Clinical trial NCT04839393
Conditions: Healthy Volunteer
Sponsor: Pfizer
Start date: 2021-04-05; Completion date: 2021-11-08
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will be conducted in 2 parts. Part A will investigate the potential effect of PF-06865571 on the pharmacokinetics (PK) of PF-06882961 in healthy adult participants. Part B will evaluate the effect of PF-06882961 on the PK of PF-06865571, as well as the effect of PF-06865571 on the PK of PF-06882961 in overweight adults or adults with obesity who are otherwise healthy.

Detailed description:

Arms: arm 1: Treatment A - PF-06882961 single dose followed by Treatment B - PF-06882961 single dose and PF-06865571 single dose arm 2: Treatment B - PF-06882961 single dose and PF-06865571 single dose followed by Treatment A - PF-06882961 single dose arm 3: Period 1: PF-06865571 single dose, Period 2: PF-06882961 twice daily dose titration, Period 3: PF-06865571 single dose and PF-06882961 twice daily dosing, Period 4: PF-06865571 twice daily dosing and PF-06882961 twice daily dosing
Interventions: intervention 1: PF-06882961 followed by PF-06882961/PF-06865571 intervention 2: PF-06882961/PF-06865571 followed by PF-06882961 intervention 3: PF-06882961 + PF-06865571
Intervention descriptions: intervention 1: Treatment A - PF-06882961 20 mg single dose followed by Treatment B - PF-06882961 20 mg single dose plus PF-06865571 300 mg single dose. There will be a washout interval between periods of at least 3 days. intervention 2: Treatment B - PF-06882961 20 mg single dose plus PF-06865571 300 mg single dose followed by Treatment A - PF-06882961 20 mg single dose. There will be a washout interval between periods of at least 3 days. intervention 3: Period 1: PF-06865571 300 mg single dose (Day 1), Period 2: PF-06882961 10 mg twice daily dose titration up to 200 mg twice daily dosing (Days 3-46), Period 3: PF-06865571 300 mg single dose (Day 47) and PF-06882961 200 mg twice daily dosing (Days 47-48), Period 4: PF-06865571 300 mg twice daily dosing and PF-06882961 200 mg twice daily dosing (Days 49-62)

Protocol documents:
Prot_000.pdf: 
PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, OPEN-LABEL STUDY TO EVALUATE THE PHARMACOKINETIC 
INTERACTIONS BETWEEN PF-06882961 AND PF-06865571 IN HEALTHY ADULT 
PARTICIPANTS (PART A) AND OVERWEIGHT ADULTS OR ADULTS WITH 
OBESITY WHO ARE OTHERWISE HEALTHY (PART B)
Study Intervention Number:
PF-06882961 and PF-06865571
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
N/A
Protocol Number:
C3421038
Phase:
1
Short Title: A Phase 1 Study to Evaluate the Pharmacokinetic Interactions Between
PF-06882961 and PF-06865571
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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PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Protocol Amendment 
#2
03 June 2021
Section 1 – Protocol Summary – Objectives 
and Endpoints, Schedule of Activities –
Part B, Section 2.2.4.2.1 – Clinical 
Pharmacokinetics of PF-06882961, Section 3 
– Objectives and Endpoints, Section 4.2 –
Scientific Rationale for Study Design, 
Section 8.8 Biomarkers, Section 9.4 –
Statistical Analyses: Added plasma CP-I and 
4-β-hydroxycholesterol/cholesterol 
assessments at specified timepoints in Part B 
and updated the background, study rationale, 
objectives/endpoints, assessments/procedures 
and statistical analyses as appropriate.
Rationale: Preliminary draft data from 
study C3421007 indicate that a decrease 
in exposure of midazolam are observed 
when co-administered with 
PF-06882961.  To investigate the 
mechanism of this interaction, 
assessment of plasma 
4-β-hydroxycholesterol/cholesterol, an 
endogenous probe for CYP3A 
induction, is being added in Part B.
In vitro studies indicate PF-06882961 
may inhibit OATP1B1 at dose(s) 
evaluated in this study.  Therefore, to 
evaluate this potential effect of 
PF-06882961, measurement of plasma 
CP-I, an endogenous probe for OATP1B 
activity, is being added in Part B.
Schedule of Activities Part B, Section 4.2 –
Scientific Rationale for Study Design, 
Table 14 – Protocol Required Safety 
Laboratory Assessments: Added Cystatin-C 
sampling at baseline and subsequent safety 
laboratory assessments.


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 3
Rationale: PF-06865571 is a 
dose-dependent inhibitor of the 
transporters OCT2/MATE in the kidney.  
As expected, increases in serum 
creatinine without a change in renal 
function (as assessed via eGFR 
determined using Cystatin-C) have been 
noted in prior studies.  This interaction 
interferes with accurate monitoring of 
renal function with serum creatinine; 
therefore, Cystatin-C sampling is being 
introduced for Part B to enable accurate 
monitoring of renal function as part of 
safety assessments during repeated
co-administration of PF-06865571 and 
PF-06882961.
Section 2.2.4.1.1 – Clinical and Safety 
Experience with PF-06882961: Added 
preliminary safety data from the C3421007 
study.
Rationale: The C3421007 preliminary 
data provides the most up-to-date 
clinical safety data with PF-06882961.
Section 5.4 – Screen Failures: Modified 
rescreening criteria to clarify that repeating of 
screening procedures and reassignment of 
new identification number is not required in 
the event of unexpected delays as long as 
laboratory results obtained prior to first dose 
administration meet eligibility criteria.
Rationale: This was an inadvertent 
inconsistency between rescreening 
language in Section 5.4 – Screen 
Failures and Section 8 – Study 
Assessments and Procedures.  Updated 
language allows for flexible rescreening 
procedures within a healthy volunteer 
population.
Section 8 – Study Assessments and 
Procedures: Modified blood sampling volume 


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 4
from 400 mL rounded up to 525 mL for 
Part B.
Rationale: Cystatin-C assessments 
require an additional 55 mL total blood 
sampling volume.  CP-I and 
4-β-hydroxycholesterol/cholesterol 
assessments require 51 mL and 16 mL 
blood sampling volume, respectively.
Protocol Amendment 
#1
12 March 2021
Section 1.1 - Synopsis, Section 4.1.1 - Part A 
Study Design; The duration of Part A is
approximately 9 weeks instead of 8 weeks.
Rationale: This was an inadvertent 
miscalculation of the number of weeks 
within the study timeline in FAP.
Section 1.1 - Synopsis, Section 3 - Objectives 
and Endpoints: Included “Assessment of 
mental health as determined by C-SSRS and 
PHQ-9 in Part B of the study” as secondary 
endpoint in Part B.
Rationale: This was an inadvertent 
exclusion in FAP.
Schedule of Activities Part A: Removed ‘X’ 
from ‘Inpatient stay at CRU’ row for the 
ET/DC visit.
Rationale: Table is now consistent with 
the Schedule of Activities in Part B. 
The Early Termination/Discontinuation 
visit is considered out-patient and does 
not require an overnight inpatient stay.
Schedule of Activities Part A: Ensured
footnotes for Day -1 activities were 
footnote ‘e’ “If participant is not discharged 
from the CRU between Periods 1 and 2, 
procedure only needs to be conducted in 
Period 1 only.”


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 5
Rationale: Error during protocol 
amendment formatting/finalization.
Schedule of Activities Part A/B, Section 
4.2 - Scientific Rationale for Study Design, 
Section 8, Study Assessments and 
Procedures,
 
 
 
 
 
Rationale: Updated terminology with 
new protocol/ICD templates.
Schedule of Activities Part A/B, 
Appendix 2-Clinical Laboratory Tests: 
Removed HepBsAb and HepBcAb from 
Screening testing.
Rationale: Removal ensures consistency 
with Exclusion Criteria #27 and 
C3421007 eligibility criteria. Sampling 
was confirmed not to be necessary for 
determination of viral exclusionary 
status.
Section 5.2-Exclusion Criteria #2: Removed 
appendectomy from list of any condition 
possibly affecting drug absorption.
Rationale: It was determined that 
appendectomy would not affect drug 
absorption and its inclusion was an 
oversight.
Section 5.2-Exclusion Criteria #19: Added 
language that an emergency use authorized or 
approved COVID-19 vaccine is considered a 
concomitant medication.
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Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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Rationale: Included COVID-19 vaccine 
language in clinical studies as per FDA 
guidance.
Section 5.2-Exclusion Criteria #27: Modified 
and added additional abnormalities in clinical 
laboratory tests, including ALT/AST, total 
bilirubin, TSH, fasting triglyceride, INR, and 
PLT.
Rationale: FDA correspondence from 
IND submission.
Section 10.1.7 - Source Documents: Added 
language for data types that may be recorded 
directly on the CRFs (ie, for which there is no 
existing written or electronic record of data) 
and is to be considered data source.
Rationale: Allow for direct data capture 
CRF input, reducing the amount of data 
transcribed from paper source 
documents to improve efficiency and 
data quality.
Section 6.7 - Stopping Rules: Added section 
and sub-section 6.7.1-6.7.3 to call out 
stopping rules for participant death, 
development of adverse events, and 
individual participant development of adverse 
events.
Rationale: FDA correspondence from 
IND submission.
Section 9.4.3 - Safety Analyses: Continuous 
cardiac monitoring removed from items to be 
reviewed and summarized.
Rationale: This was an inadvertent 
exclusion in FAP. Continuous cardiac 
monitoring/telemetry was never being 
performed in this study.
Section 9.4.3.1 - Electrocardiogram Analyses: 
Added sentence that exposure-QT analyses is 


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 7
performed, it will be reported separately, not 
as part of the CSR.
Rationale: Clarifcation as requested.
Appendix 1, Section 10.1.3 - Informed 
Consent Process: Removed last paragraph in 
section describing consent for optional 
additional research.
Rationale: Removed as per new 
ICD/protocol template guidance and 
language.
Appendix 4, Section 10.4.3 - Woman of 
Childbearing Potential, 
Section 10.4.4 - Contraception Methods: Use 
of hormonal contraception by WOCBP or 
females whose menopausal status is in doubt 
has been removed.
Rationale: Per study team discussion, 
use of hormonal contraception has been 
removed from this study to ensure no 
possible drug-drug interactions with 
study interventions and to maintain
consistency with Section 6.5.
Appendix 9, Alternative Measures During 
Public Emergencies: Added this appendix.
Rationale: Includes new template 
content, re-affirming COVID-19 testing 
eligibility and COVID-19 safety 
reporting.
Other minor spelling errors and 
inconsistencies corrected/modified throughout 
protocol to ensure accuracy and improved 
trial conduct.
Original protocol
23 December 
2020
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
1. PROTOCOL SUMMARY...................................................................................................15
1.1. Synopsis ..................................................................................................................15
1.2. Schema ....................................................................................................................17
1.2.1. Treatment Scheme for Part A .....................................................................17
1.2.2. Treatment Scheme for Part B .....................................................................17
1.3. Schedule of Activities .............................................................................................18
1.3.1. Schedule of Activities for Part A................................................................18
1.3.2. Schedule of Activities for Part B................................................................20
2. INTRODUCTION ...............................................................................................................24
2.1. Study Rationale .......................................................................................................24
2.2. Background .............................................................................................................24
2.2.1. Non-Alcoholic Steatohepatitis....................................................................24
2.2.2. Nonclinical Pharmacokinetics ....................................................................25
2.2.2.1. Nonclinical Pharmacokinetics and Metabolism of PF-
06882961...........................................................................................25
2.2.2.2. Nonclinical Pharmacokinetics and Metabolism of PF-
06865571 ...........................................................................................26
2.2.3. Nonclinical Toxicology ..............................................................................26
2.2.3.1. Summary of Toxicology Studies with PF-06882961................26
2.2.3.2. Summary of Toxicology Studies with PF-06865571................27
2.2.3.3. Summary of Toxicology Study for Co-administration of 
PF-06882961 and PF-06865571........................................................27
2.2.4. Clinical Overview.......................................................................................27
2.2.4.1. Summary of Clinical Safety......................................................27
2.2.4.2. Summary of Clinical Pharmacology and Biopharmaceutic 
Studies ...............................................................................................29
2.3. Benefit/Risk Assessment.........................................................................................30
2.3.1. Risk Assessment.........................................................................................31
2.3.2. Benefit Assessment.....................................................................................35
2.3.3. Overall Benefit/Risk Conclusion................................................................35


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Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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3. OBJECTIVES AND ENDPOINTS.....................................................................................36
4. STUDY DESIGN.................................................................................................................37
4.1. Overall Design.........................................................................................................37
4.1.1. Part A Study Design ...................................................................................37
4.1.2. Part B Study Design....................................................................................38
4.2. Scientific Rationale for Study Design.....................................................................38
4.3. Justification for Dose ..............................................................................................41
4.3.1. PF-06882961...............................................................................................41
4.3.1.1. PF-06882961 in Part A..............................................................41
4.3.1.2. PF-06882961 in Part B..............................................................41
4.3.2. PF-06865571 in Part A and Part B .............................................................42
4.4. End of Study Definition ..........................................................................................42
5. STUDY POPULATION......................................................................................................42
5.1. Inclusion Criteria.....................................................................................................43
5.2. Exclusion Criteria....................................................................................................43
5.3. Lifestyle Considerations..........................................................................................47
5.3.1. Meals and Dietary Restrictions...................................................................47
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................48
5.3.3. Activity .......................................................................................................48
5.3.4. Contraception..............................................................................................49
5.4. Screen Failures ........................................................................................................49
6. STUDY INTERVENTION..................................................................................................49
6.1. Study Intervention(s) Administered........................................................................49
6.1.1. Administration............................................................................................50
6.2. Preparation/Handling/Storage/Accountability ........................................................51
6.2.1. Preparation and Dispensing........................................................................52
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................52
6.3.1. Allocation to Study Intervention ................................................................52
6.4. Study Intervention Compliance...............................................................................54
6.5. Concomitant Therapy..............................................................................................54
6.5.1. Rescue Medicine.........................................................................................55


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Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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6.5.1.1. Management of Nausea and Vomiting......................................55
6.6. Dose Modification...................................................................................................55
6.7. Stopping Rules ........................................................................................................55
6.7.1. Participant Death ........................................................................................55
6.7.2. Individual Participant Development of Adverse Events (Part B only).......56
6.7.3. Cohort Level Assessment of Adverse Events (Part B, Period 4 only) .......56
6.8. Intervention After the End of the Study..................................................................56
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................57
7.1. Discontinuation of Study Intervention ....................................................................57
7.2. Participant Discontinuation/Withdrawal From the Study.......................................57
7.2.1. Withdrawal of Consent...............................................................................58
7.3. Lost to Follow up ....................................................................................................58
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................59
8.1. Efficacy Assessments..............................................................................................60
8.2. Safety Assessments .................................................................................................60
8.2.1. Physical Examinations................................................................................60
8.2.2. Vital Signs ..................................................................................................61
8.2.3. Electrocardiograms.....................................................................................62
8.2.4. Clinical Safety Laboratory Assessments ....................................................63
8.2.5. Suicidal Ideation and Behavior Risk Monitoring.......................................63
8.2.5.1. Columbia Suicide Severity Rating Scale (Part B only).............63
8.2.5.2. Patient Health Questionnaire-9 (Part B only) ...........................64
8.2.5.3. Referral to a Mental Health Professional ..................................64
8.2.6. COVID-19 Specific Assessments...............................................................65
8.2.7. Pregnancy Testing ......................................................................................65
8.2.8. Management of Hypoglycemia...................................................................65
8.2.8.1. Definition and Severity of Categorization of 
Hypoglycemic Adverse Event (HAE)...............................................65
8.2.9. Glucometer Monitoring of Glucose............................................................67
8.3. Adverse Events and Serious Adverse Events..........................................................67
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......67


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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8.3.1.1. Reporting SAEs to Pfizer Safety...............................................68
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................68
8.3.2. Method of Detecting AEs and SAEs ..........................................................68
8.3.3. Follow-up of AEs and SAEs.......................................................................68
8.3.4. Regulatory Reporting Requirements for SAEs...........................................69
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................69
8.3.5.1. Exposure During Pregnancy......................................................69
8.3.5.2. Exposure During Breastfeeding ................................................71
8.3.5.3. Occupational Exposure .............................................................71
8.3.6. Cardiovascular and Death Events...............................................................72
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................72
8.3.8. Adverse Events of Special Interest.............................................................72
8.3.8.1. Lack of Efficacy........................................................................72
8.3.9. Medical Device Deficiencies......................................................................72
8.3.10. Medication Errors.....................................................................................72
8.4. Treatment of Overdose............................................................................................73
8.5. Pharmacokinetics ....................................................................................................74
8.5.1. Plasma for Analysis of PF-06882961
.......75
8.5.2. Plasma for Analysis of PF-06865571.........................................................75
8.6. Pharmacodynamics..................................................................................................75
8.8. Biomarkers ..............................................................................................................76
8.8.5. Plasma for Analysis of CP-I (Part B only) .................................................76
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Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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8.8.6. Plasma for 4-β-hydroxycholesterol/cholesterol Analysis (Part B 
only).................................................................................................................76
8.9. Immunogenicity Assessments.................................................................................77
8.10. Health Economics .................................................................................................77
9. STATISTICAL CONSIDERATIONS ................................................................................77
9.1. Statistical Hypotheses .............................................................................................77
9.2. Sample Size Determination.....................................................................................77
9.2.1. Sample Size for Part A ...............................................................................77
9.2.2. Sample Size for Part B................................................................................78
9.3. Analysis Sets ...........................................................................................................79
9.4. Statistical Analyses .................................................................................................79
9.4.1. General Considerations...............................................................................79
9.4.1.1. Derivation of Pharmacokinetic and Endogenous 
Biomarker Parameters .......................................................................79
9.4.2. Statistical Methods for Pharmacokinetic Data ...........................................81
9.4.2.1. Part A – Statistical Methods for Pharmacokinetic Data............81
9.4.2.2. Part B – Statistical Methods for Pharmacokinetic and 
Endogenous Biomarker Data.............................................................82
9.4.3. Safety Analyses ..........................................................................................83
9.4.3.1. Electrocardiogram Analyses......................................................83
9.4.4. Other Analyses............................................................................................83
9.5. Interim Analyses .....................................................................................................84
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............84
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................85
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............85
10.1.1. Regulatory and Ethical Considerations ....................................................85
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................85
10.1.2. Financial Disclosure .................................................................................86
10.1.3. Informed Consent Process ........................................................................86
10.1.4. Data Protection .........................................................................................87
10.1.5. Dissemination of Clinical Study Data ......................................................87


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Final Protocol Amendment 2, 03 June 2021
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10.1.6. Data Quality Assurance ............................................................................88
10.1.7. Source Documents....................................................................................89
10.1.8. Study and Site Start and Closure ..............................................................90
10.1.9. Publication Policy.....................................................................................91
10.1.10. Sponsor’s Qualified Medical Personnel .................................................92
10.2. Appendix 2: Clinical Laboratory Tests .................................................................93
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................95
10.3.1. Definition of AE .......................................................................................95
10.3.2. Definition of SAE.....................................................................................96
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................97
10.3.4. Reporting of SAEs..................................................................................100
10.4. Appendix 4: Contraceptive Guidance .................................................................102
10.4.1. Male Participant Reproductive Inclusion Criteria..................................102
10.4.2. Female Participant Reproductive Inclusion Criteria...............................102
10.4.3. Woman of Childbearing Potential ..........................................................102
10.4.4. Contraception Methods...........................................................................103
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......106
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................108
10.8. Appendix 8: Proposed Chronology of Procedures..............................................110
10.9. Appendix 9: Alternative Measures During Public Emergencies ........................111
10.9.1. Eligibility................................................................................................111
10.9.2. Adverse Events and Serious Adverse Events.........................................111
10.10. Appendix 10: Abbreviations .............................................................................112
11. REFERENCES ................................................................................................................116
LIST OF TABLES
Table 1.
Part A – Overall Schedule of Activities ...................................................18
Table 2.
Part B – Overall Schedule of Activities....................................................20
Table 3.
Part B – Schedule of Activities for:..........................................................23
Table 4.
Part A Dosing ...........................................................................................50
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PFIZER CONFIDENTIAL
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Table 5.
Part B Dosing............................................................................................50
Table 6.
Part A Sequence 1 – Dosing Regimens for PF-06882961 and PF-
06865571 ..................................................................................................52
Table 7.
Part A Sequence 2 – Dosing Regimens for PF-06882961 and PF-
06865571 ..................................................................................................53
Table 8.
Part B – Dosing Regimens for PF-06882961 and PF-06865571..............53
Table 9.
Estimated Effect of PF-06865571 on PF-06882961 in Part A –
Expected Widths of the 90% CIs (with 80% Coverage Probability)
for Different Possible Estimated Effects and Parameters of Interest .......77
Table 10.
Estimated Effect of PF-06865571 on PF-06882961 in Part B –
Expected Widths of the 90% CIs (with 80% Coverage Probability) 
for Different Possible Estimated Effects and Parameters of Interest .......78
Table 11.
Estimated Effect of PF-06882961 on PF-06865571 in Part B –
Expected Widths of the 90% CIs (with 80% Coverage Probability) 
for Different Possible Estimated Effects and Parameters of Interest .......78
Table 12.
Part A – Plasma PK Parameters for PF-06882961 ...................................80
Table 13.
Part B – Plasma PK Parameters for PF-06882961
and PF-06865571, and Plasma CP-I Parameters ......................................80
Table 14.
Protocol Required Safety Laboratory Assessments..................................93
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 1 Study to Evaluate the Pharmacokinetic Interactions Between 
PF-06882961 and PF-06865571
Rationale: This study will evaluate the PK interactions between PF-06882961 and 
PF-06865571 in healthy adult participants (Part A) and overweight adults or adults with 
obesity who are otherwise healthy (Part B).
Objectives and Endpoints:
Objectives
Endpoints
Part A
Primary: 
Primary: 

To evaluate the effects of PF-06865571 on the single-
dose pharmacokinetics of PF-06882961 in healthy 
adult participants.

