Clinical trial NCT04621227
Conditions: Obesity
Keywords: obesity
Sponsor: Pfizer
Start date: 2020-12-15; Completion date: 2021-05-13
Enrollment: 16 participants; Allocation: NA; Intervention model: CROSSOVER

Brief summary:
A Phase 1 Study To Evaluate The Effect Of Two Steady State Doses of PF 06882961 On Rosuvastatin And Midazolam Pharmacokinetics In Otherwise Healthy Adult Participants With Obesity

Detailed description:
This study is designed to look at the effect of two doses of PF 06882961 (120 milligram (mg) twice a day (BID) and 200 mg BID) on the levels of one dose of rosuvastatin 10 mg and one dose of midazolam 2 mg, in otherwise healthy, adult participants with obesity. Total duration of study from screening to the telephone visit will be approximately 17 weeks, of which up to 63 days will be inpatient. All subjects take (i) Rosuvastatin alone, Midazolam alone, PF 06882961 alone (120 mg BID), PF 06882961 (120 mg BID) + Rosuvastatin, PF 06882961 (120 mg BID) + Midazolam, PF 06882961 (200 mg BID) alone, PF 06882961 (200 mg BID) + Rosuvastatin, PF 06882961 (200 mg BID)+ Midazolam in the study.

Arms: arm 1: Participants will receive the following treatments in this sequence : (i)Rosuvastatin alone (one dose of 10 mg), (ii) Midazolam alone (one dose of 2mg), (iii) PF 06882961 alone (120 mg twice daily), (iv) PF 06882961 (120 mg twice daily) + Rosuvastatin (one dose of 10mg), (v) PF 06882961 (120 mg) + Midazolam (one dose of 2 mg), (vi) PF 06882961 (200 mg) alone, (vii) PF 06882961 (200 mg) + Rosuvastatin (one dose of 10 mg), (viii) PF 06882961 (200 mg)+ Midazolam (one dose of 2 mg) in the study.
Interventions: intervention 1: PF-06882961 intervention 2: Rosuvastatin intervention 3: Midazolam
Intervention descriptions: intervention 1: 120 mg and 200 mg BID intervention 2: 10 mg single dose intervention 3: 2mg single dose

Protocol documents:
Prot_000.pdf: 
PF-06882961
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Page 1
A PHASE 1, OPEN -LABEL, FIXED SEQUENCE STUDY TO EVALUATE THE 
EFFECT OF TWO STEADY STATE DOSE LEVELS OF PF-06882961 ON THE 
PHARMACOKINETICS OF SINGLE ORAL DOSES OF ROSUVASTATIN AND 
MIDAZOLAM IN OTHERWISE HEALTHY ADULT PARTICIPANTS WITH 
OBESITY
Study Intervention Number:
PF-06882961
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
N/A
Protocol Number:
C3421007
Phase:
1
Short Title: A Phase 1 Study To Evaluate The Effect Of Two Steady State Doses of 
PF-06882961 On Rosuvastatin And Midazolam Pharmacokinetics In Otherwise Healthy 
Adult Participants With Obesity.
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
07 October 2020
N/A


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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 .............................................................................................14
2. INTRODUCTION ...............................................................................................................23
2.1. Study Rationale .......................................................................................................23
2.2. Background .............................................................................................................23
2.2.3. Nonclinical Safety ......................................................................................25
2.2.4. Clinical Overview.......................................................................................26
2.2.4.1. Clinical Safety...........................................................................26
2.2.4.2. Clinical Pharmacokinetics.........................................................27
2.3. Benefit/Risk Assessment.........................................................................................27
2.3.1. Risk Assessment.........................................................................................28
2.3.2. Benefit Assessment.....................................................................................31
2.3.3. Overall Benefit/Risk Conclusion................................................................31
3. OBJECTIVES AND ENDPOINTS.....................................................................................31
4. STUDY DESIGN.................................................................................................................32
4.1. Overall Design.........................................................................................................32
4.2. Scientific Rationale for Study Design.....................................................................33
4.3. Justification for Dose ..............................................................................................35
4.4. End of Study Definition ..........................................................................................36
5. STUDY POPULATION......................................................................................................36
5.1. Inclusion Criteria.....................................................................................................36
5.2. Exclusion Criteria....................................................................................................37
5.3. Lifestyle Considerations..........................................................................................41
5.3.1. Meals and Dietary Restrictions...................................................................41
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................42
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5.3.3. Activity .......................................................................................................42
5.3.4. Contraception..............................................................................................42
5.4. Screen Failures ........................................................................................................43
6. STUDY INTERVENTION..................................................................................................43
6.1. Study Intervention(s) Administered........................................................................43
6.1.1. Administration............................................................................................43
6.2. Preparation/Handling/Storage/Accountability ........................................................44
6.2.1. Preparation and Dispensing........................................................................45
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................46
6.3.1. Allocation to Study Intervention ................................................................46
6.4. Study Intervention Compliance...............................................................................46
6.5. Concomitant Therapy..............................................................................................47
6.5.1. Rescue Medicine.........................................................................................48
6.5.1.1. Management of Nausea and Vomiting......................................48
6.6. Dose Modification...................................................................................................48
6.7. Intervention After the End of the Study..................................................................48
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................48
7.1. Discontinuation of Study Intervention ....................................................................48
7.2. Participant Discontinuation/Withdrawal From the Study.......................................49
7.2.1. Withdrawal of Consent...............................................................................50
7.3. Lost to Follow up ....................................................................................................50
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................50
8.1. Efficacy Assessments..............................................................................................51
8.1.1. Imaging Assessments..................................................................................51
8.2. Safety Assessments .................................................................................................52
8.2.1. Physical Examinations................................................................................52
8.2.2. Vital Signs ..................................................................................................52
8.2.2.1. Temperature ..............................................................................53
8.2.3. Electrocardiograms.....................................................................................53
8.2.4. Clinical Safety Laboratory Assessments ....................................................54
8.2.5. Suicidal Ideation and Behavior Risk Monitoring.......................................55


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8.2.5.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................55
8.2.5.2. Patient Health Questionnaire-9 (PHQ-9) ..................................55
8.2.5.3. Referral to a Mental Health Professional ..................................55
8.2.6. Pregnancy Testing ......................................................................................56
8.2.7. Management of Hypoglycemia...................................................................56
8.2.7.1. Definition and Severity of Categorization of 
Hypoglycemic Adverse Event (HAE)...............................................56
8.2.8. Glucometer Monitoring of Glucose............................................................58
8.2.9. COVID-19 Specific Assessments...............................................................58
8.3. Adverse Events and Serious Adverse Events..........................................................58
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......59
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................59
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................60
8.3.2. Method of Detecting AEs and SAEs ..........................................................60
8.3.3. Follow-up of AEs and SAEs.......................................................................60
8.3.4. Regulatory Reporting Requirements for SAEs...........................................60
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................61
8.3.5.1. Exposure During Pregnancy......................................................61
8.3.5.2. Exposure During Breastfeeding ................................................62
8.3.5.3. Occupational Exposure .............................................................63
8.3.6. Cardiovascular and Death Events...............................................................63
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................63
8.3.8. Adverse Events of Special Interest.............................................................63
8.3.8.1. Lack of Efficacy........................................................................63
8.3.9. Medical Device Deficiencies......................................................................64
8.3.9.1. Time Period for Detecting Medical Device Deficiencies .........64
8.3.9.2. Follow-up of Medical Device Deficiencies...............................64
8.3.9.3. Prompt Reporting of Device Deficiencies to Sponsor ..............64
8.3.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................64
8.3.10. Medication Errors.....................................................................................64


