Clinical trial NCT04707313
Conditions: Obesity
Keywords: Weight loss
Sponsor: Pfizer
Start date: 2021-01-29; Completion date: 2023-10-11
Enrollment: 628 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called PF-06882961) for the potential treatment of obesity. The study will compare the experiences of participants taking the study medicine (PF-06882961) to those of participants who take placebo (a look- alike substance that contains no active study medicine). The aim is to measure the body's response to the study medicine, including any changes in participants' body weight, waist and hip measurements, how well they tolerate the study medicine, and to measure levels of the study medicine in participants' blood.

This study is seeking participants who have obesity, who do not have diabetes and who have had a stable body weight and not participated in a formal weight loss program in the 90 days before the study. The study medicine or placebo will be taken as tablets by mouth 2 times a day (1 time in the morning and 1 time in the evening).

There are 3 groups of participants (called cohorts) in this study. For participants in Cohorts 1 and 2, total study participation will be about 9 months, with 15 planned study visits (14 visits to the study clinic and 1 telephone call). For participants in Cohort 3, total study participation will be about 10 months, with 21 planned study visits (12 visits to the study clinic and 9 telephone calls).

Detailed description:

Arms: arm 1: None arm 2: The dose will be titrated with 1 week of dosing at each step to reach the target dose of 40 mg BID. arm 3: The dose will be titrated with 1 week of dosing at each step to reach the target dose of 80 mg BID. arm 4: The dose will be titrated with 1 week of dosing at each step to reach the target dose of 120 mg BID. arm 5: The dose will be titrated with 1 week of dosing at each step to reach the target dose of 160 mg BID. arm 6: The dose will be titrated with 1 week of dosing at each step to reach the target dose of 200 mg BID. arm 7: The dose will be titrated with 2 weeks of dosing at each step to reach the target dose of 120 mg BID. arm 8: The dose will be titrated with 2 weeks of dosing at each step to reach the target dose of 160 mg BID. arm 9: The dose will be titrated with 2 weeks of dosing at each step to reach the target dose of 200 mg BID. arm 10: None arm 11: The dose will be titrated with 4 weeks of dosing at each step to reach the target dose of 80 mg BID. arm 12: The dose will be titrated with 4 weeks of dosing at each step to reach the target dose of 140 mg BID. arm 13: The dose will be titrated with 4 weeks of dosing at each step to reach the target dose of 200 mg BID.
Interventions: intervention 1: Placebo (Cohorts 1 and 2) intervention 2: PF-06882961 (Cohorts 1 and 2) intervention 3: Placebo (Cohort 3) intervention 4: PF-06882961 (Cohort 3)
Intervention descriptions: intervention 1: 4 matching placebo tablets taken twice daily intervention 2: Participants will be randomized to one of 5 active target dose levels (40, 80, 120, 160 or 200 mg BID) achieved through 1-week titration steps, or 3 active target dose levels (120, 160 or 200 mg BID) achieved through 2-week titration steps, taking 4 tablets twice daily intervention 3: 2 matching placebo tablets taken twice daily intervention 4: Participants will be randomized to one of 3 active target dose levels (80, 140 or 200 mg BID) achieved through 4-week titration steps, taking 2 tablets twice daily.

Protocol documents:
Prot_000.pdf: 
PF-06882961
Protocol C3421019
Final Protocol Amendment 2, 16 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 1
A PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUP, DOSE-RANGING STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF PF-06882961 ADMINISTRATION IN ADULTS WITH OBESITY
Study Intervention Number:
PF-06882961
Study Intervention Name:
Danuglipron
US IND Number:
148671
EudraCT Number:
2020-001312-19
Protocol Number:
C3421019
Phase:
2b
Short Title: A Phase 2b Study to Evaluate the Efficacy and Safety of PF-06882961 in
Adults With Obesity
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