PF-06882961 plasma pharmacokinetic parameters: 
Cmax and AUC24.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
PF-06882961 alone and in combination with 
PF-06886571 when administered to healthy adult 
participants.

Assessment of treatment-emergent adverse events, 
clinical laboratory abnormalities, vital signs, body 
weight, and ECG parameters during the entire study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To evaluate the effects of PF-06865571 on additional 
pharmacokinetic parameters of PF-06882961 in 
healthy adult participants.

Additional PF-06882961 plasma pharmacokinetic 
parameters: Tmax.
Part B
Primary: 
Primary: 

To evaluate the effects of PF-06882961 on the 
single-dose pharmacokinetics of PF-06865571 in 
overweight adults or adults with obesity who are 
otherwise healthy.

PF-06865571 plasma pharmacokinetic parameters on 
Day 1 and Day 47: Cmax, AUClast, and AUCinf, as 
data permits.

To evaluate the effects of PF-06865571 on the 
multiple-dose pharmacokinetics of PF-06882961 in 
overweight adults or adults with obesity who are 
otherwise healthy.

PF-06882961 plasma pharmacokinetic parameters on 
Day 46 and Day 61: Cmax and AUC12.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
PF-06882961 and PF-06865571 when administered 
separately and in combination in overweight adults or 
adults with obesity who are otherwise healthy.

Assessment of treatment-emergent adverse events, 
clinical laboratory abnormalities, vital signs, body 
weight, and ECG parameters during the entire study.

Assessment of mental health as determined by 
C-SSRS and PHQ-9 in Part B of this study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To evaluate the effects of PF-06882961 on additional 
pharmacokinetic parameters of PF-06865571 in 
overweight adults or adults with obesity who are 
otherwise healthy.

Additional PF-06865571 plasma pharmacokinetic 
parameters on Day 1 and Day 47: Tmax, CL/F, Vz/F, 
and t½, as data permits.


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
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Page 16
•
To evaluate the effects of PF-06865571 on additional 
pharmacokinetic parameters of PF-06882961 in 
overweight adults or adults with obesity who are 
otherwise healthy.
•
Additional PF-06882961 plasma pharmacokinetic 
parameters on Day 46 and Day 61: Tmax and CL/F.
•
To evaluate the effects of PF-06882961 on the 
multiple-dose pharmacokinetics of PF-06865571 in 
overweight adults or adults with obesity who are 
otherwise healthy.
•
PF-06865571 plasma pharmacokinetic parameters on 
Day 61: Cmax, Tmax, and AUC12.
•
To evaluate the effects of multiple doses of 
PF-06882961 on CYP3A induction in overweight 
adults or adults with obesity who are otherwise 
healthy.
•
Morning pre-dose 4-β-hydroxycholesterol/cholesterol 
plasma ratio on Days 1, 19, 31, and 47.
•
To evaluate the effect of multiple doses of 
PF-06882961 on CP-I in overweight adults or adults 
with obesity who are otherwise healthy.
•
CP-I parameters on Days 30 and 46: AUC12 and Cmax.
Overall Design: This study will be conducted in 2 parts. Part A is an open-label, two-period, 
two-sequence, crossover cohort investigating the potential effect of PF-06865571 on the PK 
of PF-06882961 in healthy adult participants. Part B is an open-label, fixed-sequence cohort
to evaluating the effect of PF-06882961 on the PK of PF-06865571, as well as the effect of 
PF-06865571 on the PK of PF-06882961 in overweight adults or adults with obesity who are 
otherwise healthy. The effect of PF-06882961 on PF-06865571 PK will be evaluated at 
steady-state 200 mg BID doses of PF-06882961. Then, PF-06882961 and PF-06865571 will 
be coadministered for approximately 2 weeks for further evaluation of PK interactions and to 
generate additional safety and tolerability data on the combination.
Number of Participants: A cohort of approximately 8 participants will be enrolled in 
Part A. Approximately 16 participants will be enrolled in Part B such that approximately 
12 evaluable participants complete Part B.
Intervention Groups and Duration: The study interventions in this study are PF-06882961 
and PF-06865571. Both will be administered as tablets for oral administration. In Part A, 
each participant will receive a single dose of PF-06882961 in 1 period and co-administration 
of PF-06882961 and PF-06865571 in another period. The duration of Part A will be
approximately 9 weeks. In Part B, each participant will receive PF-06865571 alone, 
PF-06882961 alone, and co-administration of PF-06865571 and PF-06882961. The duration 
of Part B will be approximately 18 weeks.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods: In Part A, natural log-transformed Cmax and AUC24 of PF-06882961 
administered alone or co-administered with PF-06865571 will be analyzed using a mixed 
effect model with treatment, sequence, and period as fixed effects and participant embedded 
in sequence as a random effect to evaluate the effect of PF-06865571 on PF-06882961 PK.
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PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 17
To quantify the effect of PF-06882961 on PF-06865571 PK in Part B, natural 
log-transformed Cmax, AUClast, and AUCinf (as data permit) of PF-06865571 300 mg 
administered alone or in combination with PF-06882961 will be analyzed using a mixed 
effect model with treatment as a fixed effect and participant as a random effect. Similarly, to 
quantify the effect of  PF-06865571 on PF-06882961 PK, natural log-transformed Cmax and 
AUC12 of PF-06882961 200 mg BID administered alone or in combination with 
PF-06865571 will be analyzed using a mixed effect model with treatment as a fixed effect 
and participant as a random effect. All safety data will be summarized descriptively through 
appropriate data tabulation, descriptive statistics, categorical summaries, and graphical 
presentations.
1.2. Schema
1.2.1. Treatment Scheme for Part A
Period 1
Washout*
Period 2
Sequence 1
(n=4)
Treatment A:
20 mg PF-06882961 single dose
Washout of at 
least 3 days*
Treatment B:
20 mg PF-06882961 single dose
plus
300 mg PF-06865571 single dose
Sequence 2
(n=4)
Treatment B:
20 mg PF-06882961 single dose
plus
300 mg PF-06865571 single dose
Washout of at 
least 3 days*
Treatment A:
20 mg PF-06882961 single dose
*Each participant is planned to undergo 2 treatment periods with a washout interval between periods of at 
least 3 days following the final dose of study intervention administered in Period 1. 
1.2.2. Treatment Scheme for Part B
Period 1
Period 2
Period 3
Period 4
Days 1-2
Days 3-46
Days 47-48
Days 49-62
PF-06865571
(DGAT2)
Dose
300 mg single dose 
on Day 1 onlya
N/A
300 mg single dose 
on Day 47 onlya
300 mg BID 
on Days 49-61a
PF-06882961
(GLP-1)
Dose
N/A
10 mg BID titrated 
to 200 mg BIDb,c
200 mg BIDc
200 mg BID 
on Days 49-61b,c
a.
Dense PK sampling for measurement of PF-06865571 plasma concentrations on Day 1 (reference), Day 
47 (test), and Day 61 (summary statistics only).
b.
Dense PK sampling for measurement of PF-06882961 plasma concentrations on Day 46 (reference) and 
Day 61 (test).
c.
Doses of PF-06882961 may be reduced based on PK results of Part A of this study and safety and 
tolerability results of Study C3421007.


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 18
1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
1.3.1. Schedule of Activities for Part A
Table 1.
Part A – Overall Schedule of Activities
Visit Identifiera
Screen
Day -28 to -2
Periods 1 and 2b
ET/DC
F/Uc
Day -1
Day 1
Day 2
Hours After Dose
0
0.5
1
2
3
4
6
8
10
12
16
24
Informed consent & demography
X
Outpatient visit (after ≥10 h fast)
X
COVID-19 questionnaired
X
Xe
COVID-19 testingf
X
X
COVID-19 temperature checkg
X
X
Xh
X
X
Inpatient stay at CRU
X











Xi
Assessment of eligibility (with update on Day-1 in 
Period 1 only)
X
X
Medical and medication history 
X
Xe
Review alcohol, tobacco, and drug use
X
Xe
Review prior or concomitant treatments
X












X
X
X
Serious and non-serious adverse event monitoring
X












X
X
X
Physical examination (height and body weight at 
Screening only)j
Xj
Xj
Review contraception use
X
Xe
X
X
X
Single supine 12-lead ECG
X
Xh
X
X
Single supine BP and PR
X
Xh
X
X
PF-06882961 administration
X
PF-06865571 administrationk
Xk
Standard meals/snacksl
X
Xh
X
X
Blood samples for:
Safety laboratory tests
X
X
X
X


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 19
Visit Identifiera
Screen
Day -28 to -2
Periods 1 and 2b
ET/DC
F/Uc
Day -1
Day 1
Day 2
Hours After Dose
0
0.5
1
2
3
4
6
8
10
12
16
24
FSHm
X
Serum pregnancy testm
X
Xe
HIV, HepBsAg, HCVAb, HCV RNA testing
X
PF-06882961 PK
Xh
X
X
X
X
X
X
X
X
X
X
X
X
Urine samples for:
Urine drug screening
X
Xe,o
Urinalysis (and microscopy if needed)
X
X
X
X
a.
Day relative to start of study treatment (Day 1).
b.
There will be a washout interval of at least 3 days between periods.
c.
Follow-up contact may occur via telephone contact and must occur 28-35 days after administration of the final dose of study intervention.
d.
Check potential COVID-19 exposure to positive subject, residence or travel in area of high incidence, and COVID-19 related signs and symptoms. Conduct approximately 
24 hours before each visit and at least at each visit.
e.
If participant is not discharged from the CRU between Periods 1 and 2, procedure only needs to be conducted in Period 1 only.
f.
Testing for COVID-19 pathogen by PCR will be performed at each visit. For participants admitted for residence, a subsequent COVID-19 test will be performed after 4 days 
(ie, upon completion of 4 x 24 hours in house if not discharged between periods), or if participant develops COVID-19 like symptoms.
g.
To be done at least daily during residence.
h.
Prior to dosing. 
i.
Discharge from CRU; participants may be confined to the CRU after completion of Day 2 activities in Period 1 at the discretion of the investigator. 
j.
Complete physical examination to be conducted upon admission of Period 1 only. Brief physical examinations may be performed as appropriate at other times at the 
investigator’s discretion or if there are findings during the previous examination or new/open AEs. Height and weight to be measured at Screening only.
k.
Only for the period with Treatment B.
l.
While inpatient, meals to be provided at clock times matching nominal times of approximately 0H (breakfast), 4H (lunch), and 10H (dinner); snacks may be provided 
according to Section 5.3.1.
m.
Testing in females only: Serum β-hCG for all WOCBP; FSH for female participants to confirm post-menopausal status only.
o.
A urine drug test is to be completed for both periods of this study unless participant is not discharged between periods. In additiona. ad hoc urine drug testing may be 
conducted throughout the study at the discretion of the investigator.
CCI
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PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 20
1.3.2. Schedule of Activities for Part B
Table 2.
Part B – Overall Schedule of Activities
Visit Identifier
Screen
Period 1
(PF-06865571 Only)
Period 2
(PF-06882961 Only)
Period 3
(PF-06865571 plus 
PF-06882961)
Period 4
(PF-06865571 plus 
PF-06882961)
F/U
Visita
F/U 
Contacta ET/DC
Day in Study Periodb
-28 to -2
-1
1
2
1
2
3-43
44
1
2
1-12
13
14
-
-
-
Days in Studyc
-28 to -2
-1
1
2
3
4
5-45
46
47
48
49-60
61
62
68-71
89-96
-
Informed consent & demography
X
Outpatient visit (after ≥10 h fast)
X
X
COVID-19 questionnaired
X
X
COVID-19 testinge
X
X
Xe
COVID-19 temperature checkf
X
X
X
X
X
X
Xf
X
X
X
Xf
X
X
X
X
Inpatient stay at CRU
X










Xg
Eligibility criteria
X
X
Medical and medication history 
X
X
C-SSRS and PHQ-9
X
X
Xh
Xh
X
X
X
Review drug, alcohol/tobacco use
X
X
X
Review contraception use
X
X
X
X
X
Review prior or concomitant treatments 
X
X










X
X
X
X
Serious and nonserious AE monitoring
X
X










X
X
X
X
Standardized meals/snacksi
X










X
Physical exam (height at Screen only)j
Xj
Xj
Body weight
X
Xh
Xh
X
X
X
Supine 12-lead ECG
X
Xk
Xh
Xh
X
X
X
Supine BP and PR
X
Xk
Xh
Xh
X
X
X
PF-06882961 administrationl
Table 3
X
X
X
Table 3
Table 3
X
X
Table 3
PF-06865571 administrationl
X
Blood samples for:
Safety laboratory tests
X
X
Xh
Xh
X
X
X
Cystatin-C
X
Xh
Xh
X
X
X
PT/INR/aPTT
X
X
Xm
Xm
X
X
X
HIV, HepBsAg, HCVAb, HCV RNA
testing
X
FSHn
X
Serum pregnancy testn
X
X
Xo
Xo
TSH, lipids
X
X
Xm
Xm
X
X
X
Free T4, calcitonin, amylase, lipase, TBA
X
X
Xm
Xm
X
X
X


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 21
Visit Identifier
Screen
Period 1
(PF-06865571 Only)
Period 2
(PF-06882961 Only)
Period 3
(PF-06865571 plus 
PF-06882961)
Period 4
(PF-06865571 plus 
PF-06882961)
F/U
Visita
F/U 
Contacta ET/DC
Day in Study Periodb
-28 to -2
-1
1
2
1
2
3-43
44
1
2
1-12
13
14
-
-
-
Days in Studyc
-28 to -2
-1
1
2
3
4
5-45
46
47
48
49-60
61
62
68-71
89-96
-
HbA1c
X
PF-06882961
PK
X
PF-06865571 PK
Xp
Xq
Xp
Xq
X
 
CP-I
Xs
Xs
Xs
4-β-hydroxycholesterol/cholesterol
Xt
Xt
Xt
Urine samples for:
Urine drug screeningu
X
X
Urinalysis (& microscopy as appropriate)
X
X
Xh
Xh
X
X
X
a.
The follow-up visit will occur 7-10 days after the final dose study intervention. The follow-up contact may occur via telephone contact and must occur 28-35 days after 
administration of the final dose of study intervention.
b.
Day relative to start of Day 1 dosing of that Period.
c.
Day relative to first dose of study intervention on Day 1 of Period 1.
d.
Check potential COVID-19 exposure to positive subject, residence or travel in area of high incidence, and COVID-19 related signs and symptoms. Conduct approximately 
24 hours before and at least at each visit.
e.
Testing for COVID-19 pathogen by PCR will be performed after 4 days (ie, upon completion of 4 x 24 hours in house), or if participant develops COVID-19 like symptoms.
f.
To be done at least daily during residence.
g.
Discharge from CRU.
h.
Assessments to be performed on Days 8, 15, 22, 29, 36, 43, 50, and 57.
i.
Meals to be provided at clock times matching nominal times of approximately 0H (breakfast), 4H (lunch), and 10H (dinner), with the exception Overall Study Day 46,
Day 47, and Day 61 in which dinner will be provided at approximately 12H; snacks may be provided according to Section 5.3.1.
j.
Complete physical examination to be conducted upon admission in Period 1. Brief physical examinations may be performed as appropriate at other times at the investigator’s 
discretion or if there are findings during the previous exam or new/open AEs. Height to be measured at Screening only.  
k.
Prior to dosing.
l.
Dosing to occur BID immediately after breakfast and dinner as specified in Section 5.3.1. Morning doses will be administered immediately after breakfast. On Overall Study 
Day 46, Day 47, and Day 61, evening doses will be administered immediately after dinner approximately 12 hours after morning dosing. On all other study days, evening 
doses will be administered immediately after dinner approximately 10 hours after morning dosing.
m.
Assessments to be performed on Days 15, 29, 43, and 57.
n.
Testing in females only: Serum β-hCG for all WOCBP; FSH for female participants to confirm post-menopausal status only.
o.
Serum pregnancy test to be conducted on Day 30 and Day 60.
p.
PK sample to be collected 24 hours after Day 1 and Day 47 morning doses of PF-06865571. 
CCI
CCI
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PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 22
q.
PK sample to be collected 48 hours after Day 1 and Day 47 morning doses of PF-06865571.
s.
Samples to be collected at 0 (pre-dose), 12 and 24 hours after Day 1 morning dose of PF-06865571 and at 0 (pre-dose), 1, 2, 4, 6, 8 and 12 hours after Day 30 and Day 46 
morning doses of PF-06882961.
t.
Samples to be collected on Days 1, 19, 31, and 47 prior to morning dosing of study intervention(s).
u.
A urine drug test is to be conducted at Screening. In addition, participants may undergo ad hoc urine drug screening throughout the study at the discretion of the investigator.
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PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 23
Table 3.
Part B – Schedule of Activities for:
•
Day 1 of Period 1 (PF-06865571 ONLY) – Study Day 1.
•
Day 44 of Period 2 (PF-06882961 ONLY) – Study Day 46.
•
Day 1 of Period 3 (PF-06865571 plus PF-06882961) – Study Day 47.
•
Day 13 of Period 4 (PF-06865571 plus PF-06882961) – Study Day 61.
Hours Relative to Dosing at 0H
0
0.5
1
2
3
4
6
8
10
12
14
16
PF-06882961 administration (Periods 2, 3, and 4 only)
Xa
Xb
PF-06865571 administration (Periods 1, 3, and 4 only)
Xa
Xb,c
Blood sampling for: 
PF-06882961
PK (Periods 2 and 4 only; pre-dose in Period 3 onlyd)
Xd,e,f
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xe,f
PF-06865571 PK (Periods 1, 3, and 4 only)
Xe
X
X
X
X
X
X
X
X
Xg
Xh
Xh
a.
Dosing to occur immediately after breakfast.
b.
Dosing to occur immediately after dinner.
c.
Period 4 only.
d.
Only a predose sample will be collected on Day 1 of Period 3 (24 hours after morning dosing on Day 46 of Period 2; overall study Day 47). The full dense sampling scheme, 
including the predose sample, will occur in Periods 2 and 4.
e.
Prior to dosing.
f.
Serial PF-06882961
PK samples to be collected in Periods 2 and 4 only.
g.
The 12H PF-06865571 PK sample is to be collected in Periods 1, 3, and 4. In Period 4, the 12H sample is to be collected prior to administration of the evening dose of 
PF-06865571.
h.
Periods 1 and 3 only.
CCI
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PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 24
2. INTRODUCTION
PF-06882961 is a potent, selective, orally bioavailable, small molecule agonist of the GLP-1 
receptor and is presently in clinical development for the treatment of T2DM and obesity. 
PF-06865571 is a potent and selective inhibitor of DGAT2 being developed for the treatment 
of NASH with liver fibrosis. The current study will evaluate PK interactions following 
coadministration of PF-06882961 and PF-06865571 as a novel NCE:NCE combination 
because of the potential advantages offered by the combination over the individual 
investigational agents that could benefit a wider NASH population and/or target specific 
NASH sub-populations. The safety and tolerability of the investigational drugs administered 
together will also be assessed.
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 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 Administration of GLP-1 receptor agonists led to histological improvements in 
patients with NAFLD including resolution of NASH without worsening of fibrosis.5
DGATs catalyze the terminal step in TG synthesis; specifically, the esterification of a fatty 
acid with diacylglycerol resulting in the formation of TG.6 In mammals, 2 structurally 
unrelated DGAT enzymes (DGAT1 and DGAT2) have been characterized. DGAT1 is 
highly expressed in the intestine and plays a central role in fat absorption.7 DGAT2 is highly 
expressed in liver and adipose.8 In preclinical models, blockade of hepatic DGAT2 using 
antisense oligonucleotides results in both down-regulation of the expression of multiple 
genes encoding proteins involved in lipogenesis and parallel induction in oxidative 
pathways.9-11 The net result of these changes is a decrease in the levels of hepatic DAG and 
TG lipid which, in turn, reduces hepatocyte lipid burden and decreases hepatic very low 
density lipoprotein TG secretion.9,11 Consistent with this, administration of DGAT2 
inhibitors to patients with NAFLD reduces steatosis,11,12 a necessary but not sufficient 
component of the pathogenesis of NASH.13 PF-06865571 is postulated to decrease hepatic 
TG synthesis and hepatic lipid burden in NAFLD and NASH.
2.1. Study Rationale 
The purpose of the study is to evaluate the PK interactions between PF-06882961 and 
PF-06865571 in healthy adult participants (Part A) and overweight adults or adults with 
obesity who are otherwise healthy (Part B). 
2.2. Background 
2.2.1. Non-Alcoholic Steatohepatitis
NASH is a clinical and histological subset of NAFLD (defined as presence of ≥5% hepatic 
steatosis) that is associated with increased all-cause mortality, cirrhosis and end-stage liver 
disease, increased cardiovascular mortality, and increased incidence of both liver related and 
nonliver related cancers.14 Prevalence of NAFLD is estimated in North America to range 
from 27% to 34%, while prevalence of NASH in the general US population is estimated at 