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8.4. Treatment of Overdose............................................................................................65
8.5. Pharmacokinetics ....................................................................................................66
8.5.1. PK of Rosuvastatin .....................................................................................67
8.5.2. PK of Midazolam........................................................................................67
8.6. Pharmacodynamics..................................................................................................67
8.9. Immunogenicity Assessments.................................................................................69
8.10. Health Economics .................................................................................................69
9. STATISTICAL CONSIDERATIONS ................................................................................69
9.1. Statistical Hypotheses .............................................................................................69
9.2. Sample Size Determination.....................................................................................69
9.3. Analysis Sets ...........................................................................................................70
9.4. Statistical Analyses .................................................................................................71
9.4.1. General Considerations...............................................................................71
9.4.1.1. Derivation of Pharmacokinetic Parameters...............................71
9.4.2. Statistical Methods for Pharmacokinetic data ............................................73
9.4.3. Safety Analyses ..........................................................................................74
9.4.3.1. Electrocardiogram Interval Analyses ........................................74
9.5. Interim Analyses .....................................................................................................75
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............75
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................76
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............76
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10.1.1. Regulatory and Ethical Considerations ....................................................76
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................76
10.1.2. Financial Disclosure .................................................................................77
10.1.3. Informed Consent Process ........................................................................77
10.1.4. Data Protection .........................................................................................78
10.1.5. Dissemination of Clinical Study Data ......................................................78
10.1.6. Data Quality Assurance ............................................................................79
10.1.7. Source Documents....................................................................................81
10.1.8. Study and Site Start and Closure ..............................................................81
10.1.9. Publication Policy.....................................................................................82
10.1.10. Sponsor’s Qualified Medical Personnel .................................................82
10.2. Appendix 2: Clinical Laboratory Tests .................................................................84
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................86
10.3.1. Definition of AE .......................................................................................86
10.3.2. Definition of SAE.....................................................................................87
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................88
10.3.4. Reporting of SAEs....................................................................................91
10.4. Appendix 4: Contraceptive Guidance ...................................................................93
10.4.1. Male Participant Reproductive Inclusion Criteria....................................93
10.4.2. Female Participant Reproductive Inclusion Criteria.................................93
10.4.3. Woman of Childbearing Potential ............................................................93
10.4.4. Contraception Methods.............................................................................94
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........97
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................99
10.8. Appendix 8: Proposed Chronology of Procedures..............................................101
10.9. Appendix 9: Abbreviations .................................................................................102
11. REFERENCES ................................................................................................................106
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LIST OF TABLES
Table 1.
Overall Schedule of Activities through Period 5......................................15
Table 2.
Overall Schedule of Activities Period 6 to ET .........................................18
Table 3.
Schedule of Activities –Day 1 of Period 1 (Rosuvastatin ONLY), 
Period 4 (Rosuvastatin + PF-06882961), and Period 7 (Rosuvastatin 
+ PF-06882961)........................................................................................20
Table 4.
Schedule of Activities –Day 1 of Period 2 (Midazolam ONLY), 
Period 5 (Midazolam + PF-06882961) and Period 8 (Midazolam + 
PF-06882961) ...........................................................................................21
Table 5.
Schedule of Activities –Day 28 of Period 3 and Day 16 of Period 6 
(PF-06882961 only)..................................................................................22
Table 6.
Dosing.......................................................................................................44
Table 7.
PF-06882961 Dosing Regimens...............................................................46
Table 8.
Expected Widths of the 90% CIs (with 80% Coverage Probability) 
for Different Possible Estimated Effects and Parameters of Interest .......70
Table 9.
Plasma PK Parameters for Rosuvastatin and Midazolam.........................72
Table 11.
Protocol Required Laboratory Assessments.............................................84
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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1 Study To Evaluate The Effect Of Two Steady State Doses of 
PF-06882961 On Rosuvastatin And Midazolam Pharmacokinetics In Otherwise Healthy 
Adult Participants With Obesity.
Rationale
This is a Phase 1, open-label study to evaluate the effect of two steady state dose levels of 
PF-06882961 on the pharmacokinetics of rosuvastatin and midazolam in otherwise healthy,
adult participants with obesity. This study is intended to generate safety, tolerability, and 
pharmacokinetic data for further clinical development.
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 

To evaluate the effects of
PF-06882961 on the pharmacokinetics
of rosuvastatin in otherwise healthy
adult participants with obesity.

To evaluate the effects of
PF-06882961 on the pharmacokinetics
of midazolam in otherwise healthy
adult participants with obesity.

Rosuvastatin plasma pharmacokinetic
parameters: AUCinf (if data permits*
otherwise AUClast) in Periods 1, 4 and 7.

Midazolam plasma pharmacokinetic
parameters: AUCinf (if data permits*
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
rosuvastatin or midazolam, in
otherwise healthy adult participants
with obesity.

Assessment of treatment-emergent
adverse events, clinical laboratory
abnormalties, vital signs, body weight,
and ECG parameters during the entire
study.

Assessment of mental health as
determined by C-SSRS and PHQ-9
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* 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 rosuvastatin and midazolam objectives separately.
Overall Design
This study is a Phase 1, open-label, 8-period, fixed-sequence study to evaluate the effect of 
PF-06882961, administered at two steady-state dose levels, on the pharmacokinetics of 
rosuvastatin and midazolam, administered separately as single doses, in otherwise healthy 
adult participants with obesity. The total duration of participation from the Screening Visit 
to the FU contact will be approximately 17 weeks.
Number of Participants
A sample size of approximately 16 participants will be enrolled such that approximately 
12 evaluable participants complete the study. This minimum number of evaluable 
participants has been selected to provide sufficient precision to detect a 1.25-fold difference 
in AUCinf for either rosuvastatin or midazolam.
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 two 
steady-state dose levels, on the PK of single doses of rosuvastatin (10 mg) and midazolam
(2 mg), administered separately, in adult participants with obesity.  A multiple dose study 
will be conducted to ensure maximal clinically relevant steady-state PF-06882961 exposures 
are achieved.  The drug-drug interaction effect will be initially assessed at PF-06882961 
120 mg BID
 
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 and again at 200 mg BID
 
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. Rosuvastatin and midazolam 
will be administered within approximately 10 minutes of completion of the morning meal. 
PF-06882961 will be administered first and midazolam/rosuvastatin will be administered 
within 5 minutes of PF-06882961.
The total duration of participation from the Screening Visit to the FU contact will be 
approximately 17 weeks ie, 117 days, of which up to 63 days will be inhouse (Period 1
(rosuvastatin): 5 days, Period 2 (midazolam): 2 days, Period 3 (PF-06882961): 29 days, 
Period 4 (PF-06882961+rosuvastatin): 4 days, Period 5 (PF-06882961 + midazolam): 1 day,
Period 6 (PF-06882961): 16 days, Period 7 (PF-06882961+rosuvastatin): 4 days, Period 8
(PF-06882961 + midazolam): 2 days, FU visit 7-10 days from last dose study intervention
and FU contact 28-35 days from last dose study intervention).
Participants may be discharged on Period 2, Day 2 and return to the CRU for Period 3, Day-1
within 7 days from discharge.  Alternatively, participants may remain as inpatient on 
Period 2, Day 2 and begin Period 3, Day 1 activities the same day, without completing 
Period 3, Day -1 procedures.
Data Monitoring Committee or Other Independent Oversight Committee: No
This study will not use a DMC.
Statistical Methods
The PK data for 
 rosuvastatin and midazolam will be analyzed and reported 
separately.
Natural log-transformed AUCinf (as data permit) of rosuvastatin 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% confidence intervals will be obtained 
from the models. The adjusted mean differences and 90% confidence intervals for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% confidence intervals for the ratios. The two test treatments 
will be ‘rosuvastatin and PF-06882961 120 mg BID’ (Period 4) and ‘rosuvastatin and
PF-06882961 200 mg BID’ (Period 7), which will be reported separately in comparison to 
the reference treatment of ‘rosuvastatin alone’ (Period 1). The same analysis for 
 
 AUClast of rosuvastatin will also be conducted.
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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 rosuvastatin. The two 
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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1.2. Schema
Follow-Up (FU) visit 7-10 days from last dose of study intervention. A FU Contact visit will be 28-35 days after last dose of study 
intervention.