PF-06882961
Protocol C3421019
Final Protocol Amendment 2, 16 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 2
Document History
Document 
Version Date
Amendment 2
16 September 2022
Amendment 1
16 December 2021
Original protocol
14 September 2020
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s). 
Protocol Amendment Summary of Changes Table
Amendment 2 (16 September 2022)
Overall Rationale for the Amendment: The protocol was amended to add Cohort 3 to 
randomize approximately 112 participants across 4 additional study arms, including placebo 
and 3 PF-06882961 arms with 4-week dose titration steps to target doses of 80 mg BID, 
140 mg BID and 200 mg BID. This cohort was added to characterize the tolerability and 
efficacy profile of 4-week dose titration steps. A separate visit schedule for Cohort 3 was 
added to the protocol to correspond to the 4-week dose titration intervals and extension of the 
treatment phase to 32 weeks for this cohort, to allow sufficient treatment duration at steady 
state dosing given the longer titration steps, and to generate additional efficacy data over a 
longer treatment period.  
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Title page
Removed “26-Week” 
and “2-Part” from full 
title and short title. 
Revised title to remove 
treatment duration and 2-part 
design as these aspects are 
not applicable to all cohorts 
in the study with the addition 
of Cohort 3.
Substantial
1.1 Synopsis
Revised wording in 
relevant sections to 
reflect the addition of 
Cohort 3.
Changed the synopsis to be 
consistent with 
corresponding sections of 
the main protocol to include  
Cohort 3.
Substantial
1.2 Schema
Inserted Figures 2 & 4 
to show Cohort 3 
Overall Study Schema 
& Titration Schema.
Added diagram
representations of the study 
schema and titration schema 
for Cohort 3.
Substantial


PF-06882961
Protocol C3421019
Final Protocol Amendment 2, 16 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 3
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
1.3 Schedule of 
Activities (SoA)
Added a SoA table 
specific to Cohort 3, 
with in-clinic visits at 
4-week intervals and 
interim telephone 
contacts between visits.
A separate SoA was 
developed to reflect the 
different visit schedule and 
treatment phase duration for 
Cohort 3. 
Substantial
3 Objectives, 
Estimands, and 
Endpoints 
Revised the table and 
footnotes, to define 
End of Treatment for 
Cohort 3 as Week 32 
and specified weeks for 
Cohort 3 in endpoints 
as applicable.
The different treatment 
phase duration and visit 
schedule for Cohort 3 
required revisions to specify 
timepoints where different 
weeks will be used in the 
endpoints from what is 
applicable for Cohorts 1 
and 2. 
Substantial
2.1 Study Rationale
4.1 Overall Design
4.2 Scientific 
Rationale for Study 
Design 
4.3 Justification for 
Dose
Added details to 
describe Cohort 3 as 
applicable in sections, 
including 
randomization to 
double-blinded study 
intervention in 1 of 
4 arms (placebo: 3 
PF-06882961 arms 
with 4-week titration 
steps), the 32 week 
double-blind treatment 
phase, the rationale for 
adding Cohort 3 to 
characterize the 
tolerability and 
efficacy profile of 
4-week dose titration 
steps, with placebo 
included to maintain 
the double-blind 
aspect, and the dose 
levels of 80 mg BID, 
140 mg BID and 
200 mg BID.
Revised sections as 
applicable to add 
information to reflect the 
study design with the 
addition of Cohort 3.
Substantial


