45
4.2.2.2. PF-06882961 Administration....................................................45


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4.2.3. Parts A and B Safety Assessments .............................................................46
4.2.4. Diversity of Study Population ....................................................................46
4.2.5. Choice of Contraception/Barrier Requirements .........................................47
4.3. Justification for Dose ..............................................................................................47
4.4. End of Study Definition ..........................................................................................48
5. STUDY POPULATION......................................................................................................49
5.1. Inclusion Criteria.....................................................................................................49
5.2. Exclusion Criteria....................................................................................................50
5.3. Lifestyle Considerations..........................................................................................53
5.3.1. Meals and Dietary Restrictions...................................................................53
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................54
5.3.3. Activity .......................................................................................................54
5.3.4. Contraception..............................................................................................55
5.4. Screen Failures ........................................................................................................55
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................55
6.1. Study Intervention(s) Administered........................................................................56
6.1.1. Administration............................................................................................56
6.2. Preparation, Handling, Storage, and Accountability...............................................57
6.2.1. Preparation and Dispensing........................................................................58
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................59
6.3.1. Allocation to Study Intervention ................................................................59
6.4. Study Intervention Compliance...............................................................................61
6.5. Dose Modification...................................................................................................61
6.6. Continued Access to Study Intervention After the End of the Study......................61
6.7. Treatment of Overdose............................................................................................61
6.8. Concomitant Therapy..............................................................................................62
6.8.1. Rescue Medicine.........................................................................................63
6.8.1.1. Management of Nausea and Vomiting......................................63
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................63
7.1. Discontinuation of Study Intervention ....................................................................63
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7.2. Participant Discontinuation/Withdrawal From the Study.......................................64
7.2.1. Withdrawal of Consent...............................................................................65
7.3. Lost to Follow up ....................................................................................................65
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................65
8.1. Efficacy Assessments..............................................................................................66
8.2. Safety Assessments .................................................................................................66
8.2.1. Physical Examinations................................................................................67
8.2.2. Vital Signs ..................................................................................................68
8.2.2.1. Temperature ..............................................................................68
8.2.3. Electrocardiograms.....................................................................................68
8.2.4. Clinical Safety Laboratory Assessments ....................................................69
8.2.5. COVID-19 Specific Assessments...............................................................70
8.2.6. Management of Hypoglycemia...................................................................70
8.2.6.1. Definition and Severity of Categorization of 
Hypoglycemic Adverse Event (HAE)...............................................70
8.2.7. Glucometer Monitoring of Glucose............................................................71
8.2.8. Pregnancy Testing ......................................................................................72
8.2.9. Suicidal Ideation and Behavior Risk Monitoring.......................................72
8.2.9.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................72
8.2.9.2. Patient Health Questionnaire-9 (PHQ-9) ..................................73
8.2.9.3. Referral to a  MHP ....................................................................73
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................73
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......74
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................75
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................75
8.3.2. Method of Detecting AEs and SAEs ..........................................................75
8.3.3. Follow-Up of AEs and SAEs......................................................................75
8.3.4. Regulatory Reporting Requirements for SAEs...........................................75
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................76
8.3.5.1. Exposure During Pregnancy......................................................76
8.3.5.2. Exposure During Breastfeeding ................................................78


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8.3.5.3. Occupational Exposure .............................................................78
8.3.6. Cardiovascular and Death Events...............................................................78
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................78
8.3.8. Adverse Events of Special Interest.............................................................78
8.3.8.1. Lack of Efficacy........................................................................78
8.3.9. Medical Device Deficiencies......................................................................79
8.3.10. Medication Errors.....................................................................................79
8.4. Pharmacokinetics ....................................................................................................79
8.4.1. PK of Atorvastatin and Ortho-hydroxyatorvastatin....................................80
8.4.2. PK of Midazolam and 1-OH-Midazolam ...................................................81
8.4.3. PK of Levonorgestrel..................................................................................81
8.4.4. PK of Ethinyl Estradiol...............................................................................81
8.4.5. PK of PF-06882961....................................................................................82
8.6.5. Plasma for Analysis of 4-β-hydroxycholesterol/cholesterol (Part A 
only).................................................................................................................83
8.7. Immunogenicity Assessments.................................................................................83
8.8. Health Economics ...................................................................................................83
9. STATISTICAL CONSIDERATIONS ................................................................................83
9.1. Statistical Hypotheses .............................................................................................84
9.2. Analysis Sets ...........................................................................................................84
9.3. Statistical Analyses .................................................................................................84
9.3.1. General Considerations...............................................................................84
9.3.1.1. Derivation of Pharmacokinetic Parameters...............................84
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9.3.2. Statistical Methods for Pharmacokinetic Data ...........................................86
9.3.3. Other Safety Analyses ................................................................................87
9.3.3.1. Electrocardiogram Analyses......................................................88
9.3.4. Other Analyse(s).........................................................................................88
9.4. Interim Analyses .....................................................................................................88
9.5. Sample Size Determination.....................................................................................88
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................91
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............91
10.1.1. Regulatory and Ethical Considerations ....................................................91
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................91
10.1.2. Financial Disclosure .................................................................................92
10.1.3. Informed Consent Process ........................................................................92
10.1.4. Data Protection .........................................................................................93
10.1.5. Committees Structure ...............................................................................93
10.1.5.1. Data Monitoring Committee ...................................................93
10.1.6. Dissemination of Clinical Study Data ......................................................93
10.1.7. Data Quality Assurance ............................................................................95
10.1.8. Source Documents....................................................................................96
10.1.9. Study and Site Start and Closure ..............................................................96
10.1.10. Publication Policy...................................................................................97
10.1.11. Sponsor’s Qualified Medical Personnel .................................................98
10.2. Appendix 2: Clinical Laboratory Tests .................................................................99
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...................................................................101
10.3.1. Definition of AE .....................................................................................101
10.3.2. Definition of an SAE ..............................................................................102
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period..........................................................................104
10.3.4. Reporting of SAEs..................................................................................107
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................108
10.4.1. Male........................................................................................................108


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10.4.2. Female Participant Reproductive Inclusion Criteria...............................108
10.4.3. Woman of Childbearing Potential ..........................................................109
10.4.4. Contraception Methods...........................................................................109
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .....112
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................114
10.8. Appendix 9: Abbreviations .................................................................................116
11. REFERENCES ................................................................................................................120
LIST OF TABLES
Table 1.
Part A - Overall Schedule of Activities Screening to Period 5.................15
Table 2.
Schedule of Activities – Day 1 of Period 1 (Atorvastatin ONLY), 
Period 4 (Atorvastatin + PF-06882961 120 mg BID), and Period 7 
(Atorvastatin + PF-06882961 200 mg BID).............................................20
Table 3.
Schedule of Activities – Day 1 of Period 2 (Midazolam ONLY), 
Period 5 (Midazolam + PF-06882961 120 mg BID) and Period 8 
(Midazolam + PF-06882961 200 mg BID) ..............................................21
Table 4.
Schedule of Activities – Day 31 of Period 3 and Day 19 of Period 6 
(PF-06882961 only)..................................................................................22
Table 5.
Part B - Overall Schedule of Activities through Period 5 ........................23
Table 6.
Schedule of Activities – Day 1 of Period 1 (OC ONLY), Period 3 
(OC + PF-06882961 120 mg BID) and Period 5 (OC + PF 
06882961 200 mg BID)............................................................................28
Table 7.
Schedule of Activities – Day 31 of Period 2 and Day 19 of Period 4 
(PF-06882961 only)..................................................................................29
Table 8.
Part A Dosing ...........................................................................................56
Table 9.
Part B Dosing............................................................................................57
Table 10.
PF-06882961 Dosing Regimens Part A....................................................60
Table 11.
Plasma PK Parameters for Atorvastatin, Ortho-hydroxyatorvastatin, 
Midazolam, 1-OH-Midazolam, Levonorgestrel and Ethinyl 
Estradiol....................................................................................................85
Table 12.
Plasma PK Parameters for PF-06882961 .................................................86
Table 13.
Expected Widths of the 90% CIs (with 80% Coverage Probability) 
for Different Possible Estimated Effects and Parameters of Interest .......90
Table 14.
Protocol-Required Safety Laboratory Assessments .................................99
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: A Phase 1, 2-Part Study to Evaluate the Effect of 2 Steady-State Doses of 
PF-06882961 on Single-Dose Atorvastatin, Midazolam and Oral Contraceptive 
Pharmacokinetics in Healthy Adult Participants.
Rationale
This is a Phase 1, open-label, 2-part study to evaluate the effect of 2 steady-state dose levels 
of PF-06882961 on the SD pharmacokinetics of 1) atorvastatin and midazolam in healthy 
adult male and female participants (Part A), and 2) an OC in healthy PM female participants 
(Part B).  The intent of this study is to generate safety, tolerability, and pharmacokinetic data 
for further clinical development.
Objectives and Endpoints
Objectives
Endpoints
Part A
Primary: 
Primary: 

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of atorvastatin in healthy male 
and female adult participants. 

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of midazolam in healthy male 
and female adult participants. 

Atorvastatin plasma pharmacokinetic 
parameters: AUCinf (if data permit* otherwise 
AUClast) in Periods 1, 4 and 7.

Midazolam plasma pharmacokinetic parameters: 
AUCinf (if data permit* otherwise AUClast) in 
Periods 2, 5 and 8.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
PF-06882961 administered separately and in 
combination with atorvastatin or midazolam in 
healthy male and female adult participants.

Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and 
ECG parameters during Part A of the study.

Assessment of mental health as determined by 
C-SSRS and PHQ-9 during Part A of the study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To evaluate the effects of PF-06882961 on 
additional pharmacokinetic parameters of 
atorvastatin and midazolam in healthy male and 
female adult participants.

Additional plasma pharmacokinetic parameters 
for atorvastatin (Periods 1, 4 and 7) and 
midazolam (Periods 2, 5 and 8): Cmax and Tmax; 
and CL/F, Vz/F, t½, as data permit.

To evaluate the MD pharmacokinetics of 
PF-06882961 in healthy male and female adult 
participants.

PF-06882961 plasma pharmacokinetic 
parameters at Days 35 and 58: AUC24, Cmax, 
Tmax.

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of ortho-hydroxyatorvastatin 
in healthy male and female adult participants. 

Ortho-hydroxyatorvastatin plasma 
pharmacokinetic parameters: AUClast, Cmax, Tmax;
and AUCinf and t½ as data permit in Periods 1, 
4 and 7. Metabolite/parent 
(ortho-hydroxyatorvastatin/atorvastatin) ratios 
will also be calculated. 


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
To evaluate the effects of PF-06882961 on the 
pharmacokinetics of 1-OH-midazolam in 
healthy male and female adult participants.

To evaluate the effects of PF-06882961 on 
biomarkers of CYP3A induction. [Optional].

1-OH-midazolam plasma pharmacokinetic 
parameters: AUClast, Cmax, Tmax; and AUCinf and 
t½ as data permit in Periods 2, 5 and 8.  
Metabolite/parent 
(1-OH-midazolam/midazolam) ratios will also 
be calculated.

Morning predose 
4-β-hydroxycholesterol/cholesterol plasma ratio 
on Day 1 in Periods 2, 5, and 8.  Morning 
predose plasma-derived EVon Day 1 in 
Periods 2, 5, and 8.
Part B
Primary: 
Primary: 

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of an OC (LE/EE) in healthy
PM female participants.

LE plasma pharmacokinetic parameters: AUCinf
(if data permit* otherwise AUClast) in Periods 1, 
3 and 5.

EE plasma pharmacokinetic parameters: AUCinf
(if data permit* otherwise AUClast) in Periods 1, 
3 and 5.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
PF-06882961 administered separately and in 
combination with an OC (LE/EE) in healthy 
PM female participants.

Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and 
ECG parameters during Part B of the study.

Assessment of mental health as determined by 
C-SSRS and PHQ-9 during Part B of the study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To evaluate the effects of PF-06882961 on 
additional pharmacokinetic parameters of an OC
(LE/EE), administered separately, in healthy PM
female participants.

To evaluate the pharmacokinetics of multiple 
doses of PF-06882961 in healthy PM female 
participants.

Additional plasma pharmacokinetic parameters 
for LE and EE (both in Periods 1, 3 and 5): 
Cmax, Tmax; and CL/F, Vz/F, t½ as data permit.

PF-06882961 plasma pharmacokinetic 
parameters at Days 36 and 60: AUC24, Cmax, 
Tmax.
* Should it be deemed that too few AUCinf estimates (eg, less than 12 for a single treatment) are obtained 
from the evaluable participants, AUClast may be selected as the primary endpoint for CSR reporting.  This 
will be considered for the atorvastatin, midazolam, LE, and EE objectives separately.
Overall Design
Brief Summary
This study is a Phase 1, open-label, study that will be conducted in 2 parts. Part A is an 
open-label, 8-period, fixed-sequence design to evaluate the effect of 2 steady-state dose 
levels of PF-06882961 on the SD pharmacokinetics of atorvastatin and midazolam, 
administered separately, in healthy adult male and female participants. Part B is an 
open-label, 5-period, fixed-sequence design to evaluate the effect of 2 steady-state dose 
levels of PF-06882961 on the PK of an OC in healthy PM female participants (Part B).  


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Participants will participate in either Part A or Part B (not both), and Parts A and B are 
expected to be conducted in parallel, if possible. For participants in either Part A or Part B, 
the total duration of participation from the Screening Visit to the FU contact will be 
approximately 18 weeks.
Number of Participants
A sample size of approximately 16 participants in Part A and 16 participants in Part B will be 
enrolled such that approximately 12 evaluable participants complete each Part of the study.  
This number of evaluable participants has been selected to provide sufficient precision to 
detect a 1.25-fold difference in AUCinf for either atorvastatin, midazolam, LE, or EE.
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.
Note: "Enrolled" means a participant's agreement to participate in a clinical study following 
completion of the informed consent process and screening. A participant will be considered 
enrolled if the informed consent is not withdrawn prior to participating in any study activity 
after screening. 
Intervention Groups and Duration
For the purposes of this protocol, study intervention refers to PF-06882961.  
The purpose of this study is to characterize the effect of PF-06882961, administered at 
2 steady-state dose levels, on the PK of single doses of atorvastatin (20 mg) or midazolam 
(5 mg), administered separately, in healthy adult male and female participants (Part A), or an
OC (LE 0.15 mg/ EE 0.03 mg) in healthy PM female participants (Part B).  Titration of 
PF-06882961 doses will be utilized to achieve doses of 120 mg BID and 200 mg BID in 
Part A Table 8 and Part B Table 9. The drug-drug interaction effect will be initially assessed 
at PF-06882961 120 mg BID and again at 200 mg BID, as these doses are being studied in 
Phase 2 for T2DM and Obesity. 
PF-06882961 will be provided as tablets for oral administration.  Study intervention 
(PF-06882961) must be administered BID within approximately 10 minutes of completion of 
the morning and evening meals, approximately 10 hours apart.  Atorvastatin, midazolam or
the OC will be administered within approximately 10 minutes of completion of the morning 
meal.  PF-06882961 will be administered first and atorvastatin, midazolam or the OC will be 
administered within 5 minutes of PF-06882961.
Part A – 64 days will be in-house as follows: Period 1 (SD atorvastatin): 4 days; Period 2 
(SD midazolam): 1 day; Period 3 (BID PF-06882961 titrated to 120 mg BID): 31 days;
Period 4 (120 mg BID PF-06882961+ SD atorvastatin): 3 days; Period 5 (120 mg BID 
PF-06882961 + SD midazolam): 1 day; Period 6 (BID PF-06882961 titrated to 200 mg BID): 
19 days; Period 7 (200 mg BID PF-06882961+ SD atorvastatin): 3 days; Period 8 (200 mg 
BID PF-06882961 + SD midazolam): 2 days.


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Part B – 67 days will be in-house as follows: Period 1 (SD OC): 6 days; Period 2 (BID 
PF-06882961 titrated to 120 mg BID): 31 days; Period 3 (120 mg BID PF-06882961 + SD 
OC) 5 days; Period 4 (BID PF-06882961 titrated to 200 mg BID) 19 days; Period 5 (200 mg 
BID PF-06882961+ SD OC): 6 days.
The FU visit will occur 7-10 days from the last dose of study intervention and a FU contact
will occur 28-35 days from the last dose of study intervention.
Data Monitoring Committee or Other Independent Oversight Committee: 
This study will not use a DMC.
Statistical Methods
The PK data for PF-06882961, atorvastatin, midazolam, LE, and EE will be analyzed and 
reported separately.
Natural loge-transformed AUCinf (as data permit) of atorvastatin administered alone or 
co-administered with PF-06882961 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 ‘atorvastatin and PF-06882961 120 mg BID’ (Period 
4) and ‘atorvastatin and PF-06882961 200 mg BID’ (Period 7), which will be reported 
separately in comparison to the reference treatment of ‘atorvastatin alone’ (Period 1).  The 
same analysis for natural loge-transformed Cmax and AUClast of atorvastatin will also be 
conducted.
Natural loge-transformed AUCinf (as data permit), Cmax and AUClast of midazolam 
administered alone or co-administered with PF-06882961 will be analyzed and reported 
separately using the same mixed effect model as described above for atorvastatin.  The 2 test 
treatments will be ‘midazolam and PF-06882961 120 mg BID’ (Period 5) and ‘midazolam 
and PF-06882961 200 mg BID’ (Period 8), which will be reported separately in comparison 
to the reference treatment of ‘midazolam alone’ (Period 2).
Natural loge-transformed AUCinf (as data permit), Cmax and AUClast of LE and EE
administered alone or co-administered with PF-06882961 will be analyzed and reported 
separately using the same mixed effect model as described above for atorvastatin.  For LE, 
the 2 test treatments will be ‘levonorgestrel and PF-06882961 120 mg BID’ (Period 3) and 
‘LE and PF-06882961 200 mg BID’ (Period 5), which will be reported separately in 
comparison to the reference treatment of ‘LE alone’ (Period 1). Similarly for EE, the 2 test 
treatments will be ‘ EE and PF-06882961 120 mg BID’ (Period 3) and ‘ EE and 
PF-06882961 200 mg BID’ (Period 5), which will be reported separately in comparison to 
the reference treatment of ‘ EE alone’ (Period 1).


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1.2. Schema
PART A - Atorvastatin and Midazolam
PART B – Oral Contraceptive
1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures.  Refer to the 
STUDY ASSESSMENTS AND PROCEDURES section of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA 
table, in order to conduct evaluations or assessments required to protect the well-being of the 
participant.


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The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA 
table, in order to conduct evaluations or assessments required to protect the well-being of the 
participant.


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Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 15
Part A: Schedule of Activities
Table 1.
Part A - Overall Schedule of Activities Screening to Period 5
Visit Identifier
Abbreviations used in this table may 
be found in Appendix 9
Screening
Period 1
(Atorvastatin
only)
Period 2
(Midazolam 
only)
Period 3 
(PF-06882961 only)
Period 4
(PF-06882961 + 
Atorvastatin)
Period 5
(PF-06882961 + 
Midazolam)
Day in Study Perioda
-28 to -2
-1
1
2
3
1
1
2-7
8
9-14
15
16-22
23
24-30
31
1
2
3
1
Days in Studyb
-28 to -2
-1
1
2
3
4
5
6-11
12
13-18
19
20-26
27
28-34
35
36
37
38
39
Informed consent & demography
x
Outpatient visit (after ≥10-h fast)
x
COVID-19 pre-screeningc
x
x
Temperature checkc
x
x
















SARS-CoV-2 testingc
x
x
xd
Inpatient stay at CRU
x
















Eligibility Criteria
x
x
Medical history 
x
C-SSRS and PHQ-9
x
x
x
x
x
x
x
Review drug, alcohol/tobacco use
x
x
Review contraception use (WOCBP 
Only) (Section 5.3.4)
x
x
Review prior or concomitant 
treatments 
x
x














AE monitoring
x
x














Standardized meals/snackse
x














Physical examf (height at Screen only)
x
Body weight 
x
Table 2
Table 3
x
x
x
x
Table 4
Table 2
Table 3
Supine 12-lead ECG
x
x
x
x
x
Single, supine vital signs assessmentg
x
x
x
x
x
PF-06882961 administrationh
x
x
x
x
x
x
x
x
x
x
Atorvastatin administration
Midazolam administration
Blood Sampling for:i
-Chemistry
x
x
x
- Hematology
x
x
- PT/INR/aPTT
x
x
- FSH,j HIV, HepBsAg, HCVAb, 
HCV RNA, C-peptide
x
- HbA1c, TSH, lipids
x
x
x


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 16
Visit Identifier
Abbreviations used in this table may 
be found in Appendix 9
Screening
Period 1
(Atorvastatin
only)
Period 2
(Midazolam 
only)
Period 3 
(PF-06882961 only)
Period 4
(PF-06882961 + 
Atorvastatin)
Period 5
(PF-06882961 + 
Midazolam)
Day in Study Perioda
-28 to -2
-1
1
2
3
1
1
2-7
8
9-14
15
16-22
23
24-30
31
1
2
3
1
Days in Studyb
-28 to -2
-1
1
2
3
4
5
6-11
12
13-18
19
20-26
27
28-34
35
36
37
38
39
- Free T4, calcitonin, amylase, 
  lipase, total bile acids
x
x
x
- Serum pregnancy testj
x
x
- Atorvastatin & 
ortho-hydroxyatorvastatin PK
xk
xk
xk
xk
- Midazolam & 1-OH-midazolam PK
xl
- PF-06882961 PK
- 4-β-hydroxycholesterol/cholesterol, 
EV
Urine Sampling for:
- Urine drug testn
x
x
- Urinalysis (and microscopy, as
appropriate)
x
x
a.
Day relative to start of dosing Day 1 of that Period.
b.
Day relative to first dose of investigational product (atorvastatin) on Day 1 of Period 1.
c.
Participants will be tested for SARS-COVID-19 infection by PCR.  Test must be negative prior to admission (Period 1, Day 1). A subsequent test will be 
done if they develop COVID-19 like symptoms.  Prior to SARS-CoV-2 test, temperature check and COVID-19 pre-screening (check exposure to positive 
subject, residence or travel in area of high incidence and COVID-19 related signs and symptoms) will be done. See also Section 8.2.5 (COVID-19 Specific 
Assessments).
d.
Participants will be tested for SARS-COVID-19 infection by PCR after 4 days; ie, completion of 4 x 24 hours in house, or if they develop COVID-19 like 
symptoms).  See also Section 8.2.5 (COVID-19 Specific Assessments).
e.
Meals to be provided at approximately 0H, 4H, and 10H post AM dose; plus, snacks provided according to Section 5.3.1.
f.
Complete physical exam at Screening; otherwise, brief exam if findings during previous exam or new/open AEs, if appropriate, at investigator discretion.
g.
Includes BP and PR predose.
h.
Dosing to occur BID with breakfast and dinner Section 5.3.1.
i.
Collection following fasting duration specified in Section 5.3.1.
j.
Testing in females only: Serum β-hCG for all WOCBP; FSH for ALL female participants to confirm PM status only.  Test result should confirm no 
pregnancy prior to dosing.
CCI