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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures.  Refer to the 
STUDY ASSESSMENTS AND PROCEDURES section of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA
table, in order to conduct evaluations or assessments required to protect the well-being of the 
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Table 1.
Overall Schedule of Activities through Period 5
Visit Identifier
Screening
Period 1
(Rosuvastatin 
only)
Period 2
(Midazolam 
only)
Period 3
(PF-06882961 only)
Period 4
(PF-06882961 + 
rosuvastatin)
Period 5
(PF-06882961 
+ midazolam)
Day in Study Perioda
-28 to -2 -1
1
2
3
4
1
2
-1c
1
2-7
8
9-14
15
16-21
22
23-27 28
1
2
3
4
1
Days in Studyb
-28 to -2 -1
1
2
3
4
5
6
7c
8
9-14
15
16-21
22
23-28
29
30-34 35
36
37
38
39
40
Informed consent & demography
x
Outpatient visit (after ≥10-h fast)
x
COVID-19 pre-screeningd
x
x
xc
COVID-19 testingd
x
x
x
xc
xc
Temperature checkd
x
x
→→→→
→
xc/→
xc
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Inpatient stay at CRU
x
→→→→
→
xc/→
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
x
Review contraception use
(Section 5.3.4)
x
x
x
Review prior or concomitant 
treatments 
x
x
→→→→
→
x/→
x
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Adverse event monitoring
x
x
→→→→
→
x/→
x
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Standardized meals/snackse
x
→→→→
→
x/→
x
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Physical examf (height at Screen 
only)
x
x
Body weight
x
Table 3
Table 4
x
x
x
x
Table 5
Table 3
Table 4
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
x
Rosuvastatin administration
Midazolam administration
Blood Sampling for:i
-Chemistry
x
x
x
x
x
- Hematology
x
x
- PT/INR/aPTT
x
x
x
- FSHj, HIV, HepBsAg, HCVAb,
HCV RNA, C-peptide
x
- HbA1c, TSH, lipids
x
x
x


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Table 1.
Overall Schedule of Activities through Period 5
Visit Identifier
Screening
Period 1
(Rosuvastatin 
only)
Period 2
(Midazolam 
only)
Period 3
(PF-06882961 only)
Period 4
(PF-06882961 + 
rosuvastatin)
Period 5
(PF-06882961 
+ midazolam)
Day in Study Perioda
-28 to -2 -1
1
2
3
4
1
2
-1c
1
2-7
8
9-14
15
16-21
22
23-27 28
1
2
3
4
1
Days in Studyb
-28 to -2 -1
1
2
3
4
5
6
7c
8
9-14
15
16-21
22
23-28
29
30-34 35
36
37
38
39
40
- Free T4, calcitonin, amylase, 
  lipase, total bile acids
x
x
x
- Serum pregnancy testj
x
x
xj
- Rosuvastatin PK
xk xk xk
xk
xk
xk
- Midazolam PK
xl
 
Urine Sampling for:
- Urine drug testo
x
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 rosuvastatin on Day 1 of Period 1.
c.
Discharge from CRU. Participants may be discharged on Period 2, Day 2 and return to the CRU for Period 3, Day-1 within 7 days from discharge. 
Alternatively, participants may remain as inpatient on Period 2, Day 2 and begin Period 3, Day 1 activities the same day, without completing Period 3, 
Day -1 procedures. Temperature check, COVID-19 pre-screening, and COVID-19 testing to be performed only if participant was discharged between 
Period 2, Day 2 and returns to CRU for Period 3, Day -1. 
d.
COVID-19 test must be negative prior to admission (Period 1, Day 1 and Period 3 Day -1). Participants will be tested for SARS-COVID-19 infection by 
PCR. A subsequent test will be done after 4 days ie, completion of 4 x 24 hours in house, or if they develop COVID-19 like symptoms). Prior to COVID-19 
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.
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 and only on Period 3 Day -1 if discharged after Period 2; otherwise, brief exam if findings during previous exam or 
new/open AEs, if appropriate, at investigator discretion.
g.
Includes blood pressure and pulse rate 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.
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j.
Testing in females only : Serum β-hCG for all WOCBP; FSH for female participants to confirm post-menopausal status only. Serum pregnancy test should
be performed if participant is re-admitted on Day-1 of Period 3. Test result should confirm no pregnancy prior to dosing.
k.
For Periods 1 and 4, rosuvastatin PK should be obtained at 24H, 48H, 72H post rosuvastatin dose on Day 1 of the same periods and 96H (ie, Period 2 Day 1 
and Period 5 Day 1 predose).  
l.
For Periods 2 and 5, midazolam PK should be obtained at approximately 24H post midazolam dose on Day 1 of the same periods (ie, Period 2 Day 2 and 
Period 6 Day 1 predose).
 
o.
Participants may undergo random urine drug testing at the discretion of the investigator.
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Table 2.
Overall Schedule of Activities Period 6 to ET
Visit Identifier
Period 6
(PF-06882961 only)
Period 7
(PF-06882961 + 
rosuvastatin)
Period 8
(PF-06882961 
+ midazolam)
FU
FU Contact
Telephone
ET
Day in Study Perioda
1
2-8
9
10-15
16
1
2
3
4
1
2
-
-
-
Days in Studyb
41
42-48
49
50-55
56
57
58
59
60
61
62
68-71
89-96
-
Informed consent & demography
Outpatient visit (after ≥10-h fast)
x
COVID-19 pre-screening
COVID-19 testing
x
x
Temperature check
→
→
→
→
→
→
→
→
→
→
x
Inpatient stay at Clinical Research Unit
→
→
→
→
→
→
→
→
→
→
xc
Eligibility Criteria
Medical history 
CSSR-S 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 5
Table 3
→
→
→
Table 4
x
x
x
x
Adverse event monitoring
→
→
→
→
→
→
→
x
x
x
x
Standardized meals/snacksd
→
→
→
→
→
→
→
x
Physical exam (height at Screen only) 
xe
xe
xe
Body weight
x
x
x
x
x
Supine 12-lead ECG
x
x
x
x
Single, supine vital signs assessmentf
x
x
x
x
PF-06882961 administrationg
x
x
x
x
x
x
x
Rosuvastatin administration
Midazolam administration
Blood Sampling forh:
- Chemistry
x
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
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Table 2.
Overall Schedule of Activities Period 6 to ET
Visit Identifier
Period 6
(PF-06882961 only)
Period 7
(PF-06882961 + 
rosuvastatin)
Period 8
(PF-06882961 
+ midazolam)
FU
FU Contact
Telephone
ET
Day in Study Perioda
1
2-8
9
10-15
16
1
2
3
4
1
2
-
-
-
Days in Studyb
41
42-48
49
50-55
56
57
58
59
60
61
62
68-71
89-96
-
- Serum pregnancy testi
x
x
- Rosuvastatin PK
xj
xj
xj
x
- Midazolam PK
xk
xk
x
Urine Sampling for:
- Urine drug testm
- Urinalysis (and microscopy, as appropriate)
x
x
x
x
a.
Day relative to start of dosing Day 1 of that Period.
b.
Day relative to first dose of investigational product (rosuvastatin) on Day 1.
c.
Discharge from CRU.
d.
Meals to be provided at approximately 0H, 4H, and 10H post AM dose; plus, snacks provided according to Section 5.3.1. Note that there is no PF-06882961 
administration on Day 62. 
e.
Complete physical exam at Period 8 Day 2 and FU; otherwise, brief exam if findings during previous exam or new/open AEs, if appropriate, at investigator 
discretion.
f.
Includes blood pressure and pulse rate predose.
g.
Dosing to occur BID with breakfast and dinner. Note that there is no PF-06882961 administration on Day 62. 
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 post-menopausal status only.  
j.
In Period 7, rosuvastatin PK should be obtained at 24H, 48H, 72H, 96H (ie, Period 8 Day 1) post rosuvastatin dose on Day 1 of the same period. 
k.
In Period 8, midazolam PK should be obtained at approximately 24H post midazolam dose on Day 1 of the same period.
 
m. Participants may undergo random urine drug testing at the discretion of the investigator.
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Table 3.
Schedule of Activities –Day 1 of Period 1 (Rosuvastatin ONLY), Period 4 (Rosuvastatin + PF-06882961), and 
Period 7 (Rosuvastatin + PF-06882961)
Hours Relative to Dosing at 0H
0
1
2
3
4
5
6
8
10
12
16
Body Weight
x
Supine 12-lead ECG 
x
Supine vital sign assessmenta
x
Rosuvastatin administration
x
PF-06882961 administration (Periods 4 and 7 only)
xb
xc
Blood sampling for:d
- Chemistry
x
- Hematology (Periods 1 and 4 only)
x
-
- Rosuvastatin PK
x
x
x
x
x
x
x
x
x
x
x
Urine sampling for:
- Urinalysis and microscopy, as appropriate (Period 1 only)
x
a.
Includes blood pressure and pulse rate. 
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.
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Table 4.
Schedule of Activities –Day 1 of Period 2 (Midazolam ONLY), Period 5 (Midazolam + PF-06882961) and Period 8 
(Midazolam + PF-06882961)
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
- Rosuvastatin PK
x
- Midazolam PK
x
x
x
x
x
x
x
x
X
x
x
-
a.
Includes blood pressure and pulse rate. 
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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Table 5.
Schedule of Activities –Day 28 of Period 3 and Day 16 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
 