PF-06882961
Protocol C3421019
Final Protocol Amendment 2, 16 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 4
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
6.1. Study 
Intervention(s) 
Administered
6.1.1 
Administration
6.3.1 Allocation to 
Study Intervention
Revised the study 
intervention table to 
include Cohort 3 
details, and inserted 
separate tables to show 
titration schemes and 
target doses for 
randomized regimens 
for Cohort 3.
Added information on study 
intervention, dosing and 
titration for Cohort 3 where 
it differs from Cohorts 1 and 
2.
Substantial
8.1.3. Tertiary 
Efficacy 
Parameters: Patient 
Centered Outcome 
Assessments 
(PCOAs)
Revised the PCOA 
table to specify 
timepoints applicable 
for Cohort 3.
Some timepoints for 
administration of PCOAs for 
Cohort 3 differ from 
Cohorts 1 and 2 due to the 
different visit schedule, and 
treatment phase duration.
Substantial
8.4 Treatment of 
Overdose 
Added that Cohort 3 
overdose is defined as 
more than
tablets in 
24 hours.
The definition of overdose 
for Cohort 3 is different 
from Cohorts 1 and 2, given 
the different tablet 
configuration for dosing. 
Substantial
8.5 
Pharmacokinetics 
Added the specific 
visits with post-dose 
PK sampling for 
Cohort 3.
Visits with PK sampling for 
Cohort 3 differ from 
Cohorts 1 and 2 due to the 
different visit schedule and 
treatment phase duration. 
Substantial
9 Statistical 
Considerations
9.1. Estimands and 
Statistical 
Hypotheses
9.2. Sample Size 
Determination
9.3 Analysis Sets
9.4 Statistical 
Analyses
Added details 
regarding statistical 
considerations and 
analyses for Cohort 3, 
including that data 
from participants in 
Cohort 3 will be 
analyzed separately 
from combined 
Cohorts 1 and 2, as 
well as End of 
Treatment definition 
and sample size.
Revised subsections as 
applicable to describe 
statistical aspects for 
Cohort 3. 
Substantial
Throughout 
protocol
Revised wording to 
make references to 
visit numbers and SoA 
Changed language where 
necessary to allow for 
Substantial
CCI




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Protocol C3421019
Final Protocol Amendment 2, 16 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
approaches to manage 
mechanism of action 
based gastrointestinal-
related AEs.
regarding approaches to 
manage gastrointestinal AEs.
2.2.1 Nonclinical 
Overview 
2.2.2 Clinical 
Overview
2.3.1 Risk 
Assessment 
Revised wording to 
reflect updated 
information based on 
the most recent IB.
Revised to be consistent with 
the most recent IB.
Nonsubstantial
1.1 Synopsis
1.3 Schedule of 
Activities (SoA)
2.1 Study Rationale
3 Objectives, 
Estimands, and 
Endpoints
4 Study Design
Throughout 
protocol 
Clarified that the initial 
study design with a 
2-part double-blinded 
treatment phase was 
applicable to Cohorts 1 
and 2 and that Part B 
was approved before 
any participant reached 
the end of Part A. 
Removed wording 
referring to approaches 
for study conduct and 
data analyses if Part B 
was not approved. 
The original protocol 
included a 2-part double-
blind treatment phase with 
Part B dosing Weeks 17-26 
contingent on supportive 
data from a nonclinical 
toxicology study ongoing at 
the time of original protocol 
finalization. Part B was 
approved and all participants 
in Cohorts 1 and 2 were able 
to continue into Part B, so 
removed wording for 
alternative approaches if 
Part B was not conducted.
Nonsubstantial
Throughout 
protocol
Replaced “standard” 
with “1-week” and 
“slow” with “2-week” 
when referring to 
titration schemes for 
study arms in 
Cohorts 1 and 2.
Revised terminology for 
description of titration 
schemes for Cohorts 1 and 2 
to denote number of weeks 
rather than “standard” and 
“slow” (ie, 1-week and 
2-week, respectively) for 
consistency in how titration 
is described across all 3 
cohorts in the study.
Nonsubstantial
4.1.1. Assessment 
of Safety and 
Tolerability While 
Study is Ongoing
Added wording to 
clarify safety reviews 
performed, including 
specifying the 
frequency for 
unblinded IA by the 
Clarified wording regarding 
safety reviews.
Nonsubstantial