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 25
approximately 3-5%.15 The 5-year (67%) and 10-year (38%) survival rates for patients with 
NASH are significantly different than for those with NAFLD.16 The pooled liver-specific 
and overall mortality incidence rate estimates among those with NAFLD were calculated at 
0.77 and 15.4, respectively, per 1000 person-years. In contrast, amongst the population with 
NASH, the incidence rate estimates were 11.8 (liver-specific) and 25.6 (overall) mortality.17
During a follow-up of mean 20 years (range 0–40) equivalent to 139,163 person-years, 
12% of NAFLD patients and 2.2% of controls developed severe liver disease (p=0.001).18
Compared with controls, the risk of severe liver disease increased per stage of fibrosis. At 
the present time, treatment options are limited to management of associated conditions.19
Although there are no therapies currently approved for the treatment of NASH, a growing 
body of evidence demonstrates the urgent medical need.14
NASH is a complex disease with a multifaceted pathogenesis, involving metabolic 
dysfunction, multiple inflammatory pathways, and fibrosis.14 As a consequence, a single 
drug is unlikely to address all of the pathophysiologic components of NASH.  Combining 
therapies that engage different biological targets and provide complementary benefits on the 
disease pathophysiology could provide greater efficacy and/or better tolerability to the 
patient and/or benefit for a larger fraction of the disease population than each individual 
monotherapy.  
2.2.2. Nonclinical Pharmacokinetics
2.2.2.1. Nonclinical Pharmacokinetics and Metabolism of PF-06882961
Metabolism studies showed low turnover of PF-06882961 with some oxidative and
glucuronide metabolites. All metabolites detected in human hepatocytes were also observed
in hepatocytes from nonclinical species. PF-06882961 is expected to be cleared via hepatic
uptake by OATP, followed by metabolic clearance principally mediated by CYP3A4/5, 
followed by CYP2C8 and CYP2C19. Non-CYP enzymes also contributed to the metabolism 
of PF-06882961.
PF-06882961 is a BCRP substrate. In addition, based on in vitro data, PF-06882961 has the 
potential to inhibit intestinal BCRP with an IC50 of 0.8 μM. Based on in vitro data, 
PF-06882961 demonstrated time-dependent inhibition of CYP3A4/5. The rate of 
inactivation was not saturated within the concentration ranges tested (5-150 μM), and 
therefore, the Ki and kinact could not be calculated.
In vitro data also suggest a risk of PF-06882961 interaction with drugs for which CYP2C8
and UGT1A1 mediated metabolism constitutes the primary mechanism of clearance. At the 
dose of 200 mg BID, there is also a possibility of weak inhibition of hepatic OATP1B3, 
OATP2B1, OCT1 and uptake transporter MDR1. Static modeling of in vitro data also 
indicate that PF-06882961 has a low potential to cause DDIs as a result of induction of 
CYP3A4, or inhibition of other CYP enzymes (1A2, 2B6, 2C9, 2C19 or 2D6), other UGT 
enzymes (1A4, 1A6, 1A9, 2B7, 2B15), and uptake transporters OATP1B1, OCT2, MATE1, 
MATE2K, OAT1 and OAT3.
Refer to the IB for more details on the nonclinical PK and metabolism of PF-06882961.


PF-06882961 and PF-06865571
Protocol C3421038
Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
Page 26
2.2.2.2. Nonclinical Pharmacokinetics and Metabolism of PF-06865571
In pivotal toxicity studies up to 16-weeks in rats and monkeys, systemic exposure of 
PF-06865571 increased with increasing dose, although in a less than dose proportional 
manner.  In addition, PF-06865571 preferentially distributes into plasma versus red blood 
cells in vitro across the toxicology species and humans.  In vitro screening suggests that 
PF-06865571 is a substrate for MDR1 (also known as P-gp) and mBcrp efflux transporters.  
The major primary metabolic pathway identified from preliminary in vitro and in vivo 
metabolite profiling in human is O-deethylation with subsequent sulfation and 
glucuronidation, with no evidence of human-unique metabolites.  Reaction phenotyping 
studies indicate the total CYP contribution to PF-06865571 metabolism was >96% with 
CYP3A being the predominant isoform.  Modeling suggests a moderate risk of clinical DDI 
with PF-06865571 as a victim upon coadministration with CYP3A4 inhibitors or inducers. 
Assessment of the DDI potential for PF-06865571 was based on the mean steady-state 
unbound Cmax of 2.07 µM for PF-06865571 following oral administration at the highest 
planned clinical dose of 600 mg/day (300 mg BID).  PF-06865571 mediated DDIs associated 
with inhibition of CYP and UGT enzymes are not expected, with the exception of CYP2C9, 
intestinal CYP3A4/5, UGT1A1, UGT1A9, and UGT2B15. In human hepatocytes, 
PF-06865571 induces CYP2B6 and CYP3A4 (enzymatic and mRNA) but not CYP1A2. In 
vitro evaluations indicated that PF-06865571 has a low potential to inhibit OAT1, OAT3, 
MATE2K, OATP1B1, and OATP1B3 transporters at clinically relevant concentrations; 
however, PF-06865571 does have the potential to inhibit P-gp, BCRP, OCT1, OCT2, and 
MATE1.  
Refer to the IB for more details on the nonclinical PK and metabolism of PF-06865571.
2.2.3. Nonclinical Toxicology
2.2.3.1. Summary of Toxicology Studies with PF-06882961
PF-06882961 was administered to Wistar-Han rats and cynomolgus monkeys in oral studies 
up to 6 months in duration. In addition, PF-06882961 was evaluated in genetic toxicity 
studies, dose-range-finding and definitive EFD studies in rats and rabbits, fertility and early 
embryonic study in rats, and in vitro and in vivo phototoxicity studies. PF-06882961 was not 
genotoxic or phototoxic. 
Based on the nonclinical toxicity studies conducted, effects were observed in the 
cardiovascular and gastrointestinal systems, liver, thyroid, and Harderian gland. The 
NOAELs in the 6-month toxicity study in rats and 14-week toxicity study in monkeys with a 
4-week lead-in (ie, the longest duration nonclinical studies supporting this clinical trial) were 
associated with systemic exposures (based on AUC24) which are approximately 23x (for rat) 
and 1.2x (for monkey) higher than the clinical exposures anticipated at the highest planned 
dose of 200 mg BID in C3421038.  The NOAEL in the 14-week plus 4-week lead-in monkey 
toxicity study was based on decreases in food consumption and body weight at a higher dose, 
which are considered monitorable and reversible. Please refer to Section 5.3.3 of the IB for 
details.


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2.2.3.2. Summary of Toxicology Studies with PF-06865571
In GLP-compliant studies, PF-06865571 was administered to rats in toxicity studies up to 
6 months in duration. In the pivotal chronic 6-month toxicity study with 1-month 
(4-week) recovery, there were no adverse effects and no unique findings that were not 
evident in previous toxicity studies. All test article-related effects were reversed at the end of 
the recovery phase. The NOAEL was 1000 (500 BID) mg/kg/day, the highest dose tested, 
based on the absence of any adverse effects.
PF-06865571 was administered to cynomolgus monkeys in GLP-compliant pivotal toxicity 
studies up to 9-months in duration. In the pivotal 9-month chronic toxicity study with a 
1-month recovery, PF-06865571 was tolerated at all doses with no adverse or nonadverse 
findings. Therefore, 1000 (500 BID) mg/kg/day, the highest dose tested, was the NOAEL.
Additional details of nonclinical studies are provided in PF-06865571 IB Section 5.3, and an 
overview of the toxicity testing program is included in Table 5.3-1 of the PF-06865571 IB.
2.2.3.3. Summary of Toxicology Study for Co-administration of PF-06882961 and
PF-06865571
In the completed 2-week oral gavage toxicity study of the co-administration of PF-06882961 
and PF-06865571 in Wistar Han rats, PF-06882961 was administered once daily at 
75 mg/kg/day, and PF-06865571 was coadministered twice daily at 1000 (500 BID) 
mg/kg/day by oral gavage for 2 weeks with no adverse test-article related effects observed. 
Non-adverse test article-related effects were limited to higher liver weights in both sexes, 
minimal centrilobular hepatocellular hypertrophy in a female, lower T3, T4, and cholesterol 
in both sexes, lower triglycerides in males, and lower glucose in females. This 
coadministration was considered the NOAEL and was associated with a Cmax of 5210 ng/mL 
and 18,500 ng/mL and AUC24 of 19,300 ng•h/mL and 69,000 ng•h/mL on Day 14 in males 
and females, respectively, for PF-06882961. The corresponding PF-06865571 Cmax of 
14,000 ng/mL and 29,400 ng/mL and AUC24 of 185,000 ng•h/mL and 427,000 ng•h/mL was 
obtained on Day 14 in males and females, respectively.
2.2.4. Clinical Overview
2.2.4.1. Summary of Clinical Safety
2.2.4.1.1. Clinical and Safety Experience with PF-06882961
Three clinical studies have been completed with PF-06882961 in which 135 participants 
were dosed, and 110 participants were exposed to single or multiple doses of PF-06882961 
(Table 6-1 in the PF-06882961 IB). In addition, ongoing studies include a 16-week Phase 2 
dose ranging study in T2DM (C3421005), a multiple dose PK/PD study in Japanese 
participants with T2DM (C3421015), a single dose ADME and oral bioavailability study 
(C3421009), and a single dose formulation comparison study in healthy participants 
(C3421010). Two studies, C3421001 and C3421003, were completed in healthy participants
(total of 37 healthy participants randomized), and 1 study, C3421002, was completed in
participants with T2DM (total of 98 T2DM participants randomized). In these studies, 
PF-06882961 was found to be generally safe and well tolerated. In C3421001, 25 healthy 
participants were randomized to single ascending oral doses of PF-06882961 or placebo.  In 


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C3421003, 12 healthy participants were randomized to receive single doses of different oral 
formulations of PF-06882961.  In C3421002, 98 participants with T2DM were randomized to 
multiple ascending oral doses of PF-06882961 or placebo for 28 days. In this study
PF-06882961 doses ranging from 10 mg BID to 120 mg BID were studied.  A total of 
98 participants with T2DM on a background anti-diabetic regimen of metformin were 
randomized to receive PF-06882961 or matching placebo in a 3:1 randomization ratio, and 
92 participants completed the study.  Six participants discontinued from the study, of which 
2 discontinuations were due to treatment-related TEAEs and 4 withdrew during the treatment 
or follow-up period for non-treatment related reasons. A total of 319 TEAEs were reported, 
of which the majority of the AEs [294 (92%)] were mild in severity, 23 (7%) were moderate, 
and 2 (1%) were severe in intensity.  The most frequently reported TEAEs were nausea 
(49.0%), dyspepsia (32.7%), vomiting (26.5%), diarrhea (24.5%), headache (23.5%), and
constipation (20.4%). One participant experienced a mild TEAE of hypoglycemia.  This AE 
was non fasting, mild in severity and of limited duration.  There were no deaths and no 
treatment-related SAEs with repeated dosing of PF-06882961 in patients with T2DM. 
Overall, the doses of PF-06882961 studied in C3421002 were safe and well tolerated.
Preliminary clinical and safety data are available from the C3421007 Phase 1 study, which 
assessed the effect of PF-06882961 on the pharmacokinetics of rosuvastatin and midazolam.  
In this study, PF-06882961 doses up to 200 mg BID were administered with 4-day titration 
steps in 16 otherwise healthy, adult participants with obesity. Of these participants, 
14 completed the 17-week study duration, and 2 participants discontinued for reasons not 
related to AEs. A total of 129 TEAEs have been reported to date, of which the majority of 
the AEs (127/129) were mild in severity and 2 were moderate. There was 1 mild TEAE of 
increased transminitis (also reported as an SAE), which occurred at the end of the dosing 
duration, after co-administration of PF-06882961 200 mg BID with rosuvastatin 10 mg once 
and midazolam 2 mg once, administered seperately in successive periods. The transaminase 
levels returned to baseline levels in the follow up period. No significant elevations were 
noted in total bilirubin, alkaline phosphatase or GGT.  The most frequently reported all 
causality TEAEs in the study participants have been nausea (26), constipation (12), decreased 
GFR (12), headache (10), and vomiting (9). While there were isolated values for laboratory 
tests, vital signs and ECG intervals outside of the reference ranges, no clear adverse trends 
were apparent in these parameters.  Mild declines from baseline were noted in GFR, with 
most values remaining above 70 mL/min, and occurred in the setting of weight loss, which 
was expected with the mechanism of action. Most GFR levels returned to pre-dose levels by 
follow-up.
2.2.4.1.2. Clinical and Safety Experience with PF-06865571
Eight clinical studies with PF-06865571 have been completed (Table 6-1 in the PF-06865571 
IB). In addition, ongoing studies include a 6-week Phase 2a study evaluating PF-06865571 
in combination with an ACC inhibitor in participants with NASH (C3711005), a 48-week 
Phase 2b dose ranging study evaluating PF-06865571 alone and in combination with an ACC 
inhibitor in participants with NASH (C2541013), and a single dose ADME study in healthy 
participants (C2541007). Across the 8 completed studies, a total of 280 unique participants 
have been randomized.  This includes 132 unique healthy adult participants and 148 adults 


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with NAFLD.  Overall, 38 unique participants (14%) have been exposed to a single, oral dose 
of PF-06865571 only; and an additional 167 participants (60%) have received repeated doses 
of PF-06865571. In the clinical program, following single oral doses of PF-06865571, across 
the 300-fold dose range evaluated (ie, 5 mg to 1500 mg), the all causality, TEAEs reported in 
≥4 participants were headache (12%) and diarrhea (7%).  Upon repeated administration of 
PF-06865571, across the 20-fold dose range evaluated (ie, 90 to 1800 mg/day), TEAEs
reported in ≥7 participants across all arms evaluated were headache (11%), diarrhea (6%), 
fatigue (5%), pruritus (4%), abdominal pain (3%), and nausea (3%).  Across 5 clinical studies 
completed with repeated dosing of PF-06865571, 5 SAEs have been reported, 4 of them 
post-randomization. These include 2 deaths, both considered unrelated to study drug 
(Table 6.2-4 in PF-06865571 IB).  In the clinical experience to date, MTD has not been 
identified and with administration of PF-06865571 alone, there have been no identified 
adverse drug reactions.
2.2.4.2. Summary of Clinical Pharmacology and Biopharmaceutic Studies
2.2.4.2.1. Clinical Pharmacokinetics of PF-06882961
The clinical PK of PF-06882961 in adult participants has been evaluated in 3 completed 
studies: C3421001, C3421002, and C3421003.  The results of these completed studies are 
summarized in the PF-06882961 IB, Section 6.1.  
In study C3421001, following a single, oral dose administration of PF-06882961 to healthy 
participants at doses ranging from 3 mg to 300 mg under fasted conditions, median Tmax
ranged from 2.0 to 6.0 hours post dose.  Mean t½ values ranged from 4.3 to 6.1 hours.  
Plasma exposure, as assessed by dose-normalized geometric mean AUCinf and Cmax values, 
appeared to increase in a dose proportional manner across the 3 mg to 300 mg doses.  
Variability in PF-06882961 exposure based on geometric %CV ranged from 50% to 91% for 
Cmax and 28% to 60% for AUCinf across the 3 mg to 300 mg dose range.  
In study C3421002, following 28 days of dosing to participants with T2DM, accumulation 
was modest for the BID IR formulation treatments, with mean ratios based on 
dose-normalized AUC24 (Rac) values ranging from 1.203 to 2.009. Day 28 plasma exposure 
as measured by geometric mean AUC24 values appeared to increase in an approximate dose 
proportional manner across all IR treatments. Mean t½ values on Day 28 across all 
treatments ranged between 4.681 to 8.090 hours, and no apparent trends were observed 
across various treatments, regimens, or doses administered. Interparticipant variability for 
PF-06882961 exposure was based on geometric mean was 31%-87% for AUC24 and 
32%-94% for Cmax and on Day 28 across all treatments and cohorts. A population PK model 
based on data from C3421001 and C3421002 indicated that the exposure in T2DM 
participants (C3421002) was approximately 1.7-fold higher than that observed in healthy 
participants (C3421001) after accounting for differences in body weight between the 
participants in each study.


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Preliminary draft data from Study C3421007 indicate that PF-06882961 has the potential to 
interact with drugs metabolized by CYP3A, as observed via co-administration with the 
sensitive probe CYP3A substrate, midazolam. When co-administered with 120 mg BID 
PF-06882961, midazolam Cmax and AUClast decreased by approximately 37% and 49%, 
respectively. When co-administered with 200 mg BID PF-06882961, midazolam Cmax and 
AUClast decreased by approximately 28% and 45%, respectively.
Additionally, preliminary draft data from this study indicate a potential interaction between 
PF-06682961 and substrates of BCRP, as observed via co-administration with the sensitive 
probe BCRP substrate, rosuvastatin. When co-administered with 120 mg BID PF-06882961, 
rosuvastatin Cmax and AUClast increased approximately 2.6-fold and 2.1-fold, respectively. 
When co-administered with 200 mg BID PF-06882961, rosuvastatin Cmax and AUClast
increased approximately 4.5-fold and 2.9-fold, respectively.
2.2.4.2.2. Clinical Pharmacokinetics of PF-06865571
Upon repeated dosing of PF-06865571 with standard meals, Cmax was achieved at 1.5 to 
3 hours post dose. Steady-state plasma concentrations were achieved by Day 4, and the 
mean terminal t½ ranged from 3.3-6.9 hours. Given the short mean terminal t½ accumulation 
is likely to be negligible at a dosing frequency of Q12H/BID as minimal accumulation was 
observed upon repeated dosing at a frequency of Q8H. Dosing in the fasted state resulted in 
lower exposures (ie, AUCinf 39% lower and Cmax 34% lower than when a 1000 mg dose of 
PF-06865571 was administered with a standard meal). Across the range of repeated doses 
evaluated (90 mg/day to 1800 mg/day, administered Q8H), the plasma exposure increased in 
a dose proportional manner. Less than 2% of the PF-06865571 dose administered was 
excreted unchanged in the urine indicating that renal clearance is not a major clearance 
mechanism for PF-06865571. PF-06865571, dosed at 300 mg BID, was shown to increase 
metformin (500 mg single dose) exposure (ie, both AUCinf and Cmax) by approximately 
2-fold. 
2.3. Benefit/Risk Assessment
PF-06882961 and PF-06865571 are not expected to provide any clinical benefit to
participants in this study. This study is designed primarily to generate safety, tolerability, 
and PK data for further clinical development.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-06882961 and PF-06865571 may be found in the IB for 
PF-06882961 and separately for PF-06865571, which are the SRSDs for this study.
CCI


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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention – PF-06882961 (GLP-1 receptor agonist)
Thyroid C-cell tumors
The potential risks are based on product labeling 
for injectable GLP-1 receptor 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 
multiple endocrine neoplasia syndrome type 2 
(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-1 receptor 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-1 receptor 
agonists have not demonstrated an increased risk 
for hypoglycemia. However, when administered 
in combination with anti-diabetic agents that are 
known to have an increased risk of hypoglycemia 
(such as insulin or sulfonylureas), an increased 
risk for hypoglycemia was observed. Participants 
with obesity who do not have co-existing T2DM
would not be taking anti-diabetic agents and 
therefore would not be expected to have an 
increased risk for hypoglycemia. Only one AE of 
mild hypoglycemia has been reported in the 
clinical development program to date.
Anti-diabetic medications are prohibited in this 
study, and blood glucose is monitored as a part of 
the lab assessments at every clinical visit in this 
study.  Participants are informed about the signs 
and symptoms of hypoglycemia, and are 
monitored for these symptoms during the study.