Urine sampling for:
- Urinalysis and microscopy, as appropriate 
x
a.
Includes blood pressure and pulse rate. 
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 glucagon-like peptide 1 receptor (GLP-1R) agonist that is currently 
being developed for the treatment of type 2 diabetes mellitus. 
Glucagon-like peptide 1 (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-1 receptor 
(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. PF-06882961 is currently being investigated as an adjunct to diet and 
exercise to improve glycemic control in adult participants with T2DM.
2.1. Study Rationale 
The purpose of this phase 1, open-label, eight-period, fixed-sequence study is to evaluate the 
effect of two dose levels of PF-06882961 administered at steady state on the 
pharmacokinetics of rosuvastatin and midazolam, administered separately, in otherwise 
heathy adult participants with obesity. 
2.2. Background 
T2DM is estimated to affect more than 424 million people worldwide,5 and the prevalence of 
T2DM within the United States (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 hemoglobin (HbA1c) 
levels, suggesting a need for additional therapeutic options.
Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight
loss, and cardiovascular safety, with more than one marketed agent demonstrating 
cardiovascular benefit.8  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 and avoiding the 
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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.  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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). 
 
 
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In embryo fetal studies conducted in rabbits, the NOAEL for maternal and developmental 
toxicity was 250 mg/kg/da
 
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
As of the protocol finalization date, 3 clinical studies, C3421001, C3421002 and C3421003
have completed dosing with PF-06882961.  In C3421001 and C3421003, single oral doses of 
PF-06882961 up to 300 mg (or matching placebo) were generally safe and well-tolerated in
healthy adult participants. In the multiple dose study C3421002, PF-06882961 doses up to 
120 mg BID (or matching placebo) for 28 days were generally safe and well-tolerated in 
adult participants with T2DM on a background of metformin therapy, and safety results from 
this study are provided in Section 2.2.4.1.  Refer to the IB for more details on these studies 
and the known drug class effects of marketed injectable GLP1R agonists.
2.2.4.1. Clinical Safety
Clinical data from the completed C3421001, C3421002 and C3421003 studies are provided 
in the IB for PF-06882961.
In study C3421002, PF-06882961 doses ranging from 10 mg BID to 120 mg BID were 
generally safe and well tolerated.  A total of 98 participants with T2DM on a background 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 
treatment emergent adverse events (TEAEs), and 4 withdrew during the 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 or 92%) were 
mild in intensity, 23 (or 7%) were moderate, and 2 (or 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 TEAE of hypoglycemia, which was non-fasting, mild in severity and of 
limited duration. No deaths occurred in the C3421002 study.  Two participants experienced 
2 severe TEAEs during the study, 1 of which occurred in the dosing period and was 
considered treatment related, the other occurred during the follow-up period and was not 
considered treatment related.  One participant experienced 2 non-treatment-related SAEs,
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1 of which occurred in the follow-up period and the other occurred outside of the study 
reporting period.
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.  As has been 
reported for marketed GLP-1R agonists,8,9 increases in heart rate have been observed, with 
mean increases ranging from 5 to 15 beats per minute (bpm) across doses administered to 
date, and most heart rate values within the normal range.
2.2.4.2. Clinical Pharmacokinetics
 
 
  
 
  
 
  
 
 
  
In study C3421002, following 28 days of dosing to participants with T2DM, accumulation 
was modest for the BID IR formulation treatments
 
 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 between 4.681 to 8.090 hours, and no apparent trends were observed 
across various treatments, regimens, or doses administered. 
 
 
 
 
In study C3421003, 12 healthy participants were randomized to receive single doses of 
different oral formulations of PF-06882961.
2.3. Benefit/Risk Assessment
PF-06882961 is not expected to provide any clinical benefit to otherwise healthy participants
with obesity in this study.  This study is designed primarily to generate safety, tolerability, 
and pharmacokinetic data for further clinical development.
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More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-06882961 may be found in the investigator’s brochure, which 
is the SRSD for this study. The SRSD for the site sourced rosuvastatin (eg, Crestor) agent is
the United States package insert (USPI).10 The SRSD for the site sourced midazolam
(eg, Nayzilam) agent is the United States package insert (USPI).11
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 
type 2 diabetes mellitus would not be
taking anti-diabetic agents and therefore 
would not be expected to have an 
increased risk for hypoglycemia.  
Only one adverse event 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 
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Impairment in renal 
function
In rats, minimal renal tubular vacuolation 
was observed, but this finding was 
considered to be non-adverse.
In the clinical trial program only one mild 
adverse event (Preferred Term Blood 
creatinine increased) has been observed 
in the clinical trial program.
Per exclusion criteria, potential
participants with significant renal 
impairment are not eligible for study 
entry. Renal function is monitored 
at frequent intervals by lab 
assessments of serum blood urea 
nitrogen (BUN), creatinine and 
Estimated Glomerular Filtration 
Rate (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 adverse 
events, 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 type 2 diabetes 
mellitus.  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 type 2 diabetes mellitus.
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 mental health 
professional for further evaluation if 
needed.
Changes in heart rate and 
blood pressure
Increases in heart rate have been reported 
for marketed GLP-1R agonists, and
increases in heart rate 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.
Heart rate and blood pressure are 
monitored at frequent intervals 
during the clinical study.


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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.
A higher BMI was selected for 
inclusion criteria to minimize 
potential risk of body weight loss in 
the study population. 
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: Rosuvastatin
Skeletal muscle effects: 
These risks can occur at 
any dose level, but are 
increased at the highest 
dose (40 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 10 mg is 
administered in the 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 10 mg is 
administered in the 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 2 mg is 
administered in the 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.


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2.3.2. Benefit Assessment
While PF-06882961 is not expected to provide any clinical benefit to otherwise healthy adult 
participants with obesity in this short-term study, potential benefits for participants in this 
study 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.
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.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
•
To evaluate the effects of 
PF-06882961 on the pharmacokinetics 
of rosuvastatin in otherwise healthy 
adult participants with obesity. 
•
To evaluate the effects of 
PF-06882961 on the pharmacokinetics 
of midazolam in otherwise healthy 
adult participants with obesity. 
•
Rosuvastatin plasma pharmacokinetic 
parameters: AUCinf (if data permits*
otherwise AUClast) in Periods 1, 4 and 7.
•
Midazolam plasma pharmacokinetic 
parameters: AUCinf (if data permits*
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 
rosuvastatin or midazolam, in 
otherwise healthy adult participants 
with obesity.
•
Assessment of treatment-emergent 
adverse events, clinical laboratory 
abnormalties, vital signs, body weight, 
and ECG parameters during the entire
study.
•
Assessment of mental health as 
determined by C-SSRS and PHQ-9
during the entire study.
 