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Protocol C3421019
Final Protocol Amendment 2, 16 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
4.2 Scientific 
Rationale for Study 
Design
9.5 Interim 
Analyses
IRC is at least once 
annually during study 
conduct. 
9.5.1. PK/PD 
Unblinding Plan
Deleted sentence 
describing estimated 
timing of PK/PD data 
cuts.
Removed statement as not 
accurate at the time of the 
amendment and not needed 
to be in the protocol.
Nonsubstantial
1.1 Synopsis
Deleted
cross-references to 
other sections in the 
protocol, removed 
table numbering and 
deleted tertiary 
endpoints from the 
Objectives, Estimands, 
and Endpoints table.
Revised to be consistent with 
current protocol template for 
synopsis content.
Nonsubstantial
2.2.2.1 Clinical 
Safety 
4.2 Scientific 
Rationale for Study 
Design
4.3 Justification for 
Dose
11 References
Renumbered references 
due to deleting a 
reference in Section 2 
that was no longer 
referred to due to 
rewording, reordering 
of sentences in 
Section 4.2, and 
inserting a new 
reference in 
Section 4.3 for longer 
dose titration for 
Cohort 3.
Revised references.
Nonsubstantial
10.10 Appendix 10: 
Protocol 
Amendment 
History
Moved the Summary 
of Changes for 
Amendment 1 to 
appear in an added 
appendix 
(Appendix 10) and 
renumbered the 
Appendix for 
Abbreviations to be 
Appendix 11.
Added an appendix for 
Protocol Amendment 
History for placement of the 
Summary of Changes for the 
previous amendment to be 
consistent with the current 
protocol template.
Nonsubstantial


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Protocol C3421019
Final Protocol Amendment 2, 16 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 8
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
LIST OF FIGURES .................................................................................................................14
1. PROTOCOL SUMMARY...................................................................................................15
1.1. Synopsis ..................................................................................................................15
1.2. Schema ....................................................................................................................20
1.3. Schedule of Activities (SoA)...................................................................................23
1.3.1. SoA for Cohorts 1 and 2.............................................................................23
1.3.2. SoA for Cohort 3 ........................................................................................26
2. INTRODUCTION ...............................................................................................................30
2.1. Study Rationale .......................................................................................................30
2.2. Background .............................................................................................................30
2.2.1. Nonclinical Overview.................................................................................31
2.2.1.1. Nonclinical Pharmacokinetics and Metabolism........................31
2.2.1.2. Nonclinical Safety.....................................................................31
2.2.2. Clinical Overview.......................................................................................32
2.2.2.1. Clinical Safety...........................................................................32
2.2.2.2. Clinical Pharmacokinetics.........................................................32
2.3. Benefit/Risk Assessment.........................................................................................34
2.3.1. Risk Assessment.........................................................................................34
2.3.2. Benefit Assessment.....................................................................................37
2.3.3. Overall Benefit/Risk Conclusion................................................................37
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................37
4. STUDY DESIGN.................................................................................................................40
4.1. Overall Design.........................................................................................................40
4.1.1. Assessment of Safety and Tolerability While Study is Ongoing ...............42
4.2. Scientific Rationale for Study Design.....................................................................42
4.3. Justification for Dose ..............................................................................................44
4.4. End of Study Definition ..........................................................................................45
5. STUDY POPULATION......................................................................................................45
5.1. Inclusion Criteria.....................................................................................................45


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5.2. Exclusion Criteria....................................................................................................46
5.3. Lifestyle Considerations..........................................................................................49
5.3.1. Dietary Restrictions ....................................................................................49
5.3.2. Dietary Counseling.....................................................................................50
5.3.3. Physical Activity Counseling .....................................................................50
5.3.4. Alcohol, Caffeine, and Tobacco .................................................................51
5.3.5. Contraception..............................................................................................51
5.4. Screen Failures ........................................................................................................51
6. STUDY INTERVENTION..................................................................................................51
6.1. Study Intervention(s) Administered........................................................................52
6.1.1. Administration............................................................................................52
6.2. Preparation/Handling/Storage/Accountability ........................................................56
6.2.1. Preparation and Dispensing........................................................................57
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................57
6.3.1. Allocation to Study Intervention ................................................................57
6.3.2. Breaking the Blind......................................................................................59
6.4. Study Intervention Compliance...............................................................................59
6.5. Concomitant Therapy..............................................................................................59
6.5.1. Antihypertensive Medications....................................................................60
6.5.2. Lipid Modifying Medications.....................................................................60
6.5.3. Rescue Medicine.........................................................................................60
6.6. Dose Modification...................................................................................................60
6.6.1. Dose Titration.............................................................................................60
6.6.2. Considerations for Pausing or Stopping Active Dose(s) Based on 
Observed Safety...............................................................................................61
6.7. Intervention After the End of the Study..................................................................61
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................61
7.1. Discontinuation of Study Intervention ....................................................................61
7.2. Participant Discontinuation/Withdrawal From the Study.......................................62
7.2.1. Withdrawal of Consent...............................................................................62
7.3. Lost to Follow-up....................................................................................................63