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 17
k.
Following atorvastatin dosing on Day 1 in both Periods 1 and 4, atorvastatin and ortho-hydroxyatorvastatin PK (same collection) should be obtained at 24H, 
36H, 48H and 72H post-dose.
l.
Following midazolam dosing on Day 1 in both Periods 2 and 5, midazolam and 1-OH-midazolam PK should be obtained at approximately 24H post-dose 
(note - parent and metabolite require separate collections).
n.
Participants may undergo random urine drug testing at the discretion of the investigator.
CCI


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 18
Table 1.
Part A - Overall Schedule of Activities Period 6 to ET
Visit Identifier
Abbreviations used in this table may be found in 
Appendix 9
Period 6
(PF-06882961 only)
Period 7
(PF-06882961 + 
Atorvastatin)
Period 8
(PF-06882961 +
Midazolam)
FU
FU Contact 
Telephone
ET
Day in Study Perioda
1
2-8
9
10-18
19
1
2
3
1
2
-
-
-
Days in Studyb
40
41-47
48
49-57
58
59
60
61
62
63
69-72
90-97
-
Informed consent & demography
Outpatient visit (after ≥10-h fast)
x
COVID-19 pre-screening
Temperature check









x
x
x
SARS-CoV-2 testing
x
x
Inpatient stay at Clinical Research Unit









xc
Eligibility Criteria
Medical history 
C-SSRS and PHQ-9
x
x
x
x
x
x
Review drug, alcohol/tobacco use
x
Review contraception use (Section 5.3.4)
x
x
x
Review prior or concomitant treatments 




Table 4
Table 2


Table 3
x
x
x
x
AE monitoring






x
x
x
x
Standardized meals/snacksd






Physical exam (height at Screen only) 
xe
xe
xe
Body weight 
x
x
x
x
x
Supine 12-lead ECG
x
x
x
x
x
Single, supine vital signs assessmentf
x
x
x
x
x
PF-06882961 administrationg
x
x
x
x
x
x
Atorvastatin administration
Midazolam administration
Blood Sampling for:h
- Chemistry
x
x
x
x
- Hematology
x
x
x
- PT/INR/aPTT
x
x
x
- FSHi, HIV, HepBsAg, HCVAb, C-peptide
- HbA1c, TSH, lipids
x
x
x
- Free T4, calcitonin, amylase, lipase, total bile acids
x
x
x
- Serum pregnancy testi
x
x
x
- Atorvastatin & ortho-hydroxyatorvastatin PK
xj
xj
x


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 19
Table 1.
Part A - Overall Schedule of Activities Period 6 to ET
Visit Identifier
Abbreviations used in this table may be found in 
Appendix 9
Period 6
(PF-06882961 only)
Period 7
(PF-06882961 + 
Atorvastatin)
Period 8
(PF-06882961 +
Midazolam)
FU
FU Contact 
Telephone
ET
Day in Study Perioda
1
2-8
9
10-18
19
1
2
3
1
2
-
-
-
Days in Studyb
40
41-47
48
49-57
58
59
60
61
62
63
69-72
90-97
-
- Midazolam & 1-OH-midazolam PK
x
xk
x
- PF-06882961 PK
x
- 4-β-hydroxycholesterol/cholesterol, EV
Urine Sampling for:
- Urine drug testl
- Urinalysis (and microscopy, as appropriate)
x
x
x
a.
Day relative to start of dosing Day 1 of that Period.
b.
Day relative to first dose of investigational product (atorvastatin) on Day 1 of Period 1.
c.
Discharge from CRU. 
d.
Meals to be provided at approximately 0H, 4H, and 10H post AM dose; Note that there is no PF-06882961 administration on Day 63. 
e.
Complete physical exam at Period 8 Day 2,FU, and ET; otherwise, brief exam if findings during previous exam or new/open AEs, if appropriate, at 
investigator discretion.
f.
Includes BP and PR predose.
g.
Dosing to occur BID with breakfast and dinner.  Note that there is no PF-06882961 administration on Day 63. 
h.
Collection following fasting duration specified in Section 5.3.1.
i.
Testing in females only: Serum β-hCG for all WOCBP; FSH for female participants to confirm PM status only.  
j.
In Period 7, atorvastatin & ortho-hydroxyatorvastatin PK should be obtained at 24H, 36H, 48H, 72H post atorvastatin dose on Day 1 of the same period. 
k.
In Period 8, midazolam & 1-OH-midazolam PK should be obtained at approximately 24H post midazolam dose on Day 1 of the same period.
l.
Participants may undergo random urine drug testing at the discretion of the investigator.
CCI
CCI


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 20
Table 2.
Schedule of Activities – Day 1 of Period 1 (Atorvastatin ONLY), Period 4 (Atorvastatin + PF-06882961 
120 mg BID), and Period 7 (Atorvastatin + PF-06882961 200 mg BID)
Hours Relative to Dosing at 0H
0
0.5
1
1.5
2
4
6
9
10
12
Body Weight
x
Supine 12-lead ECG 
x
Supine vital sign assessmenta
x
Atorvastatin administration
x
PF-06882961 administration (Periods 4 and 7 only)
xb
xc
Blood sampling for:d
- Chemistry (Periods 1 and 4 only)
x
- Hematology (Periods 1 and 4 only)
x
- Atorvastatin & ortho-hydroxyatorvastatin PK
x
x
x
x
x
x
x
x
x
- PF-06882961 PK (Periods 4 and 7 only)f
x
Urine sampling for:
- Urinalysis and microscopy, as appropriate (Period 1 only)
x
a.
Includes BP and PR. 
b.
Dosing expected to occur with breakfast.
c.
Dosing expected to occur with dinner.
d.
Collection following fasting duration according to dosing frequency as specified in Meals and Dietary Restrictions. 
f.
For Periods 4 and 7 only, PF-06882961 PK sample to be drawn at 0H, approximately 24H after PF-06882961 morning dose on previous day.
CCI
CCI
CCI


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 21
Table 3.
Schedule of Activities – Day 1 of Period 2 (Midazolam ONLY), Period 5 (Midazolam + PF-06882961
120 mg BID) and Period 8 (Midazolam + PF-06882961 200 mg BID)
Hours Relative to Dosing at 0H
0
0.5
1
2
3
4
6
8
10
12
16
Supine 12-lead ECG 
x
Supine vital sign assessmenta
x
Midazolam administration
x
PF-06882961 administration (Periods 5 and 8 only)
xb
xc
Blood sampling for:d
- Atorvastatin & ortho-hydroxyatorvastatin PK
x
- Midazolam & 1-OH-midazolam PK
x
x
x
x
x
x
x
x
x
x
x
- PF-06882961 PK (Periods 5 and 8 only)
x
- 4-β-hydroxycholesterol/cholesterol, EV
x
a.
Includes BP and PR. 
b.
Dosing expected to occur with breakfast.
c.
Dosing expected to occur with dinner.
d.
Collection following fasting duration according to dosing frequency as specified in Meals and Dietary Restrictions.


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 22
Table 4.
Schedule of Activities – Day 31 of Period 3 and Day 19 of Period 6 (PF-06882961 only)
Hours Relative to Dosing at 0H
0
1
2
4
6
8
10
12
14
Supine 12-lead ECG 
x
Supine vital sign assessmenta
x
PF-06882961 administration 
xb
xc
Blood sampling for:d
- PF-06882961 PK 
x
x
x
x
x
x
x
x
x
Urine sampling for:
- Urinalysis and microscopy, as appropriate 
x
a.
Includes BP and PR. 
b.
Dosing expected to occur with breakfast.
c.
Dosing expected to occur with dinner.
d.
Collection following fasting duration according to dosing frequency as specified in Meals and Dietary Restrictions.


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 23
Part B: Schedule of Activities
Table 5.
Part B - Overall Schedule of Activities through Period 5
Visit Identifier
Abbreviations used in this table 
may be found in Appendix 9
Screening
Period 1
(OC only)
Period 2
(PF-06882961 only)
Period 3
(PF-06882961 
+ OC)
Period 4
(PF-06882961 only)
Period 5
(PF-06882961 + 
OC)
Day in Study Perioda
-28 to -2 -1
1
2-4
5
1
2-7
8
9-14
15
16-21
22
23-30 31
1
2-4
5
1
2-8
9
10-
18
19
1
2-5
6
Days in Studyb
-28 to -2 -1
1
2-4
5
6
7-12
13
14-19
20
21-26
27
28-35 36
37
38-
40
41
42 43-49 50 51-
59
60
61
62-
65
66
Informed consent & demography
x
Outpatient visit (after ≥10-h fast)
x
COVID-19 pre-screeningc
x
x
Temperature Checkc
x
x





















x
SARS-CoV-2 testingc
x
x
xd
x
Inpatient stay at CRU
x





















x
Eligibility Criteria
x
x
Medical history 
x
C-SSRS and PHQ-9
x
x
x
x
x
x
x
x
x
x
x
Review drug, alcohol/tobacco use
x
x
Review prior or concomitant 
treatments 
x
x





















x
AE monitoring
x
x





















x
Standardized meals/snackse
x





















x
Physical examf (height at Screen 
only)
x
x
Body weight 
x
Table 6
x
x
x
x
Table 7
Table 6
x
x
Table 7
Table 6
x
Supine 12-lead ECG
x
x
x
x
x
x
x
x
Single, supine vital signs 
assessmentg
x
x
x
x
x
x
x
x
PF-06882961 administrationh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
OC administration


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 24
Table 5.
Part B - Overall Schedule of Activities through Period 5
Visit Identifier
Abbreviations used in this table 
may be found in Appendix 9
Screening
Period 1
(OC only)
Period 2
(PF-06882961 only)
Period 3
(PF-06882961 
+ OC)
Period 4
(PF-06882961 only)
Period 5
(PF-06882961 + 
OC)
Day in Study Perioda
-28 to -2 -1
1
2-4
5
1
2-7
8
9-14
15
16-21
22
23-30 31
1
2-4
5
1
2-8
9
10-
18
19
1
2-5
6
Days in Studyb
-28 to -2 -1
1
2-4
5
6
7-12
13
14-19
20
21-26
27
28-35 36
37
38-
40
41
42 43-49 50 51-
59
60
61
62-
65
66
Blood Sampling for:i
-Chemistry
x
x
x
x
x
- Hematology
x
x
x
- PT/INR/aPTT
x
x
x
- HIV, HepBsAg, HCVAb, HCV 
RNA, C-peptide
x
- HbA1c, TSH, lipids
x
x
x
- Free T4, calcitonin, amylase, 
lipase, total bile acids
x
x
x
- Serum FSHj
x
- LE PK & 
EE PK
xk
xk
xk
xk
xk
xk
xk
xk
xk
- PF-06882961 PK
Urine Sampling for:
- Urine drug testm
x
x
- Urinalysis (and microscopy, as 
appropriate)
x
x
x
a.
Day relative to start of dosing Day 1 of that Period.
b.
Day relative to first dose of investigational product (OC) on Day 1 of Period 1.
CCI
CCI


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 25
c.
Participants will be tested for SARS-COVID-19 infection by PCR.  Test must be negative prior to admission (Period 1, Day 1). A subsequent test will be 
done if they develop COVID-19 like symptoms.  Prior to SARS-CoV-2 test, temperature check and COVID-19 pre-screening (check exposure to positive 
subject, residence or travel in area of high incidence and COVID-19 related signs and symptoms) will be done. See also Section 8.2.5 (COVID-19 Specific 
Assessments).
d.
Participants will be tested for SARS-COVID-19 infection by PCR on Period 1, Day 4 (ie, completion of 4 days in house) and on Period 5, Day 5 (ie, day 
prior to discharge), or if they develop COVID-19 like symptoms.  See also Section 8.2.5 (COVID-19 Specific Assessments).
e.
Meals to be provided at approximately 0H, 4H, and 10H post AM dose.
f.
Complete physical exam at Screening, and Period 5 otherwise, brief exam if findings during previous exam or new/open AEs, if appropriate, at investigator 
discretion.
g.
Includes BP and PR predose.
h.
Dosing to occur BID with breakfast and dinner Section 5.3.1. 
i.
Collection following fasting duration specified in Section 5.3.1.
j.
FSH for female participants to PM status only.  
k.
Following OC dosing on Day 1 in Periods 1, 3 and 5, LE and EE PK should be obtained at approximately 24H, 48H, 72H, 96H and 120H post-dose.
m. Participants may undergo random urine drug testing at the discretion of the investigator.
CCI


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 26
Table 5.
Cont. Part B - Overall Schedule of Activities FU to ET
Visit Identifier
FU
FU Contact Telephone
ET
Day in Study Perioda
-
-
-
Days in Studyb
72-75
94-101
-
Informed consent & demography
Outpatient visit (after ≥10-h fast)
x
COVID-19 pre-screening
Temperature check
x
SARS-CoV-2 testing
x
Inpatient stay at Clinical Research Unit
Eligibility Criteria
Medical history 
C-SSRS and PHQ-9
x
x
Review drug, alcohol/tobacco use
x
Review prior or concomitant treatments 
x
x
x
AE monitoring
x
x
x
Standardized meals/snacksc
Physical exam (height at Screen only) 
xd
xd
Body weight 
x
x
Supine 12-lead ECG
x
x
Single, supine vital signs assessmente
x
x
PF-06882961 administration
OC administration
Blood Sampling for:f
- Chemistry
x
x
- Hematology
x
x
- PT/INR/aPTT
x
x
- FSH, HIV, HepBsAg, HCVAb, C-peptide
- HbA1c, TSH, lipids
x
x
- Free T4, calcitonin, amylase, lipase, total bile acids
x
x
- LE PK and EE PK
x
- PF-06882961 PK
x
Urine Sampling for:
- Urine drug testg
- Urinalysis (and microscopy, as appropriate)
x
x
CCI
CCI
CCI


PF-06882961 
Protocol C3421047
Final Protocol, 30 August 2021
PFIZER CONFIDENTIAL
Page 27
Table 5.
Cont. Part B - Overall Schedule of Activities FU to ET
Visit Identifier
FU
FU Contact Telephone
ET
Day in Study Perioda
-
-
-
Days in Studyb
72-75
94-101
-
a.
Day relative to start of dosing Day 1 of that Period.
b.
Day relative to first dose of investigational product (OC) on Day 1 of Period 1.
c.
Meals to be provided at approximately 0H, 4H, and 10H post AM dose; Note that there is no PF-06882961 administration on Day 62. 
d.
Brief exam if findings during previous exam or new/open AEs, if appropriate, at investigator discretion.
e.
Includes BP and PR predose.
f.
Collection following fasting duration specified in Section 5.3.1.
g.
Participants may undergo random urine drug testing at the discretion of the investigator.


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Table 6.
Schedule of Activities – Day 1 of Period 1 (OC ONLY), Period 3 (OC + PF-06882961 120 mg BID) and 
Period 5 (OC + PF 06882961 200 mg BID)
Hours Relative to Dosing at 0H
0
0.5
1
1.5
2
4
8
10
12
Body weight
x
Supine 12-lead ECG 
x
Supine vital sign assessmenta
x
OC administration
x
PF-06882961 administration (Periods 3 and 5 only)
xb
xc
Blood sampling for:d
- Chemistry (Period 1 only)
x
- LE PK and EE PK
x
x
x
x
x
x
x
x
- PF-06882961 PK (Periods 3 and 5 only)
x
a.
Includes BP and PR. 
b.
Dosing expected to occur with breakfast.
c.
Dosing expected to occur with dinner.
d.
Collection following fasting duration according to dosing frequency as specified in Meals and Dietary Restrictions.
e.
If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a 
participant visit.
CCI
CCI
CCI
CCI


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Table 7.
Schedule of Activities – Day 31 of Period 2 and Day 19 of Period 4 (PF-06882961 only)
Hours Relative to Dosing at 0H
0
1
2
4
6
8
10
12
14
Supine 12-lead ECG 
x
Supine vital sign assessmenta
x
PF-06882961 administration 
xb
xc
Blood sampling for:d
- Chemistry (Period 2 only)
x
- Hematology (Period 2 only)
x
- PT/INR/aPTT (Period 2 only)
x
- HbA1c, TSH, lipids (Period 2 only)
x
- Free T4, calcitonin, amylase, 
 lipase, total bile acids (Period 2 only)
x
- PF-06882961 PK 
x
x
x
x
x
x
x
x
x
Urine sampling for:
- Urinalysis and microscopy, as 
appropriate 
x
a.
Includes BP and PR. 
b.
Dosing expected to occur with breakfast.
c.
Dosing expected to occur with dinner.
d.
Collection following fasting duration according to dosing frequency as specified in Meals and Dietary Restrictions.


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2. INTRODUCTION
PF-06882961 is an oral GLP-1R agonist that is currently being developed for the treatment of
type 2 diabetes mellitus (T2DM) and obesity. 
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-06882961 has been demonstrated, in nonclinical models, to stimulate glucose-dependent 
insulin release and suppress food intake with equivalent efficacy to an injectable peptide 
GLP-1R agonist.  
2.1. Study Rationale
The purpose of this Phase 1, open-label, fixed-sequence study is to evaluate the effect of 
2 dose levels of PF-06882961 administered to steady state on the SD pharmacokinetics of 
1) atorvastatin and midazolam in healthy adult male and female participants (Part A), and 
2) an OC in healthy PM female participants (Part B). The intent of this study is to generate 
safety, tolerability, and pharmacokinetic 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.


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Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and cardiovascular safety, with more than one marketed agent demonstrating 
cardiovascular benefit.12  Based on the clinical history of 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, while decreasing 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
In vitro primary PD studies demonstrated that, in cells expressing recombinant human and 
cynomolgus monkey GLP-1R, PF-06882961 dose dependently promotes cAMP production.  
In vivo, PF-06882961 potentiated glucose stimulated insulin secretion during an IVGTT in 
cynomolgus monkeys in a dose- and concentration-dependent manner.  PF-06882961 was 
also shown to reduce food intake in cynomolgus monkeys.  In all in vivo studies, efficacious 
plasma levels of PF-06882961 were consistent with the in vitro potency.  
Refer to the IB for more details on the nonclinical pharmacology of PF-06882961.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
The oral PK of PF-06882961 in rats and monkeys indicated rapid absorption with 
bioavailability ranging from 5% to 12%.  In repeat oral dose toxicity studies in rats and 
monkeys, systemic exposure of PF-06882961 increased with increasing dose, with no 
accumulation. 
Metabolism studies demonstrated low turnover of PF-06882961 with some oxidative and 
glucuronide metabolites.  All metabolites detected in human hepatocytes were also observed 
in hepatocytes from nonclinical species.  PF-06882961 is expected to be cleared via hepatic 
uptake by OATP, followed by metabolic clearance principally mediated by CYP (3A4/5, 
followed by CYP2C8, and CYP2C19).  Non CYP enzymes also contributed to the 
metabolism of PF-06882961.
Based on in vitro data, PF-06882961 has the potential to inhibit intestinal BCRP with an
IC50 = 0.8 µM.  
Based on in vitro data, PF-06882961 did demonstrate time-dependent inhibitory activity of 
CYP3A4/5-mediated midazolam 1’-hydroxylase and testosterone 6-hydroxylase activities. 
The rate of inactivation was not saturated within the concentration ranges tested (5 to 
150 µM), and therefore, the KI and kinact could not be calculated.