 
 
 
 
 
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rosuvastatin and midazolam, 
 
 
 
 
 
 
* 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 rosuvastatin and midazolam objectives separately.
4. STUDY DESIGN
4.1. Overall Design
This study is a phase 1, open-label, 8-period, fixed-sequence study to evaluate the effect of 
PF-06882961, administered at two steady-state dose levels, on the pharmacokinetics of 
rosuvastatin and midazolam, administered separately as single doses, in otherwise healthy 
adult participants with obesity. Approximately 16 participants will be enrolled in the study. 
Refer to Section 1.2 for study schema.  
All participants will provide informed consent and undergo Screening evaluations to
determine their eligibility.  Screening will occur within 28 days of the first dose of study 
intervention on Day 1 of Period 1.  
Participants will be admitted to the clinical research unit (CRU) on Day -1 of Period 1. The 
total duration of participation from the Screening Visit to the FU contact will be 
approximately 17 weeks ie, 117 days, of which up to 63 days will be inhouse (Period 1
(rosuvastatin): 5 days, Period 2 (midazolam): 2 days, Period 3 (PF-06882961): 29 days, 
Period 4 (PF-06882961+rosuvastatin): 4 days, Period 5 (PF-06882961 + midazolam): 1 day, 
Period 6 (PF-06882961): 16 days, Period 7 (PF-06882961+rosuvastatin): 4 days, Period 8
(PF-06882961 + midazolam): 2 days, FU visit 7-10 days from last dose study intervention
and FU contact 28-35 days from last dose study intervention).  
Participants may be discharged on Period 2, Day 2 and return to the CRU for Period 3, Day-1
within 7 days from discharge. Alternatively, participants may remain as inpatient on 
Period 2, Day 2 and begin Period 3, Day 1 activities the same day, without completing 
Period 3, Day -1 procedures. Participants who discontinue from the study before completing 
all assessments may be replaced at the discretion of the investigator and Sponsor. 
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4.2. Scientific Rationale for Study Design
The purpose of this study is to characterize the effect of PF-06882961, administered at two 
steady-state dose levels, on the PK of single doses of rosuvastatin (10 mg) and midazolam
(2 mg), administered separately, in adult participants with obesity.  A multiple dose study 
will be conducted to ensure maximal clinically relevant steady-state PF-06882961 exposures 
are achieved. The drug-drug interaction effect will be initially assessed at PF-06882961 
120 mg BID
 
 and again at 200 mg BID
 
 
Participants with a higher body mass index (BMI) range from 30.0 kg/m2 to 45.4 kg/m2 who 
are otherwise healthy will be enrolled to minimize potential clinical risk of body weight loss 
in this study and to target a similar BMI range as patients with T2DM.  Adult participants
with T2DM often have co-existing obesity and also require treatment for hyperlipidemia, and 
therefore it is likely that PF-06882961 may be co-administered with rosuvastatin in clinical 
practice. Rosuvastatin is a BCRP substrate with limited passive cellular membrane 
permeability, which makes it a probe substrate for both intestinal BCRP and liver BCRP.  
Intestinal BCRP acts as an efflux transporter limiting rosuvastatin absorption while liver 
BCRP actively excretes rosuvastatin into the bile.  As PF-06882961 may be a BCRP 
inhibitor
 
 the effect of PF-06882961 at steady state on 
the PK of rosuvastatin is being assessed in this study. The elimination half-life of 
rosuvastatin is approximately 19 hours and therefore plasma sampling will be collected for 
rosuvastatin up to 96 hours after dosing.  
Similarly, as PF-06882961 may be a time-dependent inhibitor of CYP3A4/5
 
 the effect of 
PF-06882961 at steady state on the PK of midazolam, a CYP3A4/5 substrate, is being 
assessed in this study. Based on the turnover of CYP3A4/5,12 steady state of CYP3A4/5 will 
be achieved with the repeated dosing of PF-06882961 120 mg BID and 200 mg BID. 
Midazolam is specifically metabolized by CYP3A4/5, and therefore the United States Food 
and Drug Administration (FDA) recommends the use of midazolam as the probe of choice 
for in vivo CYP3A4/5 drug metabolism and drug interaction studies.  The elimination 
half-life of midazolam is approximately 2 hours and therefore plasma sampling will be 
collected for midazolam up to 24 hours after dosing.  
 
 
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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. As 
the degree of time-dependent inhibition of CYP3A4/5 is expected to be low, only minimal 
increases in midazolam exposure are expected and standard clinical monitoring of vital signs
will be used in this study. 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.13-16  In addition, thyroid stimulating hormone 
(TSH), free thyroxine (Free T4), lipids, coagulation profile and total bile acids (TBA) will be 
assessed, based on non-adverse findings in the nonclinical studies with PF-06882961. 
Assessment of Suicidal Ideation and Behavior (SIB) by Columbia Suicide Severity Rating 
Scale (C-SSRS)17 and Patient Health Questionnaire 9 (PHQ-9)18 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/m2.16
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 hypoglycemic AEs (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.
Dosing of PF-06882961 (with or without rosuvastatin 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 rosuvastatin and midazolam (with or without 
PF-06882961) is planned to occur in the fed state, with standard breakfast.
Females of childbearing potential may be enrolled into this study given the availability of 
embryo fetal developmental toxicity studies with PF-06882961. However, as marketed 
GLP-1R agonists, in addition to rosusvastatin, 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 


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applying a 10-fold safety factor for interspecies extrapolation and a 10-fold safety factor for 
susceptible populations.19
 
4.3. Justification for Dose
PF-06882961: The DDI assessment will occur at two steady-state PF-06882961 dose levels, 
120 mg BID and 200 mg BID.
The dose of PF-06882961 120 mg BID administered in this study represents the highest dose 
being assessed in the Phase 2b dose ranging study in T2DM.  This dose was also 
administered in the Phase 1 C3421002 study and therefore will allow DDI assessment in this 
study at an anticipated exposure that was sufficiently tolerated.  Based on data from the 
C3421002 study, the glucose lowering effect of PF-06882961 is expected to be similar to that 
of marketed GLP-1R agonists. 
 
 
 
 
 
 
  
 The titration to PF-06882961
120 mg BID is planned over 4 weeks (Section 6.1.1) and from 120 mg to 200 mg BID over 
16 days, in increments of 20 mg every 4 days. These titration increments have been 
administered previously and are expected to be sufficiently tolerated.
Rosuvastatin: In a single dose escalation study, rosuvastatin was safe and well tolerated at 
doses up to 80 mg.20 The most common AEs reported were headache and rash.  There was 
no evidence of a relationship between the frequency of AEs and rosuvastatin dose.  No 
serious adverse events (SAEs) were reported. Most DDI studies involving rosuvastatin as a 
substrate are conducted at the 10 mg or 20 mg dose level.21-23  The therapeutic dose of 
rosuvastatin may be up to 40 mg.  Since PF-06882961 is expected to increase rosuvastatin
plasma exposure, ten (10) mg rosuvastatin was selected as the dose in the current study and is 
expected to be well-tolerated. 
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Midazolam: Midazolam has been administered at doses of 2-15 mg to assess CYP3A4/5 
DDIs12 and is currently recommended for clinical use as a single oral dose (0.25 to 
1.0 mg/kg) or IV administration. Therefore, a single oral dose of midazolam 2 mg will 
provide measurable PK for 24 hours and is expected to be well-tolerated even if 
PF-06882961 results in an increase in midazolam plasma exposure.
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 follow-up 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 (follow-up contact) of the last 
participant in the study.
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. Male and female participants must be 18 to 65 years of age, inclusive, at the time of 
signing the ICD.

Women can be of child-bearing potential, however, cannot be pregnant, 
breastfeeding, or planning to become pregnant while participating in the study.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.


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Weight:
3. Body Mass Index (BMI) ≥30.0 kg/m2 and not more than 45.4 kg/m2 at Screening.
4. Stable body weight, defined as <5 kg change (per participant report) for 90 days 
before Screening. 
Informed Consent:
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Any condition possibly affecting drug absorption (eg, 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 or other conditions or 
situations related to COVID-19 pandemic (eg, contact with positive case, residence or 
travel to an area with high incidence) 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 rosuvastatin or midazolam.
6. Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at 
screening. Note: women with prior diagnoses of gestational diabetes during
pregnancy only are eligible if they meet the other eligibility criteria.
7. History of myocardial infarction, unstable angina, arterial revascularization, stroke, 
New York Heart Association Functional Class II-IV heart failure, or transient 
ischemic attack within 6 months of Screening.


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8. Any malignancy not considered cured (except basal cell carcinoma and squamous cell
carcinoma of the skin); a study participant is considered cured if there has been no
evidence of cancer recurrence in the previous 5 years (from Screening).
9. Personal or family history of medullary thyroid carcinoma (MTC) or multiple 
endocrine neoplasia syndrome type 2 (MEN2), or study participants with suspected 
MTC per the investigator’s judgment.
10. Acute pancreatitis or history of chronic pancreatitis.
11. Symptomatic gallbladder disease.
12. Medical history or characteristics suggestive of genetic or syndromic obesity or 
obesity induced by other endocrinological disorders (eg, Cushing Syndrome).
13. History of major depressive disorder or history of other severe psychiatric disorders 
(eg, schizophrenia or bipolar disorder) within the last 2 years from screening.
14. Known medical history of active liver disease (other than non-alcoholic hepatic 
steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, 
alcoholic liver disease, primary sclerosing cholangitis, autoimmune hepatitis, overlap 
syndrome, or prior known drug-induced liver injury.
15. History of HIV infection.
16. Any lifetime history of a suicide attempt.
Prior/Concomitant Therapy:
17. 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 6.5 for additional details).
18. 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 rosuvastatin 
(Refer to Section 6.5 for additional details).
19. See Section 6.5 for prohibited prior/concomitant medications.
Prior/Concurrent Clinical Study Experience:
20. 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).