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Final Protocol Amendment 2, 16 September 2022
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
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8. STUDY ASSESSMENTS AND PROCEDURES...............................................................63
8.1. Efficacy Assessments..............................................................................................64
8.1.1. Primary Efficacy Parameter: Body Weight ................................................64
8.1.2. Secondary Efficacy Parameters: Waist and Hip Circumference ................65
8.1.3. Tertiary Efficacy Parameters: Patient Centered Outcome 
Assessments (PCOAs) .....................................................................................66
8.1.3.1. Eating-Related Factors Daily Diary..........................................67
8.1.3.2. Patient’s Global Impression of Severity (PGI-S)......................67
8.1.3.3. Patient’s Global Impression of Change (PGI-C).......................68
8.1.3.4. PROMIS® Fatigue Custom 9-item Version ..............................68
8.1.3.5. PROMIS® Physical Function Custom 13-item Version............68
8.1.3.6. Impact of Weight on Quality of Life–Lite (IWQOL-Lite) 
Clinical Trials Version ......................................................................68
8.1.3.7. SF-36v2® Health Survey...........................................................68
8.2. Safety Assessments .................................................................................................69
8.2.1. Physical Examinations................................................................................69
8.2.2. Vital Signs ..................................................................................................69
8.2.2.1. Blood Pressure and Pulse Rate..................................................69
8.2.3. Electrocardiograms.....................................................................................70
8.2.4. Clinical Safety Laboratory Assessments ....................................................71
8.2.5. Management of Hypoglycemia...................................................................71
8.2.5.1. Definition and Severity of Hypoglycemic Adverse Event 
(HAE) ................................................................................................72
8.2.6. Mental Health Questionnaires ....................................................................73
8.2.6.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................73
8.2.6.2. Patient Health Questionnaire-9 (PHQ-9) ..................................73
8.2.6.3. Referral to a Mental Health Professional ..................................74
8.2.7. Pregnancy Testing ......................................................................................74
8.3. Adverse Events and Serious Adverse Events..........................................................74
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......75
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................75
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................76
)


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8.3.2. Method of Detecting AEs and SAEs ..........................................................76
8.3.3. Follow-up of AEs and SAEs.......................................................................76
8.3.4. Regulatory Reporting Requirements for SAEs...........................................76
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................77
8.3.5.1. Exposure During Pregnancy......................................................77
8.3.5.2. Exposure During Breastfeeding ................................................78
8.3.5.3. Occupational Exposure .............................................................79
8.3.6. Cardiovascular and Death Events...............................................................79
8.3.7. Disease Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................79
8.3.8. Adverse Events of Special Interest.............................................................79
8.3.8.1. Lack of Efficacy........................................................................79
8.3.9. Medical Device Deficiencies......................................................................79
8.3.10. Medication Errors.....................................................................................80
8.4. Treatment of Overdose............................................................................................80
8.5. Pharmacokinetics ....................................................................................................81
8.6. Pharmacodynamics..................................................................................................82
8.7. Genetics...................................................................................................................82
8.7.1. Specified Genetics ......................................................................................82
8.7.2. Banked Biospecimens for Genetics............................................................82
8.8. Biomarkers ..............................................................................................................82
8.8.1. Specified Gene Expression (RNA) Research .............................................82
8.8.2. Specified Protein Research.........................................................................82
8.8.3. Specified Metabolomic Research ...............................................................82
8.8.4. Banked Biospecimens for Biomarkers .......................................................82
8.9. Immunogenicity Assessments.................................................................................83
8.10. Health Economics .................................................................................................83
9. STATISTICAL CONSIDERATIONS ................................................................................83
9.1. Estimands and Statistical Hypotheses.....................................................................83
9.2. Sample Size Determination.....................................................................................84
9.3. Analysis Sets ...........................................................................................................86