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In vitro data also suggest a risk of PF-06882961 interaction with drugs for which CYP2C8 
and UGT1A1 mediated metabolism constitutes the primary mechanism of clearance.  At the 
dose of 200 mg BID, there is also a possibility of weak inhibition of hepatic OATP1B3, 
OATP2B1, OCT1 and uptake transporter MDR1.  Static modeling of in vitro data also 
indicate that PF-06882961 has a low potential to cause DDIs as a result of induction of 
CYP3A4, or inhibition of other CYP enzymes (1A2, 2B6, 2C9, 2C19 or 2D6), other UGT 
enzymes (1A4, 1A6, 1A9, 2B7, 2B15), and uptake transporters OATP1B1, OCT2, MATE1, 
MATE 2K, OAT1 and OAT3.  See Section 6.8 for use of permitted and prohibited
medications.  
Refer to the IB for more details on the nonclinical PK and metabolism of PF-06882961.
2.2.3. Nonclinical Safety
General toxicology studies have been completed in cynomolgus monkeys up to 6 months in 
duration (with a 3-week lead-in and 1-month recovery) and in rats up to 6 months in duration 
with a 1-month recovery.  The exposure limits for plasma concentrations of PF-06882961 for 
clinical studies are based on the exposure at the NOAEL dose of 250 mg/kg/day in the 
6-month with 1-month recovery toxicology study in rats, due to the fact that findings in 
monkeys such as decreased food intake and body weight loss are reversible and monitorable 
in a clinical setting. In the 6-month toxicity study in rats with 1-month recovery the NOAEL 
was 250 mg/kg/day based on species specific toxicity at a higher dose.  The exposure
margins at 250 mg/kg/day were 41-fold (Cmax, free) and 23-fold (AUC24, free), to the 
predicted human exposures at the highest planned dose of PF-06882961 in this study, which 
is 200 mg BID.
A NOAEL was not established in the cynomolgus monkey 6 month toxicity study with 
3-week lead-in and 1-month recovery, due to early euthanasia of 3 animals administered 
≥50 mg/kg/day who had clinical signs associated with adverse microscopic findings in the 
kidney and heart, which were unique to this study and had not been observed in animals 
exposed for longer duration in previous studies with similar doses.  Based on the available 
data, none of the microscopic findings observed in these moribund animals appear to be 
consistent with primary toxicological effects.  Rather, they are more consistent with 
secondary events related to prolonged inanition and the resulting negative energy state.  
Exposure margins at 50 mg/kg/day were 0.71- and 5.1-fold for Cmax (free) in males and 
females, respectively, and were 0.41- and 2.2 -fold for AUC24 (free) in males and females, 
respectively, to the predicted human exposures at the highest planned dose of PF-06882961 
in this study (200 mg BID).
Other toxicology studies completed in cynomolgus monkeys include a 14-week study with a 
4-week lead-in (18 weeks total exposure) and a 13-week investigative toxicology study with 
3-week lead-in (16 weeks total exposure), in which the NOAELs were 100 mg/kg/day and 
150 mg/kg/day (highest dose administered), respectively.  At the NOAEL dose of 
100 mg/kg/day in the 14-week study with 4-week lead-in, exposure margins were 1.6-fold 
and 1.2-fold for Cmax (free) and AUC24 (free), respectively, based on the lack of adverse 
findings in animals that survived to the scheduled necropsy.  At the NOAEL dose of 


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150 mg/kg/day in the 13-week study with 3-week lead-in, exposure margins were 9.5- and 
6.9-fold for Cmax (free) in males and females, respectively, and were 8.8- and 7.9-fold for 
AUC24 (free) in males and females, respectively, based on the absence of adverse effects in 
the study.  These exposure margins are versus the predicted human exposures at the highest 
planned dose of PF-06882961 in this study (200 mg BID).
Embryo fetal developmental studies were completed in rats and rabbits.  Based on the lack of 
maternal toxicity or adverse effects on embryo-fetal development, the NOAEL for maternal 
and developmental toxicity in rats was 500 mg/kg/day (highest dose evaluated).  The 
exposures at 500 mg/kg/day provide margins of approximately 81-fold (Cmax, free) and 
105-fold (AUC24, free), to the predicted human exposures at the highest dose of 
PF-06882961 in this study (200 mg BID).
In embryo fetal studies conducted in rabbits, the NOAEL for maternal and developmental 
toxicity was 250 mg/kg/day, with margins of approximately 18-fold (Cmax, free) and 5.5-fold 
(AUC24, free), to the predicted human exposures at the highest dose of PF-06882961 in this 
study (200 mg BID).
PF-06882961 was negative in genetic toxicity testing and photosafety endpoints.  A risk 
assessment of the target organ toxicities noted in the repeat dose toxicity studies is provided 
in the IB.  
Refer to the IB for more details on the nonclinical safety of PF-06882961.
2.2.4. Clinical Overview and Safety
Three clinical studies have been completed with PF-06882961 in which 135 participants 
were dosed, and 110 participants were exposed to single or multiple doses of PF-06882961 
(Table 6-1 in the PF-06882961 IB). In addition, ongoing studies include a 16-week, Phase 2 
dose-ranging study in T2DM (C3421005), a MD PK/PD study in Japanese participants with 
T2DM (C3421015), a SD ADME and oral bioavailability study (C3421009), and a SD
formulation comparison study in healthy participants (C3421010). 
Two studies, C3421001 and C3421003, were completed in healthy participants (total of 
37 healthy participants randomized.  One study, C3421002, was completed in participants 
with T2DM (total of 98 T2DM participants randomized). In these studies, PF-06882961 was 
found to be generally safe and well tolerated. In C3421001, 25 healthy participants were 
randomized to single, ascending, oral doses of PF-06882961 or placebo.  In C3421003, 
12 healthy participants were randomized to receive single doses of different oral formulations 
of PF-06882961.  In C3421002, 98 participants with T2DM were randomized to multiple,
ascending, oral doses of PF-06882961 or placebo for 28 days. In this study PF-06882961 
doses ranging from 10 mg BID to 120 mg BID were studied.  A total of 98 participants with 
T2DM on a background anti-diabetic regimen of metformin were randomized to receive 
PF-06882961 or matching placebo in a 3:1 randomization ratio, and 92 participants 
completed the study.  Six participants discontinued from the study, of which 
2 discontinuations were due to treatment-related TEAEs, and 4 withdrew during the 


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treatment or follow-up period for non-treatment related reasons. A total of 319 TEAEs were 
reported, of which the majority of the AEs [294 (92%)] were mild in severity, 23 (7%) were 
moderate, and 2 (1%) were severe in intensity.  The most frequently reported TEAEs were
nausea (49.0%), dyspepsia (32.7%), vomiting (26.5%), diarrhea (24.5%), headache (23.5%),
and constipation (20.4%). One participant experienced a mild TEAE of hypoglycemia.  This 
AE was non-fasting, mild in severity and of limited duration.  There were no deaths and no 
treatment-related SAEs with repeat dosing of PF-06882961 in patients with T2DM. Overall, 
the doses of PF-06882961 studied in C3421002 were safe and well-tolerated.
Preliminary clinical and safety data are available from the C3421007 Phase 1 study, which 
assessed the effect of PF-06882961 on the PK of rosuvastatin and midazolam.  In this study, 
PF-06882961 doses up to 200 mg BID were administered with 4-day titration steps in 
16 otherwise healthy, adult participants with obesity.  Of these participants, 14 completed the 
17-week study duration, and 2 participants discontinued for reasons not related to AEs.  A 
total of 129 TEAEs have been reported to date, of which the majority of the AEs (127/129) 
were mild in severity and 2 were moderate.  There was 1 mild TEAE of increased 
transaminitis (also reported as an SAE), which occurred at the end of the dosing duration, 
after co-administration of PF-06882961 200 mg BID with single doses of rosuvastatin 10 mg 
and midazolam 2 mg, administered separately in successive periods.  The transaminase levels 
returned to baseline levels in the FU period.  No significant elevations were noted in total 
bilirubin, alkaline phosphatase or GGT.  The most frequently reported all causality TEAEs in 
the study participants have been nausea (26), constipation (12), decreased GFR (12), 
headache (10), and vomiting (9).  While there were isolated values for laboratory tests, vital 
signs and ECG intervals outside of the reference ranges, no clear adverse trends were 
apparent in these parameters.  In this study, body weight loss was noted with a mean percent 
change from baseline of 10.1% by the end of the dosing period.  Mild declines from baseline 
were noted in GFR, with most values remaining above 70 mL/min.  These declines in GFR
occurred in the setting of weight loss, which was expected based on the mechanism of action
of PF-06882961.  Most GFR levels returned to pre-dose levels by the follow-up visit.  
2.2.4.1. Clinical Pharmacokinetics
The clinical PK of PF-06882961 in adult participants has been evaluated in 3 completed 
studies: C3421001, C3421002 and C3421003.  The results of these completed studies are 
summarized in the PF-06882961 IB.  
In Study C3421001, PF-06882961 appeared to demonstrate linear PK in healthy participants
following single, oral doses ranging from 3 mg to 300 mg under fasted conditions.  Median 
Tmax ranged from 2.0 to 6.0 hours post dose, while mean t½ values ranged from 4.3 to 
6.1 hours. 


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In Study C3421002, following 28 days of dosing to participants with T2DM, accumulation 
was modest for the BID IR formulation treatments, with mean ratios based on dose 
normalized AUC24 (Rac) values ranging from 1.203-2.009.  Day 28 plasma exposure as 
measured by geometric mean AUC24 values appeared to increase in an approximate dose 
proportional manner across all IR treatments.  Mean t½ values on Day 28 across all 
treatments ranged from 4.681 to 8.090 hours, and no apparent trends were observed across 
various treatments, regimens, or doses administered.  Inter-participant variability for 
PF-06882961 exposure based on geometric mean values was 31%-87% for AUC24 and 
32%-94% for Cmax on Day 28 across all treatments and cohorts.  A population PK model 
based on data from C3421001 and C3421002 indicated that the exposure in T2DM 
participants (C3421002) was approximately 1.7-fold higher than that observed in healthy 
participants (C3421001) after accounting for differences in body weight between the 
participants in each study.
Preliminary PK data from study C3421007 suggest induction of CYP3A based on 
observations of decreases in midazolam AUClast and Cmax of 49% and 37%, respectively, 
during co-administration with PF-06882961 120 mg BID, and decreases in midazolam 
AUClast and Cmax of 49% and 29%, respectively, during co-administration with PF-06882962 
200 mg BID.  Midazolam median Tmax occurred 0.5 hours earlier during PF-06882961 
co-administration at both the 120 mg BID and 200 mg BID dosing regimens.  Additionally, 
mean t1/2 were shorter for both the 120 mg BID and 200 mg BID PF-06882961 dose groups
at 6.6 hr (23% CV) and 6.9 hr (26% CV), respectively, vs 8.1 hr (25% CV) during 
administration of midazolam alone. Finally, the 1-hydroxy-midazolam/midazolam 
(metabolite/parent) ratios increased during co-administration with PF-06882961, providing 
further support for CYP3A induction.  To further investigate the mechanism of this 
interaction, plasma 4--hydroxycholesterol/cholesterol and EV samples, used as endogenous 
probes for CYP3A induction, will be collected and analyzed in this study.
Based on preliminary PK data from Study C3421007, increases in rosuvastatin AUClast and 
Cmax of 2.0-fold and 2.6-fold, respectively, were observed during co-administration with 
PF-06882961 120 mg BID, while increases for AUClast and Cmax of 2.8-fold and 4.4-fold,
respectively, were observed during co-administration with PF-06882962 200 mg BID.  
Systemic exposures of PF-06882961 (both AUClast and Cmax) increased in a greater than 
dose-proportional manner from the 120 mg BID to the 200 mg BID dose in Study C3421007.  
Dose-normalized AUClast and Cmax were 18.4 ng*hr/mL and 1.3 ng/mL, respectively, 
following 120 mg BID administration, and 29.8 ng*hr/mL and 2.8 ng/mL, respectively, 
following 200 mg BID administration.
2.3. Benefit/Risk Assessment
PF-06882961 is not expected to provide any clinical benefit to the healthy adult male and 
female participants or healthy PM female participants in this study.  This study is designed 
primarily to generate safety, tolerability, and PK data for further clinical development.


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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06882961 may be found in the IB, which is the SRSD for this study.  
The SRSD for the site sourced atorvastatin (eg, Lipitor) product is the USPI.13 The SRSD for 
the site sourced midazolam (midazolam hydrochloride syrup) product is the USPI.13 The 
SRSD for the site sourced OC (0.15 mg LE/0.03 mg EE) product is the USPI.14
2.3.1. Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention PF-06882961
Thyroid C-cell tumors
The potential risks are based on product 
labeling for injectable GLP-1R agonists 
(ie, liraglutide, dulaglutide, 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. 
Thyroid C-cell tumors have not been 
observed with PF-06882961 in clinical 
or nonclinical studies.
Potential participants with a 
personal or family history of 
medullary thyroid carcinoma or 
MEN2 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 and 
dulaglutide). 
Pancreatitis has not been observed in the 
PF-06882961 clinical trial program.
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 the clinical 
studies.  
Hypoglycemia
Clinical trials with injectable GLP-1R
agonists have not demonstrated an 
increased risk for hypoglycemia.  
However, when administered in 
combination with anti-diabetic agents 
that are known to have an increased risk 
of hypoglycemia (such as insulin or 
sulfonylureas), an increased risk for 
hypoglycemia was observed.  
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.  
Only one AE of mild hypoglycemia has 
been reported in the 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 at every clinical 
visit in this study.  Participants are 
informed about the signs and 
symptoms of hypoglycemia, and 
are monitored for these symptoms 
during the study.
Impairment in renal 
function
In rats, minimal renal tubular 
vacuolation was observed, but this 
finding was considered to be 
non-adverse.
Per exclusion criteria, potential 
participants with significant renal 
impairment are not eligible for 
study entry.  Renal function is 
monitored at frequent intervals by 


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In the clinical trial program only one 
mild adverse event (Preferred Term 
Blood creatinine increased) has been 
observed in the clinical trial program.
lab assessments of serum BUN, 
creatinine and eGFR.
Gastrointestinal adverse 
reactions
The potential risks are based on product 
labeling for injectable GLP-1R agonists 
(ie, liraglutide, exenatide and 
dulaglutide).
In addition, gastrointestinal AEs, the 
majority of which were mild in severity, 
have been observed in the clinical 
program with PF-06882961.  In 
nonclinical studies with PF-06882961, 
gastrointestinal adverse effects have 
been seen in rats and monkeys.
Participants are monitored during 
the clinical studies to prevent 
potential sequelae of any severe 
gastrointestinal reactions, 
eg, dehydration.  Concomitant 
medication for nausea is permitted 
in the study.  Additionally, 
PF-06882961 will be titrated from 
10 mg BID dose to 120 mg BID 
over 28 days and from 120 mg BID 
to 200 mg BID over 16 days in the 
study. 
Diabetic retinopathy 
complications
The potential risk is based on the product 
labeling for the injectable GLP-1R 
agonist semaglutide for T2DM.  This 
risk has not been listed in the prescribing 
information for other marketed GLP-1R 
agonists.
There are no nonclinical or clinical data 
involving PF-06882961 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 
agonist liraglutide for obesity.  This risk 
has not been listed in the prescribing 
information for other marketed GLP-1R 
agonists for T2DM.
There are no nonclinical or clinical data 
involving PF-06882961 to suggest an 
increased risk of suicidal ideation and 
behavior.
Suicidal ideation and behavior, 
along with symptoms of depression, 
will be monitored at frequent 
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 and 
blood pressure
Increases in HR have been reported for 
marketed GLP-1R agonists, and 
increases in HR have been observed with 
PF-06882961 administration, with most 
HR values within the normal range.  In 
addition, declines in systolic blood 
pressure have been noted at higher doses 
of PF-06882961.
HR and BP are monitored at 
frequent intervals during the 
clinical study.
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-06882961.
Weight is collected at multiple 
timepoints and will be monitored 
throughout the trial.


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Acute gallbladder disease
The potential risk is based on the product 
labeling for the injectable GLP-1R 
agonist liraglutide for obesity and also 
exenatide.  
Acute gallbladder disease has not been 
observed in the PF-06882961 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: Atorvastatin
Skeletal muscle effects: 
These risks can occur at 
any dose level, but are 
increased at the highest 
dose (80 mg).  Concurrent 
administration of some 
lipid-lowering therapies 
(fibrates or niacin) 
increases the risk of 
adverse skeletal muscle 
effects.
Risk based on product labeling.
Single dose of 20 mg is 
administered in this study and poses 
minimal risk.  Other lipid-lowering 
therapies will not be administered 
as concomitant medications in this 
study.
Liver enzyme 
abnormalities.
Risk based on product labeling.
Single dose of 20 mg is 
administered in this study and poses 
minimal risk.  Liver enzymes will 
be monitored throughout the study 
as part of the safety labs.
Study Intervention: Midazolam
Respiratory depression
Risk based on product labeling.
A single dose of 5 mg is 
administered in the study and poses 
minimal risk.  Participants will be 
monitored in an inpatient clinical 
research unit.
Study Intervention: LE/EE
Increased BP.
Risk based on product labeling.
A single dose of 0.15 mg LE/0.03 
mg EE is administered in this study 
and poses minimal risk.  
Participants will be monitored in an 
inpatient clinical research unit.
Other
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 SOA.
2.3.2. Benefit Assessment
While PF-06882961 is not expected to provide any clinical benefit to the healthy participants
in this short-term study, potential benefits may include 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.


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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06882961 may be found in the IB, which is SRSD for this study.
2.3.3. Overall Benefit/Risk Conclusion
Considering all available clinical and nonclinical data, the benefit-risk profile of 
PF-06882961 supports clinical development in participants with T2DM and obesity.
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with PF-06882961 are justified by the anticipated benefits that may 
be afforded to participants with PF-06882961.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Part A
Primary: 
Primary: 

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of atorvastatin in healthy 
male and female adult participants. 

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of midazolam in healthy 
male and female adult participants. 

Atorvastatin plasma pharmacokinetic parameters: 
AUCinf (if data permit* otherwise AUClast) in 
Periods 1, 4 and 7.

Midazolam plasma pharmacokinetic parameters: 
AUCinf (if data permit* otherwise AUClast) in 
Periods 2, 5 and 8.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
PF-06882961 administered separately and in 
combination with atorvastatin or midazolam in 
healthy male and female adult participants.

Assessment ofTEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and ECG 
parameters during Part A of the study.

Assessment of mental health as determined by 
C-SSRS and PHQ-9 during Part A of the study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To evaluate the effects of PF-06882961 on 
additional pharmacokinetic parameters of 
atorvastatin and midazolam in healthy male 
and female adult participants.

To evaluate the MD pharmacokinetics of PF-
06882961 in healthy male and female adult 
participants.

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of 
ortho-hydroxyatorvastatin in healthy male and 
female adult participants.

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of 1-OH-midazolam in 
healthy male and female adult participants.

Additional plasma pharmacokinetic parameters for 
atorvastatin (Periods 1, 4 and 7) and midazolam 
(Periods 2, 5 and 8): Cmax, Tmax, CL/F, Vz/F, t½, as 
data permit.

PF-06882961 plasma pharmacokinetic parameters 
at Days 35 and 58: AUC24, Cmax, Tmax.

Ortho-hydroxyatorvastatin plasma 
pharmacokinetic parameters: AUClast, Cmax, Tmax; 
and AUCinf and t½ as data permit in Periods 1, 
4 and 7.  Metabolite/parent 
(ortho-hydroxyatorvastatin/ atorvastatin) ratios 
will also be calculated.

1-OH-midazolam plasma pharmacokinetic 
parameters: AUClast, Cmax, Tmax; and AUCinf and t½
as data permit in Periods 2, 5 and 8.  


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
To evaluate the effects of PF-06882961 on 
biomarkers of CYP3A induction. [Optional].
Metabolite/parent (1-OH-midazolam/midazolam) 
ratios will also be calculated.

Morning predose 
4--hydroxycholesterol/cholesterol plasma ratio 
on Day 1 in Periods 2, 5, and 8.  Morning predose 
plasma-derived EV on Day 1 in Periods 2, 5, and 
8.
Part B
Primary: 
Primary: 

To evaluate the effects of PF-06882961 on the 
pharmacokinetics of an OC (LE/EE) in 
healthy PM female participants.

LE plasma pharmacokinetic parameters: AUCinf (if 
data permit* otherwise AUClast) in Periods 1, 
3 and 5.

EE plasma pharmacokinetic parameters: AUCinf (if 
data permit* otherwise AUClast) in Periods 1, 
3 and 5.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
PF-06882961 administered separately and in 
combination with an OC (LE/EE) in healthy 
PM female participants.

Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and ECG 
parameters during Part B of the study.

Assessment of mental health as determined by 
C-SSRS and PHQ-9 in Part B of this study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To evaluate the effects of PF-06882961 on 
additional pharmacokinetic parameters of an 
OC (LE/EE), administered separately, in 
healthy PM female participants.

To evaluate the MD pharmacokinetics of 
PF-06882961 in healthy PM female 
participants.

Additional plasma pharmacokinetic parameters for 
LE and EE (both in Periods 1, 3 and 5): Cmax, Tmax, 
CL/F, Vz/F, t½, as data permit.

PF-06882961 plasma pharmacokinetic parameters 
at Days 36 and 60: AUC24, Cmax, Tmax.
* Should it be deemed that too few AUCinf estimates (eg, less than 12 for a single treatment) are obtained 
from the evaluable participants, AUClast may be selected as the primary endpoint for CSR reporting.  This 
will be considered for the atorvastatin, midazolam, LE and EE objectives separately.
4. STUDY DESIGN
4.1. Overall Design
This study will be conducted in 2 parts.  Part A will evaluate the effect of 2 steady-state dose 
levels of PF-06882961 on the SD pharmacokinetics of atorvastatin and midazolam.  Part B 
will evaluate the effect of 2 steady-state dose levels of PF-06882961 on the SD
pharmacokinetics of an OC.  Participants will participate in either Part A or Part B (not both), 
and Parts A and B expected to be conducted in parallel, if possible.


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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 for both Parts A and B.  Participants who discontinue from 
the study before completing all assessments may be replaced at the discretion of the 
investigator and Sponsor.
PF-06882961 will be provided as tablets for oral administration.  Study intervention 
(PF-06882961) must be administered BID within approximately 10 minutes of completion of 
the morning and evening meals, approximately 10 hours apart.  Atorvastatin, midazolam and 
the OC will be administered within approximately 10 minutes of completion of the morning 
meal.  PF-06882961 will be administered first and atorvastatin, midazolam or OC will be 
administered within 5 minutes of PF-06882961.
4.1.1. Part A
Part A of this study is an open-label, 8-period, fixed-sequence study to evaluate the effect of 
PF-06882961, administered at 2 PK steady-state dose levels, on the SD PK of atorvastatin
and midazolam, administered separately, in healthy adult male and female participants with a 
BMI ranging from 20.0 kg/m2 to <30.0 kg/m2.  
Approximately 16 subjects will be enrolled in Part A.  
The total duration of participation from the Screening Visit (28 days) to the FU contact will 
be approximately 18 weeks; ie, 125 days, of which 64 days will be in-house as follows: 
Period 1 (SD atorvastatin): 4 days; Period 2 (SD midazolam): 1 day; Period 3 (BID 
PF-06882961 titrated to 120 mg BID): 31 days; Period 4 (120 mg BID PF-06882961+ SD 
atorvastatin): 3 days; Period 5 (120 mg BID PF-06882961 + SD midazolam): 1 day; Period 6
(BID PF-06882961 titrated to 200 mg BID): 19 days; Period 7 (200 mg BID PF-06882961+ 
SD atorvastatin): 3 days; Period 8 (200 mg BID PF-06882961 + SD midazolam): 2 days
(Table 8).
The FU visit will occur 7-10 days from the last dose of study intervention and a FU contact
will occur 28-35 days from the last dose of study intervention.
4.1.2. Part B
Part B of this study is an open-label, 5-period, fixed-sequence study to evaluate the effect of 
PF-06882961, administered at 2 PK steady-state dose levels, on the SD PK of an OC (LE and 
EE) in healthy, PM female participants with a BMI ranging from 20.0 kg/m2 to <30.0 kg/m2. 
Approximately 16 subjects will be enrolled in Part B.