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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 AE (Preferred Term: blood creatinine 
increased) has been observed.
Per exclusion criteria, potential participants with 
significant renal impairment are not eligible for 
study entry. Renal function is monitored at 
frequent intervals by lab assessments of serum 
BUN, creatinine, and eGFR.
Gastrointestinal adverse reactions
The potential risks are based on product labeling
for injectable GLP-1 receptor agonists 
(ie, liraglutide, exenatide and dulaglutide).
In addition, gastrointestinal AEs, the majority of 
which were mild in severity, have been observed 
in the clinical program with PF-06882961. In 
nonclinical studies with PF-06882961, 
gastrointestinal AEs have been observed 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 200 mg BID 
over 44 days in this study. 
Exclusion criteria include any factor that may 
affect drug absorption, such as bariatric surgery, 
active inflammatory bowel disease or an intestinal 
resection.
Diabetic retinopathy complications
The potential risk is based on the product 
labeling for the injectable GLP-1 receptor agonist 
semaglutide for T2DM. This risk has not been 
listed in the prescribing information for other 
marketed GLP-1 receptor agonists. There are no 
nonclinical or clinical data involving 
PF-06882961 to suggest an increased risk of 
diabetic retinopathy complications.
Study excludes participants with T1DM or T2DM 
or secondary forms of diabetes.
Suicidal ideation and behavior
The potential risk is based on the product 
labeling for the injectable GLP-1 receptor agonist 
liraglutide for obesity. This risk has not been 
listed in the prescribing information for other 
marketed GLP-1 receptor agonists for T2DM.
There are no nonclinical or clinical data 
involving PF-06882961 to suggest an increased 
risk of suicidal ideation and behavior.
Suicidal ideation and behavior, along with 
symptoms of depression, will be monitored at 
frequent intervals during the study using the 
C-SSRS and PHQ-9 questionnaires, with referral 
to a mental health professional for further 
evaluation if needed.


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Changes in heart rate and blood pressure
Increases in HR have been reported for marketed 
GLP-1 receptor agonists (eg, liraglutide), and 
increases in HR have been observed with 
PF-06882961 administration, with most HR 
values within the normal range. There have been 
incidences of HR >120 bpm in the clinical 
program to date and no AEs related to elevations 
in HR. In addition, declines in systolic BP have 
been noted at higher doses of PF-06882961.
BP, PR, and ECGs will be monitored at frequent 
intervals during the clinical study.
Declines in body weight
Decreased appetite and body weight loss have 
been reported for marketed GLP-1 receptor 
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-1 receptor 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 – PF-06865571 (DGAT2 inhibitor)
Food effect resulting in change in PF-06865571
exposure
PF-06865571 exposures are lower in fasted state 
than in fed state.
Study interventions will be taken with a meal.
Fetal skeletal variations as a result of transient 
developmental delay
In an embryo-fetal development toxicity study in 
rats, lower fetal body weight and skeletal 
anomalies observed at all doses with NOAEL for 
this developmental toxicity not identified. In an 
embryo-fetal development toxicity study in 
rabbits, no developmental toxicity observed.
Communicated through Section 7 of the 
PF-06865571 IB (Jan-2020).
Enrollment of WOCBP restricted to those using 
effective contraception.
In males who are sexually active with a female 
partner of childbearing potential, use of barrier 
methods not required/mandated given safety 
margins ≥100-fold.


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Other
Risk of COVID-19 infection for participants
During the pandemic, healthy participants could 
be infected with the SARS-COV-2 virus through 
study participation. This could lead to increased 
health risk for participants and others in the study
and could lead to confounding AE with study 
intervention.
COVID-19 specific assessments according to 
SoA.


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2.3.2. Benefit Assessment
While PF-06882961 and PF-06865571 are not expected to provide any clinical benefit to 
otherwise healthy adult participants with obesity in this study, potential benefits for 
participants in this study may include receiving medical evaluations/assessments associated 
with clinical study visits (eg, physical examinations, ECGs, clinical safety laboratory 
assessments), and contributing to the process of developing a potential new therapy for 
NASH with liver fibrosis.
2.3.3. Overall Benefit/Risk Conclusion
In consideration of the available clinical and nonclinical data, and the measures taken to 
minimize risk to participants in this study, the overall benefit/risk profile supports clinical 
testing of the combination of PF-06882961 and PF-06865571. 


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3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Part A
Primary: 
Primary: 
•
To evaluate the effects of PF-06865571 on the 
single-dose pharmacokinetics of PF-06882961 in 
healthy adult participants.
•
PF-06882961 plasma pharmacokinetic parameters: 
Cmax and AUC24.
Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of 
PF-06882961 alone and in combination with 
PF-06886571 when administered to healthy adult 
participants.
•
Assessment of treatment-emergent adverse events, 
clinical laboratory abnormalities, vital signs, body 
weight, and ECG parameters during the entire study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 
•
To evaluate the effects of PF-06865571 on additional 
pharmacokinetic parameters of PF-06882961 in 
healthy adult participants.
•
Additional PF-06882961 plasma pharmacokinetic 
parameters: Tmax.
Part B
Primary: 
Primary: 
•
To evaluate the effects of PF-06882961 on the 
single-dose pharmacokinetics of PF-06865571 in 
overweight adults or adults with obesity who are 
otherwise healthy.
•
PF-06865571 plasma pharmacokinetic parameters on 
Day 1 and Day 47: Cmax, AUClast, and AUCinf, as 
data permits.
•
To evaluate the effects of PF-06865571 on the 
multiple-dose pharmacokinetics of PF-06882961 in 
overweight adults or adults with obesity who are 
otherwise healthy.
•
PF-06882961 plasma pharmacokinetic parameters on 
Day 46 and Day 61: Cmax and AUC12.
Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of 
PF-06882961 and PF-06865571 when administered 
separately and in combination in overweight adults or 
adults with obesity who are otherwise healthy.
•
Assessment of treatment-emergent adverse events, 
clinical laboratory abnormalities, vital signs, body 
weight, and ECG parameters during the entire study.
•
Assessment of mental health as determined by 
C-SSRS and PHQ-9 in Part B of the study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 
•
To evaluate the effects of PF-06882961 on additional 
pharmacokinetic parameters of PF-06865571 in 
overweight adults or adults with obesity who are 
otherwise healthy.
•
Additional PF-06865571 plasma pharmacokinetic 
parameters on Day 1 and Day 47: Tmax, CL/F, Vz/F, 
and t½, as data permits.
•
To evaluate the effects of PF-06865571 on additional 
pharmacokinetic parameters of PF-06882961 in 
overweight adults or adults with obesity who are
otherwise healthy.
•
Additional PF-06882961 plasma pharmacokinetic 
parameters on Day 46 and Day 61: Tmax and CL/F.
•
To evaluate the effects of PF-06882961 on the 
multiple-dose pharmacokinetics of PF-06865571 in 
overweight adults or adults with obesity who are 
otherwise healthy.
•
PF-06865571 plasma pharmacokinetic parameters on 
Day 61: Cmax, Tmax, and AUC12.
CCI


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
To evaluate the effects of multiple doses of 
PF-06882961 on CYP3A induction in overweight 
adults or adults with obesity who are otherwise 
healthy.

Morning pre-dose 4-β-hydroxycholesterol/cholesterol 
plasma ratio on Days 1, 19, 31, and 47.

To evaluate the effect of multiple doses of 
PF-06882961 on coproporphyrins I in overweight 
adults or adults with obesity who are otherwise 
healthy.

CP-I parameters on Days 30 and 46: AUC12 and Cmax.
4. STUDY DESIGN
4.1. Overall Design
This study will be conducted in 2 parts. Part A will evaluate the effect of PF-06865571 on 
the PK of PF-06882961. Part B will evaluate the effect of PF-06882961 on the PK of 
PF-06865571, as well as the effect of PF-06865571 on the PK of PF-06882961.
4.1.1. Part A Study Design
Part A of this study is an open-label, two-period, two-sequence, crossover study to 
investigate the potential effect of PF-06865571 on the single-dose PK of PF-06882961 in a 
cohort of approximately 8 participants who complete both treatment periods. The sequences 
are planned to be executed in parallel.
All doses of PF-06882961 and PF-06865571 will be administered with meals. 
All participants will provide informed consent and undergo screening evaluations to 
determine their eligibility. Screening will occur within 28 days prior to administration of the 
study intervention for each participant on Day 1. Participants will be admitted to the CRU on 
Day -1. Each participant is planned to undergo two treatment periods, in a randomized order, 
as outlined in Section 1.2.1, with a washout interval between periods of at least 3 days 
following the final dose of study intervention administered in Period 1. 
Participants will be discharged from the study on Day 2 of period 2. Between periods, 
participants may be discharged after Day 2 of Period 1 or be confined to the CRU until the 
completion of Day 2 activities of Period 2 at the discretion of the investigator. A follow-up 
contact will occur 28-35 days after the final dose of study intervention. For individual 
participants, the total duration of participation from the screening visit to the follow-up 
contact will be approximately 9 weeks. 
Participants who withdraw from Part A of the study for non-safety-related reasons, or who 
are unable to complete both treatment periods in the study, may be replaced at the discretion 
of the sponsor upon consultation with the investigator. 


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4.1.2. Part B Study Design
Part B of this study will be conducted as an open-label, fixed-sequence study to evaluate the 
effect of PF-06882961 on the single-dose PK of PF-06865571, as well as the effect of 
PF-06865571 on the multiple-dose PK of PF-06882961 in overweight adults or adults with 
obesity who are otherwise healthy. 
In Period 1, a single oral dose of PF-06865571 will be administered. Following titration of 
PF-06882961 to a maximal steady-state dose to be determined as described in Section 4.3
(Period 2), the effect of steady-state administration of PF-06882961 on a single oral dose of 
PF-06865571 will be assessed (Period 3). Following Period 3, multiple doses of 
PF-06865571 will be administered with a maximally tolerated dose of PF-06882961 to be 
determined as described in Section 4.3 (Period 4) to assess the effect of steady-state doses of 
PF-06865571 on multiple dose PK of PF-06882961. The titration scheme is outlined in 
Section 6.1.1 and Section 6.3.1.
Approximately 16 participants will be enrolled such that approximately 12 evaluable 
participants complete Part B. The study schema is outlined in Section 1.2.2.
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 CRU on Day -1 of Period 1. The total duration of 
participation from Screening to the follow-up contact will be approximately 18 weeks. The 
follow-up visit will occur 7-10 days after the final dose of study intervention. The follow-up 
contact may occur via telephone contact and will occur 28-35 days after the final dose study 
intervention. Participants who withdraw from Part B of the study for non-safety-related 
reasons before completing all assessments may be replaced at the discretion of the 
investigator and Sponsor.
4.2. Scientific Rationale for Study Design
The purpose of this study is to characterize the effect of PF-06865571 on the PK of 
PF-06882961, as well as the effect of PF-06882961 on the PK of PF-06865571. Based on in 
vitro studies, PF-06882961 has a low risk of time-dependent inhibition of CYP3A4. 
PF-06865571 has modest risk of induction of CYP3A. Both PF-06882961 and PF-06865571 
are CYP3A substrates with fm values of 0.50 and 0.68, respectively.
In addition, PF-06865571 is also an inhibitor of P-gp and BCRP, and PF-06882961 is a 
BCRP substrate in vitro. Therefore, in order to address the potential for increased exposure 
of PF-06882961 caused by a potential interaction with PF-06865571, the effect of 
PF-06865571 on the PK of PF-06882961 will first be evaluated in Part A followed by a 
pause to evaluate the PK results and inform doses for Part B. Healthy adult participants will 
be enrolled in Part A.


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Part A of the study is not a definitive assessment of the effect of PF-06865571 on the PK of 
PF-06882961 because the duration of dosing of PF-06865571 is not adequate to assess 
potential inductive effects. However, because Part B is to be conducted at the highest 
tolerated dose of PF-06882961, and PF-06865571 has the potential to increase PF-06882961 
concentrations via inhibition of BCRP, Part A is being conducted in advance of Part B to 
mitigate potential for PF-06882961 exposures in this study beyond what was previously 
assessed in prior clinical experience.
In Part B, multiple dosing will be used to ensure maximal clinically relevant steady-state 
PF-06882961 exposures are achieved in order to more fully evaluate potential CYP3A 
time-dependent inhibition by PF-06882961 and potential CYP3A induction by PF-06865571. 
Based on in vitro data, the risk of time-dependent inhibition of CYP3A by PF-06882961 is 
low, so increases in PF-06865571 exposures are not expected. In fact, the preliminary data 
from the C3421007 DDI study indicate that PF-06882961 co-administration decreased the 
exposure of midazolam, a probe 3A4 substrate. To investigate the mechanism of this 
interaction, plasma 4--hydroxycholesterol/cholesterol, used as an endogenous probe for 
CYP3A induction, will be collected and analyzed in this study.
At the PF-06882961 200 mg BID dose, there is a possibility of weak inhibition of the hepatic 
uptake transporters OATP1B3 and OATP2B1.  CP-I has been reported to be used as an 
endogenous probe for OATP1B activities.  In the clinical DDI study of rosuvastatin and 
rifampicin, CP-I exposure (AUC24) was increased by 4.0-fold with co-administration of 
rifampicin, a potent OATP1B1 inhibitor, compared to the group of rosuvastatin alone.28
Therefore, CP-I will be assessed in Part B to evaluate the potential effect of PF-06882961 on 
OATP1B at higher doses (ie, 120 and 200 mg BID).  This data could help understand the 
contribution of OATP1B inhibition to the rosuvastatin exposure increase observed in the 
C3421007 study where rosuvastatin was co-administered with PF-06882961.  In the study 
mentioned above, it was also suggested that CP-I plasma concentration at baseline were 
constant and independent of time, but changed rapidly following co-administration with 
rifampicin and returned back to baseline within 24 hours. 28  Therefore, three blood samples 
will be taken at different timepoints prior to PF-06882961 treatment in Part B to determine 
baseline CP-I concentrations followed by CP-I concentration time profiles over 12 hours for 
both PF-06882961 120 mg and 200 mg BID at steady-state, respectively.
Participants with a higher BMI range from 25 kg/m2 to 40 kg/m2 who are overweight or 
obese but otherwise healthy will be enrolled in Part B to target a similar BMI range as 
patients with NASH. Adult participants with NASH often have co-existing obesity, and 
PF-06882961 will likely be co-administered with PF-06865571 in a future clinical efficacy 
study. 
The elimination half-lives of PF-06882961 and PF-06865571 are approximately ≤8 hours
and ≤7 hours, respectively, following single and multiple dosing. Therefore, plasma 
sampling will be collected for 24 hours after dosing in Part A and for 12 to 48 hours after 
dosing in Part B.


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Clinical laboratory tests, assessments of vital signs, body weight, 12-lead ECGs, physical 
examinations, and AE monitoring will provide data to evaluate the safety and tolerability of 
PF-06882961 and PF-06865571 when dosed alone and in combination. Vital signs will be 
monitored at frequent intervals, as both increases in HR and mild decreases in systolic BP 
have been observed with PF-06882961 administration. Body weight will be measured at 
timepoints in the SoA because GLP-1 receptor agonists have been shown to decrease food 
intake and body weight.
As part of the clinical safety laboratory tests, fasting blood glucose will be used to assess 
changes in glycemic parameters. In addition, calcitonin, amylase, and lipase will be 
assessed, as these laboratory parameters have been shown to increase with marketed GLP-1
receptor agonists.20-23 In addition, TSH, free T4, lipids, coagulation profile, and TBA will 
also be assessed based on non-adverse findings in the nonclinical studies with PF-06882961. 
Furthermore, PF-06865571 is a dose-dependent inhibitor of the transporters OCT2/MATE in 
the kidney and, as expected, this has been observed to cause increases in serum creatinine in 
previous clinical studies with PF-06865571 without a change in renal function, as assessed 
via measurements of Cystatin-C.  Therefore, Cystatin-C (and eGFR using 
CKD-EPI-Cystatin-C) will be measured in Part B to accurately monitor renal function 
starting at baseline and throughout the study.  Assessment of suicidal ideation and behavior 
will be conducted using C-SSRS,24 and PHQ-925 will also be performed based on the 
potential risk related to the product labeling for the injectable GLP-1 receptor agonist 
liraglutide23 in patients with BMI ≥30 kg/m2.
While GLP-1 receptor 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 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 both PF-06882961 and PF-06865571 is planned to occur in the fed state, 
immediately after standard breakfast and dinner, because this is the anticipated mode of 
administration in clinical use. 
Human reproductive safety data are not currently available for co-administration of 
PF-06882961 and PF-06865571. Marketed GLP-1 receptor agonists are listed as 
contraindicated in pregnancy. 
CCI


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Embryo-fetal developmental studies with PF-06882961 alone and PF-06865571 alone have 
been completed, and findings have been noted (refer to Section 2.3.1). The use of a highly 
effective method of contraception is required by females of childbearing potential who are 
enrolled in this study. Refer to Section 5.3.4, Section 6.5, and Appendix 4 for additional 
details. 
The potential risk of exposure to PF-06882961 and/or PF-06865571 in a sexual partner of a 
male participant in this study via ejaculate is low, and therefore no contraception (condom) 
use in male participants is warranted. The calculated safety margin is ≥100-fold between the 
estimated partner exposure due to seminal transfer and the NOAEL for serious 
manifestations of developmental toxicity in nonclinical studies.  The safety margin of 
100-fold is based on applying a 10-fold safety factor for interspecies extrapolation and a 
10-fold safety factor for susceptible populations.26
 
4.3. Justification for Dose
4.3.1. PF-06882961
4.3.1.1. PF-06882961 in Part A
A single oral dose of 20 mg of PF-06882961 will be used in Part A. Doses up to 120 mg 
were previously administered in the Phase 1 C3421002 study and were sufficiently well 
tolerated. Because only modest exposure increases of PF-06882961 are anticipated in this 
study, a 20 mg dose of PF-06882961 is anticipated to be safe and generally well tolerated in 
healthy adult participants even if a potential PK drug-drug interaction increases the exposure 
of PF-06882961.
4.3.1.2. PF-06882961 in Part B
The highest planned steady-state dose in the Phase 2 obesity POC study is 200 mg BID 
(C3421019). Similarly, 200 mg BID is the highest planned steady-state dose in a drug 
interaction study (C3421007) investigating the effect of PF-06882961 on the PK of 
midazolam (3A4 substrate) and rosuvastatin (BCRP substrate). Based on a population PK 
analysis of Phase 1 data including both T2DM and non-T2DM participants, the exposure in 
T2DM participants are projected to be 1.7-fold higher than non-T2DM. Based on this 
analysis, the exposure in participants with obesity in these studies are expected to be 
comparable to the exposure of 120 mg BID in T2DM, which was generally well tolerated in 
the multiple ascending dose study C3421002. However, no clinical data are available (at the 
time of finalization of this protocol) evaluating doses >120 mg BID in any participant 
population. 
Preliminary safety and tolerability data from C3421007 will be reviewed prior to final dose 
and titration scheme selection for this study. If 200 mg BID is well tolerated in C3421007, 
then a steady-state dose of 200 mg BID will be used in this study. If 200 mg BID is not well 
tolerated in C3421007, then a lower steady-state dose will be selected for this study. 
CCI


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Accordingly, the maximal practical and well tolerated dose of PF-06882961 is envisioned for 
use in this study. This is consistent with expectation that the PF-06882961 dose needed for 
treatment of NASH is similar to that required for maximal efficacy in obesity.
The titration to PF-06882961 200 mg BID is planned over approximately 44 days but may 
also be revised based on C3421007 study results. Part B doses of PF-06882961 may be 
reduced if PF-06865571 increases PF-06882961 AUC24 by >50% in Part A.
The titration scheme is outlined in Section 6.1.1 and Section 6.3.1.
4.3.2. PF-06865571 in Part A and Part B
300 mg doses of PF-06865571 will be administered in both parts of this study. PF-06865571 
doses at 300 mg BID are expected to have an acceptable safety and tolerability profile, with 
minimal risk to the participants of study, because oral doses of PF-06865571 as high as 
600 mg Q8H have demonstrated an acceptable safety and tolerability profile after 14 days of 
oral administration. Given the short t½, PF-06865571 is anticipated to have minimal 
steady-state accumulation. The 300 mg BID dose of PF-06865571 administered in this study 
represents the highest dose being assessed in the Phase 2 study in participants with 
biopsy-proven NASH with fibrosis. Doses achieving exposures greater than 300 mg BID 
were also administered in the Phase 1 C2541002 study and will therefore allow DDI 
assessment in this study at anticipated exposures that were sufficiently tolerated.
A positive food effect has been observed in previous clinical studies with PF-06865571.  
Therefore, to maximize exposures, and to dose PF-06865571 similarly to how it will be 
dosed in future studies, PF-06865571 will be administered with food.
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, approximately 28 to 35 days after the 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.


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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. Male and female participants who are overtly healthy (other than being overweight or 
obese in Part B only) as determined by medical evaluation including medical history, 
physical examination, and laboratory tests.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
4. BMI and total body weight:

Part A: BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb);

Part B: BMI ≥25 kg/m2 and not more than 40 kg/m2 at Screening; 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 


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allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy,
bariatric surgery, active inflammatory bowel disease, or an intestinal resection).
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-1 receptor agonists.
5. Known intolerance or hypersensitivity to DGAT2 inhibitors.
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.
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 or multiple endocrine 
neoplasia syndrome type 2, or study participants with suspected medullary thyroid 
carcinoma 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.