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21. Known prior participation in a trial involving PF-06882961.
Diagnostic Assessments: At screening unless indicated
22. A Patient Health Questionnaire (PHQ-9) score ≥15 obtained at Screening or Day -1 in 
Study.
23. Response of “yes” to question 4 or 5, or on any behavioral question on the C-SSRS at 
Screening or Day -1 in Study.
24. A positive urine drug test.
25. 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.
26. 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.
27. 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 aminotransferase (AST) or alanine aminotransferase (ALT) level 
≥2 times the upper limit of normal (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 >1.5 times the ULN or <LLN.

Serum calcitonin > the ULN.


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
Amylase or lipase > the ULN.

Fasting blood glucose ≥126 mg/dL.

Fasting C-peptide <0.8 ng/mL.

Estimated glomerular filtration rate (eGFR) <80 mL/min/1.73 m2 as calculated by 
the Chronic Kidney Disease Epidemiology Collaboration (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 COVID-19 test.
Other Exclusions: At screening unless indicated
28. Participation in a formal weight reduction program (eg, Weight Watchers) within 
90 days prior to Screening.
29. 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).
30. Current use of tobacco or nicotine containing products in excess of the equivalent of 
5 cigarettes per day.
31. Known or suspected illicit drug use.
32. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing randomization (Day-1). 
33. History of sensitivity to heparin or heparin induced thrombocytopenia if Hep-lock is 
used for IV blood draw.
34. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
35. 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.


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5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 8 hours prior 
to any safety laboratory and the morning predose PK evaluations (Periods 1-8).

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. 
Rosuvastatin or midazolam when administered alone will be given within 
approximately 10 minutes of completion of the morning meal. 
PF-06882961 will be administered first and the single dose of midazolam/rosuvastatin
will be administered within 5 minutes of PF-06882961 for the periods where 
midazolam/rosuvastatin 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 rosuvastatin and midazolam also.

Dinner will be provided approximately 10 hours after dosing with study intervention. 
This applies to rosuvastatin and midazolam 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 on Period 8 Day 2.  

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.


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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. Tobacco or nicotine use must not exceed the limits specified in 
exclusion criterion for subjects who leave the CRU after Period 2 and return back for 
Period 3 of the study.

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 clinical 
research unit (CRU) and continue abstaining from alcohol until collection of the final 
PK sample on Period 8 Day 2.  Participants may undergo an alcohol breath test or 
blood alcohol test at the discretion of the investigator. Intake of alcohol must not
exceed the limits specified in exclusion criterion for subjects who leave the CRU after 
Period 2 and return back for Period 3 of the study.
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.

In order to standardize the conditions on PK sampling days, participants will be
required to refrain from lying down 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
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).  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.


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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 study-specific study participant identification number
(SSID) number. This criterion would also apply to participants who screened for this study 
more than 28 days prior to dosing.
6. STUDY INTERVENTION
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.
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 oral rosuvastatin 10 mg tablets will be supplied by the CRU.
Commercially available midazolam oral syrup (2 mg/mL) will be supplied by the CRU.
6.1.1. Administration
Participants will receive PF-06882961 (morning dose), rosuvastatin or midazolam as 
applicable per SoA at approximately 0800 hours (plus or minus 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, rosuvastatin, midazolam 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 6. 
Modification of dosing of PF-06882961 maybe permitted upon sponsor approval only. See 
Section 6.6.


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Table 6.
Dosing
Study Period
Days in Study
Drug & Dosage
Period 1, Day 1 
1
Rosuvastatin 10 mg QD
Period 2, Day 1
5
Midazolam 2 mg QD
Period 3, Days 1-4
8-11
PF-06882961 10 mg BID
Period 3, Days 5-8
12-15
PF-06882961 20 mg BID
Period 3, Days 9-12
16-19
PF-06882961 40 mg BID
Period 3, Days 13-16
20-23
PF-06882961 60 mg BID
Period 3, Days 17-20
24-27
PF-06882961 80 mg BID
Period 3, Days 21-24
28-31
PF-06882961 100 mg BID
Period 3, Days 25-28
32-35
PF-06882961 120 mg BID
Period 4, Day 1
36
PF-06882961 120 mg BID + Rosuvastatin 10 mg QD
Period 4, Days 2-4
37-39
PF-06882961 120 mg BID 
Period 5, Day 1
40
PF-06882961 120 mg BID + Midazolam 2 mg QD
Period 6, Days 1-4
41-44
PF-06882961 140 mg BID
Period 6, Days 5-8
45-48
PF-06882961 160 mg BID
Period 6, Days 9-12
49-52
PF-06882961 180 mg BID
Period 6, Days 13-16
53-56
PF-06882961 200 mg BID
Period 7, Day 1
57
PF-06882961 200 mg BID + Rosuvastatin 10 mg QD
Period 7, Days 2-4
58-60
PF-06882961 200 mg BID
Period 8, Day 1
61
PF-06882961 200 mg BID + Midazolam 2 mg QD
6.2. Preparation/Handling/Storage/Accountability

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.

Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.

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 


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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.

Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.

Study interventions should be stored in their original containers.

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.

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.
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 rosuvastatin and midazolam 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.


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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, 
2 digit 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 Periods 3 to 8, participants will receive the PF-06882961 doses as described in Table 7.
Table 7.
PF-06882961 Dosing Regimens
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
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.


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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. Concomitant Therapy
Study participants will abstain from all concomitant treatments, except for the treatment of
adverse events, as described in the Exclusion Criteria sections of this protocol.
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. 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 rosuvastatin.
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 6.5.1.1).
Sites are encouraged to contact the sponsor should there be questions as to whether a 
medication is permitted or prohibited.
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.
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.
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.


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6.5.1. 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 8.2.7).
6.5.1.1. 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 2.2.4.1).  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.
6.6. Dose Modification
If participants are not able to tolerate titration to higher doses of PF-06882961 
(ie, ≥160 mg BID), titration to the next dose level may be delayed temporarily or titration to 
maximum tolerated dose may be permitted, with Sponsor approval only.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, 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 8.2.5, 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.


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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 Early Term 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.
ECG Changes 
See Appendix 7 for additional guidance of ECG findings of potential clinical concern.
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 as described in Section 8.2.5.
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.


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Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
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 and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not 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.


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Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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 
556 mL.  The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 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.
8.1.1. Imaging Assessments 
Not Applicable.


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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
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.
8.2.2. Vital Signs
Vital signs (systolic BP, diastolic BPand pulse rate) 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 


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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 pulse rate is acceptable; however, 
when done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
See Appendix 8 for proposed chronology of procedures for nominal time points when vital 
sign assessments coincide with other procedures.
8.2.2.1. Temperature
Body temperature will be measured at the timepoints listed in the SoA.  No eating, drinking, 
or smoking is allowed for 15 minutes prior to this 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 heart rate 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. Suicidal Ideation and Behavior Risk Monitoring
8.2.5.1. Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an interview based rating scale to systematically assess suicidal ideation and 
suicidal behavior.17  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.
8.2.5.1.1. Rater Qualifications
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
participants in this study.  The minimum qualifications a rater must meet for each study 
rating assessment will be outlined in the guidance document provided to each participating 
site.  The level of experience with the target population (or equivalent), specific scale 
experience (or equivalent), and certification required (if applicable) will be listed and used to 
determine whether a rater is approved for a given assessment.  The rater must become 
certified to perform selected study assessments before he or she can participate in the conduct 
of the study.  For specifically defined assessments, rater training and standardization 
exercises may be conducted, and written 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.
8.2.5.2. Patient Health Questionnaire-9 (PHQ-9)
The PHQ-920 is a 9 item self-report scale for the assessment of depressive symptoms.18  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 and Day -1 indicates
clinically significant depression and serves as an exclusion criterion for this study (see 
Section 5.2).
8.2.5.3. Referral to a Mental Health Professional
A participant should be referred to a MHP for the following reasons:

Response of “yes” to question 4 or 5, or on any 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.