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The total duration of participation from the Screening Visit (28 days) to the FU contact will 
be approximately 18 weeks; ie, 125 days, of which 67 days will be in-house as follows: 
Period 1 (SD OC): 6 days; Period 2 (BID PF-06882961 titrated to 120 mg BID): 31 days; 
Period 3 (120 mg BID PF-06882961 + SD OC) 5 days; Period 4 (BID PF-06882961 titrated 
to 200 mg BID) 19 days; Period 5 (200 mg BID PF-06882961+ SD OC): 6 days (Table 9).
The FU visit will occur 7-10 days from the last dose of study intervention and a FU contact
will occur 28-35 days from the last dose of study intervention.
4.2. Scientific Rationale for Study Design
The purpose of this study is to characterize the effect of PF-06882961, administered at 
2 steady-state dose levels, on the PK of single doses of atorvastatin (20 mg), midazolam 
(5 mg), and an OC (LE 0.15 mg/EE 0.03 mg), administered separately, in healthy adult 
participants.  
Titration of PF-06882961 doses will be utilized to achieve doses of 120 mg BID and 
200 mg BID in Part A and Part B. The DDI effect will be initially assessed at PF-06882961 
120 mg BID and again at 200 mg BID, as these doses are being studied in Phase 2 for T2DM 
and obesity. PF-06882961 will be administered for a duration of 7 days at each of the 
120 mg BID and 200 mg BID dosing regimens prior to administration of the SD atorvastatin, 
midazolam, or OC treatments in each of the relevant study periods in both Parts A
(atorvastatin or midazolam Table 8) and B (OC) Table 9 to ensure that clinically relevant 
steady-state PF-06882961 exposures are achieved and to assess the CYP3A induction
potential of PF-06882961, should that be a mechanism contributing to any DDI observations 
in this study.  
4.2.1. Part A
4.2.1.1. Midazolam Administration
Prior publications have demonstrated lower clearance of CYP3A substrates in participants 
with obesity, in addition to alterations in clearance after body weight loss.14,15,16,17  To 
minimize potential impact of body weight or weight loss on clearance of CYP3A substrates, 
this study will enroll participants with a BMI ranging from 20.0 kg/m2 to <30.0 kg/m2, which 
represents a different study population than that studied in the previously conducted 
C3421007 study. Additionally, since preliminary results from study C3421007 indicate 
possible induction of CYP3A, midazolam will be used as a “sensitive substrate” of CYP3A 
in this study to assess the impact of MD PF-06882961 administration on its PK. To further 
investigate the mechanism of this interaction, plasma 4--hydroxycholesterol/cholesterol and 
EV samples, used as endogenous probes for CYP3A induction, will be collected and 
analyzed in this study.
Midazolam is rapidly absorbed after oral administration and is subject to substantial intestinal 
and hepatic first-pass metabolism. Food effect has not been tested using midazolam HCl 
syrup; however, when a 15 mg oral tablet of midazolam was administered with food to 


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adults, the absorption and disposition of midazolam was not affected. The extent of plasma 
protein binding of midazolam is moderately high and concentration independent. In adults 
and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma 
protein, principally albumin. In healthy volunteers, α-hydroxymidazolam is bound to the 
extent of 89%.13
Midazolam is primarily metabolized in the liver and gut by human CYP3A4 to its 
pharmacologic active metabolite, α-hydroxymidazolam, followed by glucuronidation of the 
α-hydroxyl metabolite which is present in unconjugated and conjugated forms in human 
plasma. The α-hydroxymidazolam glucuronide is then excreted in urine.  Midazolam is also 
metabolized to 2 other minor metabolites: 4-hydroxy metabolite (about 3% of the dose) and 
1,4-dihydroxy metabolite (about 1% of the dose) are excreted in small amounts in the urine 
as conjugates.13
Six SD pharmacokinetic studies involving healthy adults yield pharmacokinetic parameters 
for midazolam in the following ranges: volume of distribution, 1 to 3.1 L/kg; elimination 
half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance, 0.25 to 0.54 L/hr/kg. 
In a study comparing normals (n=20) and obese patients (n=20) the mean half-life was 
greater in the obese group (5.9 hours vs. 2.3 hours), which was attributed to an increase of 
approximately 50% in the volume of distribution corrected for total body weight.13,18,19  
Plasma samples for midazolam and 1-OH-midazolam will be collected in this study for up to 
24 hours after dosing, which is expected to be adequate given the average 2 to 3 hour 
elimination half-life in non-obese subjects. 
Single, oral doses of midazolam ranging from 5 to 7.5 mg have been safely administered in 
previous internal Pfizer drug-drug interaction studies (A5351012, B3291023, C1061016), 
and the 5 mg midazolam dose is expected to be well-tolerated in the healthy male and female 
participants in this study as well.
4.2.1.2. Atorvastatin Administration
Adults with T2DM often require treatment for hyperlipidemia, therefore, it is likely that 
PF-06882961 may be co-administered with atorvastatin in clinical practice. Since 
preliminary results from study C3421007 indicate possible induction of CYP3A, atorvastatin 
will be used as a “moderate sensitive substrate” of CYP3A in this study to assess the impact 
of MD PF-06882961 administration on its PK. 
Atorvastatin is rapidly absorbed after oral administration; Cmax (plasma) occurs within 1 to 
2 hours.  The absolute bioavailability of atorvastatin (parent drug) is approximately 14%.  
The low systemic availability is attributed to presystemic clearance in gastrointestinal 
mucosa and/or hepatic first-pass metabolism.  Food decreases the rate and extent of drug 
absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC.  
Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) 
following evening drug administration compared with morning.  Plasma concentrations of 
atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly 
subjects (age ≥65 years) than in young adults.13


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Atorvastatin is also a substrate of the hepatic transporters, OATP1B1 and OATP1B3.  
Metabolites of atorvastatin are substrates of OATP1B1.  Additionally, atorvastatin is 
identified as a substrate of the efflux transporter BCRP, which may limit its intestinal 
absorption and biliary clearance.13  Intestinal BCRP acts as an efflux transporter limiting 
atorvastatin absorption, while liver BCRP actively excretes atorvastatin into the bile.  
As both in vitro data and preliminary results from Study C3421007 indicate that 
PF-06882961 is a BCRP inhibitor, and in vitro data indicate that PF-06882961 may pose a 
potential risk for OATP inhibition at higher doses (200 mg BID), the current study may also 
provide insight into the net effect of CYP3A induction and BCRP/OATP inhibition on the 
PK of atorvastatin during MD administration of PF-06882961.
Because the elimination half-lives of atorvastatin and its ortho-hydroxylated metabolite range 
from 11 to 18 hours following single doses,13,20,21 plasma will be collected for up to 72 hours 
after dosing for determination of PK parameters.  
Atorvastatin is generally well-tolerated by healthy participants following single, oral, 
ascending doses as high as 80 mg.22  Adverse reactions have usually been mild and transient.  
For more complete information, please refer to the US Package Insert for atorvastatin.13
4.2.1.3. PF-06882961 Administration
A dense PK profile will be collected for PF-06882961 after reaching the target doses of 
PF-06882961 for each DDI assessment; ie, 120 mg BID in Period 3, Day 31 and 200 mg BID 
in Period 6, Day 19, to better understand the PK in healthy male and female participants, and 
to allow for PK comparisons with the T2DM and obesity participants included in studies 
C3421002 and C3421007, respectively. 
PF-06882961 will be administered via 4-day titration increments up to the 120 mg BID 
regimen in Period 3 prior to the administration of atorvastatin and midazolam in Periods 4 
and 5, respectively.  Likewise, PF-06882961 will be administered via 4-day titration 
increments up to the 200 mg BID regimen in Period 6 prior to administration of atorvastatin 
and midazolam in Periods 7 and 8, respectively (Section 6.1.1, Table 8).  The PF-06882961 
dosing regimen is designed to achieve and maintain PK steady-state for approximately 7 days 
prior to assessment of the interaction with atorvastatin or midazolam.  This will enable any 
interaction that is present to be assessed under conditions that are expected to increase the 
potential for maximal induction at the PF-06882961 doses being studied. 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-06882961 doses at which 
atorvastatin and midazolam PK interactions are evaluated may be adjusted.  
Dosing of PF-06882961 (with or without atorvastatin or midazolam) is planned to occur in 
the fed state, with standard breakfast and dinner, as this is the anticipated mode of 
administration in clinical use.  Dosing of atorvastatin or midazolam (with or without 
PF-06882961) is planned to occur in the fed state, with a standard breakfast.


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4.2.2. Part B
4.2.2.1. Oral Contraceptive Administration
The estrogens and progestins contained in oral contraceptives are substrates for CYP3A4/5 
and other inducible metabolic enzymes.  Because the anticipated target population for 
PF-06882961 will include females of childbearing potential who may use an OC, a third 
objective of this study is to estimate the effect of MD administration of 120 mg BID and 
200 mg BID PF-06882961 on the SD PK of an OC containing 0.15 mg LE and 0.03 mg EE
in healthy, PM female participants.  
The mean (SD) half-lives of LE and EE are 29.8 (8.3) and 15.4 (3.2) hours,14 respectively; 
therefore, plasma will be collected for up to 120 hours after dosing for determination of PK 
parameters. The effect of food on the rate and the extent of LE and EE absorption following 
oral administration of LE and EE tablets has not been evaluated.14
A dense PK profile will be collected for PF-06882961 after reaching the target doses of 
PF-06882961 for each DDI assessment; ie, 120 mg BID in Period 2, Day 31 and 200 mg BID 
in Period 4, Day 19, to better understand the PK in healthy, PM female participants, and to 
allow for PK comparisons with the T2DM and obesity participants included in studies 
C3421002 and C3421007, respectively. 
Oral contraceptive use has been shown to cause an increase in BP that is reversible when the 
oral contraception is discontinued.  The use of an OC agent containing 30 µg EE and 150 ug 
LE was associated with a small increase in both systolic and diastolic BP.23  Although the 
risk of increased BP is expected to be small following SD administration of the OC in this 
study, BP effects resulting from co-administration of PF-06882961 with the OC will be 
monitored as described below.  For more complete information, please refer to the Package 
Insert for the OC.14
4.2.2.2. PF-06882961 Administration
PF-06882961 will be administered via 4-day titration increments up to the 120 mg BID 
regimen in Period 2 prior to the administration of the OC Period 3.  Likewise, PF-06882961 
will be administered via 4-day titration increments up to the 200 mg BID regimen in Period 4 
prior to administration of the OC Period 5 (Section 6.1.1, Table 9).  The PF-06882961 dosing 
regimen is designed to achieve and maintain PK steady-state for approximately 7 days prior 
to assessment of the interaction with the OC.  This will enable any interaction that is present 
to be assessed under conditions that are expected to increase the potential for maximal 
induction at the PF-06882961 doses being studied.  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-06882961 doses at which the OC (LE/EE) PK
interactions are evaluated may be adjusted.  
Dosing of PF-06882961 (with or without OC) is planned to occur in the fed state, with 
standard breakfast and dinner, as this is the anticipated mode of administration in clinical use.  
Dosing of the OC (with or without PF-06882961) is planned to occur in the fed state, with a 
standard breakfast.


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4.2.3. Parts A and B Safety Assessments 
Clinical laboratory tests, assessments of vital signs, body weight, and 12-lead ECGs, physical 
examinations, and AE monitoring will provide data to evaluate the safety and tolerability of 
PF-06882961.  Vital signs will be monitored at frequent intervals, as both increases in HR 
and mild decreases in systolic BP have been observed with PF-06882961 administration.  
Body weight will be measured at timepoints in the SoA, as GLP-1R agonists have been 
shown to decrease food intake and body weight.  COVID-19 specific assessments have been 
incorporated to minimize the risks of COVID-19 related complications to participants and the 
study site personnel.
As part of the clinical safety laboratory tests, fasting blood glucose and HbA1c, will be used 
to assess changes in glycemic parameters in this study population.  In addition, calcitonin, 
amylase, and lipase will be assessed, as these laboratory parameters have been shown to 
increase with marketed GLP-1R agonists.24-26  In addition, TSH, free T4, lipids, coagulation 
profile and TBA will be assessed, based on non-adverse findings in the nonclinical studies 
with PF-06882961.  Assessment of SIB by C-SSRS27 and PHQ-928 will also be performed 
based on the potential risk related to the product labeling for the injectable GLP-1R agonist 
liraglutide in patients with BMI ≥30 kg/m2.29
While GLP-1R agonists typically are not associated with hypoglycemia unless 
co-administered with anti-diabetic agents that can cause hypoglycemia (such as insulin or 
sulfonylureas), blood glucose concentrations will be monitored throughout the study via 
laboratory assessments, and monitoring of symptomatic HAEs will be performed.  In 
addition, all participants will be instructed regarding the symptoms associated with, and 
management of, hypoglycemia, which will permit the monitoring of symptomatic HAEs.
In Part A of this study, WOCBP may be enrolled given the availability of embryo fetal 
developmental toxicity studies with PF-06882961.  However, as marketed GLP-1R agonists, 
in addition to atorvastatin, are listed as contraindicated in pregnancy, the use of a highly 
effective method of contraception is required and measures will be taken to limit the risk of 
pregnancy in the female population enrolled (see SoA and Appendix 4).
The potential risk of exposure to PF-06882961 in a sexual partner of a male participant in 
this study via ejaculate is low, and therefore no contraception (condom) use in male 
participants is warranted.  The calculated safety margin is ≥100 fold between the estimated 
partner exposure due to seminal transfer and the NOAEL for serious manifestations of 
developmental toxicity in nonclinical studies.  The safety margin of 100-fold is based on 
applying a 10-fold safety factor for interspecies extrapolation and a 10-fold safety factor for 
susceptible populations.30
4.2.4. Diversity of Study Population  
Not applicable.


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4.2.5. Choice of Contraception/Barrier Requirements 
Human reproductive safety data are limited for PF-06882961, but there is no suspicion of 
human teratogenicity based on the completed nonclinical embryo-fetal developmental 
studies.  Therefore, the use of a highly effective method of contraception is required for 
Part A only (see Appendix 4).  
 
4.3. Justification for Dose
PF-06882961:
The DDI assessment will occur at 2 PK steady-state PF-06882961 dose levels, 120 mg BID 
and 200 mg BID.  These doses represent the highest doses being assessed in the Phase 2
studies for T2DM and obesity. The 120 mg BID and 200 mg BID doses were also 
administered in the Phase 1 midazolam and rosuvastatin DDI study (C3421007) and will, 
therefore, allow DDI assessment in this study at an anticipated exposure that was sufficiently 
tolerated.  Exposure margins for PF-06882961 120 mg BID and 200 mg BID are given in
Section 2.2.3. 
The titration to PF-06882961 120 mg BID is planned to occur over an approximately 24-day 
period, and from 120 mg to 200 mg BID over 12 days, in increments of 20 mg every 4 days
(Section 6.1.1, Table 8 and Table 9).  These titration increments have been administered
previously in Study C3421007 and were sufficiently tolerated.  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-06882961 doses at which atorvastatin, 
midazolam or the OC PK interactions are evaluated may be adjusted.  
Atorvastatin:
In a SD escalation study, atorvastatin was safe and well tolerated at doses up to 80 mg.  The 
only adverse event that occurred in more than 2 participants per treatment was headache. All 
episodes were of mild or moderate intensity. Other drug-related side effects included 
sporadic reports of diarrhea, flatulence, and nausea. There was no clear relationship between 
atorvastatin dose and the frequency or intensity of AEs. No SAEs were reported.22
The dose range for atorvastatin in clinical practice is 10 to 80 mg QD, with recommended 
starting doses of 10 or 20 mg QD.13  Since it is unknown whether PF-06882961 will decrease 
or increase atorvastatin plasma exposure in this study, 20 mg atorvastatin was selected as the 
dose.  This dose should allow for adequate quantification of atorvastatin and its 
ortho-hydroxylated metabolite in plasma should the net result of PF-06682961 
co-administration be CYP3A induction.  
CCI


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Furthermore, a 20 mg dose of atorvastatin is expected to be well-tolerated should systemic 
exposures increase due to net BCRP/OATP inhibition.  Although atorvastatin is a substrate 
for the BCRP, OATP1B1, and OATP1B3 transporters, and PF-0682961 was shown to inhibit 
BCRP as evidenced by the increased rosuvastatin exposures observed in Study 3421007, the 
20 mg dose is expected to be safe.  Maximal increases for rosuvastatin AUC and Cmax in 
Study C3421007 were approximately 2.6-fold and 4.4-fold, respectively, at the 200 mg BID 
dose of PF-06882961.  Since rosuvastatin is a more sensitive BCRP substrate than 
atorvastatin, any increases in exposure observed for atorvastatin due to BCRP inhibition in 
the current study are not expected to be a greater than 4-fold.  Furthermore, in vitro data do 
not indicate a potential for inhibition of OATP1B1 by PF-06882961, and only weak 
inhibition of OATP1B3 at 200 mg BID PF-06882961. Finally, based on the midazolam
results from Study 3421007, some degree of CYP3A induction is likely such that the net 
result of transporter inhibition and enzyme induction is not expected to result in atorvastatin
exposures that exceed that of a single 80 mg dose, which is a clinically prescribed dose.
Midazolam:
Midazolam has been administered at doses of 2-15 mg to assess CYP3A4/5 DDIs31 and was 
well tolerated at a dose of 2 mg in Study C3421007.  Likewise, a single, oral 5 mg dose of 
midazolam in this study should allow for adequate quantification of midazolam and its 
1-OH-metabolite in plasma for 24 hours and is expected to be well-tolerated.
LE/EE:
The OC selected for this study contains a fixed dose of 0.15 mg LE and 0.03 mg EE.  The 
amounts of estrogen and progestin in this preparation are comparable to those found in many 
of the commonly prescribed OCs, and have been used in a number of published OC 
drug-drug interaction studies with other CYP3A inducers, such as phenytoin and
carbamazepine.32
Doses presented are projected based on the available clinical data, but may be modified 
based on emerging safety, tolerability, and/or PK data.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the FU contact visit, approximately 28 to 35 days post last dose of study 
intervention.
The end of the study is defined as the date of the last visit (FU contact) of the last participant 
in the study.


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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Part A Only - Healthy male and female participants must be 18 to 65 years of age, 
inclusive, at the time of signing the ICD (healthy is defined as no clinically relevant 
abnormalities identified by a detailed medical history, physical examination, 
including blood pressure and pulse rate measurement, standard 12-lead ECG and 
clinical laboratory tests).

Women can be of child-bearing potential, however, cannot be pregnant, 
breastfeeding, or planning to become pregnant while participating in the study and 
may not be taking oral contraceptives.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
2. Part B Only - Healthy PM female participants between 40 and 65 years of age, 
inclusive, at the time of signing the ICD (healthy is defined as no clinically relevant 
abnormalities identified by a detailed medical history, physical examination, 
including BP and PR measurement, standard 12-lead ECG and clinical laboratory 
tests).  Subjects must be amenorrheic for at least 12 months.  Women who are 
60 years of age or younger must also have an FSH that is within the laboratory’s 
reference range for PM women.
Type of Participant and Disease Characteristics:
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
4. BMI- 20.0 kg/m2 to <30.0 kg/m2 at Screening. 


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5. Stable body weight, defined as <5 % change (per participant report) for 90 days 
before Screening. 
Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or 
pancreatic insufficiency). 
3. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
4. Known intolerance or hypersensitivity to GLP-1R agonists.
5. Known hypersensitivity to atorvastatin or midazolam (for participants in Part A), or 
LE and EE (for participants in Part B).
6. Personal or family history of MTC or MEN2 or study participants with suspected 
MTC per the investigator’s judgment.
7. Symptomatic gallbladder disease.
8. History of major depressive disorder or history of other severe psychiatric disorders 
(eg, schizophrenia or bipolar disorder) within the last 2 years from screening.
9. Any lifetime history of a suicide attempt.


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Prior/Concomitant Therapy:
10. 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 6.8 Concomitant Therapy for additional details).
11. Systemic therapy with any of the medications that are moderate or strong CYP3A4/5, 
CYP2C9 and/or CYP2C19 inhibitors within 28 days or 5 half-lives (whichever is 
longer) or moderate or strong CYP3A, CYP2C9 and/or CYP2C19 inducers within 
28 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention (Refer to Section 6.8 for additional details). 
12. Systemic therapy with inhibitors of the BCRP transporter within 28 days or 
5 half-lives (whichever is longer) prior to the first dose of study intervention. (Refer 
to Section 6.8 for additional details). 
13. Current use of any prohibited concomitant medication(s) or those unwilling/unable to 
use a permitted concomitant medication(s). Refer to Section 6.8 Concomitant 
Therapy.
Prior/Concurrent Clinical Study Experience:
14. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention
used in this study (whichever is longer). 
15. Known prior participation in a trial involving PF-06882961.
Diagnostic Assessments:
16. A PHQ-9 score ≥15 obtained at Screening or Day -1 in Study.
17. 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.
18. A positive urine drug test. 
19. 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.


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20. 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).  
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.
21. 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%.

Aspartate AST or ALT level ≥2 times the ULN.

Total bilirubin level ≥1.5 times the 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 the ULN or <LLN.

Serum calcitonin > the ULN.

Amylase or lipase > the ULN.

Fasting blood glucose ≥126 mg/dL. 

Fasting C-peptide <0.8 ng/mL.

eGFR <70 mL/min/1.73 m2 as calculated by the CKD-EPI equation.

Positive testing for HIV, HepBsAg, 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.  Hepatitis B vaccination is allowed.

A positive SARS-CoV-2 test.
Other Exclusions: at Screening unless indicated
22. Participation in a formal weight reduction program (eg, Weight Watchers) within 
90 days prior to Screening.


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23. 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).
24. Current use of tobacco or nicotine containing products in excess of the equivalent of 
5 cigarettes per day.
25. Known or suspected illicit drug use.
26. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing randomization (Day-1). 
27. History of sensitivity to heparin or heparin induced thrombocytopenia if Hep-lock is 
used for IV blood draw.
28. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
29. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members. 
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) for at least 8 hours 
prior to any safety laboratory and the morning predose PK evaluations (Periods 1-8 in 
Part A and Periods 1-5 in Part B).

Water may be consumed as desired (ad libitum).

Participants should begin consumption of a standard breakfast (morning) and evening 
meal approximately 30 minutes prior to dosing.  The breakfast and evening meal 
(dinner) will be consumed over approximately a 20 minute period, with the study 
intervention (PF-06882961) administered within approximately 10 minutes of 
completion of the meal.  Participants will be encouraged to complete the entire meal.
Study intervention (PF-06882961) must be administered BID approximately 10 hours 
apart. 
Atorvastatin, midazolam or OC when administered alone will be given within 
approximately 10 minutes of completion of the morning meal. 


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PF-06882961 will be administered first and the single dose of atorvastatin, 
midazolam or the OC will be administered within 5 minutes of PF-06882961 for the 
periods in which atorvastatin, midazolam, or the OC are co-administered with 
PF-06882961. 

Noncaffeinated drinks (except red wine, grapefruit or grapefruit-related citrus fruit 
juices—see below) may be consumed with meals and the evening snack.  

Lunch will be provided approximately 4 hours after dosing with study intervention 
(PF-06882961).  This applies to atorvastatin, midazolam and the OC also.