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9.4. Statistical Analyses .................................................................................................87
9.4.1. General Considerations...............................................................................87
9.4.1.1. Analyses for Continuous Endpoints..........................................87
9.4.1.2. Analyses for Categorical Endpoints..........................................87
9.4.2. Primary Endpoint(s)....................................................................................87
9.4.3. Secondary Endpoint(s)................................................................................88
9.4.4. Tertiary/Exploratory Endpoint(s) ...............................................................89
9.4.5. Other Safety Analyses ................................................................................90
9.4.5.1. Electrocardiogram Interval Analyses ........................................90
9.4.6. Other Analyse(s).........................................................................................90
9.5. Interim Analyses .....................................................................................................90
9.5.1. PK/PD Unblinding Plan..............................................................................91
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............91
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................92
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............92
10.1.1. Regulatory and Ethical Considerations ....................................................92
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................92
10.1.2. Financial Disclosure .................................................................................93
10.1.3. Informed Consent Process ........................................................................93
10.1.4. Data Protection .........................................................................................94
10.1.5. Dissemination of Clinical Study Data ......................................................94
10.1.6. Data Quality Assurance ............................................................................96
10.1.7. Source Documents....................................................................................97
10.1.8. Study and Site Start and Closure ..............................................................97
10.1.9. Publication Policy.....................................................................................98
10.1.10. Sponsor’s Qualified Medical Personnel .................................................99
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................100
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................102
10.3.1. Definition of AE .....................................................................................102


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10.3.2. Definition of SAE...................................................................................103
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs During 
the Active Collection Period..........................................................................105
10.3.4. Reporting of SAEs..................................................................................108
10.4. Appendix 4: Contraceptive Guidance .................................................................110
10.4.1. Male Participant Reproductive Inclusion Criteria..................................110
10.4.2. Female Participant Reproductive Inclusion Criteria...............................110
10.4.3. Woman of Childbearing Potential ..........................................................110
10.4.4. Contraception Methods...........................................................................111
10.5. Appendix 5: Genetics..........................................................................................113
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......114
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................116
10.8. Appendix 8: Prohibited Prior/Concomitant Medications....................................118
10.9. Appendix 9: Proposed Chronology of Procedures..............................................122
10.10. Appendix 10: Protocol Amendment History.....................................................123
10.11. Appendix 11: Abbreviations .............................................................................129
11. REFERENCES ................................................................................................................133
LIST OF TABLES
Table 1.
Titration and Dosing Schemes for Cohorts 1 and 2..................................54
Table 2.
Titration and Dosing Schemes for Cohorts 3 ...........................................55
Table 3.
Target Doses for Randomized Regimens for Cohorts 1 and 2.................58
Table 4.
Target Doses for Randomized Regimens for Cohort 3 ............................58
Table 5.
Patient Reported Outcome Measures........................................................66
Table 6.
Protocol Required Laboratory Assessments...........................................100
Table 7.
Prohibited medications that may interact (at the PK level) with PF-
06882961 ................................................................................................118
Table 8.
Other Prohibited Medications.................................................................120