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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 two or more occassions 
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. 
8.2.6. Pregnancy Testing
Pregnancy tests must be serum test with 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.  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.  
8.2.7. 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 8.2.7.1 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.
8.2.7.1. 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.


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HAE is defined as one of the following:24
a.
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a glucose value of <70 mg/dL (3.9 mmol/L) using either glucometer 
(fingerstick blood glucose) at the study site or sponsor-identified central/local
laboratory (blood glucose).
b. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose value of <70 mg/dL (3.9 mmol/L), using 
glucometer at the study site or sponsor identified central/local laboratory, and the 
clinical picture includes prompt resolution with food intake, subcutaneous glucagon, 
or IV glucose.
c.
Probable symptomatic hypoglycemia: An event during which symptoms of HAE are 
not accompanied by a glucose determination but was presumably caused by a glucose 
concentration of <70 mg/dL (3.9 mmol/L), and the clinical picture includes prompt 
resolution with food intake, subcutaneous glucagon, or IV glucose.
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 one of the following neurological symptoms:

Memory loss.

Confusion.

Uncontrolled behavior.

Irrational behavior.

Unusual difficulty in awakening.

Suspected seizure.

Seizure.

Loss of consciousness.


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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.
8.2.8. Glucometer Monitoring of Glucose
Monitoring of fingerstick blood glucose (FSBG) using glucometer measurements is not 
required per protocol, but may be obtained if the investigator or participant notes symptoms 
of hypoglycemia.
If obtained, FSBG readings will be maintained at the CRU in source documents, and only the 
glucose results from the laboratory will be reported in the study database.
If an FSBG result is ≤70 mg/dL, a second FSBG should be obtained to confirm the glucose 
value, in addition to a venous sample that will be sent to the clinical laboratory for 
confirmation.  If the value from this second FSBG is also ≤70 mg/dL, the second value will 
be recorded as a hypoglycemic AE.  FSBG will continue to be monitored until the glucose 
value returns to >70 mg/dL.  Samples may be taken more frequently if deemed necessary by 
the investigator.  
8.2.9. COVID-19 Specific Assessments
Participants will be pre-screened for COVID-19 related symptoms and risks25,26 and tested 
for SARS-CoV-2 infection by PCR prior to being admitted to the clinic for confinement and 
a subsequent COVID-19 test will be performed after 4 days (ie, upon completion of 
4 x 24 hours in house), or if they develop COVID-19 like symptoms.
Additional testing may be conducted as required by local regulations or by the Principal 
Investigator. Results must be negative for admission to the CRU.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).


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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).
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 and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively 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 AE or SAE after the participant has concluded 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.


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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.
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/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 towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.


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An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure 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 male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception. 

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 exposure during pregnancy: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then exposes his female 
partner prior to or around the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after 
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
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), 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.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.


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
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 inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information 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 is 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.
8.3.9.1. Time Period for Detecting Medical Device Deficiencies
Not Applicable.
8.3.9.2. Follow-up of Medical Device Deficiencies
Not Applicable.
8.3.9.3. Prompt Reporting of Device Deficiencies to Sponsor
Not Applicable.
8.3.9.4. Regulatory Reporting Requirements for 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.
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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.
Other examples include, but are not limited to:

The administration of expired study intervention.

The administration of an incorrect study intervention.

The administration of an incorrect dosage.

The administration of study intervention that has undergone temperature excursion
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use.
8.4. 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 rosuvastatin10 and midazolam11 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.
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 
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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.
8.5. Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of rosuvastatin, 
midazolam 
as specified in the SoA.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF.  Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to 
samples to be collected more than 10 hours after dose administration at outpatient/follow-up 
visits with visit windows.
Samples collected for analyses of study intervention 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
 
Samples collected for measurement of plasma concentrations of study intervention will be 
analyzed using a validated analytical method in compliance with applicable SOPs.  
 
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.
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8.5.1. PK of Rosuvastatin
Samples will be used to evaluate the PK of rosuvastatin.  Blood samples of approximately 
5 mL, to provide a minimum of plasma volume of 2 mL, will be collected into appropriately 
labeled tubes containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) for 
measurement of plasma concentrations of rosuvastatin 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.
 
 
8.5.2. PK of Midazolam
Samples will be used to evaluate the PK of midazolam.  Blood samples of approximately
2 mL, to provide a minimum of plasma volume of 0.8 mL, will be collected into 
appropriately labeled tubes containing dipotassium ethylenediaminetetraacetic acid 
(K2EDTA) for measurement of plasma concentrations of 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.
 
 
 
 
 
 
 
 
 
 
 
8.6. Pharmacodynamics
Not applicable.
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8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. 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.
9.1. Statistical Hypotheses
No formal statistical hypothesis testing will be performed in this study.
9.2. Sample Size Determination
A sample size of approximately 16 participants will be enrolled such that approximately 
12 evaluable participants complete the study. This minimum number of evaluable 
participants has been selected to provide sufficient precision to detect a 1.25-fold difference 
in AUCinf for either rosuvastian or midazolam as described below. 
The primary comparisons of interest are as follows:

For rosuvastatin AUCinf:

The co-administration of rosuvastatin and PF-06882961 120 mg BID (Period 4) 
versus rosuvastatin alone (Period 1, reference treatment).

The co-administration of rosuvastatin and PF-06882961 200 mg BID (Period 7) 
versus rosuvastatin 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).
The expected widths of the 90% confidence intervals with 80% coverage probability for 
these comparisons are shown in Table 8, for a range of possible effects based on a sample 
size of 12 participants.


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Table 8.
Expected Widths of the 90% CIs (with 80% Coverage Probability) for 
Different Possible Estimated Effects and Parameters of Interest
Parameter
Estimated Effect
(Test/Reference)
AUCinf
Probable
90% CI
Probable
CI Width
AUCinf (Rosuvastin 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%
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 
rosuvastatin and midazolam. These estimates are based on data from previous internal DDI 
studies of rosuvastatin or midazolam.
9.3. 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 Rosuvastastin, midazolam
and/or PF-06882961 and in whom at least 1 plasma 
concentration value is reported.


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Participant Analysis 
Set
Description
PK Parameter Set
The PK parameter analysis population is defined as all
participants who received at least 1 dose of rosuvastatin, 
midazolam and/or PF-06882961 and have at least 1 of the PK 
parameters of interest calculated.
Should vomiting occur after co-administration of 
rosuvastatin/midazolam 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.
9.4. 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.
9.4.1. General Considerations
9.4.1.1. Derivation of Pharmacokinetic Parameters
The plasma PK parameters for rosuvastatin and midazolam following single dose 
administration (either alone or in co-administration with PF-06882961) will be derived from 
the concentration-time profiles as detailed in Table 9 below.
 
Actual PK sampling times will be used in the derivation of PK parameters. In the case that 
actual PK sampling times are not available, nominal PK sampling time will be used in the 
derivation of PK parameters.
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Table 9.
Plasma PK Parameters for Rosuvastatin and Midazolam
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.
 
 
 
 
 
* as data permit.
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9.4.2. Statistical Methods for Pharmacokinetic data
The PK data for rosuvastatin, midazolam 
 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, 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 log-transformed AUCinf (as data permit) of rosuvastatin 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% confidence intervals will be obtained 
from the models. The adjusted mean differences and 90% confidence intervals for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% confidence intervals for the ratios. The two test treatments 
will be ‘rosuvastatin and PF-06882961 120 mg BID’ (Period 4) and ‘rosuvastatin and 
PF-06882961 200 mg BID’ (Period 7), which will be reported separately in comparison to 
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the reference treatment of ‘rosuvastatin alone’ (Period 1). The same analysis for natural 
log-transformed 
 AUClast of rosuvastatin will also be conducted.
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 rosuvastatin. The two 
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 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 rosuvastatin and midazolam
 
will be separately summarized descriptively by treatment.
9.4.3. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, 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 pulse rate abnormalities of potential clinical concern will 
be described.  Safety data will be presented in tabular and/or graphical format and 
summarized descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.  
COVID-19 specific assessments data will be considered source data and will not be required 
to be reported.
9.4.3.1. Electrocardiogram Interval Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR
interval, and QRS complex will be summarized by treatment and time.
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9.5. 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. 
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a DMC.
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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 and 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.
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 guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (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.  
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 ICH GCP that the investigator becomes aware 
of.