Dinner will be provided approximately 10 hours after dosing with study intervention. 
This applies to atorvastatin, midazolam and the OC also.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to Period 1 
Day 1 until collection of the final PK blood sample in Part A, Period 8, Day 2 or 
Part B, Period 5, Day 6.  

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.
5.3.2. Caffeine, Alcohol, and Tobacco

Tobacco or nicotine use may be allowed according to CRU practices.  Tobacco or 
nicotine use will not be permitted during frequent sampling procedures, and will not 
be permitted within 2 hours prior to any vital sign or ECG assessments.  Tobacco or 
nicotine use will also not be permitted 2 hours before and 2 hours following any dose 
of study intervention.  

Caffeine containing products will be permitted during the study with the following 
restrictions: caffeine containing products may not be consumed within 1 hour prior to 
measuring vital signs and ECGs.

Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample in Part A, 
Period 8, Day 2 or Part B, Period 5, Day 6.  Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.  
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.


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
In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down for 4 hours after dosing in the morning on days of 
post-dose PK sample collections (except when required for BP, pulse rate, and ECG 
measurements).
5.3.4. Contraception
Part A
WOCBP Only - The investigator or his or her designee, in consultation with the participant, 
will confirm that the participant has selected an appropriate method of contraception for the 
individual participant and his or her partner(s) from the permitted list of contraception 
methods (see Appendix 4) and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use highly effective 
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception) considering that their risk for 
pregnancy may have changed since the last visit.  In addition, the investigator or designee 
will instruct the participant to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the participant or partner.
Part B
Not applicable. 
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently dosed in the study.  Screen failure data are collected and remain as 
source and are not reported to the clinical database.
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 intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-06882961.


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6.1. Study Intervention(s) Administered
10 mg, 40 mg, and 100 mg PF-06882961 tablets will be supplied by Pfizer to the CRU in 
bulk along with individual dosing containers, as necessary, for unit dosing.
Commercially available midazolam oral syrup (2 mg/mL) will be supplied by the CRU. 
Commercially available oral atorvastatin 20 mg tablets will be supplied by the CRU.
Commercially available OC tablets (LE 0.15 mg/EE 0.03 mg) will be supplied by the CRU. 
6.1.1. Administration
Participants will receive PF-06882961 (morning dose), atorvastatin, midazolam or OC as 
applicable per the SoA at approximately 0800 hours (±2 hours).  Participants will receive the 
evening dose of PF-06882961 approximately 10 hours after the morning dose of 
PF-06882961. Details on meals and dietary requirements and activity restrictions on dosing 
days are given in Section 5.3.  
Investigator site personnel will administer PF-06882961, atorvastatin, midazolam or the OC 
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.
Administration of study intervention will occur according to the following Dosing Periods 
and Dosing Days, also listed in the SoA and Table 8.
Modification of dosing of PF-06882961 maybe permitted upon Sponsor approval only. See
Section 6.5. 
Table 8.
Part A Dosing
Study Period
Days in Study
Drug and Dosage
Period 1, Days 1-3
1
SD Atorvastatin
Period 2, Days 1
4
SD Midazolam
Period 3, Days 1-4
5-8
PF-06882961 10 mg BID
Period 3, Days 5-8
9-12
PF-06882961 20 mg BID
Period 3, Days 9-12
13-16
PF-06882961 40 mg BID
Period 3, Days 13-16
17-20
PF-06882961 60 mg BID
Period 3, Days 17-20
21-24
PF-06882961 80 mg BID
Period 3, Days 21-24
25-28
PF-06882961 100 mg BID
Period 3, Days 25-31
29-35
PF-06882961 120 mg BID
Period 4, Day 1
36
PF-06882961 120 mg BID+ SD Atorvastatin
Period 4, Days 2-3
37-38
PF-06882961 120 mg BID
Period 5, Day 1
39
PF-06882961 120 mg BID+ SD Midazolam
Period 6, Days 1-4
40-43
PF-06882961 140 mg BID
Period 6, Days 5-8
44-47
PF-06882961 160 mg BID
Period 6, Days 9-12
48-51
PF-06882961 180 mg BID
Period 6, Days 13-19
52-58
PF-06882961 200 mg BID
Period 7, Day 1
59
PF-06882961 200 mg BID+ SD Atorvastatin


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Study Period
Days in Study
Drug and Dosage
Period 7, Days 2-3
60-61
PF-06882961 200 mg BID
Period 8, Days 1-2
62-63*
PF-06882961 200 mg BID+ SD Midazolam
* There is no PF-06882961 administration on Day 63.
Table 9.
Part B Dosing
Study Period
Days in Study
Drug and Dosage
Period 1, Days 1-5
1
SD OC
Period 2, Days 1-4
6-9
PF-06882961 10 mg BID
Period 2, Days 5-8
10-13
PF-06882961 20 mg BID
Period 2, Days 9-12
14-17
PF-06882961 40 mg BID
Period 2, Days 13-16
18-21
PF-06882961 60 mg BID
Period 2, Days 17-20
22-25
PF-06882961 80 mg BID
Period 2, Days 21-24
26-29
PF-06882961 100 mg BID
Period 2, Days 25-31
30-36
PF-06882961 120 mg BID
Period 3, Day 1
37
PF-06882961 120 mg BID+ SD OC
Period 3, Days 2-5
38-41
PF-06882961 120 mg BID
Period 4, Days 1-4
42-45
PF-06882961 140 mg BID
Period 4, Days 5-8
46-49
PF-06882961 160 mg BID
Period 4, Days 9-12
50-53
PF-06882961 180 mg BID
Period 4, Days 13-19
54-60
PF-06882961 200 mg BID
Period 5, Day 1
61
PF-06882961 200 mg BID+ SD OC
Period 5, Days 2-6
62-66*
PF-06882961 200 mg BID
* There is no PF-06882961 administration on Day 66.
Following an overnight fast of at least 10 hours, participants will receive study intervention
at approximately 0800 hours (±2 hours). Investigator site personnel will administer study 
intervention during each period 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.
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, PR, and ECG measurements), 
eating, and drinking beverages other than water during the first 4 hours after dosing.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 


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must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record.
7. 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, 
participant in accordance with this protocol.  Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.


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Tablets will be prepared at the CRU in the individual dosing containers by 2 operators, 1 of 
whom is an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist).  
The tablets will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements. 
Commercially available products atorvastatin, midazolam and the OC 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.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation 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.  The first four digits of the SSID will reflect the sponsor-assigned site number and 
the remaining four-digits will reflect each participant’s unique number assigned in 
chronological order as informed consent is obtained. In addition, on Day 1 of Period 1, each 
participant who is dosed with the investigational product will be assigned a separate, distinct 
number (as provided to the site by the Sponsor at the start of the study) to enable execution of 
Sponsors’standard processes for analysis of all PK-related samples.
In Part A (Periods 3 to 8) and Part B (Periods 2 to 5, participants will receive the 
PF-06882961 doses as described in Table 10.


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Table 10.
PF-06882961 Dosing Regimens Part A
Period & 
PF-06882961 Dose 
(dosed twice daily)
Number of PF-06882961 Tablets
Total Number of 
Tablets
10 mg
40 mg
100 mg
Period 3: 10 mg
1
-
-
1
Period 3: 20 mg
2
-
-
2
Period 3: 40 mg
-
1
-
1
Period 3: 60 mg
2
1
-
3
Period 3: 80 mg
-
2
-
2
Period 3: 100 mg
-
-
1
1
Period 3: 120 mg
2
-
1
3
Period 4: 120 mg
2
-
1
3
Period 5: 120 mg
2
-
1
3
Period 6: 140 mg
-
1
1
2
Period 6: 160 mg
2
1
1
4
Period 6: 180 mg
-
2
1
3
Period 6: 200 mg
-
-
2
2
Period 7: 200 mg
-
-
2
2
Period 8: 200 mg
-
-
2
2
PF-06882961 Dosing Regimens Part B
Period & 
PF-06882961 Dose 
(dosed twice daily)
Number of PF-06882961 Tablets
Total Number of 
Tablets
10 mg
40 mg
100 mg
Period 2: 10 mg
1
-
-
1
Period 2: 20 mg
2
-
-
2
Period 2: 40 mg
-
1
-
1
Period 2: 60 mg
2
1
-
3
Period 2: 80 mg
-
2
-
2
Period 2: 100 mg
-
-
1
1
Period 2: 120 mg
2
-
1
3
Period 3: 120 mg
2
-
1
3
Period 3: 120 mg
2
-
1
3
Period 4: 140 mg
-
1
1
2
Period 4: 160 mg
2
1
1
4
Period 4: 180 mg
-
2
1
3
Period 4: 200 mg
-
-
2
2
Period 5: 200 mg
-
-
2
2
Period 5: 200 mg
-
-
2
2
Study intervention will be dispensed at the study visits as summarized in the SoA. Returned 
study intervention must not be redispensed to the participants.


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6.4. Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.  Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5. Dose Modification
If participants are not able to tolerate titration to higher doses of PF-06882961 
(eg, ≥160 mg BID), 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. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. Treatment of Overdose
For this study, any dose of PF-06882961 greater than 600 mg within a 24-hour time period 
will be considered an overdose. 
For this study, overdose for atorvastatin,13 midazolam15 and the OC16 will be per the USPI 
label.
There is no specific treatment for an overdose for PF-06882961.  Treatment of overdose
should consist of general supportive measures.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-06882961 (whichever 
is longer). 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.


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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 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 medical monitor based on the clinical evaluation of the participant.
6.8. 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 of the medications that are 
moderate or strong CYP3A4/5, CYP2C9 and/or CYP2C19 inhibitors within 28 days or 
5 half-lives (whichever is longer) or moderate or strong CYP3A, CYP2C9 and/or CYP2C19 
inducers within 28 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention.
Hormonal contraceptives are not allowed to be used in participants who are WOCBP (see
Appendix 4).
Females using hormonal contraceptives 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.
Systemic therapy with inhibitors of the BCRP or OATP transporters within 28 days or 
5 half-lives (whichever is longer) prior to the first dose of study intervention.
Limited use of nonprescription medications that are not believed to affect participant safety 
or the overall results of the study may be permitted on a case-by-case basis 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 6.8.1.1).
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 as listed in the SoA.


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Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment.  Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
6.8.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with PF-06882961; standard medical 
supportive care must be provided to manage the AEs, including administration of 
carbohydrates to treat HAEs (see Section 8.2.6).
6.8.1.1. Management of Nausea and Vomiting
Nausea and vomiting have been reported with administration of GLP-1R agonists and also 
with administration of PF-06882961 (see Section 2.2.4).  Study participants complaining of 
nausea may be managed conservatively with bed rest and/or fluid management at the 
discretion of the investigator.  If the nausea and vomiting are not amenable to conservative 
management, anti emetics (eg, prochlorperazine, promethazine, ondansetron) may be 
administered at the investigator’s discretion with notification to the sponsor and entry in the 
CRF.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention 
(definitive discontinuation).  Reasons for definitive 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 beta human chorionic 
gonadotropin (-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 8.2.9, 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.


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Note that discontinuation of study intervention does not represent withdrawal from the study.  
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated for 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, posttreatment study follow-up, 
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up.

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.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study.  Participants should be questioned regarding 
their reason for withdrawal.  
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/ET procedures will not be viewed as 
protocol deviations so long as the participant’s safety was preserved.


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7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.


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Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
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
350 mL in Part A and 675 mL in Part B.  In Part B of the study, the total blood volume taken 
does not exceed 550 mL in any given 60-day consecutive period of time.  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 60 consecutive days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.


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8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
Complete physical exam will be done at time points specified in the SoA otherwise, brief 
exam if findings during previous exam 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.  Height will be 
measured at screening only.  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).  The scale must 
be placed on a stable, flat surface. 
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.

Remove the contents of their pockets. 

While remaining still during the measurement.
Height and weight will also be measured and recorded as per the SoA. For measuring 
weight, a scale with appropriate range and resolution is used and must be placed on a stable, 
flat surface. Participants must remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains. They must also remove the contents of their pockets and remain 
still during measurement of weight. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Section 8.3.1 to 8.3.3.


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8.2.2. Vital Signs
Vital signs (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 supine rest.  The same arm 
(preferably the dominant arm) will be used throughout the study.  Participants should be 
instructed not to speak during measurements.  When triplicate measurements are obtained, 
they should be collected approximately 2 minutes apart. 
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.  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 PR 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 PR should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and PR will be permitted, 
as necessary, to ensure appropriate collection of safety data.
8.2.2.1. 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.
8.2.3. 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, QT, and QTcF intervals 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 10 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to screening measurements.  Additional ECG monitoring will occur if 
a) a postdose QTcF interval is increased by ≥60 msec from the screening and is >450 msec; 
or b) an absolute QTcF value is ≥500 msec for any scheduled ECG.  If either of these 
conditions occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes 
apart to confirm the original measurement.  If the QTcF values from these repeated ECGs 
remain above the threshold value, then a single ECG must be repeated at least hourly until 
QTcF values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.


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If a) a postdose QTcF interval remains ≥30 msec from the screening and is >450 msec; or 
b) an absolute QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator); or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring.  A cardiologist should be 
consulted if QTc intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within [28-35 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 medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
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. 


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8.2.5. COVID-19 Specific Assessments
Participants will be tested for SARS-CoV-2 infection by PCR prior to being admitted to the 
clinic for confinement and a subsequent SARS-CoV-2 test will be performed after 4 days 
(ie, upon completion of 4 x 24 hours in house), or if they develop symptoms suggestive of 
COVID-19. 
Additional testing may be required by local regulations or by the Principal Investigator.
Results must be negative for admission to the CRU. 
8.2.6. 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 8.2.6.1 below.
For medical management of hypoglycemia, the investigator may administer oral 
carbohydrate, glucagon, or IV glucose according to his or her medical judgment.  At a 
minimum however, treatment or administration of a scheduled meal should be given if 
glucose falls <60 mg/dL for at least 15 minutes, irrespective of whether the study participant 
exhibits symptoms.  Investigators may choose to administer treatment sooner if subjects have 
bothersome symptoms of hypoglycemia along with glucose values of ≤70 mg/dL.
8.2.6.1. 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:33
a.
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a glucose value of <70 mg/dL (3.9 mmol/L) using either glucometer 
(fingerstick blood glucose) at the study site or sponsor-identified central/local 
laboratory (blood glucose).
b. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose value of <70 mg/dL (3.9 mmol/L), using 
glucometer at the study site or sponsor identified central/local laboratory, and the 
clinical picture includes prompt resolution with food intake, subcutaneous glucagon, 
or IV glucose.


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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.
8.2.7. 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.


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If obtained, FSBG readings will be maintained at the CRU in source documents, and only the 
glucose results from the laboratory will be reported in the study database.
If an FSBG result is ≤70 mg/dL, a second FSBG should be obtained to confirm the glucose 
value, in addition to a venous sample that will be sent to the clinical laboratory for 
confirmation.  If the value from this second FSBG is also ≤70 mg/dL, the second value will 
be recorded as a hypoglycemic AE.  FSBG will continue to be monitored until the glucose 
value returns to >70 mg/dL. Samples may be taken more frequently if deemed necessary by 
the investigator.  
8.2.8. Pregnancy Testing 
Part A
Pregnancy tests may be urine or serum tests, but 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 the participant’s receiving the study intervention/study treatment. 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. 
Part B
Not applicable.
8.2.9. Suicidal Ideation and Behavior Risk Monitoring 
8.2.9.1. Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an interview based rating scale to systematically assess suicidal ideation and 
suicidal behavior.27  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.
8.2.9.1.1. 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 


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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 and signed 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 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.
8.2.9.2. Patient Health Questionnaire-9 (PHQ-9)
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms.28  The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in the SoA.  A PHQ-9 score of ≥15 at Screening or Day -1 indicates clinically 
significant depression and serves as an exclusion criterion for this study (see Section 5.2).
8.2.9.3. Referral to a MHP
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 a 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. 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.


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AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
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 he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.


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8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.


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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.
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 


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
If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after 
the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 
A female is found to be breastfeeding while being exposed or having been exposed to study 
intervention (ie, environmental exposure). An example of environmental exposure during 
breastfeeding is a female family member or healthcare provider who reports that she is 
breastfeeding after having been exposed to the study intervention by ingestion.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form regardless of 
whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Not applicable.


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8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. 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.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of atorvastatin, 
ortho-hydroxyatorvastatin, midazolam, 1-OH-midazolam, LE, EE and PF-06882961 as
specified in the SoA.


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The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF.  Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. 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 concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study, for 
metabolite identification and/or evaluation of the bioanalytical method, or for other internal 
exploratory purposes.
Samples collected for measurement of plasma concentrations of study intervention will be 
analyzed using a validated analytical method in compliance with applicable SOPs.  Potential 
metabolites may be analyzed with either validated or exploratory methods.
Genetic analyses will not be performed on these samples unless consent for this was included 
in the informed consent.  Participant confidentiality will be maintained.
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 deviation from the specified sample handling 
procedure resulted in compromised sample integrity, will be considered a protocol deviation.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment.  The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.4.1. PK of Atorvastatin and Ortho-hydroxyatorvastatin
Samples will be used to evaluate the PK of atorvastatin and ortho-hydroxyatorvastatin
(primary metabolite).  Blood samples of approximately 4 mL, to provide plasma volume of 
approximately 2 mL, will be collected into appropriately labeled tubes containing K2EDTA 
for measurement of plasma concentrations of atorvastatin and ortho-hydroxyatorvastatin as 
specified in the SoA.  Instructions for the collection and handling of biological samples will 
be provided in the laboratory manual or by the sponsor.  The actual date and time (24-hour 
clock time) of each sample will be recorded.


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Samples collected for analyses of atorvastatin (plasma) and ortho-hydroxyatorvastatin 
concentration may also be used to evaluate safety 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.
8.4.2. PK of Midazolam and 1-OH-Midazolam
Samples will be used to evaluate the PK of midazolam and 1-OH-midazolam.  Blood 
samples of approximately 4 mL, to provide two aliquots of plasma volume of approximately
1 mL each, will be collected into appropriately labeled tubes containing K2EDTA for 
measurement of plasma concentrations of midazolam and 1-OH-midazolam as specified in 
the SoA.  Instructions for the collection and handling of biological samples will be provided 
in the laboratory manual or by the sponsor.  The actual date and time (24 hour clock time) of 
each sample will be recorded.
Samples collected for analyses of midazolam and 1-OH-midazolam (plasma) concentration 
may also be used to evaluate safety 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.
8.4.3. PK of Levonorgestrel
Samples will be used to evaluate the PK of LE.  Blood samples of approximately 6 mL, to 
provide plasma volume of approximately 3 mL, will be collected into appropriately labeled 
tubes containing K2EDTA for measurement of plasma concentrations of LE as specified in 
the SoA.  Instructions for the collection and handling of biological samples will be provided 
in the laboratory manual or by the sponsor.  The actual date and time (24-hour clock time) of 
each sample will be recorded.
Samples collected for analyses of LE plasma concentration may also be used to evaluate 
safety 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.
8.4.4. PK of Ethinyl Estradiol
Samples will be used to evaluate the PK of EE.  Blood samples of approximately 6 mL, to 
provide plasma volume of approximately 3 mL, will be collected into appropriately labeled 
tubes containing K2EDTA for measurement of plasma concentrations of EE as specified in 
the SoA.  Instructions for the collection and handling of biological samples will be provided 
in the laboratory manual or by the sponsor.  The actual date and time (24 hour clock time) of 
each sample will be recorded.
Samples collected for analyses of EE plasma concentration may also be used to evaluate 
safety aspects related to concerns arising during or after the study, for metabolite 
identification and/or evaluation of the bioanalytical method, or for other internal exploratory 
purposes.


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8.4.5. PK of PF-06882961 
Samples will be used to evaluate the PK of PF-06882961.  Blood samples of approximately 
2 mL, to provide plasma volume of approximately 1 mL , will be collected into appropriately 
labeled tubes containing K2EDTA for measurement of plasma concentrations of 
PF-06882961 as specified in the SoA.  Instructions for the collection and handling of 
biological samples will be provided in the laboratory manual or by the sponsor.  The actual 
date and time (24-hour clock time) of each sample will be recorded.
Samples collected for analyses of PF-06882961 plasma concentration may also be used to 
evaluate safety aspects or efficacy related to concerns arising during or after the study, for 
metabolite identification and/or evaluation of the bioanalytical method, or for other internal 
exploratory purposes.
 
 
 
 
 
 
 
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8.6.5. Plasma for Analysis of 4-β-hydroxycholesterol/cholesterol (Part A only)
Blood samples of approximately 4 mL, to provide plasma volume of approximately 2 mL, 
will be collected into appropriately labeled tubes containing lithium heparin for the analysis 
of 4-β-hydroxycholesterol and cholesterol at times specified in the SoA.  Instructions for the 
collection and handling of biological samples will be provided in the laboratory manual.
Samples collected for analyses of 4-β-hydroxycholesterol/cholesterol plasma concentration 
may also be used to evaluate safety aspects or efficacy 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.
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
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9.1. Statistical Hypotheses
No formal statistical hypothesis testing will be performed in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention
"Enrolled" means a participant's agreement to participate in a 
clinical study following completion of the informed consent 
process. 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
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 received at least 1 dose of atorvastatin, midazolam, an 
oral contraceptive and/or PF-06882961 and in whom at least
1 plasma concentration value is reported.
PK Parameter Set
The PK parameter analysis population is defined as all 
participants who received at least 1 dose of atorvastatin,
midazolam, an oral contraceptive and/or PF-06882961 and 
have at least 1 of the PK parameters of interest calculated. 
Should vomiting occur after co-administration of atorvastatin, 
midazolam, or the oral contraceptive with PF-06882961, the 
resulting PK parameters 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
9.3.1.1. Derivation of Pharmacokinetic Parameters
The plasma PK parameters for atorvastatin, ortho-hydroxyatorvastatin, midazolam,
1-OH-midazolam, LE and EE following SD administration (either alone or in 
co-administration with PF-06882961) will be derived from the concentration-time profiles as 


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detailed in Table 11 below.  The plasma PK parameters for PF-06882961 following MD
administration will be derived from the concentration-time profiles as detailed in Table 12
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.
Table 11.
Plasma PK Parameters for Atorvastatin, Ortho-hydroxyatorvastatin, 
Midazolam, 1-OH-Midazolam, Levonorgestrel and Ethinyl Estradiol
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). 
Ortho-
hydroxyatorvastatin/atorvastatin 
ratio
Atorvastatin metabolite/parent 
ratio
Ortho-hydroxyatorvastatin 
AUC/atorvastatin AUC
1-OH-midazolam/midazolam 
ratio
Midazolam metabolite/parent 
ratio
1-OH-midazolam AUC/midazolam 
AUC
* as data permit; CL/F and Vz/F will not be calculated for ortho-hydroxyatorvastatin or 1-OH-midazolam.