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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. See Section 6.5 for prohibited prior/concomitant medications.
Prior/Concurrent Clinical Study Experience:
19. 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).  An emergency use authorized or approved 
COVID-19 vaccine is considered a concomitant medication.
20. Known prior participation in a clinical trial with PF-06882961 or PF-06865571.
Diagnostic Assessments:
21. Part B only: A Patient Health Questionnaire (PHQ-9) score ≥15 obtained at Screening 
or Day -1.
22. Part B only: Response of “yes” to question 4 or 5, or on any behavioral question on 
the C-SSRS at Screening or Day -1.
23. A positive urine drug test.
24. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest.  If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
25. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may
affect participant safety or interpretation of study results (eg, baseline QTc 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 the 
baseline uncorrected QT interval is >450 msec, this interval should be rate-corrected 
using the Fridericia method and the resulting QTcF should be used for decision 
making and reporting.  If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG 
should be repeated 2 more times and the average of the 3 QTc or QRS values should 
be used to determine the participant’s eligibility. Computer-interpreted ECGs should 


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be overread by a physician experienced in reading ECGs before excluding 
participants.
26. A positive COVID-19 test at or after screening.
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%.

AST or ALT > ULN.

Total bilirubin level > ULN; participants with a history of Gilbert's syndrome may 
have direct bilirubin measured and are eligible for this study provided the direct 
bilirubin level is ≤ULN.

TSH > ULN or < LLN.

Serum calcitonin > ULN.

Amylase or lipase > ULN.

Fasting blood glucose ≥126 mg/dL.

Fasting triglycerides >200 mg/dL.

INR > ULN.

PLT < LLN.

eGFR <80 mL/min/1.73 m2 as calculated by the CKD-EPI equation.

Positive testing for HIV, HepBsAg, or HCVAb. Study participants positive for 
HCVAb are to be excluded unless known to have been treated with a known 
curative therapy and negative for HCV RNA. Hepatitis B vaccination is allowed.
Other Exclusions (at Screening unless indicated):
28. Participation in a formal weight reduction program (eg, Weight Watchers) within 
90 days prior to Screening.


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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 dose 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.
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 evaluations and the morning predose PK evaluations.

Water may be consumed as desired (ad libitum).

Participants should begin consumption of a standard breakfast (morning) and dinner 
(evening) approximately 30 minutes prior to dosing. The breakfast and dinner will be 
consumed over approximately a 20 minute period, with the study intervention 
administered within approximately 10 minutes after completion of the meal. 
Participants will be encouraged to complete the entire meal. Study intervention will 
be administered as outlined in Section 6.1.1. 

Noncaffeinated drinks (except red wine, grapefruit or grapefruit-related citrus fruit 
juices; see below) may be consumed with meals and the evening snack. Caffeine 
containing drinks may be consumed during the study but not within 1 hour prior to 
measuring vital signs and ECGs (see Section 5.3.2).


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
Lunch will be provided approximately 4 hours after morning dosing.

On Overall Study Day 46, Day 47, and Day 61 in Part B, dinner will be provided 
approximately 12 hours after morning dosing. On all other study days in both Part A 
and Part B, dinner will be provided approximately 10 hours after morning dosing.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein.  The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco

Tobacco or nicotine use may be allowed according to CRU practices but not in excess 
of the equivalent of 5 cigarettes per day as outlined in Section 5.2.

Tobacco or nicotine use will not be permitted during frequent sampling procedures 
and will not be permitted within 2 hours prior to any vital sign or ECG assessments. 
Tobacco or nicotine use will also not be permitted 2 hours before and 2 hours 
following any dose of study intervention. 

Caffeine containing products will be permitted during the study with the following 
restrictions: caffeine containing products may not be consumed within 1 hour prior to 
measuring vital signs and ECGs.

Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample of the study. 
Participants may undergo an alcohol breath test or blood alcohol test at the discretion 
of the investigator.
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted.

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down, eating, and drinking beverages other than water 
during the first 4 hours after morning dosing on days of post-dose PK sample 
collections (except when required for BP, PR, and ECG measurements). 


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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 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  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.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported to the clinical database.
A participant who qualified for this protocol but did not enroll within the 28-day screening 
window due to unexpected delays (eg, delayed drug shipment), will not be required to 
rescreen if the laboratory results obtained prior to first dose administration meet eligibility 
criteria.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
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 and
PF-06865571. 
6.1. Study Intervention(s) Administered
PF-06882961 tablets (10 mg, 40 mg, and 100 mg) will be supplied by Pfizer to the CRU in 
bulk along with individual dosing containers, as necessary, for unit dosing.
PF-06865571 tablets (100 mg) will be supplied by Pfizer to the CRU in bulk along with 
individual dosing containers, as necessary, for unit dosing.


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6.1.1. Administration
All PF-06882961 and PF-06865571 doses will be administered with food in both Part A and 
Part B as described in Section 5.3.1. 
In Part A, participants will receive study intervention as applicable per SoA. Doses will be 
administered with breakfast at approximately 0800 hours (plus or minus 2 hours).
In Part B, participants will receive PF-06882961 and PF-06865571 as applicable per SoA. 
Morning doses will be administered at approximately 0800 hours (plus or minus 2 hours). 
For BID dosing on Overall Study Day 46, Day 47, and Day 61, evening dosing of 
PF-06865571 and/or PF-06882961 will occur approximately 12 hours after morning dosing. 
On all other study days, evening dosing of PF-06865571 and/or PF-06882961 will occur 
approximately 10 hours after morning dosing. 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 and PF-06865571 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 as listed in the SoA and Table 4 (Part A) and 
Table 5 (Part B).
Table 4.
Part A Dosing
Study Treatment
Drug and Dosage
Treatment A
Day 1: PF-06882961 20 mg single dose
Treatment B
Day 1: PF-06882961 20 mg single dose plus PF-06865571 300 mg single dose
Table 5.
Part B Dosing
Study Period
Days in Study
Drug and Dosage
Period 1, Day 1
1
PF-06865571 300 mg single dose
Period 1, Day 2
2
No study intervention administered
Period 2, Days 1-4
3-6
PF-06882961 10 mg BID
Period 2, Days 5-8
7-10
PF-06882961 20 mg BID
Period 2, Days 9-12
11-14
PF-06882961 40 mg BID
Period 2, Days 13-16
15-18
PF-06882961 60 mg BID
Period 2, Days 17-20
19-22
PF-06882961 80 mg BID
Period 2, Days 21-24
23-26
PF-06882961 100 mg BID
Period 2, Days 25-28
27-30
PF-06882961 120 mg BID
Period 2, Days 29-32
31-34
PF-06882961 140 mg BIDa
Period 2, Days 33-36
35-38
PF-06882961 160 mg BIDa
Period 2, Days 37-40
39-42
PF-06882961 180 mg BIDa
Period 2, Days 41-44
43-46
PF-06882961 200 mg BIDa
Period 3, Day 1
47
PF-06865571 300 mg single dose plus PF-06882961 200 mg BIDa
Period 3, Day 2
48
PF-06882961 200 mg BIDa
Period 4, Days 1-13
49-61
PF-06865571 300 mg BID plus PF-06882961 200 mg BIDa


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Study Period
Days in Study
Drug and Dosage
Period 4, Day 14
62
No study intervention administered
a.
Doses of PF-06882961 may be reduced based on PK results of Part A of this study and safety and 
tolerability results of Study C3421007.
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 
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.


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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. 
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
This is an 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 4 digits of the assigned participant number will reflect the 
sponsor-assigned site number and the remaining 4 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 of both Part A and Part B, each participant who is dosed with 
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 the sponsor’s standard 
processes for analysis of all PK-related samples.
Participants will receive doses of PF-06882961 and PF-06865571 as described in Table 6
(Part A Sequence 1), Table 7 (Part A Sequence 2), and Table 8 (Part B).
Table 6.
Part A Sequence 1 – Dosing Regimens for PF-06882961 and PF-06865571
Period
Day
AM/
PM
Dose
Number of PF‑06882961 
Tablets
Number of 
PF‑06865571 
Tablets
Total Number 
of Tablets
10 mg
40 mg
100 mg
100 mg
1
1
AM
20 mg PF‑06882961
2
2
2
1
AM
20 mg PF‑06882961
and 
300 mg PF‑06865571
2
3
5


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Table 7.
Part A Sequence 2 – Dosing Regimens for PF-06882961 and PF-06865571
Period
Day
AM/
PM
Dose
Number of PF‑06882961 
Tablets
Number of 
PF‑06865571 
Tablets
Total Number 
of Tablets
10 mg
40 mg
100 mg
100 mg
1
1
AM
20 mg PF‑06882961
and 
300 mg PF‑06865571
2
3
5
2
1
AM
20 mg PF‑06882961
2
2
Table 8.
Part B – Dosing Regimens for PF-06882961 and PF-06865571
Period
Day(s)
in 
Study
AM/
PM
Dose
Number of PF‑06882961 
Tablets
Number of 
PF‑06865571 
Tablets
Total 
Number 
of Tablets
10 mg
40 mg
100 mg
100 mg
1
1
AM
300 mg PF‑06865571
3
3
2
N/A
No study intervention 
administered
0
2
3-6
AM
10 mg PF‑06882961
1
1
PM
10 mg PF‑06882961
1
1
7-10
AM
20 mg PF‑06882961
2
2
PM
20 mg PF‑06882961
2
2
11-14
AM
40 mg PF‑06882961
1
1
PM
40 mg PF‑06882961
1
1
15-18
AM
60 mg PF‑06882961
2
1
3
PM
60 mg PF‑06882961
2
1
3
19-22
AM
80 mg PF‑06882961
2
2
PM
80 mg PF‑06882961
2
2
23-26
AM
100 mg PF‑06882961
1
1
PM
100 mg PF‑06882961
1
1
27-30
AM
120 mg PF‑06882961
2
1
3
PM
120 mg PF‑06882961
2
1
3
31-34
AM
140 mg PF‑0688296a
1
1
2
PM
140 mg PF‑06882961a
1
1
2
35-38
AM
160 mg PF‑06882961a
2
1
1
4
PM
160 mg PF‑0688296a
2
1
1
4
39-42
AM
180 mg PF‑0688296a
2
1
3
PM
180 mg PF‑06882961a
2
1
3
43-46
AM
200 mg PF‑06882961a
2
2
PM
200 mg PF‑06882961a
2
2
3
47
AM
200 mg PF‑06882961a
and
300 mg PF‑06865571
2
3
5
PM
200 mg PF‑06882961a
2
2
48
AM
200 mg PF‑06882961a
2
2
PM
200 mg PF‑06882961a
2
2
4
49-61
AM
200 mg PF‑06882961a
and
300 mg PF‑06865571
2
3
5
PM
200 mg PF‑06882961a
and
300 mg PF‑06865571
2
3
5
62
N/A
No study intervention 
administered
0


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Period
Day(s)
in 
Study
AM/
PM
Dose
Number of PF‑06882961 
Tablets
Number of 
PF‑06865571 
Tablets
Total 
Number 
of Tablets
10 mg
40 mg
100 mg
100 mg
a.
Doses of PF-06882961 may be reduced based on PK results of Part A of this study and safety and tolerability results 
of Study C3421007.
6.4. Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.  Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5. Concomitant Therapy
Study participants will abstain from all concomitant treatments, except for the treatment of 
adverse events, as described in Section 5.2 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. 
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.


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All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment.  Treatments taken after the first dose of study intervention
will be documented as concomitant treatments.
6.5.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with PF-06882961 or PF-06865571; 
standard medical supportive care must be provided to manage the AEs, including 
administration of carbohydrates to treat HAEs (see Section 8.2.8).
6.5.1.1. Management of Nausea and Vomiting
Nausea and vomiting have been reported with administration of GLP-1 receptor agonists and 
also with administration of PF-06882961. 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 
(eg, >120 mg BID) in Part B, titration to the next dose level may be delayed temporarily or 
titration to maximum tolerated dose may be permitted with Sponsor approval only.
Part B doses of PF-06882961 may be reduced in this study based on safety and tolerability 
results of Study C3421007. The duration of each titration step may also be revised. Part B 
doses of PF-06882961 may be reduced if PF-06865571 increases PF-06882961 AUC24 by 
>50% in Part A. 
6.7. Stopping Rules
6.7.1. Participant Death
In the event that there is death of a participant, trial conduct will be paused and the death 
assessed for causality and relatedness by the medical monitor.
Sponsor will notify the FDA in the event of a participant death in accordance with IND 
safety reporting requirements under 21 CFR 312.32(a) and 312.32(c)(1).


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6.7.2. Individual Participant Development of Adverse Events (Part B only)
If a participant experiences a severe AE, and the AE is assessed to be related to GLP-1 
receptor agonist pharmacology and/or anticipated to develop toleration (eg, nausea, vomiting, 
anorexia), dosing may continue with protocol permitted mitigations as needed 
(eg, antiemetics; see Section 6.5 Concomitant Therapy).  If the anticipated improvement in 
tolerability is not observed, the study intervention dosing will be discontinued for that 
participant. 
If the AE is not known to be related to GLP-1 receptor agonist pharmacology, not anticipated 
to develop toleration, or has not yet been assessed as unrelated to study intervention, dosing 
of study intervention should be discontinued for the affected participant and the AE should 
be assessed for causality and relatedness.
6.7.3. Cohort Level Assessment of Adverse Events (Part B, Period 4 only)
During Part B (Period 4) if: 
a.
Three participants develop the “same” moderate AE; 
or
b. Two participants develop the “same” severe AE;
and
c.
If the AE is not known to be related to GLP-1 receptor agonist pharmacology.
The trial should be paused and AE should be assessed for causality and relatedness.  If the 
medical team/medical monitor and investigator together deem causality to be unrelated to 
study intervention use, trial conduct may be continued.  
If (a) or (b) occur, but not (c), ie, an AE is assessed to be related to GLP-1 receptor agonist 
pharmacology and/or anticipated to develop toleration (eg, nausea, vomiting, anorexia), 
dosing may continue with protocol permitted mitigations as needed (eg, antiemetics; see 
Section 6.5 Concomitant Therapy).  If the anticipated improvement in tolerability is not 
observed, the study intervention dosing will be discontinued for that participant.
6.8. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.


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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 -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.
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 through the follow-up contact. 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;


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
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.
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.


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The following actions must be taken if a participant fails to return to the clinic for or 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.
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.  If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.


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A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections
may be used without repeat collection, as appropriate.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
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 
140 mL for Part A and approximately 525 mL for Part B.  The actual collection times of 
blood sampling may change.  Additional blood samples may be taken for safety assessments 
at times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
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. 
CCI


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A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
A complete physical exam will be done at time points specified in the SoA, otherwise, brief 
exam will be conducted 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
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements. 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 
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Additional collection times, or changes to collection times, of BP and PR 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.
8.2.3. 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 QTc 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 baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTc interval is increased by ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QTc 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 QTc values from these repeated ECGs remain 
above the threshold value, then a single ECG must be repeated at least hourly until QTc 
values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.
If a) a postdose QTc interval remains ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, 
at the discretion of the investigator); or c) QTc 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 QTc 
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.


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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. 
8.2.5. Suicidal Ideation and Behavior Risk Monitoring
8.2.5.1. Columbia Suicide Severity Rating Scale (Part B only)
The C-SSRS is an interview based rating scale to systematically assess suicidal ideation and 
suicidal behavior.24 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 
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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 (Part B only)
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms.25 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.
A clinically-qualified MHP is a MHP with appropriate training in the assessment of suicide 
risk, according to local clinical practice standards and regulations, who would normally 
evaluate the risk for suicidal ideation and behavior in a patient.
Participants who have recurrent suicidal ideation or behavior during the study should be 
discontinued from the study and treated appropriately. If a study participant endorses a 4 or 
5 on the ideation subscale or any behavioral item of the C-SSRS on 2 or more occasions and 
is confirmed to have active suicidal ideation or behavior on both occasions by a risk 
assessment conducted by a qualified MHP, then the participant should be discontinued from 
the study and treated appropriately.
Participants who meet criteria for referral to a MHP, but refuse evaluation and/or treatment 
by a MHP, must be assessed by the investigator to determine if the participant should be
discontinued from dosing or from the study.


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8.2.6. COVID-19 Specific Assessments
Participants will be tested for COVID-19 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 required by local regulations or by the Principal Investigator.
8.2.7. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study interventions. 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.
8.2.8. 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 CRF. For the definition of a hypoglycemic episode and severity 
categorization see Section 8.2.8.1 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.
8.2.8.1. Definition and Severity of Categorization of Hypoglycemic Adverse Event 
(HAE)
The investigator must assess the glucose values reported by the central/local laboratory, as 
well as any signs or symptoms reported by the study participant.
HAE is defined as one of the following:27
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).


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b. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose value of <70 mg/dL (3.9 mmol/L), using 
glucometer 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.
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.


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


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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.
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: 


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
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 
the last dose of study intervention.

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;


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
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.

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.


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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
This section is not applicable because efficacy is not expected in the study population.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.


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Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
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.
Any dose of PF-06865571 greater than 1800 mg within a 24-hour time period will be 
considered an overdose.
There is no specific treatment for an overdose for PF-06882961 or PF-06865571. 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 or 
PF-06865571 (whichever is longer).   
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.


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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 
basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of PF-06882961, 
and PF-06865571 (Part B only) 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 measurement of plasma concentrations of PF-06882961,
and PF-06865571 will be analyzed using validated analytical methods in compliance with 
applicable SOPs. Potential metabolites may be analyzed with either validated or exploratory 
methods.
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
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 resulting 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.
CCI
CCI


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8.5.1. Plasma for Analysis of PF-06882961
Blood samples of approximately 3 mL, to provide a minimum of approximately 1.2 mL
plasma, will be collected for measurement of plasma concentrations of PF-06882961
as specified in the SoA. Instructions for the collection and handling of 
biological samples will be provided in the laboratory manual or by the sponsor. The actual 
date and time (24-hour clock time) of each sample will be recorded.
Samples will be used to evaluate the PK of PF-06882961
. Samples 
collected for analyses of PF-06882961
plasma concentrations may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study, for metabolite identification and/or evaluation of the bioanalytical method, or for other 
internal exploratory purposes.
8.5.2. Plasma for Analysis of PF-06865571
Blood samples of approximately 3 mL, to provide a minimum of approximately 1.2 mL
plasma, will be collected for measurement of plasma concentrations of PF-06865571 as 
specified in the SoA. Instructions for the collection and handling of biological samples will 
be provided in the laboratory manual or by the sponsor. The actual date and time (24-hour 
clock time) of each sample will be recorded.
Samples will be used to evaluate the PK of PF-06865571. Samples collected for analyses of 
PF-06865571 plasma concentrations may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, or for other internal exploratory purposes.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
 
 
 
 
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.
 