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10.1.2. Financial Disclosure
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study 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, HIPAA 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 the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the 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.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research.  The optional 
additional research does not require the collection of any further samples. The investigator 
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may 


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withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a participant's agreement to allow specimens to be 
used for additional research. Participants who decline to participate in this optional
additional research will not provide this separate signature.
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 identification. 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. 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.
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.


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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 available data from these trials 
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.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.


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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (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, remote, or on-site monitoring), are provided in the
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
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, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.


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10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. 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 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.


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Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
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.
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.
10.1.10. 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 Team Roster.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site staff cannot be reached to 
provide advice on a medical question or problem originating from another healthcare 
professional not involved in the participant’s participation in the study.  The contact number 
can also be used by investigator staff if they are seeking advice on medical questions or 


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problems; however, it should be used only in the event that the established communication 
pathways between the investigator site and the study team are not available.  It is therefore 
intended to augment, but not replace, the established communication pathways between the 
investigator site and the study team for advice on medical questions or problems that may 
arise during the study.  For sites other than a Pfizer CRU, the contact number is not intended 
for use by the participant directly, and if a participant calls that number, 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 11.
Protocol Required 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 total bile acids
PT/INR/aPTT
COVID-19 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


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Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
Serum β-hCG for all WOCBP.
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-1, Period 3 Day-1 and at the 
discretion of the investigator.
d.
For all female participants to confirm post-menopausal status only.
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; β-hCG = beta human chorionic gonadotropin; BUN = blood urea nitrogen; 
CO2 = carbon dioxide; COVID-19 = corona-virus disease 2019; eGFR = estimated glomerular filtration rate; 
FSH = follicle stimulating hormone; GGT = gamma-glutamyl transferase; HbA1c = glycated hemoglobin; 
HCVAb = Hepatitis C Virus Antibody; HCV RNA = Hepatitis C Virus RNA; HDL-C = high density lipoprotein 
cholesterol; HepBsAg = Hepatitis B Surface Antigen; HIV = Human Immunodeficiency Virus; INR = international 
normalized ratio; LDL-C = low density lipoprotein cholesterol; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; qual = qualitative; 
RBC = red blood cell; THC = Tetrahydrocannabinol; TSH = thyroid stimulating hormone; WBC = white blood cell; 
WOCBP = women of child bearing potential.
Investigators must document their review of each laboratory safety report.
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.  
 
  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.
CCI


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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 conditions 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/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 which 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 SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
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 detained (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 


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baseline is not considered an AE.
d. Results in persistent 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) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
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.

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 patient 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.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  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 


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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, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP supplemental 
form for EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/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/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/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/SAE.


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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: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE.  Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
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/SAE.

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.

The investigator will use clinical judgment to determine the relationship.

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/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/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 


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information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor.  In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this causal 
relationship in the source documents and CRF, and report such an assessment in the 
dedicated section of the CT SAE Report Form and in accordance with the SAE 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

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) in order 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 


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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 Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
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. 
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.


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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. 

Female on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
Highly Effective Methods That Have Low User Dependency
1. Intrauterine device.
2. Bilateral tubal occlusion.
3. Vasectomized partner.


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
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).


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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 an “adaptor” 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 cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
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 and liver imaging (eg, biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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


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<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 8: Proposed Chronology of Procedures
For the procedures described below, where multiple procedures are scheduled at the same 
timepoint(s) relative to dosing, the following chronology of events should be adhered to:
•
12 lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing (as applicable for pre-dose collection) (see Section 8.2.3); 
•
Vital Signs (BP, PR): obtain after 12 lead ECG collection but prior to obtaining blood 
samples and prior to dosing (as applicable for pre-dose collection) (see Section 8.2.2); 
•
Temperature: obtain after 12 lead ECG collection but prior to obtaining blood 
samples and prior to dosing (as applicable for pre-dose collection) (see
Section 8.2.2.1);
•
Fasting blood samples [for safety (see Section 8.2.4, PK (see Section 8.5), 
after assessment of 12 lead ECG and vital signs but prior to dosing (as 
applicable for pre-dose collection); 
•
For the post-dose PK blood collections (see Section 8.5): if collection time coincides 
with time of a meal/snack, these blood samples should be collected just prior to the 
meal/snack;
•
Other pre-dose procedures: obtain sample/perform procedure as close as possible to
the scheduled time, but may be obtained before or after blood sample collection(s); 
•
Dosing: must occur with the morning meal; and where applicable, after any pre-dose 
blood sample collection(s).
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10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
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
 
AV
atrioventricular
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
β-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
Clast
predicted plasma concentration at the last quantifiable time point 
estimated from the log-linear regression analysis
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
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Abbreviation
Term
%CV
percent coefficient of variation 
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ET
early termination
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSBG
fingerstick blood glucose
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP-1 
glucagon-like peptide 1 
GLP-1 R
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
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
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


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Abbreviation
Term
IVGTT
intravenous glucose tolerance test 
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
LFT
liver function test
MATE
multidrug and toxin extrusion protein 
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
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
OCT
organic cation transporter 
PD
pharmacodynamic(s)
PHQ-9
Patient Health Questionnaire-9
PK
pharmacokinetic(s)
PR
pulse rate
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
Once a day
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
Rac
mean ratios based on dose normalized AUC24
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SToD
study team on demand
SSID
study-specific subject identification 
SUSAR
suspected unexpected serious adverse reaction


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Abbreviation
Term
T2DM
type 2 diabetes mellitus
T4
thyroxine
TBA
total bile acids
TBili
total bilirubin
TEAEs
treatment emergent adverse events 
THC
tetrahydrocannabinol
TSH
thyroid stimulating hormone
UGT
uridine 5'-diphospho glucuronosyltransferase 
glucuronosyltransferase
ULN
upper limit of normal
US
United States
USPI
United States package insert 
WBC
white blood cell
WOCBP
woman of childbearing potential
C
CI
CCI
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11. REFERENCES
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Martin P, Gillen M, Ritter J, et al. Effects of fostamatinib on the pharmacokinetics of 
oral contraceptive, warfarin, and the statins rosuvastatin and simvastatin: results rrom
Phase I clinical studies. Drugs RD 2016;16(1):93-107.
22.
Cooper KJ, Martin PD, Dane AL, et al. Effect of itraconazole on the pharmacokinetics 
of rosuvastatin. Clin Pharmacol Ther 2003;73(4):322-9.
23.
Stopfer P, Giessmann T, Holh K, et al. Effects of metformin and furosemide on 
rosuvastatin pharmacokinetics in healthy volunteers: implications for their use as probe 
drugs in a transporter cocktail. Eur J Drug Metab Pharmacokinet 2018;43(1): 69-80.
24. American Diabetes Association. Standards of medical care in diabetes -2019. Diabetes 
Care. January 2019;42(Suppl 1): S1-S193.
25.
Centers for Disease Control and Prevention. Interim Clinical Guidance for Management 
of Patients with Confirmed Coronavirus Disease (COVID-19). 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-
patients.html (Accessed on September 21, 2020).


PF-06882961
C3421007
Final Protocol, 07 October 2020
PFIZER CONFIDENTIAL
Page 108
26.
Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2
(COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html
(Accessed on September 22, 2020).

SAP_001.pdf: 
Protocol C3421007 (PF-06882961) Statistical Analysis Plan 
 
 
 
PFIZER CONFIDENTIAL  
Page 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol C3421007 
 
 
 
 
A PHASE 1, OPEN LABEL, FIXED SEQUENCE STUDY TO EVALUATE THE 
EFFECT OF TWO STEADY STATE DOSE LEVELS OF PF-06882961 ON THE 
PHARMACOKINETICS OF SINGLE ORAL DOSES OF ROSUVASTATIN AND 
MIDAZOLAM IN OTHERWISE HEALTHY ADULT PARTICIPANTS WITH 
OBESITY 
 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
2.0 
 
Date:  
24 May 2021 
 
 
 
 
 
 
 NOTE: Italicized text within this document has been taken verbatim from the Protocol.


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