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Table 12.
Plasma PK Parameters for PF-06882961
Parameter
Definition
Method of Determination
AUC24
Area under the plasma 
concentration-time profile from 
time zero to time 24 hours.
AUCτ1 (area under the plasma 
concentration-time profile where 
τ1 = 0 to 10 hours) +AUCτ2 (area 
under the plasma 
concentration-time profile where 
τ2 = 10 to 24 hours).
Cmax
Maximum plasma concentration 
observed from time zero to 
10 hours.
Observed directly from data.
Tmax
Time for Cmax.
Observed directly from data as time 
of first occurrence.
9.3.2. Statistical Methods for Pharmacokinetic Data
The PK data for atorvastatin, ortho-hydroxyatorvastatin, midazolam, 1-OH-midazolam, LE, 
EE and PF-06882961 will be analyzed and reported separately.
Plasma concentrations will be listed and summarized descriptively by PK sampling time and 
treatment (dosing alone vs. co-administration or dose by Part of study, as applicable).
Individual participant and median profiles of the concentration-time data will be plotted by
treatment. 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 for plasma samples. Median profiles will be presented on both linear-linear 
and log-linear scales.
Natural loge-transformed AUCinf (as data permit) of atorvastatin administered alone or 
co-administered with PF-06882961 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 ‘atorvastatin and PF-06882961 120 mg BID’ (Period 
4) and ‘atorvastatin and PF-06882961 200 mg BID’ (Period 7), which will be reported 
separately in comparison to the reference treatment of ‘atorvastatin alone’ (Period 1).  The 
same analysis for natural loge-transformed Cmax and AUClast of atorvastatin will also be 
conducted.
Natural loge-transformed AUCinf (as data permit), Cmax and AUClast of midazolam 
administered alone or co-administered with PF-06882961 will be analyzed and reported 
separately using the same mixed effect model as described above for atorvastatin.  The 2 test 
treatments will be ‘midazolam and PF-06882961 120 mg BID’ (Period 5) and ‘midazolam 
and PF-06882961 200 mg BID’ (Period 8), which will be reported separately in comparison 
to the reference treatment of ‘midazolam alone’ (Period 2).


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Natural loge-transformed AUCinf (as data permit), Cmax and AUClast of LE and EE
administered alone or co-administered with PF-06882961 will be analyzed and reported 
separately using the same mixed effect model as described above for atorvastatin.  For LE, 
the 2 test treatments will be ‘LE and PF-06882961 120 mg BID’ (Period 3) and ‘LE and 
PF-06882961 200 mg BID’ (Period 5), which will be reported separately in comparison to 
the reference treatment of ‘LE alone’ (Period 1). Similarly for EE, the 2  test treatments will 
be ‘ EE and PF-06882961 120 mg BID’ (Period 3) and ‘ EE and PF-06882961 200 mg BID’ 
(Period 5), which will be reported separately in comparison to the reference treatment of ‘ EE
alone’ (Period 1).
In the event that less than 12 participants have PK parameters related to co-administration 
with PF-06882961 200 mg BID, the above mixed effect models may 
additionally/alternatively include PK parameters from the maximum tolerated dose of 
PF-06882961 (if applicable), where further details will be included in the SAP.
The above and other PK parameters for atorvastatin, ortho-hydroxyatorvastatin, midazolam, 
1-OH-midazolam, LE and EE, and PK parameters for PF-06882961, will be separately 
summarized descriptively by treatment.
The plasma 4--hydroxycholesterol, cholesterol and EV concentrations will be summarized 
descriptively by period (Day 1 in Periods 2, 5, and 8 in Part A only). The plasma ratios of
4--hydroxycholesterol/cholesterol will also be summarized descriptively by period.  Percent 
change for the 4--hydroxycholesterol/cholesterol ratio from baseline (Day 1 Period 2 in 
Part A) will be reported, where further details will be included in the SAP. Exploratory EV 
data are not planned to be included in the CSR.
9.3.3. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, PR, body weight 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 PR 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.  


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9.3.3.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, HR, QTcF interval, PR interval, 
and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
9.3.4. Other Analyse(s)
Tertiary/Exploratory analyses not included in the pharmacokinetic or safety analyses outlined 
above will be documented in the SAP. 
 
9.4. Interim Analyses
No formal interim analysis will be conducted for this study.  As this is an open-label study, 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK modeling, and/or supporting clinical 
development. 
9.5. Sample Size Determination
A sample size of approximately 16 participants will be enrolled into each part of the study 
separately (for a total of approximately 32 participants), such that approximately 
12 evaluable participants complete each part of the study (for a total of approximately 
24 participants).  This number of evaluable participants has been selected to provide 
sufficient precision to detect a 1.25-fold difference in AUCinf for either atorvastatin, 
midazolam, LE or EE as described below. 
The primary comparisons of interest are as follows:
Part A:
•
For atorvastatin AUCinf: 
•
The co-administration of atorvastatin and PF-06882961 120 mg BID (Period 4) 
versus atorvastatin alone (Period 1, reference treatment).
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
The co-administration of atorvastatin and PF-06882961 200 mg BID (Period 7) 
versus atorvastatin alone (Period 1, reference treatment).

For midazolam AUCinf:

The co-administration of midazolam and PF-06882961 120 mg BID (Period 5) 
versus midazolam alone (Period 2, reference treatment).

The co-administration of midazolam and PF-06882961 200 mg BID (Period 8) 
versus midazolam alone (Period 2, reference treatment).
Part B:

For LE AUCinf: 

The co-administration of LE (as an OC) and PF-06882961 120 mg BID (Period 3) 
versus LE alone (Period 1, reference treatment). 

The co-administration of LE and PF-06882961 200 mg BID (Period 5) versus LE 
alone (Period 1, reference treatment). 

For EE AUCinf: 

The co-administration of EE (as an OC) and PF-06882961 120 mg BID (Period 3) 
versus EE alone (Period 1, reference treatment). 

The co-administration of EE and PF-06882961 200 mg BID (Period 5) versus EE
alone (Period 1, reference treatment). 
The expected widths of the 90% CIs with 80% coverage probability for these comparisons 
are shown in Table 13 for a range of possible effects based on a sample size of 
12 participants for Parts A and B separately.


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Table 13.
Expected Widths of the 90% CIs (with 80% Coverage Probability) for 
Different Possible Estimated Effects and Parameters of Interest
Parameter
Estimated Effect
(Test/Reference)
Probable
90% CI
Probable
CI Width
AUCinf (Part A: atorvastatin or
midazolam)
75%
60 to 94%
34%
100%
80 to 125%
45%
125%
100 to 156%
56%
150%
120 to 187%
67%
200%
160 to 250%
89%
AUCinf (Part B: LE or EE)
75%
64% to 88%
24%
100%
86% to 117%
31%
125%
107% to 146%
39%
150%
128% to 175%
47%
200%
171% to 234%
63%
These estimates are based on an assumed conservative standard deviation of 
0.284 (equivalent to a geometric coefficient of variation of 29%) in logeAUCinf for both 
atorvastatin and midazolam in Part A of the study. For LE or EE in Part B of the study, these 
estimates are based on an assumed conservative standard deviation of 0.20 (equivalent to a 
geometric coefficient of variation of 20%) in logeAUCinf.  These estimates are based on data 
from previous internal DDI studies of atorvastatin, midazolam or an oral contraceptive of
LE/EE.


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


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


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Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password-protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
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, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.


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


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes source data and its origin can be found in the clinical 
monitoring plan, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.


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The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications,
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.


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The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the SToD system. 
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, 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 investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number 
is not intended for use by the participant directly; if a participant calls that number directly, 
he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 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
eGFR
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST
ALT
Total bilirubin
Direct bilirubin
Indirect bilirubin
GGT
Alkaline phosphatase
Uric acid
Albumin
Total protein
Urinalysis:

pH

Glucose (qual)

Protein (qual)

Blood (qual)

Ketones

Nitrites

Leukocyte 
esterase

Urobilinogen

Urine bilirubin

Microscopya
HbA1c
Serum pregnancy test 
(-hCG)b
Lipid panel:

Total cholesterol

Direct LDL-C

HDL-C

Triglycerides
TSH
Free T4
Calcitonin
Amylase
Lipase
Serum TBA
PT/INR/aPTT
SARS-CoV-2 test
Urine drug screeningc
Screening only:
FSHd
C-peptide (fasting)
HIV
HepBsAg
HCVAb
HCV RNA
Additional Tests (Needed 
for Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
CK
GGT
PT/INR
Total bile 
acidsAcetaminophen drug 
and/or protein adduct levels
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
Part A Only - Serum -hCG for all WOCBP.


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c.
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-1and at the discretion of the 
investigator.
d.
For all female participants to confirm PM status only.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.


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


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


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


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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; 
(2) nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF.
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE).**
Environmental or 
occupational exposure to 
the product under study 
to a non-participant (not 
involving EDP or EDB).
None.  Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using CT SAE Report Form and EDP Supplemental Form; if the EDP is associated with an 
SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form which would also include details 
of any SAE that might be associated with the EDB. 
*** Environmental or Occupational exposure: AEs or SAEs associated with occupational exposure are 
reported to Pfizer Safety using the CT SAE Report Form. 


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
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.

Moderate: Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.

Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self 
care ADL. Self care ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.


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


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
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male
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
Female Participant Options
Part A
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 definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below 
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).  The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention.

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with high user dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention, 
which corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s).  In addition, a second effective method of contraception, as 
described below, must be used.  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. 
Part B
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 definitions below in Section 10.4.3).


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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;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
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
Part A
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.


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Highly Effective Methods That Have Low User Dependency 
1. Intrauterine device.
2. Bilateral tubal occlusion.
3. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
Sexual abstinence.

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent:

Male or female condom with or without spermicide.

Cervical cap, diaphragm, or sponge with spermicide.

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).
Part B
Not Applicable. 


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CCI


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI.  
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample). In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, TBA, and alkaline phosphatase. Consideration should also be given to 
drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: 
ie, rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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


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10.8. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
ADL
activities of daily living
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCinf
area under the plasma concentration-time profile from 
time zero extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from 
time zero to the time of the last quantifiable 
concentration (Clast)
AUCτ1
area under the plasma concentration-time profile 
where τ1 = 0 to 10 hours
AUCτ2
area under the plasma concentration-time profile 
where τ1 = 10 to 24 hours
AUC24
area under the plasma concentration-time profile from 
time zero to time 24 hours
AV
atrioventricular
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
C-SSRS
Columbia Suicide Severity Rating Scale
cAMP
3’-5’-cyclic adenosine monophosphate 
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical 
Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL/F
apparent oral clearance


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Abbreviation
Term
Clast
predicted plasma concentration at the last quantifiable 
time point estimated from the log-linear regression 
analysis
Cmax
maximum plasma concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
%CV
percent coefficient of variation 
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
EC
ethics committee
ECC
Emergency Contact Card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
EE
ethinyl estradiol
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ET
early termination
EudraCT
European Clinical Trials Database
EV
extracellular vesicles
FSBG
fingerstick blood glucose
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GLP-1 
glucagon-like peptide 1 
GLP-1R
glucagon-like peptide 1 receptor 
HAE
hypoglycemic adverse event
HbA1c
hemoglobin A1c
HepBsAg 
hepatitis B surface antigen
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
HDL-C
high density lipoprotein cholesterol


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Abbreviation
Term
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IC50
50% inhibitive concentration
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IMP
investigational medicinal product 
IND
Investigational New Drug 
INR
international normalized ratio
IP 
investigational product 
IPAL
Investigational Product Accountability Log
IR
immediate release
IRB
Institutional Review Board
IV
intravenous(ly)
IVGTT
intravenous glucose tolerance test 
kel
first-order elimination rate constant
KI
apparent inactivation constant at half-maximal rate of 
inactivation
kinact
maximal inactivation rate 
K2EDTA
dipotassium ethylenediaminetetraacetic acid 
LBBB
left bundle branch block
LDL-C
low density lipoprotein cholesterol
LE
levonorgestrel
LFT
liver function test
MATE
multidrug and toxin extrusion protein 
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MD
multiple-dose
MDR
multidrug resistance
MEN2
multiple endocrine neoplasia syndrome type 2 
MHP
mental health professional
msec
millisecond
MTC
medullary thyroid carcinoma
N/A
not applicable
NOAEL
no-observed-adverse-effect level
OATP
organic anion transporting polypeptides
OC
oral contraceptive
OCT
organic cation transporter 
PCR
polymerase chain reaction


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Abbreviation
Term
PD
pharmacodynamic(s)
PHQ-9
Patient Health Questionnaire-9
PK
pharmacokinetic(s)
PM
post-menopausal
PR
pulse rate
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
once daily
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
QTL
quality tolerance limits
Rac
mean ratios based on dose normalized AUC24
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
single-dose; standard deviation
SIB
Suicidal Ideation and Behavior 
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SToD
study team on demand
SSID
study-specific subject identification number
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
terminal half-life
T2DM
type 2 diabetes mellitus
T4
thyroxine
TBA
total bile acids
TBili
total bilirubin
TEAE
treatment emergent adverse event 
THC
tetrahydrocannabinol
Tmax
time to Cmax
TSH
thyroid stimulating hormone
UGT
uridine 5'-diphospho glucuronosyltransferase 
ULN
upper limit of normal
US
United States
USPI
United States Package Insert 
Vz/F
apparent volume of distribution
WBC
white blood cell
WOCBP
woman 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, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology. 1986;119(4):1467-75.
2.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet. 1987;2(8571):1300-4.
3.
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol.
1997;273(5):E981-8.
4.
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest. 1998;101(3):515-20.
5.
IDF Diabetes Atlas; 9th Edition. Available from: http://www.idf.org/diabetesatlas.
Accessed 04 Feb 2019.
6.
Menke A, Casagrande S, Geiss L,et al. Prevalence of and trends in diabetes among 
adults in the United States,1988-2012. JAMA. 2015;314(10):1021-9.
7.
Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and 
microvascular complications of type 2 diabetes (UKPDS 35): prospective observational 
study. BMJ. 2000;321:405-12.
8.
Guh DP, Zhang W, Bansback N, et al. The incidence of co-morbidities related to 
obesity and overweight: a systematic review and meta-analysis. BMC Public Health.
2009;9:88.
9.
Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with overweight 
and obesity using standard body mass index categories: a systematic review and 
meta-analysis. JAMA. 2013;309(1):71-82.
10.
The GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 
195 countries over 25 years. N Engl J Med. 2017;377(1):13-27.
11.
Anderson JW, Konz EC, Frederich RC, et al. Long-term weight-loss maintenance: a 
meta-analysis of US studies. Am J Clin Nutr. 2001;74(5):579-84.
12.
Drucker DL. The ascending GLP-1 road from clinical safety to reduction of 
cardiovascular complications. Diabetes. 2018;67:1710-9. 


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13.
Lipitor.  Highlights of Prescribing Information. Revised April2019.  Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020702s073lbl.pdf.
Accessed 24 AUG 2021Midazolam Hydrochloride Syrup CIV. August 2015. Available 
from: https://docs.boehringer-
ingelheim.com/Prescribing%20Information/PIs/Roxane/Midazolam/MidazolamHClSyr
up.pdf. Accessed 24 AUG 2021.
14.
Levonorgestrel and Ethinyl Estradiol Tablets USP, 0.15 mg /0.03 mg. United States 
Prescribing Information. Revised May, 2016. Available from:
https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=068199a9-ef22-
4061-bb76-1ee58f726018. Accessed 24 AUG 2021Brill MJ, Diepstraten J, van Rongen 
A, et al.  Impact of obesity on drug metabolism and elimination in adults and children. 
Clin Pharmacokinet. 2012;51(5):277-304.
15.
AbernethyDR, Greenblatt DJ, Divoll M, et al.  The influence of obesity on the 
pharmacokinetics of oral alprazolam and triazolam.  ClinPharmacokinet. 1984;9(2):177-
83.
16.
Caraco Y, Zylber-Katz E, Berry EM, et al. Significant weight reduction in obese 
subjects enhances carbamazepine elimination. Clin Pharmacol Ther. 1992;51(5): 501-6.
17.
Brill,MJ, van Rongen A, van Dongen EP, et al.  The pharmacokinetics of the CYP3A 
substrate midazolam in morbidly obese patients before and one year after bariatric 
surgery. Pharm Res. 2015;32:3927–36.
18.
Midazolam Injection, USP. United States Prescribing Information.  March 2017. 
Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208878Orig1s000lbl.pdf.
Accessed 24 AUG 2021
19.
Greenblatt DJ, Abernethy DR, Locniskar A, et.al. Effect of age, gender, and obesity on 
midazolam kinetics. Anesthesiology. 1984;61(1):27-35.
20.
GarcíaMJ, Reinoso RF, Sánchez Navarro A, et al. Clinical pharmacokinetics of statins. 
Methods Find Exp Clin Pharmacol. 2003:25(6):457-81. 
21.
Robert LL, Matthys KE, Verpooten GA, et al. Pharmacokinetics of atorvastatin and its 
metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis 
patients.  Nephrol Dial Transplant, 2003:18:967–76.
22.
Posvar EL, Radulovic LL, Cilla DD JR, et.al. Tolerance and pharmacokinetics of 
single-dose atorvastatin, a potent inhibitor of HMG-coA reductase, in healthy subjects. J 
Ciin Pharmacol. 1996;36:728-31.
23.
Nichols M, Robinson, G, Bounds, W, et al.  Effect of four combined oral contraceptives 
on blood pressure in the pill-free interval. Contraception. 1993;47:367-76.


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OZEMPIC® (semaglutide). United States Prescribing Information. January 2020.  
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https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdf.
Accessed 02 Apr 2020.
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TRULICITY® (dulaglutide). United States Prescribing Information. February 2020. 
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Accessed 02 Apr 2020.
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SAXENDA® (liraglutide). United States Prescribing Information. March 2020.  
Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206321s011lbl.pdf.
Accessed 02 Apr 2020.
27.
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.
28.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity
measure. J Gen Intern Med. 2001;16(9):606-13.
29.
VICTOZA® (liraglutide). United States Prescribing Information. June 2019.  Available 
from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022341s031lbl.pdf.
Accessed 02 Apr 2020.
30.
Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update.  
Clin Transl Med. 2016;5(1):23-37.
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University of Washington, School of Pharmacy, Drug Interaction Solutions.  Available 
from: https://www.druginteractionsolutions.org/. Accessed 24 AUG 2021
32.
Crawford P, Chadwick DJ, Martin C, et al. The interaction of phenytoin and 
carbamazepine with combined oral contraceptive steroids.  Br J Clin Pharmac. 
1990;30:892-6.
33.
American Diabetes Association. Standards of medical care in diabetes -2019. Diabetes 
Care. 2019;42(Suppl 1): S1-S193.
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Rodrigues AD, van Dyk M, Sorich MJ, et al. Exploring the use of serum-derived small 
extracellular vesicles as liquid biopsy to study the induction of hepatic cytochromes 
P450 and organic anion transporting polypeptides. Clin Pharmacol Ther. 
2021;110(1):248-58.