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8.8.5. Plasma for Analysis of CP-I (Part B only)
Blood samples of approximately 3 mL, to provide a minimum of approximately 1.2 mL 
plasma, will be collected into appropriately labeled tubes containing K2EDTA for 
measurement of plasma concentrations of CP-I at times specified in the SoA.  Samples 
collected for measurement of plasma concentrations of CP-I will be analyzed using a 
validated analytical method in compliance with applicable SOPs.  Instructions for the 
collection and handling of biological samples will be provided in the laboratory manual.
8.8.6. Plasma for 4-β-hydroxycholesterol/cholesterol Analysis (Part B only)
Blood samples of approximately 4 mL, to provide a minimum of approximately 1.6 mL 
plasma, will be collected into appropriately labeled tubes containing lithium heparin for the 
analysis of 4-β-hydroxycholesterol and cholesterol at times specified in the SoA.  
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual.
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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
9.2.1. Sample Size for Part A
Approximately 8 participants will be enrolled in Part A of this study. The expected widths of 
the 90% confidence intervals with 80% coverage probability for these comparisons are 
shown in Table 9 for a range of possible effects based on sample sizes of 6, 8, and 
10 participants. These estimates are based on an assumed standard deviation of 0.200 in 
logeAUC24 for PF-06882961 obtained from an internal single ascending dose study.
Table 9.
Estimated Effect of PF-06865571 on PF-06882961 in Part A – Expected 
Widths of the 90% CIs (with 80% Coverage Probability) for Different 
Possible Estimated Effects and Parameters of Interest
Parameter
N
Estimated Effect
(Test/Reference)
AUC24
Probable
90% CI
Probable 
CI Width
AUC24
(PF-06882961)
6
100%
74 to 135%
61%
150%
111 to 203%
92%
200%
148 to 270%
122%
8
100%
79 to 126%
47%
150%
119 to 189%
70%
200%
159 to 252%
94%
10
100%
82 to 122%
39%
150%
123 to 182%
59%
200%
165 to 243%
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9.2.2. Sample Size for Part B
A sample size of approximately 16 participants will be enrolled in Part B such that 
approximately 12 evaluable participants complete the study.
To characterize the effect of PF-06865571 on PF-06882961 PK parameters, the expected 
widths of the 90% confidence intervals with 80% coverage probability for these comparisons 
are shown in Table 10 for a range of possible effects based on sample sizes of 12, 14, and 
16 participants. These estimates are based on an assumed standard deviation of 0.308 in 
logeAUC24 for PF-06882961 obtained from an internal multiple ascending dose study. These 
estimates also assume similar variability between AUC12 and AUC24.
Table 10.
Estimated Effect of PF-06865571 on PF-06882961 in Part B – Expected 
Widths of the 90% CIs (with 80% Coverage Probability) for Different 
Possible Estimated Effects and Parameters of Interest
Parameter
N
Estimated Effect
(Test/Reference)
AUC24
Probable
90% CI
Probable 
CI Width
AUC24
(PF-06882961)
12
50%
39% to 65%
26%
75%
58% to 97%
40%
100%
77% to 130%
53%
14
50%
40% to 63%
24%
75%
59% to 95%
36%
100%
79% to 127%
48%
16
50%
40% to 62%
22%
75%
60% to 93%
33%
100%
81% to 124%
44%
To characterize the effect of PF-06882961 on PF-06865571 PK parameters, the expected 
widths of the 90% confidence intervals with 80% coverage probability for these comparisons 
are shown in Table 11 for a range of possible effects based on sample sizes of 12, 14, and 
16 participants. These estimates are based on an assumed conservative standard deviation of 
0.12 in logeAUCinf for PF-06865571 obtained from an internal single ascending dose study.
Table 11.
Estimated Effect of PF-06882961 on PF-06865571 in Part B – Expected 
Widths of the 90% CIs (with 80% Coverage Probability) for Different 
Possible Estimated Effects and Parameters of Interest
Parameter
N
Estimated Effect
(Test/Reference)
AUCinf
Probable
90% CI
Probable 
CI Width
AUCinf
(PF-06865571)
12
100%
90% to 111%
20%
125%
113% to 138%
25%
150%
136% to 166%
30%
200%
181% to 221%
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14
100%
91% to 110%
18%
125%
114% to 137%
23%
150%
137% to 164%
28%
200%
182% to 219%
37%
16
100%
92% to 109%
17%
125%
115% to 136%
21%
150%
138% to 163%
25%
200%
184% to 218%
34%
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 PF-06882961 
and/or PF-06865571 and in whom at least 1 plasma 
concentration value is reported.
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 and Endogenous Biomarker Parameters
PK parameters for PF-06882961,
and PF-06865571 (Part B 
only) will be derived (if data permit) from the plasma concentration-time data using standard 
noncompartmental methods for Part A and Part B as defined in Table 12 and Table 13, 
respectively. AUC12 and Cmax for CP-I in Part B will be derived (Table 13).  Plasma 
4-β-hydroxycholesterol/cholesterol at each collection time in Part B will also be calculated.  
Actual PK sampling times will be used in the derivation of PK parameters.
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Table 12.
Part A – Plasma PK Parameters for PF-06882961
Parameter
Definition
Method of Determination
AUC24
Area under the plasma concentration-time 
curve from time 0 to time 24 hours 
post-dose
Linear/log trapezoidal method
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
Table 13.
Part B – Plasma PK Parameters for PF-06882961,
 and 
PF-06865571, and Plasma CP-I Parameters
Parameter
Compound
Day
Definition
Method of Determination
AUClast
PF-06865571
1 and 47
Area under the plasma 
concentration-time curve 
from time zero to the time 
of the last quantifiable 
concentration (Clast).
Linear/log trapezoidal method.
AUCinf*
PF-06865571
1 and 47
Area under the plasma 
concentration-time curve 
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.
AUC12
PF-06865571
61
Area under the plasma 
concentration-time curve 
from time 0 to time 
12 hours post-dose.
Linear/log trapezoidal method.
PF-06882961 
46 and 61
CP-I
30 and 46
Cmax
PF-06865571
1, 47, and 61
Maximum plasma 
concentration.
Observed directly from data.
PF-06882961 
46 and 61
CP-I
30 and 46
Tmax
PF-06865571
1, 47, and 61
Time for Cmax.
Observed directly from data as 
time of first occurrence.
PF-06882961 
46 and 61
t1/2*
PF-06865571
1 and 47
Terminal half-life.
Loge(2)/kel, where kel is the 
terminal phase rate constant 
calculated by a linear 
regression of the log-linear 
concentration-time curve. 
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Parameter
Compound
Day
Definition
Method of Determination
Only those data points judged 
to describe the terminal 
log-linear decline will be used 
in the regression.
CL/F*
PF-06865571
1 and 47
Apparent oral clearance.
Single Dose = Dose/AUCinf;
Multiple Dose = Dose/AUC12
PF-06882961
46 and 61
Vz/F*
PF-06865571
1 and 47
Apparent oral volume of 
distribution.
Single Dose = 
Dose/(AUCinf*kel);
* If data permit.
9.4.2. Statistical Methods for Pharmacokinetic Data
The PK parameters listed in Table 12 and Table 13 will be summarized descriptively for 
Part A and Part B by treatment as applicable for each analyte.
9.4.2.1. Part A – Statistical Methods for Pharmacokinetic Data
Plasma concentrations of PF-06882961 will be listed and summarized descriptively by PK 
sampling time and treatment (dosing alone versus 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 Cmax and AUC24 of PF-06882961 administered alone or 
co-administered with PF-06865571 will be analyzed using a mixed effect model with 
treatment, sequence, and period as a fixed effects and participant embedded in sequence 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 reference treatment will be “PF-06882961 
20 mg” administered alone, whereas the test treatment will be “PF-06882961 20 mg plus 
PF-06865571 300 mg BID”.
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9.4.2.2. Part B – Statistical Methods for Pharmacokinetic and Endogenous Biomarker
Data
Plasma concentrations of PF-06882961,
PF-06865571, and CP-I will be listed 
and summarized descriptively by sampling time and treatment (dosing alone versus 
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 Cmax, AUClast, and AUCinf (as data permit) of PF-06865571
300 mg BID 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 test treatment will be  “PF-06865571 300 mg plus PF‑06882961 
200 mg BID” (Period 3), which will be reported separately in comparison to the reference 
treatment of “PF-06865571 300 mg” (Period 1).
Natural log-transformed AUC12 and Cmax of PF‑06882961 200 mg BID administered alone or 
co-administered with PF-06865571 300 mg BID will be analyzed and reported separately 
using the same mixed effect model as described above.  The test treatment will be 
“PF-06865571 300 mg BID plus PF‑06882961 200 mg BID” (Period 4), which will be 
reported separately in comparison to the reference treatment of “PF‑06882961 200 mg BID 
administered alone” (Period 2). 
The above and other PK parameters for PF-06865571, and PK parameters for PF-06882961, 
will be separately summarized descriptively by treatment.
The mean of CP-I plasma concentrations on Day 1 will serve as baseline.
Change from baseline in AUC12/12 and Cmax for CP-I 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 against the reference will be obtained and corresponding 90% CIs 
will be reported from the models.  The test treatments will be “PF-06882961 120 mg BID” 
(Day 30) and “PF-06882961 200 mg BID” (Day 46) and reference treatment is “No 
PF-06882961” (Day 1).  Additionally, AUC12, AUC12/12 and Cmax for CP-I will be separately 
summarized descriptive by treatment.
The plasma 4-β-hydroxycholesterol/cholesterol ratios will be summarized descriptively by 
day.  Individual subject and median plots will be produced by day (Days 1, 19, 31, and 47).  
Percent change of the 4-β-hydroxycholesterol/cholesterol ratio from baseline will be
summarized descriptively by day.
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9.4.3. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants.  Any clinical 
laboratory, ECG, BP, and PR abnormalities of potential clinical concern will be described.  
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported.
COVID‑19 specific assessments data will be considered source data and will not be required 
to be reported.
9.4.3.1. Electrocardiogram Analyses
For each part, 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.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment 
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450‑480
>480‑500
>500
Increase from baseline
30‑60
>60
In addition, an attempt may be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach. If a PK/PD 
relationship is found, the impact of participant factors (covariates) on the relationship may be 
examined. If the exposure-QT analyses is performed, it will be reported separately, not as 
part of the CSR.
9.4.4. Other Analyses 
Tertiary/exploratory analyses not included in the PK or safety analyses outlined above will
be documented in the SAP.


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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 dose-escalation decisions, 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 
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10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study 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.
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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.
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.


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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.
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.


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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.
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.


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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.
A document must be available at the investigative site that identifies those data that will be 
recorded on the CRF and for which the CRF will be the source document.
The following data types collected post-screening visit may be recorded directly on the CRFs 
(ie, for which there is no existing written or electronic record of data) and is to be considered 
source data:
•
Prior and concomitant treatments;
•
Non-drug treatments;
•
Serious and non-serious adverse events;
•
Hypoglyemic adverse events;
•
Medication errors;
•
Body weight;
•
Vital signs (blood pressure and pulse rate);
•
Study intervention dosing administration;
•
Safety laboratory sample collection;
•
•
PK blood sample collection;
•
Participant disposition;
•
Withdrawal of consent.
Definition of what constitutes source data can be found in the clinical 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.
CCI


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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.
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.


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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 
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 14.
Protocol Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
eGFRa
Cystatin-C 
eGFR, using CKD-EPI-
Cystatin-Cb
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
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyc
COVID-19 testing
Serum pregnancy test (-hCG)d
Urine drug screeninge
Lipid panel:
Total cholesterol
Direct LDL-C
HDL-C
Triglycerides
TSH
Free T4
Calcitonin
Amylase
Lipase
Serum total bile acids
PT/INR/aPTT
At screening only:

HbA1c

FSHf

HIV

HepBsAg

HCVAb

HCV RNA
a.
Part A – all safety assessment timepoints and Part B – Screening only.
b.
Part B – all safety assessment timepoints beyond Screening.
c.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
d.
Serum -hCG for all WOCBP.
e.
The minimum requirement for drug screening includes cocaine, THC, opiates, opioids, benzodiazepines, 
and amphetamines (others are site and study specific).
f.
For confirmation of postmenopausal status only.
Investigators must document their review of each laboratory safety report.


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Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.  Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings.  These data will not be included in the CSR.  Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.  Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including 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.


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Hospitalization for elective treatment of a preexisting condition that did not worsen from 
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 


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


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


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
The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4. Appendix 4: Contraceptive 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
for both PF-06882961 and PF-06865571.
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 risks 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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Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate:
ie, rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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


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Final Protocol Amendment 2, 03 June 2021
PFIZER CONFIDENTIAL
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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);
•
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).
CCI


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Final Protocol Amendment 2, 03 June 2021
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10.9. Appendix 9: Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories).
10.9.1. Eligibility
COVID-19 testing is mandated for this study. A patient should be excluded if he/she has a 
positive test result for COVID-19 infection, is known to have asymptomatic infection, or is 
suspected of having COVID-19.
10.9.2. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an AE or SAE and 
appropriate medical intervention provided.  It is recommended that the investigator consult 
the study medical monitor regarding how to manager study intervention, including 
termporary or permanent discontinuation of study intervention.


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Final Protocol Amendment 2, 03 June 2021
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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
ACC
acetyl-CoA carboxylase
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC12
area under the plasma concentration-time curve from time zero to 
time 12 hours post-dose
AUC24
area under the plasma concentration-time curve from time zero to
time 24 hours post-dose
AUCinf
area under the plasma concentration-time curve from time zero 
extrapolated to infinite time
AUClast
area under the plasma concentration-time curve from time zero to 
the time of the last quantifiable concentration (Clast)
AV
atrioventricular
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
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL/F
apparent oral clearance
Clast
time of the last quantifiable concentration
Cmax
maximum plasma concentration
CP-I
coproporphyrin I
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease-19
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CCI
CCI


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Abbreviation
Term
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CT
clinical trial
CV
coefficient of variation
CYP
cytochrome P450
DAG
diacylglycerol
DC
discontinuation
DDI
drug-drug interaction
DGAT
diacylglycerol acyltransferase
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EFD
embryo-fetal development
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
fm
fraction metabolized
FAP
final approved protocol
FDA
Food and Drug Administration
FSBG
fingerstick blood glucose
FSH
follicle-stimulating hormone
F/U
follow-up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
GLP-1
glucagon-like peptide 1
HAE
hypoglycemic adverse event
HbA1c
hemoglobin A1c
HepBsAg 
hepatitis B surface antigen
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HDL-C
high density lipoprotein cholesterol
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
CCI


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Abbreviation
Term
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
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(ly)
K2EDTA
dipotassium ethylenediaminetetraacetic acid
kel
elimination rate constant
Ki
apparent inactivation constant at half-maximal rate of inactivation
kinact
maximal inactivation rate
LBBB
left bundle branch block
LDL-C
low density lipoprotein cholesterol
LFT
liver function test
LLN
lower limit of normal
MATE
multidrug and toxin extrusion protein
mBcrp
mouse breast cancer resistance protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
multi-drug resistance
MEN2
multiple endocrine neoplasia syndrome type 2
MHP
mental health professional
mRNA
messenger ribonucleic acid
msec
millisecond
MTD
maximum tolerated dose
N/A
not applicable
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NCE
new chemical entity
NOAEL
no observed adverse effect level
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PCR
polymerase chain reaction
PD
pharmacodynamics
CCI


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Abbreviation
Term
P-gp
P-glycoprotein
PHQ-9
Patient Health Questionnaire-9
PK
pharmacokinetics
PLT
platelet
PR
pulse rate
PT
prothrombin time
PVC
premature ventricular contraction/complex
Q8H
every 8 hours
Q12H
every 12 hours
QT
time from beginning of the QRS complex to the end of the T wave
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
Rac
accumulation ratio
RBC
red blood cells
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SoA
Schedule of Activities
SOP
standard operating procedure
SRSD
single reference safety document
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
t½
terminal half-life
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
T4
thyroxine
TBA
total bile acids
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TG
triglycerides
THC
tetrahydrocannabinol
TSH
thyroid-stimulating hormone
Tmax
time for Cmax
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
Vz/F
apparent oral volume of distribution
WBC
white blood cell
WOCBP
woman of childbearing potential


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11. REFERENCES
1.
Ørskov C, Holst JJ, Knuhtsen S,et al. Glucagon-like peptides GLP-1 and GLP-2, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology 1986;119(4):1467-75.
2.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet 1987;2(8571):1300-4.
3.
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 
1997;273(5):E981-8.
4.
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest 1998;101(3):515-20.
5.
Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients 
with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, 
placebo-controlled phase 2 study. Lancet 2016; 387(10019):679-90.
6.
Yen CL, Stone SJ, Koliwad S, et al. Thematic review series: glycerolipids. DGAT 
enzymes and triacylglycerol biosynthesis. J Lipid Res 2008; 49(11):2283-301.
7.
Buhman KK, Smith SJ, Stone SJ, et al. DGAT1 is not essential for intestinal 
triacylglycerol absorption or chylomicron synthesis. J Biol Chem 2002; 
277(28):25474-9.
8.
Cases S, Stone SJ, Zhou P, et al. Cloning of DGAT2, a second mammalian 
diacylglycerol acyltransferase, and related family members. J Biol Chem 2001; 
276(42):38870-6.
9.
Yu XX, Murray SF, Pandey SK, et al. Antisense oligonucleotide reduction of DGAT2 
expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology 
2005; 42(2):362-71.
10.
Choi CS, Savage DB, Kulkarni A, et al. Suppression of diacylglycerol acyltransferase-2 
(DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced 
hepatic steatosis and insulin resistance. J Biol Chem 2007; 282(31):22678-88.
11.
Amin NB, Carvajal-Gonzalez S, Purkal J, et al. Targeting diacylglycerol acyltransferase 
2 for the treatment of nonalcoholic steatohepatitis. Sci Transl Med 2019 11: eaav9701.
12.
Saxena A, Chidsey K, Somayaji V. Diacylglycerol acyltransferase 2 (DGAT2) inhibitor 
PF-06865571 reduces liver fat by MRI-PDFF after 2 weeks in adults with NAFLD. 
Hepatology 2019; 70(1) 1260A.


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Protocol C3421038
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Page 117
13.
Day CP, James OF. Hepatic steatosis: innocent bystander or guilty party? Hepatology 
1998; 27(6):1463-6.
14.
Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug 
and biomarker development for nonalcoholic steatohepatitis: findings and 
recommendations from an American Association for the Study of Liver Diseases-U.S. 
Food and Drug Administration Joint Workshop. Hepatology 2015; 61(4):1392-405.
15.
Fazel Y, Koenig AB, Sayiner M, et al. Epidemiology and natural history of non-
alcoholic fatty liver disease. Metab Clin Exp 2016; 65(8):1017-25.
16.
LaBrecque D, Abbas Z, Anania F, et al. Nonalcoholic fatty liver disease and 
nonalcoholic steatohepatitis. In: WGO Global Guidelines NAFLD/NASH (long 
version). Milwaukee, WI: World Gastroenterology Organisation; 2012: 29 pages.
17.
Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic 
fatty liver disease--meta-analytic assessment of prevalence, incidence, and outcomes. 
Hepatology 2016; 64(1):73-84.
18.
Hagstrom H, Nasr P, Ekstedt M, et al. Risk for development of severe liver disease in 
lean patients with nonalcoholic fatty liver disease: A long-term follow-up study. 
Hepatol Commun 2017; 2(1):48-57.
19.
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of 
nonalcoholic fatty liver disease: practice guidance from the American Association for 
the Study of Liver Diseases. Hepatology 2018; 67(1):328-57.
20.
VICTOZA® (liraglutide). United States Prescribing Information. June 2019.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022341s031lbl.pdf 
Accessed 02 Apr 2020.
21.
OZEMPIC® (semaglutide). United States Prescribing Information. January 2020.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdf 
Accessed 02 Apr 2020.
22.
TRULICITY® (dulaglutide). United States Prescribing Information. February 2020.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125469s033lbl.pdf 
Accessed 02 Apr 2020.
23.
SAXENDA® (liraglutide). United States Prescribing Information. March 2020.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206321s011lbl.pdf 
Accessed 02 Apr 2020.
24.
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.


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Page 118
25.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med 2001;16(9):606-13.
26.
Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update. 
Clin Transl Med 2016;5(1):23-37.
27.
American Diabetes Association. Standards of medical care in diabetes 2019. Diabetes 
Care. January 2019;42(Suppl 1): S1-S193.
CCI

SAP_001.pdf: 
        Protocol C3421038 (PF-06882961 and PF-06865571 ) 
Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 1
Protocol C3421038
A PHASE 1, OPEN-LABEL STUDY TO EVALUATE THE PHARMACOKINETIC 
INTERACTIONS BETWEEN PF-06882961 AND PF-06865571 IN HEALTHY ADULT 
PARTICIPANTS (PART A) AND OVERWEIGHT ADULTS OR ADULTS WITH 
OBESITY WHO ARE OTHERWISE HEALTHY (PART B)
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
07-Jul-2021


        Protocol C3421038 (PF-06882961 and PF-06865571 ) 
Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives, Endpoints, and Estimands............................................................7
2.1.1. Primary Estimand(s) .....................................................................................8
2.1.2. Secondary Estimand(s) .................................................................................8
2.1.3. Additional Estimand(s).................................................................................8
2.2. Study Design .............................................................................................................8
2.2.1. Treatment Scheme for Part A .......................................................................9
2.2.2. Treatment Scheme for Part B .......................................................................9
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoint(s) ................................................................................................10
3.2. Secondary Endpoint(s) ............................................................................................11
3.2.1. Safety Endpoints.........................................................................................11
3.2.2. Assessment of Mental Health (Part B Only) ..............................................12
3.2.2.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................12
3.2.2.2. Patient Health Questionnaire (PHQ-9)......................................12
3.2.3. Other Safety Endpoints (Part B only).........................................................12
3.3. Tertiary Endpoint(s) ................................................................................................12
3.4. Baseline Variables...................................................................................................13
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................15
5.1. Hypotheses and Decision Rules ..............................................................................15
5.2. General Methods .....................................................................................................15
5.2.1. Analyses for Binary Endpoints...................................................................15
5.2.2. Analyses for Continuous Endpoints ...........................................................15


        Protocol C3421038 (PF-06882961 and PF-06865571 ) 
Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 3
5.2.3. Analyses for Categorical Endpoints ...........................................................15
5.3. Methods to Manage Missing Data ..........................................................................15
5.3.1. Pharmacokinetic Concentrations Below the Limit of Quantification.........15
5.3.2. Deviations, Missing Concentrations and Anomalous Values.....................15
5.3.3. Pharmacokinetic Parameters.......................................................................16
5.3.4. 4-β-hydroxycholesterol, cholesterol and Coproporphyrins I 
Concentrations and Parameters........................................................................16
6. ANALYSES AND SUMMARIES ......................................................................................16
6.1. Primary Endpoint ....................................................................................................16
6.1.1. PF-06882961 PK Parameters......................................................................16
6.1.1.1. Effects of PF-06865571 on Single Dose PF-06882961 PK 
Parameters (Part A) ...........................................................................18
6.1.1.2. Effect of PF-06865571 on the Multi-Dose of PF-
06882961 PK Parameters  (Part B) ...................................................19
6.1.2. PF-06865571 PK Parameters......................................................................19
6.1.2.1. Effect of PF-06882961 on Single Dose PF-06865571 PK 
Parameters (Part B)............................................................................21
6.2. Secondary Endpoint(s) ............................................................................................21
6.2.1. Demographic and Physical Examination Data ...........................................21
6.2.2. Discontinuation(s).......................................................................................22
6.2.3. Adverse Events ...........................................................................................22
6.2.4. Hypoglycemia (Part B only).......................................................................22
6.2.5. Laboratory Data..........................................................................................22
6.2.6. Vital Signs Data..........................................................................................22
6.2.7. Electrocardiogram (ECG)...........................................................................23
6.2.8. C-SSRS (Part B Only) ................................................................................23
6.2.9. PHQ-9 (Part B only) ...................................................................................23
6.3. Other Endpoint(s)....................................................................................................24
6.3.1. Change from Baseline in PT, INR, aPTT (Part B only) .............................24
CCI