SAP_001.pdf: 
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Protocol C3421047 
 
 
 
 
A PHASE 1, OPEN-LABEL, TWO-PART STUDY TO EVALUATE THE EFFECT OF 
TWO STEADY-STATE DOSE LEVELS OF PF-06882961 ON THE 
PHARMACOKINETICS OF SINGLE ORAL DOSES OF ATORVASTATIN AND 
MIDAZOLAM IN HEALTHY ADULTS AND AN ORAL CONTRACEPTIVE IN 
HEALTHY POST-MENOPAUSAL FEMALES 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
1.0 
 
Date:  
14 Oct 2021    


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TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................4 
LIST OF FIGURES ...................................................................................................................5 
APPENDICES ...........................................................................................................................5 
1. VERSION HISTORY ............................................................................................................6 
2. INTRODUCTION .................................................................................................................7 
2.1. Study Objectives, Endpoints, and Estimands ............................................................7 
2.2. Study Design .............................................................................................................9 
2.2.1. Part A ............................................................................................................9 
2.2.2. Part B ..........................................................................................................10 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................11 
3.1. Primary Endpoint(s) ................................................................................................11 
3.1.1. Part A ..........................................................................................................11 
3.1.2. Part B ..........................................................................................................12 
3.2. Secondary Endpoint(s) ............................................................................................13 
3.2.1. Safety Endpoints .........................................................................................13 
3.2.2. Assessment of Mental Health .....................................................................14 
3.2.2.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................14 
3.2.2.2. Patient Health Questionnaire (PHQ-9) ......................................14 
3.2.3. Exploratory Safety Endpoints .....................................................................14 
3.3. Other Endpoint(s) ....................................................................................................15 
3.3.1. Part A ..........................................................................................................15 
3.3.1.1. Additional plasma PK Parameters for atorvastatin and 
midazolam .........................................................................................15 
3.3.1.2. Plasma PK Parameters for PF-06882961 ..................................15 
3.3.1.3. Plasma PK Parameters for Ortho-hydroxyatorvastatin and 
1-OH-midazolam ...............................................................................16 
3.3.1.4. Biomarkers of CYP3A Induction (Optional) ............................17 
3.3.2. Part B ..........................................................................................................17 


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3.3.2.1. Additional plasma PK Parameters for LE and EE ....................17 
3.3.2.2. Plasma PK Parameters for PF-06882961 ..................................18 
3.3.3. Banked Biospecimens .................................................................................18 
3.4. Baseline Variables ...................................................................................................18 
3.5. Safety Endpoints .....................................................................................................19 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ...................................................19 
5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................20 
5.1. Hypotheses and Decision Rules ..............................................................................20 
5.2. General Methods .....................................................................................................20 
5.2.1. Treatment Labels and Groupings ................................................................20 
5.2.1.1. Part A .........................................................................................20 
5.2.1.2. Part B .........................................................................................20 
5.2.2. Analyses for Continuous Endpoints ...........................................................21 
5.2.3. Analyses for Categorical Endpoints ...........................................................21 
5.2.4. Mixed Effects Model ..................................................................................21 
5.3. Methods to Manage Missing Data ..........................................................................21 
5.3.1. Plasma PK Parameters ................................................................................22 
6. ANALYSES AND SUMMARIES ......................................................................................22 
6.1. Primary Endpoint(s) ................................................................................................23 
6.1.1. Part A ..........................................................................................................23 
6.1.1.1. AUCinf and AUClast for atorvastatin and midazolam .................23 
6.1.2. Part B ..........................................................................................................25 
6.1.2.1. AUCinf  and AUClast for LE and EE ...........................................25 
6.2. Secondary Endpoint(s) ............................................................................................26 
6.2.1. Adverse Events ...........................................................................................26 
6.2.2. Laboratory Data ..........................................................................................27 
6.2.3. Vital Signs ..................................................................................................27 
6.2.4. Electrocardiogram (ECG) ...........................................................................28 
6.2.5. C-SSRS .......................................................................................................28 


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6.2.6. PHQ-9 .........................................................................................................28 
6.2.7. Mental Health Risk Assessment .................................................................28 
6.2.8. Exploratory Safety Endpoints .....................................................................29 
6.3. Other Endpoint(s) ....................................................................................................29 
6.3.1. Part A ..........................................................................................................29 
6.3.1.1. Additional plasma PK Parameters for atorvastatin and 
midazolam .........................................................................................29 
6.3.1.2. Plasma PK Parameters for PF-06882961 ..................................30 
6.3.1.3. Ortho-hydroxyatorvastatin and 1-OH-midazolam ....................31 
6.3.1.4. Biomarkers of CYP3A Induction (Optional) ............................33 
6.3.2. Part B ..........................................................................................................33 
6.3.2.1. Additional plasma PK Parameters for LE and EE ....................33 
6.3.2.2. Plasma PK Parameters for PF-06882961 ..................................35 
6.4. Subset Analyses .......................................................................................................35 
6.5. Baseline and Other Summaries and Analyses .........................................................35 
6.5.1. Baseline Summaries ....................................................................................35 
6.5.2. Study Conduct and Participant Disposition ................................................35 
6.5.3. Concomitant Medications and Nondrug Treatments ..................................35 
6.5.4. Other Screening Data ..................................................................................35 
6.6. Safety Summaries and Analyses .............................................................................36 
7. INTERIM ANALYSES .......................................................................................................36 
7.1. Introduction .............................................................................................................36 
7.2. Interim Analyses and Summaries ............................................................................36 
8. REFERENCES ....................................................................................................................36 
9. APPENDICES .....................................................................................................................37 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ..................................................................................6 
Table 2. Summary of primary atorvastatin and midazolam plasma PK parameters to be 
calculated ..................................................................................................12 


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Table 3. Summary of primary LE and EE plasma PK parameters to be calculated ................12 
Table 4. Summary of additional atorvastatin and midazolam plasma PK parameters to 
be calculated .............................................................................................15 
Table 5. Summary of PF-06882961 plasma PK parameters to be calculated ..........................16 
Table 6. Summary of ortho-hydroxyatorvastatin and 1-OH-midazolam plasma PK 
parameters to be calculated .......................................................................16 
Table 7. Summary of parameters to be calculated for exploratory analysis ............................17 
Table 8. Summary of additional LE and EE plasma PK Parameters to be calculated .............18 
Table 9. Summary of PF-06882961 plasma PK parameters to be calculated ..........................18 
Table 10. Summary statistics for primary PK parameters for atorvastatin and 
midazolam .................................................................................................23 
Table 11. Summary statistics for primary PK parameters for LE and EE ...............................25 
Table 12. Summary statistics for additional plasma PK parameters for atorvastatin and 
midazolam .................................................................................................29 
Table 13. Summary statistics for plasma PK parameters for PF-06882961 ............................30 
Table 14. Summary statistics for plasma PK parameters for ortho-hydroxyatorvastatin 
and 1-OH-midazolam ...............................................................................32 
Table 15. Summary statistics for additional plasma PK parameters for LE and EE ...............34 
 
LIST OF FIGURES 
Figure 1 Part A Study Design ..................................................................................................10 
Figure 2 Part B Study Design ..................................................................................................11 
 
APPENDICES 
Appendix 1. Summary of PK Analyses (Mixed Effects Model) .............................................37 
Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....37 
Appendix 3. C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events and 
Codes ........................................................................................................38 
Appendix 4. List of Abbreviations...........................................................................................39 
 
 


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1. VERSION HISTORY 
Table 1. 
Summary of Changes  
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1.0 
14 Oct 2021 
 
Original 
30 Aug 2021 
N/A 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3421047.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment. 
This is a Phase 1, open-label, 2-part study to evaluate the effect of 2 steady-state dose levels 
of PF-06882961 on the single-dose (SD) pharmacokinetics of 1) atorvastatin and midazolam 
in healthy adult male and female participants (Part A), and 2) an oral contraceptive (OC) in 
healthy post-menopausal (PM) female participants (Part B). The intent of this study is to 
generate safety, tolerability, and pharmacokinetic data for further clinical development. 
2.1. Study Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Part A 
 
Primary: 
Primary 
• To evaluate the effects of PF-06882961 on 
the pharmacokinetics of atorvastatin in 
healthy male and female adult participants. 
 • To evaluate the effects of PF-06882961 on 
the pharmacokinetics of midazolam in 
healthy male and female adult participants. 
• Atorvastatin plasma pharmacokinetic 
parameters: AUCinf (if data permit* 
otherwise AUClast) in Periods 1, 4 and 7.  
• Midazolam plasma pharmacokinetic 
parameters: AUCinf (if data permit* 
otherwise AUClast) in Periods 2, 5 and 8. 
Secondary: 
Secondary: 
• To evaluate the safety and tolerability of 
PF-06882961 administered separately and 
in combination with atorvastatin or 
midazolam in healthy male and female adult 
participants. 
• Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and 
ECG parameters during Part A of the study. 
 • Assessment of mental health as 
determined by C-SSRS and PHQ-9 during 
Part A of the study. 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
• To evaluate the effects of PF-06882961 on 
additional pharmacokinetic parameters of 
atorvastatin and midazolam in healthy male 
and female adult participants. 
• Additional plasma pharmacokinetic 
parameters for atorvastatin (Periods 1, 4 
and 7) and midazolam (Periods 2, 5 and 8): 


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Cmax and Tmax; and CL/F, Vz/F, t½, as data 
permit. 
• To evaluate the MD pharmacokinetics of 
PF-06882961 in healthy male and female 
adult participants. 
• To evaluate the effects of PF-06882961 on 
the pharmacokinetics of ortho-
hydroxyatorvastatin in healthy male and 
female adult participants. 
• To evaluate the effects of PF-06882961 on 
the pharmacokinetics of 1-OH-midazolam in 
healthy male and female adult participants 
 
 
 
• To evaluate the effects of PF-06882961 on 
biomarkers of CYP3A induction. [Optional]. 
• PF-06882961 plasma pharmacokinetic 
parameters at Days 35 and 58: AUC24, Cmax, 
Tmax. 
• Ortho-hydroxyatorvastatin plasma 
pharmacokinetic parameters: AUClast, Cmax, 
Tmax; and AUCinf and t½ as data permit in 
Periods 1, 4 and 7. Metabolite/parent 
(ortho-hydroxyatorvastatin/atorvastatin) 
ratios will also be calculated. 
• 1-OH-midazolam plasma pharmacokinetic 
parameters: AUClast, Cmax, Tmax; and AUCinf 
and t½ as data permit in Periods 2, 5 and 8. 
Metabolite/parent (1-OH-
midazolam/midazolam) ratios will also be 
calculated.  
• Morning predose 4-β-
hydroxycholesterol/cholesterol plasma ratio 
on Day 1 in Periods 2, 5, and 8. Morning 
predose plasma-derived EV on Day 1 in 
Periods 2, 5, and 8. 
Part B 
 
Primary: 
Primary: 
• To evaluate the effects of PF-06882961 on 
the pharmacokinetics of an OC (LE/EE) in 
healthy PM female participants. 
• LE plasma pharmacokinetic parameters: 
AUCinf (if data permit* otherwise AUClast) in 
Periods 1, 3 and 5.  
• EE plasma pharmacokinetic parameters: 
AUCinf (if data permit* otherwise AUClast) in 
Periods 1, 3 and 5. 
 
 


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Secondary: 
Secondary: 
• To evaluate the safety and tolerability of 
PF-06882961 administered separately and 
in combination with an OC (LE/EE) in 
healthy PM female participants. 
• Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, body weight, and 
ECG parameters during Part B of the study.  
• Assessment of mental health as determined 
by C-SSRS and PHQ-9 during Part B of the 
study. 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
• To evaluate the effects of PF-06882961 on 
additional pharmacokinetic parameters of 
an OC (LE/EE), administered separately, in 
healthy PM female participants. 
 • To evaluate the pharmacokinetics of 
multiple doses of PF-06882961 in healthy 
PM female participants 
• Additional plasma pharmacokinetic 
parameters for LE and EE (both in Periods 
1, 3 and 5): Cmax, Tmax; and CL/F, Vz/F, t½ 
as data permit.  
• PF-06882961 plasma pharmacokinetic 
parameters at Days 36 and 60: AUC24, Cmax, 
Tmax. 
*Should it be deemed that too few AUCinf estimates (eg, less than 12 for a single treatment) 
are obtained from the evaluable participants, AUClast may be selected as the primary 
endpoint for CSR reporting. This will be considered for the atorvastatin, midazolam, LE, 
and EE objectives separately.  
There are no estimands for this study. 
2.2. Study Design 
This study will be conducted in 2 parts. Part A will evaluate the effect of 2 steady-state dose 
levels of PF-06882961 on the SD pharmacokinetics of atorvastatin and midazolam. Part B 
will evaluate the effect of 2 steady-state dose levels of PF-06882961 on the SD 
pharmacokinetics of an OC. Participants will participate in either Part A or Part B (not 
both), and Parts A and B are expected to be conducted in parallel, if possible. Participants 
who discontinue from the study before completing all assessments may be replaced at the 
discretion of the investigator and Sponsor. 
2.2.1. Part A 
Part A of this study is an open-label, 8-period, fixed-sequence study to evaluate the effect of 
PF-06882961, administered at 2 PK steady-state dose levels, on the SD PK of atorvastatin 
and midazolam, administered separately, in healthy adult male and female participants with 
a BMI ranging from 20.0 kg/m2 to <30.0 kg/m2. Approximately 16 subjects will be enrolled 
in Part A. The total duration of participation from the Screening Visit (28 days) to the FU 


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contact will be approximately 18 weeks; ie, 125 days, of which 64 days will be in-house as 
shown in Figure 1. 
Figure 1 Part A Study Design 
 
The FU visit will occur 7-10 days from the last dose of study intervention and a FU contact 
will occur 28-35 days from the last dose of study intervention. 
2.2.2. Part B 
Part B of this study is an open-label, 5-period, fixed-sequence study to evaluate the effect of 
PF-06882961, administered at 2 PK steady-state dose levels, on the SD PK of an OC (LE 
and EE) in healthy, PM female participants with a BMI ranging from 20.0 kg/m2 to <30.0 
kg/m2. Approximately 16 subjects will be enrolled in Part B. The total duration of 
participation from the Screening Visit (28 days) to the FU contact will be approximately 18 
weeks; ie, 125 days, of which 67 days will be in-house as shown in Figure 2. 
 


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Figure 2 Part B Study Design 
 
The FU visit will occur 7-10 days from the last dose of study intervention and a FU contact 
will occur 28-35 days from the last dose of study intervention. 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS 
Blood samples for pharmacokinetic (PK) analysis of atorvastatin, ortho-hydroxyatorvastatin, 
midazolam, 1-OH-midazolam, levonorgestrel (LE), ethinyl estradiol (EE) and PF-06882961 
will be collected according to the Schedule of Activities given in the protocol.  
PK parameters will be calculated (if possible) from the concentration-time data using 
standard noncompartmental methods. 
3.1. Primary Endpoint(s) 
3.1.1. Part A 
• Atorvastatin plasma pharmacokinetic parameters: AUCinf (if data permit* otherwise 
AUClast) in Periods 1, 4 and 7.  
• Midazolam plasma pharmacokinetic parameters: AUCinf (if data permit* otherwise 
AUClast) in Periods 2, 5 and 8. 
*Should it be deemed that too few AUCinf estimates (eg, less than 12 for a single treatment) 
are obtained from the evaluable participants, AUClast may be selected as the primary 


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endpoint for CSR reporting. This will be considered for the atorvastatin and midazolam 
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 using 
standard non-compartmental methods: 
Table 2. Summary of primary atorvastatin and midazolam plasma PK parameters to be 
calculated 
Parameter 
Analysis Scale 
Atorvastatin 20 mg 
(Periods 1, 4 and 7) 
Midazolam 5 mg 
(Periods 2, 5 and 8) 
AUCinf* 
ln 
A, D 
A, D 
AUClast 
ln 
A, D 
A, D 
*=if data permit. Abbreviations: A=analyzed using a statistical model; D=displayed with 
descriptive statistics; ln=natural-log transformed. 
3.1.2. Part B 
• LE plasma pharmacokinetic parameters: AUCinf (if data permit* otherwise AUClast) 
in Periods 1, 3 and 5.  
• EE plasma pharmacokinetic parameters: AUCinf (if data permit* otherwise AUClast) 
in Periods 1, 3 and 5. 
*Should it be deemed that too few AUCinf estimates (eg, less than 12 for a single treatment) 
are obtained from the evaluable participants, AUClast may be selected as the primary 
endpoint for CSR reporting. This will be considered for the LE and EE 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 3 will be determined using 
standard non-compartmental methods: 
Table 3. Summary of primary LE and EE plasma PK parameters to be calculated 
Parameter 
Analysis Scale 
LE 0.15 mg      
(Periods 1, 3 and 5) 
EE 0.03 mg    
(Periods 1, 3 and 5) 
AUCinf* 
ln 
A, D 
A, D 
AUClast 
ln 
A, D 
A, D 
*=if data permit. Abbreviations: A=analyzed using a statistical model; D=displayed with 
descriptive statistics; ln=natural-log transformed. 


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3.2. Secondary Endpoint(s) 
3.2.1. Safety Endpoints 
• Assessment of TEAEs, clinical laboratory abnormalities, vital signs, body weight, and 
ECG parameters during Part A of the study.  
• Assessment of TEAEs, clinical laboratory abnormalities, vital signs, body weight, and 
ECG parameters during Part B of the study.  
All safety endpoints will be considered separately for the two parts of the study. 
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,  
• vital signs data,  
• body weight,  
• Electrocardiogram (ECG) results. 
For laboratory, vital signs and ECG data there will be two separate definitions for baseline 
that will be calculated separately (where applicable):  
i) using a fixed baseline of the last pre-dose measurement in Period 1. (“Baseline 1”)  
ii) using a fixed baseline of the last pre-dose measurement in Period 2 (Part B) or Period 
3 (Part A). (“Baseline 2”) 
Change from baseline will therefore be calculated twice for each relevant safety endpoint 
using (i) and (ii) above. Data collected in Periods 1 and 2 (Part A only) will not have a 
change from baseline calculated based on the 2nd definition. 
Definitions of baseline body weight for exploratory safety analyses are described in Section 
3.2.3. 


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3.2.2.  Assessment of Mental Health 
• Assessment of mental health as determined by C-SSRS and PHQ-9 during Part A of 
the study. 
• Assessment of mental health as determined by C-SSRS and PHQ-9 during Part B of 
the study. 
3.2.2.1. Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a validated tool to evaluate suicidal ideation and behavior. 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 3 
Baseline is defined as the last pre-dose measurement in Period 1. For this endpoint the 
screening visit will be labelled as ‘Lifetime’ in tables and the recent history (i.e. past 12 
months) will also be reported separately.  
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). 
*The SoA can be found in Section 1 of the protocol.  
The PHQ-9 total score will be derived for each time point separately by summing the 
responses to the 9 questions. 
 Baseline is defined as the last pre-dose measurement in Period 1. 
3.2.3. Exploratory Safety Endpoints 
• 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 
There will be two separate definitions for baseline that will be calculated separately: 
i) using a fixed baseline of the last pre-dose measurement in Period 1. (“Baseline 1”)  


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ii) using a fixed baseline of the last pre-dose measurement in Period 2 (Part B) or Period 
3 (Part A). (“Baseline 2”)  
Change from baseline will therefore be calculated twice for the above endpoints. Data 
collected in Periods 1 and 2 (Part A only) will not have a change from baseline calculated 
based on the 2nd definition. 
3.3. Other Endpoint(s) 
3.3.1. Part A 
3.3.1.1. Additional plasma PK Parameters for atorvastatin and midazolam 
• Additional plasma pharmacokinetic parameters for atorvastatin (Periods 1, 4 and 7) 
and midazolam (Periods 2, 5 and 8): Cmax and Tmax; and CL/F, Vz/F, t½, as data 
permit. 
The additional plasma PK parameters for atorvastatin and midazolam in Table 4 will be 
determined using standard non-compartmental methods: 
Table 4. Summary of additional atorvastatin and midazolam plasma PK parameters to 
be calculated 
Parameter 
Analysis Scale 
Atorvastatin 20mg 
(Periods 1, 4 and 7) 
Midazolam 5mg 
(Periods 2, 5 and 8) 
Cmax 
ln 
A, D 
A, D 
Tmax 
            R 
D 
 D 
t1/2* 
R 
D 
D 
CL/F* 
ln 
D 
D 
Vz/F* 
ln 
D  
D 
*=if data permit. Abbreviations: A=analyzed using a statistical model; D=displayed with 
descriptive statistics; ln=natural-log transformed; R=raw (untransformed). 
3.3.1.2. Plasma PK Parameters for PF-06882961 
• PF-06882961 plasma pharmacokinetic parameters at Days 35 and 58: AUC24, Cmax, 
Tmax. 
The plasma PK parameters for PF-06882961 in Table 5 will be determined using standard 
non-compartmental methods. 


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Table 5. Summary of PF-06882961 plasma PK parameters to be calculated 
Parameter 
Analysis Scale 
PF-06882961 120mg 
(Day 35) 
PF-06882961 200mg   
(Day 58) 
AUC24 
ln 
 D 
 D 
Cmax 
ln 
D 
 D 
Tmax 
R 
D 
D 
Abbreviations: D=displayed with descriptive statistics; ln=natural-log transformed; R=raw 
(untransformed). 
3.3.1.3. Plasma PK Parameters for Ortho-hydroxyatorvastatin and 1-OH-midazolam 
• Ortho-hydroxyatorvastatin plasma pharmacokinetic parameters: AUClast, Cmax, Tmax; 
and AUCinf and t½ as data permit in Periods 1, 4 and 7. Metabolite/parent (ortho-
hydroxyatorvastatin/atorvastatin) ratios will also be calculated. 
• 1-OH-midazolam plasma pharmacokinetic parameters: AUClast, Cmax, Tmax; and 
AUCinf  and t½ as data permit in Periods 2, 5 and 8. Metabolite/parent (1-OH-
midazolam/midazolam) ratios will also be calculated.  
The plasma PK parameters for ortho-hydroxyatorvastatin and 1-OH-midazolam in Table 6 
will be determined using standard non-compartmental methods. 
Table 6. Summary of ortho-hydroxyatorvastatin and 1-OH-midazolam plasma PK 
parameters to be calculated 
Parameter 
Analysis Scale 
Atorvastatin 20mg 
(Periods 1, 4 and 7) 
Midazolam 5mg 
(Periods 2, 5 and 8) 
AUCinf* 
ln 
D 
D 
AUClast 
ln 
D 
D 
Cmax 
ln 
D 
D 
Tmax 
R 
D 
D 
t1/2* 
R 
D 
D 
Metabolite/parent  
AUCinf* ratioa 
(MRAUCinf) 
R 
D 
D 
Metabolite/parent  
AUClast ratioa 
(MRAUClast) 
R 
D 
D 


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Metabolite/parent  
Cmax ratioa 
(MRCmax) 
R 
D 
D 
*If data permit. aDetermined as both ortho-hydroxyatorvastatin AUC or Cmax / atorvastatin 
AUC or Cmax and 1-OH-midazolam AUC or Cmax / midazolam AUC or Cmax separately as 
applicable. Abbreviations: D=displayed with descriptive statistics; ln=natural-log 
transformed; R=raw (untransformed). 
3.3.1.4. Biomarkers of CYP3A Induction (Optional) 
• Morning predose 4-β-hydroxycholesterol/cholesterol plasma ratio on Day 1 in 
Periods 2, 5, and 8. Morning predose plasma-derived EV on Day 1 in Periods 2, 5, 
and 8. 
The associated objective related to these endpoints is optional and the results may not be 
reported in the CSR. 
Table 7. Summary of parameters to be calculated for exploratory analysis 
Parameter 
Analysis Scale 
Morning predose Measurement   
(Periods 2, 5, 8 Day 1) 
4-β-hydroxycholesterol 
concentration 
R 
D 
Cholesterol concentration 
R 
D 
4-β-hydroxycholesterol/cholesterol 
plasma ratio 
R 
D 
EV concentration 
R 
D 
Abbreviations: D=displayed with descriptive statistics; R=raw (untransformed). 
For the parameters listed in Table 7, baseline will be defined as the measurement taken 
predose at Day 1 on Period 2. The percent change from baseline in plasma ratios of 4-β-
hydroxycholesterol/cholesterol will additionally be calculated by first calculating the ratios, 
then the percent change from baseline at each post-dose time point (Day 1 in Periods 5 and 
8). 
3.3.2. Part B 
3.3.2.1. Additional plasma PK Parameters for LE and EE 
• Additional plasma pharmacokinetic parameters for LE and EE (both in Periods 1, 3 
and 5): Cmax, Tmax, CL/F, Vz/F, t½, as data permit.  


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The additional plasma PK parameters for LE and EE in Table 8 will be determined using 
standard non-compartmental methods 
Table 8. Summary of additional LE and EE plasma PK Parameters to be calculated 
Parameter 
Analysis Scale 
LE 0.15 mg       
(Periods 1, 3 and 5) 
EE 0.03 mg    
(Periods 1, 3 and 5) 
Cmax 
ln 
A, D 
A, D 
Tmax 
            R 
D 
 D 
t1/2* 
R 
D 
D 
CL/F* 
ln 
D 
D 
Vz/F* 
ln 
D  
D 
*=if data permit. Abbreviations: A=analyzed using a statistical model; D=displayed with 
descriptive statistics; ln=natural-log transformed; R=raw (untransformed). 
3.3.2.2.  Plasma PK Parameters for PF-06882961 
• PF-06882961 plasma pharmacokinetic parameters at Days 36 and 60: AUC24, Cmax, 
Tmax 
The PK parameters for PF-06882961 in Table 9 will be determined using standard non-
compartmental methods. 
Table 9. Summary of PF-06882961 plasma PK parameters to be calculated 
Parameter 
Analysis Scale 
PF-06882961 120 mg 
(Day 36) 
PF-06882961 200 mg   
(Day 60) 
AUC24 
ln 
 D 
 D 
Cmax 
ln 
D 
 D 
Tmax 
R 
D 
D 
Abbreviations: D=displayed with descriptive statistics; ln=natural log-transformed; R=raw 
(untransformed). 
3.3.3. Banked Biospecimens 
Banked biospecimens will be collected and retained for future analyses, but will not be 
analyzed specifically for this study and will not be included in the CSR. 
3.4. Baseline Variables 
Not Applicable. 


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3.5. Safety Endpoints 
See Section 3.2 for details.  
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/Randomly assigned to study 
intervention 
"Enrolled" means a participant's agreement to 
participate in a clinical study following completion 
of the informed consent process. 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 
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 received at least 1 dose of 
atorvastatin, midazolam, an oral contraceptive 
and/or PF-06882961 and in whom at least 1 
plasma concentration value is reported. 
PK Parameter Set 
The PK parameter analysis population is defined 
as all participants who received at least 1 dose of 
atorvastatin, midazolam, an oral contraceptive 
and/or PF-06882961 and have at least 1 of the PK 
parameters of interest calculated. Should vomiting 
occur after co-administration of atorvastatin, 
midazolam, or the oral contraceptive with PF-
06882961, 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 
5.2.1. Treatment Labels and Groupings 
5.2.1.1. Part A 
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 
Atorvastatin 20mg (Period 1) 
2 
Midazolam 5mg (Period 2) 
3 
PF-06882961 titration up to 120mg BID (Period 3) 
4 
PF-06882961 120mg BID + Atorvastatin 20mg (Period 4) 
5 
PF-06882961 120mg  BID + Midazolam 5mg (Period 5) 
6 
PF-06882961 titration up to 200mg BID  (Period 6) 
7 
PF-06882961 200mg BID + Atorvastatin 20mg (Period 7) 
8 
PF-06882961 200mg BID + Midazolam 5mg (Period 8) 
 
5.2.1.2. Part B 
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 5 as: 
Period 
Treatment Label 
1 
0.15mg LE & 0.03mg EE (Period 1) 
2 
PF-06882961 titration up to 120mg BID (Period 2) 
3 
PF-06882961 120mg BID + 0.15mg LE & 0.03mg EE  (Period 3) 
4 
PF-06882961 titration up to 200mg BID (Period 4) 
5 
PF-06882961 200mg BID + 0.15mg LE & 0.03mg EE  (Period 5) 
 


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5.2.2. 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. 
5.2.3. Analyses for Categorical Endpoints 
Categorical variables will be presented using summary statistics: number of observations and 
percentages. 
5.2.4. 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 mean differences (Test-reference) and corresponding 90% 
confidence intervals (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. 
This model will be applied separately to Part A and Part B. 
The mixed effects model will be implemented using SAS Proc Mixed, with REML 
estimation method and the Kenward-Roger degrees of freedom algorithm. 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 (LLQ). 
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 “<LLQ”, where LLQ 
will be replaced with the value for the LLQ.  
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.  


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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 PK Parameters 
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. 
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 
treatment [1]), 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. 


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6.1. Primary Endpoint(s) 
6.1.1. Part A 
6.1.1.1. AUCinf and AUClast for atorvastatin and midazolam  
AUCinf  and AUClast for atorvastatin and midazolam alone and co-administered with 
PF-06882961 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) of atorvastatin administered alone or co-
administered with PF-06882961 will be analyzed using a mixed effect model as described in 
Section 5.2.4. The 2 test treatments will be ‘atorvastatin and PF-06882961 120 mg BID’ 
(Period 4) and ‘atorvastatin and PF-06882961 200 mg BID’ (Period 7), which will be 
reported separately in comparison to the reference treatment of ‘atorvastatin alone’ (Period 
1). The same analysis will also be performed for natural loge-transformed AUClast of 
atorvastatin. 
Natural loge transformed AUCinf (as data permit) and AUClast of midazolam administered 
alone or co-administered with PF-06882961 will be analyzed and reported separately using 
the same mixed effect model as described above for atorvastatin. The 2 test treatments will be 
‘midazolam and PF-06882961 120 mg BID’ (Period 5) and ‘midazolam and PF-06882961 
200 mg BID’ (Period 8), which will be reported separately in comparison to the reference 
treatment of ‘midazolam alone’ (Period 2). 
In the event that participants do not successfully titrate to the target PF-06882961 doses by 
the end of Periods 3 and/or 6, the related PK parameters for atorvastatin and midazolam 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 atorvastatin) and 2 (for midazolam) would be 
included in the models. 
AUCinf and AUClast will be summarized for each treatment (atorvastatin and midazolam will 
be reported in separate tables) as specified in Table 10. 
Table 10. Summary statistics for primary PK parameters for atorvastatin and 
midazolam 
Parameter  
Summary Statistics 
AUCinf & AUClast   
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum, geometric 
mean and geometric cv%. 


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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. 
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 and individual datapoints. 
These will be produced for atorvastatin and midazolam PK parameters separately. 
6.1.1.1.1. Sensitivity/Supplementary Analyses 
In the event that fewer than 12 participants have PK parameters of atorvastatin and/or 
midazolam related to co-administration with PF-06882961 200mg BID, the following 
sensitivity analyses will be considered for reporting:  
− If at least 4 participants reached the same maximum tolerated dose (MTD) of 
PF-06882961 (≥160mg BID, but not 200mg BID) with associated PK parameters 
estimated, this data may be included in the model and the PF-06882961 dose would 
be reported as an additional ‘test’ treatment (compared to the reference treatment of 
atorvastatin/midazolam alone) in the mixed effects models described above. This data 
may also be reported as a separate treatment group for all associated PK parameter 
summaries (e.g. in separate summaries of atorvastatin, midazolam and PF-06882961 
PK parameters) 
− If fewer than 4 participants have PK parameters related to co-administration with 
PF-06882961 200mg BID, this data may be excluded from the mixed effects models 
and the dose wouldn’t be reported as part of the model output. These data may also 
not be reported in associated PK parameter summaries (including PF-06882961 PK 
parameters) 
− If there are multiple different MTDs of PF-06882961, all related PK parameters 
would be included in the model and the dose of PF-06882961 would be included as a 
continuous covariate (rather than factor). These doses may be reported as separate 
treatment groups for all associated PK parameter summaries depending on the 
minimum number of participants per group 
If conducted, the above sensitivity analyses may replace the primary mixed effects models 
described above. Furthermore, an additional physiologically-based PK or other related model 
may be explored if fewer than 12 participants have PK parameters as above to further 
characterize the relationship between PK of PF-06882961 and PK of atorvastatin and/or 
midazolam, which would be reported outside of the CSR. 


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6.1.2. Part B  
6.1.2.1. AUCinf  and AUClast for LE and EE  
AUCinf  and AUClast for LE and EE alone and co-administered with PF-06882961 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 LE and EE administered 
alone or co-administered with PF-06882961 will be analyzed and reported separately using 
the same mixed effect model as described for atorvastatin in Section 6.1.1.1. For LE, the 2 
test treatments will be ‘LE and PF-06882961 120mg BID’ (Period 3) and ‘LE and PF-
06882961 200mg BID’ (Period 5), which will be reported separately in comparison to the 
reference treatment of ‘LE alone’ (Period 1). Similarly for EE, the 2 test treatments will be ‘ 
EE and PF-06882961 120mg BID’ (Period 3) and ‘ EE and PF-06882961 200mg BID’ 
(Period 5), which will be reported separately in comparison to the reference treatment of ‘ 
EE alone’ (Period 1). 
In the event that participants do not successfully titrate to the target PF-06882961 doses by 
the end of Periods 2 and/or 4, the related PK parameters for LE and EE 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 would be included in the models. 
AUCinf and AUClast will be summarized for LE and EE (reported in separate tables) as 
specified in Table 11. 
Table 11. Summary statistics for primary PK parameters for LE and EE 
Paramater  
Summary Statistics 
AUCinf & AUClast   
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. 
The following plots will be presented: 


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− Box and whisker plots for individual PK parameters (AUCinf and AUClast) will be 
presented by treatment and overlaid with geometric means and individual datapoints. 
These will be produced for LE and EE PK parameters separately. 
6.1.2.1.1. Sensitivity/Supplementary Analyses 
In the event that fewer than 12 participants have PK parameters LE and EE related to co-
administration with PF-06882961 200 mg BID, the following sensitivity analyses will be 
considered for reporting:  
− If at least 4 participants reached the same maximum tolerated dose (MTD) of 
PF-06882961 (≥160 mg BID, but not 200 mg BID) with associated PK parameters 
estimated, this data may be included in the model and the PF-06882961 dose would 
be reported as an additional ‘test’ treatment (compared to the reference treatment of 
LE/EE alone) in the mixed effects models described above. This data may also be 
reported as a separate treatment group for all associated PK parameter summaries 
(e.g. in separate summaries of LE, EE and PF-06882961 PK parameters)  
− If fewer than 4 participants have PK parameters related to co-administration with 
PF-06882961 200 mg BID, this data may be excluded from the mixed effects models 
and the dose wouldn’t be reported as part of the model output. These data may also 
not be reported in associated PK parameter summaries and listings (including 
PF-06882961 PK parameters) 
− If there are multiple different MTDs of PF-06882961, all related PK parameters 
would be included in the model and the dose of PF-06882961 would be included as a 
continuous covariate (rather than factor). These doses may be reported as separate 
treatment groups for all associated PK parameter summaries depending on the 
minimum number of participants per group 
If conducted, the above sensitivity analyses may replace the primary mixed effects models 
described above. Furthermore, an additional physiologically-based PK or other related model 
may be explored if fewer than 12 participants have PK parameters as above to further 
characterize the relationship between PK of PF-06882961 and PK of LE and/or EE, which 
would be reported outside of the CSR. 
6.2. Secondary Endpoint(s) 
Secondary endpoints will be reported separately for Part A and Part B of the study. 
6.2.1. 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. 


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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. 
6.2.2. 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 summaries will be presented separately for each of the baselines defined in 
Section 3.2.1. Laboratory abnormality summary and listing tables will only be produced for 
Baseline 1. In summary and listing tables, laboratory abnormalities occurring pre-dose on 
Day 1 during Periods 2-8 (Part A) or Periods 2-5 (Part B) 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). 
6.2.3. Vital Signs 
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarized by treatment and time point, according to sponsor 
reporting standards using the safety population defined in Section 4. Summaries will be 
presented separately for each of the baselines defined in Section 3.2.1.  
Mean absolute values and mean changes from baseline for systolic and diastolic blood 
pressure and pulse rate will be plotted against time point. On each plot there will be 1 line for 
each treatment with all treatments on the same plot. Corresponding individual plots of 
changes from baseline will also be produced for each treatment. These will be produced 
separately for each of the baselines defined in Section 3.2.1.  
Maximum and minimum absolute values and changes from baseline 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. These will be produced for Baseline 1 only as defined in Section 3.2.1. Values 
meeting the categorical criteria occurring pre-dose on Day 1 during Periods 2-8 (Part A) or 
Periods 2-5 (Part B) 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). 


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6.2.4. Electrocardiogram (ECG) 
Absolute values and changes from baseline in QT interval, heart rate, Fridericia method 
corrected QT (QTcF) interval, pule rate (PR) interval and QRS interval will be summarized 
by treatment and time point using sponsor reporting standards using the safety population 
defined in Section 4. Tables will be paged by parameter. Summaries will be presented 
separately for each of the baselines defined in Section 3.2.1. 
Mean changes from baseline for QT interval, heart rate and QTcF interval will be plotted 
against time point. On each plot there will be 1 line for each treatment with all treatments 
included on the same plot. Corresponding individual plots of changes from baseline will also 
be produced for each treatment. These will be produced separately for each of the baselines 
defined in Section 3.2.1.  
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. These will be produced 
for Baseline 1 only as defined in Section 3.2.1. Values meeting the categorical criteria 
occurring pre-dose on Day 1 during Periods 2-8 (Part A) or Periods 2-5 (Part B) 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). 
6.2.5. C-SSRS 
Screening, 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 5.2.3. 
6.2.6. 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 5.2.3. 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 5.2.2. 
6.2.7. 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 5.2.3. 


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6.2.8. Exploratory Safety Endpoints 
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 5.2.2 using the safety population defined in Section 4. These will be 
produced separately for each of the baselines defined in Section 3.2.3. 
6.3. Other Endpoint(s) 
6.3.1. Part A 
6.3.1.1. Additional plasma PK Parameters for atorvastatin and midazolam 
Cmax, Tmax, CL/F, Vz/F, t½ for atorvastatin and midazolam alone and co-administered with 
PF-06882961 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 (atorvastatin and 
midazolam will be reported in separate tables) as specified in Table 12. 
Table 12. Summary statistics for additional plasma PK parameters for atorvastatin and 
midazolam 
Parameter 
Summary Statistic 
Cmax, CL/F, Vz/F 
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric cv%. 
Tmax 
N, median, minimum, maximum. 
t1/2* 
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum. 
*if data permits. 
Natural log-transformed Cmax of atorvastatin administered alone or co-administered with 
PF-06882961 will be analyzed using a mixed effects model as described in Section 5.2.4, 
using the same approach as outlined in Section 6.1.1.1 for AUCinf and AUClast. The same 
mixed effects analysis will also be performed for natural log-transformed Cmax of midazolam. 
The following plots will be presented: 
− Box and whisker plots for individual Cmax values will be presented by treatment and 
overlaid with geometric means and individual datapoints. These will be produced for 
atorvastatin and midazolam PK parameters separately. 


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The following summaries will additionally be presented for the plasma concentration data of 
atorvastatin and midazolam (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 and analyte (i.e. atorvastatin or midazolam) 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 and analyte), 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. Two plots will be presented for each scale: one for the 
three treatments with atorvastatin and another for the three treatments with 
midazolam. 
− 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 atorvastatin and midazolam 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 atorvastatin and one for the three 
treatments with midazolam. 
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. 
6.3.1.2. Plasma PK Parameters for PF-06882961 
Plasma PK parameters for PF-06882961 as described in Section 3.3.1.2 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-06882961 as 
required in Table 13. 
Table 13. Summary statistics for plasma PK parameters for PF-06882961 
Parameter 
Summary Statistics 
AUC24, Cmax 
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric cv% 


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Tmax 
N, median, minimum, maximum. 
The following plots will be presented: 
− Box and whisker plots for individual PK parameters of PF-06882961 (AUC24 and 
Cmax) will be presented by treatment and overlaid with geometric means and 
individual datapoints. 
The following summaries will additionally be presented for the plasma concentration data of 
PF-06882961 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-06882961 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-06882961 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-06882961 treatment periods in the same plot.  
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. 
6.3.1.3. Ortho-hydroxyatorvastatin and 1-OH-midazolam 
AUCinf*, AUClast, Cmax, Tmax, t½* and the respective metabolite/parent AUCinf*, AUClast and 
Cmax ratios for ortho-hydroxyatorvastatin and 1-OH-midazolam alone and co-administered 
with PF-06882961 will be listed and summarized descriptively 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.  


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AUCinf*, AUClast, Cmax, Tmax, t½* and the respective metabolite/parent AUCinf*, AUClast and 
Cmax ratios will be summarized for each metabolite (ortho-hydroxyatorvastatin and 
1-OH-midazolam will be reported in separate tables) as specified Table 14. 
Table 14. Summary statistics for plasma PK parameters for ortho-hydroxyatorvastatin 
and 1-OH-midazolam 
Parameter 
Summary Statistics 
AUCinf*, AUClast, Cmax, 
metabolite/parent ratios  
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%. 
Tmax 
N, median, minimum, maximum. 
t1/2* 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum. 
*if data permit. 
Natural log-transformed AUCinf*, AUClast and Cmax for ortho-hydroxyatorvastatin and 
1-OH-midazolam alone and co-administered with PF06882961 will be analyzed separately 
using a mixed effects model as described in Section 5.2.4, using the same approach as 
outlined in Section 6.1.1.1 for AUCinf and AUClast. This will produce 6 separate modelled 
results for the different metabolite parameters.  
The following plots will be presented: 
− Box and whisker plots for individual PK parameters (AUCinf*, AUClast, Cmax and 
metabolite/parent ratios) will be presented by treatment and overlaid with geometric 
means and individual datapoints. These will be produced for ortho-hyrodyatorvastatin 
and 1-OH-midazolam PK parameters separately. 
The following summaries will additionally be presented for the plasma concentration data of 
ortho-hydroxyatorvastatin and 1-OH-midazolam (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 and analyte (i.e. ortho-hydroxyatorvastatin or 1-OH-midazolam) 
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 and analyte), 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. Two plots will be presented for each scale: one for 
ortho-hydroxyatorvastatin and another for 1-OH-midazolam. 


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− 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 ortho-hydroxyatorvastatin and 
1-OH-midazolam 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 ortho-hydroxyatorvastatin and one for the three treatments with 
1-OH-midazolam. 
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. 
6.3.1.4. Biomarkers of CYP3A Induction (Optional) 
Plasma 4-β-hydroxycholesterol, cholesterol and EV concentrations for participants in the PK 
Concentration Set (as defined in Section 4) will be summarized by treatment (i.e. pre-dose at 
Day 1 in Periods 2, 5, and 8) as outlined in Section 5.2.2.  
Absolute values and percent change from baseline in plasma ratios of 
4-β-hydroxycholesterol/cholesterol will also be summarized descriptively by treatment as 
outlined in Section 5.2.2.  
The following plots will be presented: 
− Box and whisker plots for the absolute values and percent change from baseline in the 
plasma ratio above will be presented by treatment and overlaid with individual data 
points. 
6.3.2. Part B 
6.3.2.1. Additional plasma PK Parameters for LE and EE 
Cmax, Tmax, CL/F, Vz/F, t½* for LE and EE alone and co-administered with PF-06882961 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 (LE and EE will be 
reported in separate tables) as specified in Table 15. 
 
 


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Table 15. Summary statistics for additional plasma PK parameters for LE and EE 
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. 
t1/2* 
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum. 
*if data permits. 
Natural log-transformed Cmax of LE administered alone or co-administered with 
PF-06882961 will be analyzed using a mixed effects model as described in Section 5.2.4, 
using the same approach as outlined in Section 6.1.2.1 for AUCinf and AUClast. The same 
mixed effects analysis will also be performed for natural log-transformed Cmax of EE. 
The following plots will be presented: 
− Box and whisker plots for individual Cmax values will be presented by treatment and 
overlaid with geometric means and individual datapoints. These will be produced for 
LE and EE PK parameters separately. 
The following summaries will additionally be presented for the plasma concentration data of 
LE and EE (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 and analyte (i.e. LE or EE) 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 and analyte), 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. Two plots will be presented for each scale: one with LE 
concentrations for the 3 treatments with OC and one with EE concentrations for the 3 
treatments with OC. 
− 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, 


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with a line for each participant per scale). Plots for LE and EE 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 with LE concentrations for the 3 treatments with OC and one with EE 
concentrations for the 3 treatments with OC. 
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. 
6.3.2.2.  Plasma PK Parameters for PF-06882961 
Summary of PF-06882961 PK parameters in Part B of the study will be calculated and 
presented similar as in Part A (Section 6.3.1.2).  
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 by Part and overall across all participants in the safety population 
(as defined in Section 4), as described in Sections 5.2.2 or 5.2.3 (as appropriate). 
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. Separate tables will be created for Part A and Part B. 
6.5.3. Concomitant Medications and Nondrug Treatments 
All prior and concomitant medication(s) as well as non-drug treatment(s) will be provided in 
separate listings for Part A and Part B. 
6.5.4. Other Screening Data 
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.  


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6.6. Safety Summaries and Analyses 
See Section 6.2. 
7. INTERIM ANALYSES 
7.1. Introduction 
No formal interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK modeling, and/or supporting clinical 
development. 
7.2. Interim Analyses and Summaries 
Not Applicable. 
8. REFERENCES 
 
[1] Considerations, Bioavailabilty and Bioequivalence Studies Submitted in NDAs or INDs 
- General, Draft Guidance from the FDA., 2014.  
 


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9. APPENDICES 
Appendix 1. Summary of PK Analyses (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; 
Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern 
Categories for QTcF: 
 
Absolute value of QTcF (msec) 
>450 and ≤480 >480 and ≤500 
>500 
Increase from baseline in QTcF (msec) 
>30 and ≤60 
>60 
 
Categories for PR and QRS: 
 
PR (ms) 
max. ≥300 
PR (ms) 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 
Systolic BP (mm Hg) change from baseline 
max. decrease ≥30 
max. increase ≥30 
Diastolic BP (mm Hg) 
min <50 
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. C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events and 
Codes 
C-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 
Prepatory actions towards imminent 
suicidal behaviors 
“Yes” on “Prepatory Acts or 
Behavior” 
Self-injurious Behavior, no Sucidial Intent 
1 
Self-injurious behavior, no suicidal 
intent 
“Yes” on “Has subject engaged in 
Nonsuicidal 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”. 
 
 
 


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Appendix 4. List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
AUC 
area under the concentration-time curve 
BID 
twice daily 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
BPM 
beats per minute 
C-CASA 
Columbia-Classification Algorithm of Suicide Assessment 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CI 
confidence interval 
CL 
clearance 
CL/F 
apparent oral clearance 
Cmax 
maximum observed concentration 
CSR 
clinical study report 
(%)CV 
(percent) coefficient of variation 
ECG 
electrocardiogram 
EE 
ethinyl estradiol  
EV 
extracellular vesicles 
FU 
follow up 
HbA1c 
hemoglobin A1c 
LE 
levonorgestrel 
LLQ 
lower limit of quantification 
ln 
natural logartihm 
MTD 
maximum tolerated dose 
msec 
millisecond 
NC 
not calculated 
ND 
not done 
NS 
no sample 
OC 
oral contraceptive 
PK 
pharmacokinetic(s) 
PHQ-9 
Patient Health Questionnaire-9 
PM 
post-menopausal 
PR  
pulse rate 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
SAP 
statistical analysis plan 
SD 
single-dose 


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Abbreviation 
Term 
SoA 
schedule of activities 
t1/2 
terminal half life 
TEAE 
treatment emergent adverse event 
Tmax 
time to Cmax 
Vz/F 
apparent volume of distribution