        Protocol C3421038 (PF-06882961 and PF-06865571 ) 
Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 4
6.3.2. Change from Baseline in TSH, Lipids (Part B only)..................................24
6.3.3. Change from Baseline in Free T4, Calcitonin, Amylase, Lipase, TBA 
(Part B only).....................................................................................................24
6.3.4. Change from Baseline in Body Weight (Part B Only) ...............................24
6.3.5. Coproporphyrins I (Part B).........................................................................24
6.3.6. 4-β-hydroxycholesterol/Cholesterol Ratio..................................................26
6.4. Subset Analyses.......................................................................................................27
6.5. Baseline and Other Summaries and Analyses.........................................................27
6.5.1. Baseline Summaries....................................................................................27
6.5.2. Study Treatment Exposure .........................................................................27
6.5.4. Screening and Other Special Purpose Data ................................................27
7. INTERIM ANALYSES.......................................................................................................27
8. REFERENCES ....................................................................................................................27
9. APPENDICES .....................................................................................................................28
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
Table 2.
Part A – Plasma PK Parameters for PF-06882961 ...................................10
Table 3.
Part B – Plasma PK Parameters for PF-06882961
 
and PF-06865571......................................................................................10
Table 4.
Part B – Plasma CP-I Parameters .............................................................13
Table 5.
PF-06882961 and 
PK Parameters to be Summarized 
Descriptively per Day...............................................................................17
Table 6.
PF-06865571 PK Parameters to be Summarized Descriptively ...............19
Table 7.
CP-I Parameters to be Summarized Descriptively per Day......................25
LIST OF FIGURES
No table of figures entries found.
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APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................29
Appendix 2. Data Derivation Details.......................................................................................29
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................29
Appendix 2.2. Endpoint Derivations .......................................................................................29
Appendix 2.3. Example SAS Code for Statistical Analyses....................................................29
Appendix 2.3.1. Analysis for DDI interaction (Part A):..........................................................29
Appendix 2.3.2. Analysis for DDI interaction (Part B):..........................................................29
Appendix 3. List of Abbreviations...........................................................................................30
Appendix 4. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....34
Appendix 5. C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events and 
Codes ........................................................................................................35


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated Protocol / 
Amendment
Rationale
Specific Changes
1
07-Apr-2021
Protocol Amendment 1
12-Mar-2021
N/A
N/A
2
07-Jul-2021
Protocol Amendment 2 
03-Jun-2021
Preliminary draft data from 
study C3421007 indicate 
that a decrease in exposure 
of midazolam are observed 
when co-administered with 
PF-06882961.  To 
investigate the mechanism 
of this interaction, 
assessment of plasma 
4-β-hydroxycholesterol/cho
lesterol, an endogenous 
probe for CYP3A 
induction, is being added in 
Part B.
In vitro studies indicate PF-
06882961 may inhibit 
OATP1B1 at dose(s) 
evaluated in this study.  
Therefore, to evaluate this 
potential effect of 
PF-06882961, measurement 
of plasma CP-I, an 
endogenous probe for 
OATP1B activity, is being 
added in Part B.
Section 2.1 
modified to 
introduce 
endogeneous 
endpoints,
Sections 3.3, 5.3.4, 
6.3.5 and 6.3.6 
created to specify 
the analyses and 
reporting of the 
endogeneous 
endpoints.
Appendix 4 
modified to 
introduce 
acronyms related 
to the enedgoneous 
endpoints
2. INTRODUCTION
This study will evaluate the PK interactions between PF-06882961 and PF-06865571 in 
healthy adult participants (Part A) and overweight adults or adults with obesity who are 
otherwise healthy (Part B)


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This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3421038.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Part A
Primary: 
Primary: 
To evaluate the effects of PF-06865571 on the single-dose 
pharmacokinetics of PF-06882961 in healthy adult 
participants.
PF-06882961 plasma pharmacokinetic parameters: Cmax
and AUC24.
Secondary: 
Secondary: 
To evaluate the safety and tolerability of PF-06882961 
alone and in combination with PF-06886571 when 
administered to healthy adult participants.
Assessment of treatment-emergent adverse events, clinical 
laboratory abnormalities, vital signs, body weight, and 
ECG parameters during the entire study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 
To evaluate the effects of PF-06865571 on additional 
pharmacokinetic parameters of PF-06882961 in healthy 
adult participants.
Additional PF-06882961 plasma pharmacokinetic 
parameters: Tmax.
Part B
Primary: 
Primary: 
To evaluate the effects of PF-06882961 on the 
single-dose pharmacokinetics of PF-06865571 in 
overweight adults or adults with obesity who are 
otherwise healthy.
PF-06865571 plasma pharmacokinetic parameters 
on Day 1 and Day 47: Cmax, AUClast, and AUCinf, as 
data permits.
To evaluate the effects of PF-06865571 on the 
multiple-dose pharmacokinetics of PF-06882961 in 
overweight adults or adults with obesity who are 
otherwise healthy.
PF-06882961 plasma pharmacokinetic parameters 
on Day 46 and Day 61: Cmax and AUC12.
Secondary: 
Secondary: 
To evaluate the safety and tolerability of 
PF-06882961 and PF-06865571 when administered 
separately and in combination in overweight adults 
or adults with obesity who are otherwise healthy.
Assessment of treatment-emergent adverse events, 
clinical laboratory abnormalities, vital signs, body 
weight, and ECG parameters during the entire 
study.
Assessment of mental health as determined by C-SSRS 
and PHQ-9 in Part B of this study.
Tertiary/Exploratory: 
Tertiary/Exploratory: 
To evaluate the effects of PF-06882961 on 
additional pharmacokinetic parameters of 
PF-06865571 in overweight adults or adults with 
obesity who are otherwise healthy.
Additional PF-06865571 plasma pharmacokinetic 
parameters on Day 1 and Day 47: Tmax, CL/F, Vz/F, 
and t½, as data permits.


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To evaluate the effects of PF-06865571 on 
additional pharmacokinetic parameters of 
PF-06882961 in overweight adults or adults with 
obesity who are otherwise healthy.
Additional PF-06882961 plasma pharmacokinetic 
parameters on Day 46 and Day 61: Tmax and CL/F.
To evaluate the effects of PF-06882961 on the 
multiple-dose pharmacokinetics of PF-06865571 in 
overweight adults or adults with obesity who are
otherwise healthy.
PF-06865571 plasma pharmacokinetic parameters 
on Day 61: Cmax, Tmax, and AUC12.
To evaluate the effects of multiple doses of PF-06882961 
on CYP3A induction in overweight adults or adults with 
obesity who are otherwise healthy.
Morning pre-dose 4-β-hydroxycholesterol/cholesterol 
plasma ratio on Days 1, 19, 31, and 47.
To evaluate the effect of multiple doses of PF-06882961 on 
coproporphyrins I in overweight adults or adults with 
obesity who are otherwise healthy.
CP-I parameters on Days 30 and 46: AUC12 and Cmax.
2.1.1. Primary Estimand(s)
Not applicable 
2.1.2. Secondary Estimand(s)
Not applicable 
2.1.3. Additional Estimand(s)
Not applicable 
2.2. Study Design
This study will be conducted in 2 parts. 
Part A is an open-label, two-period, two-sequence, crossover cohort investigating the 
potential effect of PF-06865571 on the PK of PF-06882961 in healthy adult participants. 
Part B is an open-label, fixed-sequence cohort to evaluating the effect of PF-06882961 on 
the PK of PF-06865571, as well as the effect of PF-06865571 on the PK of PF-06882961 in 
overweight adults or adults with obesity who are otherwise healthy.  The effect of PF-
06882961 on PF-06865571 PK will be evaluated at steady-state at a dose of up to 200 mg 
BID of PF-06882961.  Then, PF-06882961 and PF-06865571 will be coadministered for 
approximately 2 weeks for further evaluation of PK interactions and to generate additional 
safety and tolerability data on the combination.
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A cohort of approximately 8 participants will be enrolled in Part A. Approximately 16 
participants will be enrolled in Part B such that approximately 12 evaluable participants 
complete Part B. 
2.2.1. Treatment Scheme for Part A
Period 1
Washout*
Period 2
Sequence 1
(n=4)
Treatment A:
20 mg PF-06882961 single dose
Washout of at
least 3 days*
Treatment B:
20 mg PF-06882961 single dose
plus
300 mg PF-06865571 single dose
Sequence 2
(n=4)
Treatment B:
20 mg PF-06882961 single dose
plus
300 mg PF-06865571 single dose
Washout of at 
least 3 days*
Treatment A:
20 mg PF-06882961 single dose
*Each participant is planned to undergo 2 treatment periods with a washout interval between periods of at 
least 3 days following the final dose of study intervention administered in Period 1. 
2.2.2. Treatment Scheme for Part B
Period 1
Period 2
Period 3
Period 4
Days 1-2
Days 3-46
Days 47-48
Days 49-62
PF-06865571
(DGAT2)
Dose
300 mg single dose 
on Day 1 onlya
N/A
300 mg single dose 
on Day 47 onlya
300 mg BID 
on Days 49-61a
PF-06882961
(GLP-1)
Dose
N/A
10 mg BID titrated 
to 200 mg BIDb,c
200 mg BIDc
200 mg BID 
on Days 49-61b,c
a.
Dense PK sampling for measurement of PF-06865571 plasma concentrations on Day 1 (reference), Day 
47 (test), and Day 61 (summary statistics only).
b.
Dense PK sampling for measurement of PF-06882961 plasma concentrations on Day 46 (reference) and 
Day 61 (test).
c.
Doses of PF-06882961 may be reduced based on PK results of Part A of this study and safety and 
tolerability results of Study C3421007.
In all study parts (Part A and Part B), participants will remain on-site (inpatient study) for 
the duration of the dosing period, followed by one follow-up outpatient visit.  A further 
follow-up contact with participants will be conducted at least 28 days and up to 35 days after 
the last administration of IP; this contact may be done via a phone call.
The study will be conducted in the US.  


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Participants who discontinue prior to completion of the study may be replaced, at the 
discretion of the principal investigator (PI) and sponsor (applicable to part A only).
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Blood samples for PK analysis of PF-06865571, PF-06882961
will be 
taken according to the Schedule of Activities (SoA) given in the protocol. 
In Part A, plasma PF-06882961 PK parameters following single administration of
PF-06882961 will be derived using standard noncompartmental methods, as data permit, for 
each treatment, from the concentration time profiles as follows:
Table 2.
Part A – Plasma PK Parameters for PF-06882961
Parameter
Analysis Scale
PF-06882961
AUC24
ln
D
Cmax
ln
D
Tmax
R
D
Key: D=displayed with descriptive statistics, ln=natural-log transformed, R=raw 
(untransformed)
In Part B, plasma PF-06865571, PF-06882961,
PK parameters following 
single administration of PF-06865571 and PF-06882961 or multiple-dose of PF-06882961 
will be derived using standard noncompartmental methods, as data permit, for each treatment 
and day (as appropriate), from the concentration time profiles as follows:
Table 3.
Part B – Plasma PK Parameters for PF-06882961, 
 and 
PF-06865571
Parameter
Compound 
Days
Analysis 
Scale
Reporting
AUClast
PF-06865571
1 and 47
ln
D
AUCinf*
PF-06865571
1 and 47
ln
D
AUC12
PF-06865571
61
ln
D
PF-06882961 
46 and 61
Cmax
PF-06865571
1, 47, and 61
ln
D
PF-06882961 
46 and 61
Tmax
PF-06865571
1, 47, and 61
R
D
PF-06882961
46 and 61
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t1/2*
PF-06865571
1 and 47
R
D
CL/F*
PF-06865571
1 and 47
ln
D
PF-06882961
46 and 61
Vz/F*
PF-06865571
1 and 47
ln
D
Key: D=displayed with descriptive statistics, ln=natural-log transformed, R=raw (untransformed), 
*=if data permits
3.2. Secondary Endpoint(s)
3.2.1. Safety Endpoints
•
Assessment of treatment-emergent adverse events, clinical laboratory abnormalities, 
vital signs, body weight and ECG parameters during the entire study.
Any events occurring following start of study intervention (i.e. treatment) will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the most recent treatment taken.
A 3-tier approach for summarizing adverse events (AEs) will not be used due to the low 
number of participants planned to be recruited. 
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
adverse events,
•
laboratory data,
•
vital signs data,
•
body weight
•
ECG results.
For laboratory, vital signs and ECG data there will be two separate definitions for baseline 
that will be calculated depending on the study part:
i)
For Part A, using the last pre-dose measurement within each respective 
treatment Period
ii)
For Part B, using a fixed baseline of the last pre-dose measurement in Period 
1.
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Change from baseline will therefore be calculated twice for each relevant safety endpoint 
using (i) and (ii) above.
Definitions of baseline body weight for exploratory safety analyses are described in Section 
3.2.3.
3.2.2. Assessment of Mental Health (Part B Only)

Assessment of mental health as determined by C-SSRS and PHQ-9 during the entire 
study.
3.2.2.1. Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a validated tool to evaluate suicidal ideation and behavior. Data relevant to 
the assessment of suicidality will be mapped to the Columbia-Classification Algorithm of 
Suicide Assessment (C-CASA) codes as given in Appendix 5.
Baseline is defined as the last pre-dose measurement in Period 1. For this endpoint the
screening visit will be labelled as ‘Lifetime’ in tables and the recent history (i.e. past 12 
months) will also be reported separately.
3.2.2.2. Patient Health Questionnaire (PHQ-9)
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in the SoA for Part B.
Baseline is defined as the last pre-dose measurement in Period 1 Day 1.
3.2.3. Other Safety Endpoints (Part B only)

Change from baseline in PT/INR/aPTT, TBA, HbA1c, body weight, lipids, TSH, Free 
T4, calcitonin, amylase, and lipase at all post-dose time points as outlined in the SoA
for Part B.
Baseline is defined as the last pre-dose measurement in Period 1 Day 1.
3.3. Tertiary Endpoint(s)
In Part B, plasma samples for analysis of 4-β-hydroxycholesterol/cholesterol ratio and CP-I 
concentrations will be taken according to the Schedule of A.
Plasma CP-I parameters will be derived using standard noncompartmental methods, as data 
permit, for each treatment and day (as appropriate), from the concentration time profiles as 
follows:


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Table 4.
Part B – Plasma CP-I Parameters
Parameter
Marker
Days
Analysis 
Scale
Reporting
AUC12
CP-I
30 and 46
ln
D
Cmax
CP-I
30 and 46
ln
D
Key: D=displayed with descriptive statistics, ln=natural-log transformed
3.4. Baseline Variables
Baseline for all parameters discussed in Section 5 and 6 will be defined as the values assessed 
on as the closest measurement before dosing (ie pre-dose on Day 1 0H).
When three assessements are performed at baseline, the baseline will be the average of the 
three values (eg Vital Signs).
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are randomized but not treated. If a participant takes a treatment that is not 
consistent with the treatment they are randomized to, for example takes a treatment out of 
sequence or takes the same treatment twice, then they will be reported under the treatment 
that they actually receive for all safety, PK and PD analyses, where applicable.
Participants who experience events that may affect their PK profile (eg vomiting) may be 
excluded from the PK analysis. At the discretion of the pharmacokineticist a concentration 
value may also be excluded if the deviation in sampling time is of sufficient concern or if the 
concentration is anomalous for any other reason. 
A full list of protocol deviations (eg medication errors) will be compiled and reviewed to 
identify major and minor deviations prior to database closure.
Population
Description
Enrolled 
All participants who sign the ICD.
Randomly assigned to 
investigational product
All participants randomly assigned to investigational 
product regardless of whether or not the investigational 
product was administered.


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Population
Description
Evaluable
All participants randomly assigned to investigational 
product and who take at least 1 dose of investigational 
product.  Participants will be analyzed according to the 
product they actually received.
Safety
All participants randomly assigned to investigational 
product and who take at least 1 dose of investigational 
product. Participants will be analyzed according to the 
product they actually received.
PF-06865571 PK 
Concentration Set
The PF-06865571 PK concentration population is defined as 
all randomized participants who received at least 1 dose of 
PF-06865571 and in whom at least 1 plasma concentration 
value is reported.
PF-06865571 PK 
Parameter Set
The PF-06865571 PK parameter population is defined as all 
randomized participants who received at least 1 dose of PF-
06865571 and in whom at least 1 parameter value is 
reported.
PF-06882961
PK Concentration Set
The PF-06882961 concentration population is defined as all 
randomized participants who received at least 1 dose of 
PF-06882961 and in whom at least 1 plasma concentration 
value is reported.
PF-06882961
PK Parameter Set
The PF-06882961 PK parameter population is defined as all 
randomized participants who received at least 1 dose of 
PF-06882961 and in whom at least 1 parameter value is 
reported.
Endogenous biomarker 
Concentration Set
The endogenous biomarker concentration population is 
defined as all randomized participants who received at least 
1 dose of PF-06882961 and in whom at least 1 plasma 
concentration (4-β-hydroxycholesterol and cholesterol or 
CP-I) value is reported.
Endogenous biomarker
Parameter Set
The endogenous biomarker parameter population is defined 
as all randomized participants who received at least 1 dose of 
PF-06882961 and in whom at least 1 CP-I or 4-β-
hydroxycholesterol/cholesterol parameter value is reported.


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5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
Not applicable
5.2. General Methods
5.2.1. Analyses for Binary Endpoints
Not applicable
5.2.2. Analyses for Continuous Endpoints
Continuous endpoints and relevant safety endpoints will be presented using summary 
statistics: number of observations, arithmetic mean, standard deviation, median, minimum 
and maximum values.
5.2.3. Analyses for Categorical Endpoints
Categorical endpoints and relevant safety endpoints will be presented using summary statistics: 
number of observations, counts and percentages.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
In all exploratory safety data presentations (except listings), concentrations below the limit of 
quantification (BLQ) will be set to the lower limit of quantification (LLQ).
5.3.1. Pharmacokinetic Concentrations Below the Limit of Quantification
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  In listings BLQ values will be reported as “<LLOQ”, where 
LLOQ will be replaced with the value for the lower limit of quantification.
5.3.2. Deviations, Missing Concentrations and Anomalous Values
In PK summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist/clinical team.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.


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Participants who experience events that may affect their PK profile (e.g. lack of compliance 
with dosing or vomiting) may be excluded from the PK analysis. At the discretion of the
pharmacokineticist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.3.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (ie, not calculated). Note that NC values will not be generated beyond 
the day that a participant discontinues.
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with ≥3 evaluable measurements.
If a participant receives a dose that was not assigned based on the randomized titration 
scheme (for example due to a down-titration), the PK data from that Day will not be included 
in the calculation of summary statistics but will be included in listings.
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed in 
the body), this will be footnoted in summary tables and will not be included in the calculation 
of summary statistics or statistical analyses.
5.3.4. 4-β-hydroxycholesterol, cholesterol and Coproporphyrins I Concentrations and 
Parameters
Rules described in Section 5.3.1, and Section 5.3.2 will be used to manage concentrations 
below limit of quantification, deviations, missing concentrations and anomalous value for the 
markers of CYP3-A induction (ie 4-β-hydroxycholesterol/cholesterol ratio), and OATP1B1 
Activity (ie coproporphyrins I).
Rules described in Section 5.3.3 will apply to derive parameters for Coproporphyrins I 
(CP-I) and 4-β-hydroxycholesterol/cholesterol ratio.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
6.1.1. PF-06882961 PK Parameters 
Applicable to Parts A, and B – Analyses reported for each part separately.


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•
Estimand strategy:  Not applicable
•
Analysis set:  PF-06882961 Concentration and  Pharmacokinetic Parameter Set 
To assess the pharmacokinetics of PF-06882961 in Part A and Part B 
the PK parameters detailed in Section 3.1 will be 
listed and summarized for participants in the PK analysis set (as defined in Section 4).  
Missing values will be handled as detailed in Section 5.3 along with handling of values 
where participants received a dose that was not assigned based on the titration scheme). Each 
PK parameter will be summarized by treatment (eg differentiating different doses and dosing 
frequencies as required), Study Part and Study Day/Period (as appropriate). 
The parameters will include the set of summary statistics as specified in the table below:
Table 5.
PF-06882961
PK Parameters to be Summarized 
Descriptively per Day
Part
Parameter
Days
Summary Statistics
A
AUC24, Cmax
-
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum, geometric 
mean and geometric cv%.
Tmax
-
N, median, minimum, maximum.
B
AUC12, Cmax, 
CL/F*
46 and 61
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum, geometric 
mean and geometric cv%.
Tmax
46 and 61
N, median, minimum, maximum.
* if data permits
There will be one summary table presenting all PK parameters. The treatment subheading 
will include the study part, analyte, dose information and day (Day 46 or Day 61).  As per 
Section 5.3.3, data collected on days that participants received anything other than the 
assigned dose based on the titration scheme will only be listed and not summarized as part of 
the summary table.
The following plots will be presented:
•
Box and whisker plots for individual PK parameters of PF-06882961 (AUC24, and
Cmax) will be presented by treatment and overlaid with geometric means for Part A.
•
Box and whisker plots for individual PK parameters of PF-06882961 (AUC12, Cmax) 
will be presented by treatment and overlaid with geometric means for Part B.
Presentations for PF-06882961
concentrations will include:
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•
a listing of all concentrations sorted by participant ID, treatment, and matrix and 
nominal time postdose.  The concentration listing will also include the actual times.  
Deviations from the nominal time will be given in a separate listing.
•
a summary of concentrations by treatment, and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.
•
median concentration time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment period. One plot for each scale will be presented which 
will include the different PF-06882961 treatment periods in the same plot.
•
mean concentrations time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment period. One plot for each scale will be presented which 
will include the different PF-06882961 treatment periods in the same plot.
•
individual concentration time plots by treatment period (on both linear and semi-log 
scales) against actual time post-dose (there will be separate spaghetti plots for each
treatment period, with a line for each participant per scale)
The length of time used for the x-axes of these plots will be decided on review of the data, 
and will depend on how long PF-06882961 concentration is quantifiable in the plasma.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual participant plots by time, the actual PK sampling time will 
be used.
6.1.1.1. Effects of PF-06865571 on Single Dose PF-06882961 PK Parameters (Part A)
Natural log-transformed Cmax and AUC24 of PF-06882961 administered alone or 
co-administered with PF-06865571 will be analyzed using a mixed effect model with 
treatment, sequence, and period as a fixed effects and participant embedded in sequence as a 
random effect.  The Kenward-Roger approximation will be used for estimating degrees of 
freedom for the model parameters. 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 reference treatment will be “PF-06882961 
20 mg” administered alone, whereas the test treatment will be “PF-06882961 20 mg plus 
PF-06865571 300 mg BID”


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6.1.1.2. Effect of PF-06865571 on the Multi-Dose of PF-06882961 PK Parameters 
(Part B)
To analyze the effects of PF-06865571 on multi-dose PF-06882961 PK parameters, natural 
log-transformed AUC12 and Cmax of PF‑06882961 200 mg BID administered alone (Period 2 
– Day 46) or co-administered with PF-06865571 300 mg BID (Period 4 – Day 61) will be
analyzed using a mixed effect model including treatment as fixed effects and participant as 
random effect. The Kenward-Roger approximation will be used for estimating degrees of 
freedom for the model parameters. 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 test treatment will be 
“PF-06865571 300 mg BID plus PF‑06882961 200 mg BID” (Period 4 – Day 61), which 
will be reported separately in comparison to the reference treatment of “PF‑06882961 
200 mg BID administered alone” (Period 2 – Day 46).
6.1.2. PF-06865571 PK Parameters 
Applicable to Part B only.

Estimand strategy:  Not applicable

Analysis set:  PF-06865571 Concentration and  Pharmacokinetic Parameter Set 
To assess the pharmacokinetics of PF-06865571, the PK parameters detailed in Section 3.1
will be listed and summarized for participants in the PK analysis set (as defined in Section 4).  
Missing values will be handled as detailed in Section 5.3 along with handling of values 
where participants received a dose that was not assigned based on the titration scheme). Each 
PK parameter will be summarized by treatment (eg differentiating different doses and dosing 
frequencies as required), and Study Day  as applicable. 
The parameters will include the set of summary statistics as specified in the table below:
Table 6.
PF-06865571 PK Parameters to be Summarized Descriptively
Parameter
Days
Summary Statistics
AUClast, AUCinf*,
CL/F*, Vz/F*
1 and 47 
N, arithmetic mean, median, cv%, 
standard deviation, minimum, maximum, 
geometric mean and geometric cv%.
Tmax
1, 47 and 61
N, median, minimum, maximum.
t1/2*
1, and 47
N, arithmetic mean, median, cv%, 
standard deviation, minimum, maximum.


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Cmax
1, 47 and 61
N, arithmetic mean, median, cv%, 
standard deviation, minimum, maximum, 
geometric mean and geometric cv%.
AUC12
61
N, arithmetic mean, median, cv%, 
standard deviation, minimum, maximum, 
geometric mean and geometric cv%.
* if data permits
There will be one summary table presenting all PK parameters. The treatment subheading 
will include the analyte, dose information and day (Day 1, Day 47 or Day 61).  As per
Section 5.3.3, data collected on days that participants received anything other than the 
assigned dose based on the titration scheme will only be listed and not summarized as part of 
the summary table.
The following plots will be presented:
•
Box and whisker plots for individual PK parameters of PF-06865571 (AUClast, 
AUCinf*, and Cmax) will be presented by treatment and overlaid with geometric means.
Presentations for PF-06865571 concentrations will include:
•
a listing of all concentrations sorted by participant ID, treatment, and matrix and 
nominal time postdose.  The concentration listing will also include the actual times.  
Deviations from the nominal time will be given in a separate listing.
•
a summary of concentrations by treatment, and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.
•
median concentration time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment period. One plot for each scale will be presented which 
will include the different PF-06865571 treatment periods in the same plot.
•
mean concentrations time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment period. One plot for each scale will be presented which 
will include the different PF-06865571 treatment periods in the same plot.
•
individual concentration time plots by treatment period (on both linear and semi-log 
scales) against actual time post-dose (there will be separate spaghetti plots for each
treatment period, with a line for each participant per scale)


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The length of time used for the x-axes of these plots will be decided on review of the data, 
and will depend on how long PF-06865571 concentration is quantifiable in the matrix.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used; for individual participant plots by time, the actual PK sampling time will 
be used.
6.1.2.1. Effect of PF-06882961 on Single Dose PF-06865571 PK Parameters (Part B)
To analyze the effects of PF-06882961 on single-dose PF-06865571 PK parameters, natural 
log-transformed Cmax, AUClast, and AUCinf (as data permit) of PF-06865571 300 mg BID 
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. The 
Kenward-Roger approximation will be used for estimating degrees of freedom for the model 
parameters. 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 test treatment will be  “PF-06865571 300 mg plus PF‑06882961 
200 mg BID” (Period 3 – Day 47), which will be reported separately in comparison to the 
reference treatment of “PF-06865571 300 mg” (Period 1 – Day 1).
6.2. Secondary Endpoint(s)
6.2.1. Demographic and Physical Examination Data
Applicable to Parts A, and B – Analyses reported for each part separately.
A breakdown of demographic data will be provided for age, gender, race, and ethnicity.  The 
physical measurement (weight, body mass index and height) at baseline will also be 
summarized.  Each will be summarized by treatment and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
For Part B only, an additional table summarizing the screening data of free T4, TSH, 
calcitonin, amylase, lipase, lipids, PT/INR/aPTT, TBA and HbA1c will be produced as 
above.
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Finally, data collected at screening that are used for inclusion/exclusion criteria, such as 
laboratory data (unless noted above) will be reported for randomized participants. 
6.2.2. Discontinuation(s)
Applicable to Parts A and B – Analyses reported for each part separately.
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.
6.2.3. Adverse Events
Applicable to Parts A, and B – Analyses reported for each part separately:
Adverse events will be reported in accordance with the sponsor reporting standards.
Incidence and severity of treatment emergent adverse event (TEAE) tables will additionally 
be produced (‘All causality’ and ‘Treatment related’, separately) to summarise the total 
number of adverse events by preferred term, which will be reported by treatment group and 
overall in accordance with sponsor reporting standards using the safety analysis set defined in 
Section Section 4
6.2.4. Hypoglycemia (Part B only)
Any hypoglycemic AEs will be listed in a separate table and summarized categorically by
treatment as per Section 5.2.3 using the safety population defined in Section 4
6.2.5. Laboratory Data
Applicable to Parts A, and B – Analyses reported for each part separately:
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards using the safety population defined in Section 4   Baseline is as defined in 
Section 3.4.
6.2.6. Vital Signs Data
Applicable to Parts A, and B – Analyses reported for each part separately:
Absolute values and change from baseline in supine systolic and diastolic blood pressure and 
pulse rate will be summarized by treatment, time post-dose and day, according to sponsor 
reporting standards. Tables will be paged by parameter.  Baseline is as defined in Section 3.4.


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Mean changes from baseline for supine systolic and diastolic blood pressure and pulse rate 
will be plotted against time post-dose and day.  On each plot there will be 1 line for each 
treatment.  
Maximum absolute values and changes from baseline for vital signs will be summarized 
descriptively by treatment using categories as defined in Section 5.2.3.  Numbers and 
percentages of subjects meeting the categorical criteria will also be provided.  All planned 
and unplanned post-dose timepoints will be counted in these categorical summaries.  All 
values meeting the criteria of potential clinical concern will be listed.
6.2.7. Electrocardiogram (ECG)
Applicable to Parts A, and B – Analyses reported for each part separately.
Absolute values and changes from baseline in QT interval, heart rate, QTcF interval, PR 
interval and QRS interval will be summarized by treatment, time postdose, and day using 
sponsor reporting standards using the safety population defined in Section 4 Tables will be 
paged by parameter.  Baseline is as defined in Section 3.4.
Mean changes from baseline in ECG parameters will be plotted against day.  On each plot 
there will be 1 line for each treatment.  Corresponding individual plots of changes from 
baseline will also be produced for each treatment.
Numbers and percentages of subjects meeting the categorical criteria will be provided. All 
planned and unplanned post-dose time-points will be counted in these categorical 
summaries. All values meeting the criteria of potential clinical concern will be listed.
Listings of subjects with any single post-dose value 500 msec will also be produced for 
QTcF. 
QTcB will be listed only and not summarized.
6.2.8. C-SSRS (Part B Only)
Screening, baseline and post-baseline C-SSRS data (mapped to C-CASA scores as described 
in Section 3.2.2.1) using the safety population defined in Section 4 will be summarized 
categorically by treatment and time point as outlined in Section 5.2.3.
6.2.9. PHQ-9 (Part B only)
Baseline and post-baseline PHQ-9 data (responses to each of the 9 items) using the safety 
population defined in Section 4 will be summarized categorically for each question separtely 
by treatment and time point as outlined in Section 5.2.3.


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6.3. Other Endpoint(s) 
6.3.1. Change from Baseline in PT, INR, aPTT (Part B only)

Estimand strategy:  Not applicable

Analysis set:  Safety Population Set
Absolute values and change from baseline will be summarized descriptively by treatment and 
timepoint as described in Section 5.2.2
6.3.2. Change from Baseline in TSH, Lipids (Part B only)

Estimand strategy:  Not applicable

Analysis set:  Safety Population Set
Absolute values and change from baseline will be summarized descriptively by treatment and 
timepoint as described in Section 5.2.2
6.3.3. Change from Baseline in Free T4, Calcitonin, Amylase, Lipase, TBA (Part B only)

Estimand strategy:  Not applicable

Analysis set:  Safety Population Set
Absolute values and change from baseline will be summarized descriptively by treatment and 
timepoint as described in Section 5.2.2
6.3.4. Change from Baseline in Body Weight (Part B Only)
The change from baseline and percent change from baseline to all post-dose timepoints as 
specified in the SoA will be calculated.

Estimand strategy:  Not applicable

Analysis set: Safety Population Set
Absolute values, change from baseline, and percent change from baseline will be 
summarized descriptively by treatment and day as per Section 5.2.2
6.3.5. Coproporphyrins I (Part B)
Estimand strategy:  Not applicable
Analysis set: Endogenous biomarker Concentration and Parameter Population Set


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To assess the effects of PF-06882961 on coproporphyrins I (CP-I) in Part B, the CP-I 
parameters detailed in Section 3.3 will be listed and summarized for participants in the 
endogenous biomarker analysis set (as defined in Section 4) .  Missing values will be handled 
as detailed in Section 5.3 along with handling of values where participants received a dose 
that was not assigned based on the titration scheme). Each CP-I parameter will be 
summarized by treatment (eg differentiating different doses and dosing frequencies as 
required), Study Part and Study Day/Period (as appropriate). 
The parameters will include the set of summary statistics as specified in the table below:
Table 7.
CP-I Parameters to be Summarized Descriptively per Day
Part
Parameter
Days
Summary Statistics
AUC12, AUC12/12
(ie Cav), Cmax
30 and 46
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum, geometric 
mean and geometric cv%.
On Day 1, individual Cav and individual Cmax will be the mean of CP-I plasma concentrations
and will serve as baseline to calculate individual change from baseline for each parameter on 
Day 30 and Day 46. These individual calculated means will also be used for Day1 graphical 
presentations.
Change from baseline in Cav and Cmax for CP-I 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 against the reference will be obtained and 
corresponding 90% CIs will be reported from the models.  The test treatments will be 
“PF-06882961 120 mg BID” (Day 30) and “PF-06882961 200 mg BID” (Day 46) and 
reference treatment is “No PF-06882961” (Day 1).  
There will be one summary table presenting all parameters. The treatment subheading will 
include the dose information and day (Day 1, Day 30 or Day 46).  As per Section 5.3, data 
collected on days that participants received anything other than the assigned dose based on 
the titration scheme will only be listed and not summarized as part of the summary table.
The following plots will be presented:
•
Box and whisker plots for individual parameters of CP-I (ie Cav and Cmax) will be 
presented by treatment and overlaid with geometric means.
Presentations for CP-I concentrations will include:
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•
a listing of all concentrations sorted by participant ID, treatment, and nominal time 
postdose.  The concentration listing will also include the actual times.  Deviations 
from the nominal time will be given in a separate listing.
•
a summary of concentrations by treatment, and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.
•
median concentration time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment period. One plot for each scale will be presented which 
will include the different PF-06882961 treatment periods in the same plot.
•
mean concentrations time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment period. One plot for each scale will be presented which 
will include the different PF-06882961 treatment periods in the same plot.
•
individual concentration time plots by treatment period (on both linear and semi-log 
scales) against actual time post-dose (there will be separate spaghetti plots for each 
treatment period, with a line for each participant per scale)
For summary statistics, median and mean plots by sampling time, the nominal blood 
sampling time will be used; for individual participant plots by time, the actual blood 
sampling time will be used.
6.3.6. 4-β-hydroxycholesterol/Cholesterol Ratio
The percent change from baseline to all post-dose timepoints as specified in the SoA will be 
calculated.
•
Estimand strategy:  Not applicable
•
Analysis set: Endogenous biomarker Concentration and Parameter Population Set
Absolute values, and percent change from baseline will be summarized descriptively by 
treatment and day as per Section 5.2.2
The following plot will be presented:
•
Box and whisker plots will be presented by treatment and overlaid with geometric 
means.


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6.4. Subset Analyses
Not applicable. 
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
For each part of the study, and for each endpoint defined in this statistical analysis, baseline 
assessment will be summarized by treatment as per Section 5.2.2 and Section 5.2.3.
6.5.2. Study Treatment Exposure
For each part of the study, participant treatment exposure groups will be reported. Frequency 
counts will be supplied for participant discontinuation(s) by treatment.
Data will be reported in accordance with the sponsor reporting standards.
 
6.5.4. Screening and Other Special Purpose Data
For each part of the study, prior medication(s) and non-drug treatment(s), serum FSH 
concentrations, urine drug screen, will be obtained at Screening.
These data will be listed.
7. INTERIM ANALYSES
Not applicable because, as this is a sponsor-open study, the sponsor will conduct unblinded 
reviews of the data during the course of the study for the purpose of safety assessment and 
facilitating dose-escalation decisions.  In addition, these reviews may facilitate PK/PD 
modeling and/or supporting clinical development.
8. REFERENCES
1.
Pfizer Guidance for Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-antiarrhythmic Drugs; Members of the Cardiovascular Safety & 
Advisory Council (CVSAC); January 26, 2018.
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9. APPENDICES


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Appendix 1. Summary of Efficacy Analyses
Not Applicable fo this study
Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Visit Windows in Reporting
Not Applicable fo this study.
Appendix 2.2. Endpoint Derivations
Not Applicable fo this study
Appendix 2.3. Example SAS Code for Statistical Analyses
Appendix 2.3.1. Analysis for DDI interaction (Part A):
/* To compare Test PK Parameter to the Reference PK Parameter where l&var = 
log(&var)*
   proc mixed data = input_dataset method = reml;
class participant treatment period sequence;
model l&var = treatment period sequence /ddfm = kr residual;
random participant(sequence);
lsmeans treatment;
estimate ‘trt1 – trt1’ treatment  -1 1 / cl alpha = 0.1;
    run;
Appendix 2.3.2. Analysis for DDI interaction (Part B):
/* To compare Test PK Parameter to the Reference PK Parameter where l&var = log(&var)*
proc mixed data=tab.pk;
class Day Participant;
model l&var= Day / ddfm=KR;
random participant;
lsmeans Day;
Estimate 'Test vs Reference' Day -1 1 / cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;


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Appendix 3. List of Abbreviations
Abbreviation
Term
Abs
absolute
AE
adverse event
ANCOVA
analysis of covariance
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AUC
area under the plasma concentration-time curve
AUC12
area under the plasma concentration-time curve from time zero to 
time 12 hours post-dose
AUC24
area under the plasma concentration-time curve from time zero to 
time 24 hours post-dose
AUCinf
area under the plasma concentration-time curve from time zero 
extrapolated to infinite time
AUClast
area under the plasma concentration-time curve from time zero to the 
time of the last quantifiable concentration (Clast)
AV
atrioventricular
BLQ
below the limit of quantitation
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CI
confidence interval
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL/F
apparent oral clearance
Cmax
maximum plasma concentration
COVID-19
coronavirus disease-19
CP-I
Coproporphyrins I
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CT
clinical trial
CV
coefficient of variation
DC
discontinuation
DDI
drug-drug interaction
DGAT
diacylglycerol acyltransferase
DILI
drug-induced liver injury


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Abbreviation
Term
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
EAC
event adjudication committee
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EFD
embryo-fetal development
ET
early termination
EudraCT
European Clinical Trials Database
F/U
follow-up
FAP
final approved protocol
FAS
full analysis set
FDA
Food and Drug Administration
fm
fraction metabolized
FSBG
fingerstick blood glucose
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLIMMIX
generalized linear mixed-effects model with repeated measures
GLP
Good Laboratory Practice
GLP-1
glucagon-like peptide 1
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMR
geometric mean ratio
HAE
hypoglycemic adverse event
HbA1c
hemoglobin A1c
HDL-C
high density lipoprotein cholesterol
HR
heart rate
ICD
informed consent document
ICH
International Council for Harmonisation
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product
ITT
intent-to-treat
IV
intravenous(ly)
kel
elimination rate constant
Ki
apparent inactivation constant at half-maximal rate of inactivation
kinact
maximal inactivation rate


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Abbreviation
Term
LDL-C
low density lipoprotein cholesterol
LFT
liver function test
LLN
lower limit of normal
LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LOD
limit of detection
LS
least-squares
LSM
least-squares mean
MAR
missing at random
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
multi-drug resistance
MedDRA
Medical Dictionary for Regulatory Activities
MHP
mental health professional
mITT
modified intent-to-treat
MMRM
mixed-effects model with repeated measures
MMTT
mixed meal tolerance test
MNAR
missing not at random
mRNA
messenger ribonucleic acid
msec
millisecond
MTD
maximum tolerated dose
N/A
not applicable
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NNT
number needed to treat
NOAEL
no-observed-adverse-effect level
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OATP1B1
organic anion transporting polypeptide 1B1
OCT
organic cation transporter
PD
pharmacodynamic(s)
PHQ-9
Patient Health Questionnaire-9
PK
pharmacokinetic(s)
PLT
platelet
PP
per-protocol
PPAS
per-protocol analysis set
PR
pulse rate
PT
prothrombin time
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Abbreviation
Term
PVC
premature ventricular contraction/complex
QT
time from beginning of the QRS complex to the end of the T wave
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
Rac
accumulation ratio
RBC
red blood cells
RR
relative risk
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SGS
Statistical Guidance Standards
SoA
Schedule of Activities
SOP
standard operating procedure
SRSD
single reference safety document
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
t½
terminal half-life
T4
thyroxine
TA
therapeutic area
TBA
total bile acids
TEAE
treatment-emergent adverse event
TG
triglycerides
THC
tetrahydrocannabinol
Tmax
time for Cmax
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
Vz/F
apparent oral volume of distribution
WBC
white blood cell
WHO 
World Health Organization
WHODD
World Health Organization Drug Dictionary
WOCBP
woman of childbearing potential


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Appendix 4. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Absolute value of QTcF (msec)
450 and 480
>480 and 500
>500
Increase from baseline in QTcF
(msec)
30 and 60
>60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from baseline
Baseline >200 
and max. 
≥25% increase
Baseline ≤200 and 
max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) 
increase from 
baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120
Standing pulse rate (bpm)
min. <40
max. >140


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