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LIST OF FIGURES
Figure 1.
Overall Study Schema for Cohorts 1 and 2 ..............................................20
Figure 2.
Overall Study Schema for Cohort 3..........................................................21
Figure 3.
Titration Schema for Cohorts 1 and 2.......................................................21
Figure 4.
Titration Schema for Cohort 3..................................................................22
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 2b Study to Evaluate the Efficacy and Safety of PF-06882961 in Adults 
With Obesity
Rationale
This multicenter, Phase 2b, randomized, double-blind, placebo-controlled, parallel group, 
dose-ranging study is being conducted in adults with obesity.  This study will assess the
efficacy, safety, tolerability and PK of PF-06882961 in adults with obesity and is intended to 
enable selection of efficacious doses for future clinical development of PF-06882961 for 
weight loss in adults with obesity.
Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus 
placebo on body weight in 
participants with obesity.
•
Estimand 1: This estimand is 
intended to provide a 
population level estimate of 
the mean treatment effect 
(PF-06882961 versus 
placebo) on a continuous 
endpoint in all evaluable 
participants while on 
treatment.
•
Percent CFB in body weight at 
End of Treatment.a
Secondary: 
Secondary:
Secondary: 
•
To characterize the safety 
and tolerability of multiple 
dose levels of PF-06882961 
administered to participants 
with obesity.
•
There are no defined 
estimands for these 
endpoints and they will be 
analyzed using Pfizer data 
standards as applicable.
•
Incidence of treatment emergent 
AEs [AEs and SAEs], and 
clinically significant abnormal 
laboratory, vital signs and ECG 
parameters. 
•
Assessment of mental health as 
determined by C-SSRS and 
PHQ-9.
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus 
placebo on additional 
parameters of body weight 
in participants with obesity.
•
Estimand 2: This estimand is 
intended to provide a 
population level estimate of 
the odds ratio treatment 
effect (PF-06882961 versus 
placebo) on a binary 
endpoint in all evaluable 
•
Response as defined by a body 
weight loss of ≥5% from baseline 
at End of Treatment.a


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Objectives
Estimands
Endpoints
participants while on 
treatment.
•
Estimand 1 as above.
•
Cohorts 1 and 2: Percent CFB in 
body weight at Weeks 2, 4, 6, 8, 
10, 12, 16, 18 and 22.
•
Cohort 3: Percent CFB in body 
weight at Weeks 4, 8, 12, 16, 20, 
24 and 28.
•
Estimand 3: This estimand is 
intended to provide a
population level estimate of 
the mean treatment effect 
(PF-06882961 versus 
placebo) on a continuous 
endpoint in all evaluable 
participants while on 
treatment. 
•
Absolute CFB in waist 
circumference at End of 
Treatment.a
•
Estimand 4: This estimand 
will be similar to 3 above.
•
Absolute CFB in waist-to-hip 
ratio at End of Treatment.a
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus 
placebo on glycemic 
parameters in participants 
with obesity.
•
Estimand 5: This estimand 
will be similar to 3 above.
•
Cohorts 1 and 2: Absolute CFB 
in HbA1c at Weeks 16 and 26.
•
Cohort 3: Absolute CFB in 
HbA1c at Weeks 16, 24 and 32.
•
Estimand 6: This estimand 
will be similar to 3 above.
•
Absolute CFB in FPG at each 
planned in-clinic study visit up 
through the End of Treatment 
visit.b
Note: For all endpoints, baseline is defined as the result closest prior to dosing at V3 (Day 1).
a.
End of Treatment defined as Week 26 for Cohorts 1 and 2, and as Week 32 for Cohort 3.
b.
For Cohorts 1 and 2, this includes Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26; for Cohort 3, this includes 
Weeks 4, 8, 12, 16, 20, 24, 28 and 32. 
Overall Design
This is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel group, 
study to assess the efficacy, safety, tolerability and PK of twice daily oral administration of 
PF-06882961 in adult participants with obesity.  There are 3 Cohorts included in the study: 
Cohort 1 under the original protocol, Cohort 2 added under Amendment 1, and Cohort 3 
added under Amendment 2.
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Eligible participants who maintain acceptable compliance during a 2-week placebo run-in 
period are randomized on Day 1 to double-blinded study intervention. For Cohort 1, 
participants were randomized into 1 of 9 study arms (placebo: 5 PF-06882961 arms with 
1-week titration steps: 3 PF-06882961 arms with 2-week titration steps).  Additional 
participants were enrolled into the placebo and 3 2-week titration arms as part of Cohort 2, 
which was added to better characterize the tolerability and efficacy profile of the 2-week 
titration schemes, relative to the 1-week titration schemes, with placebo included to maintain 
the double-blind study design.  For Cohort 2, all SoA activities are the same as for the 
original cohort (Cohort 1) of randomized participants. In Cohort 3, participants will be 
randomized to 1 of 4 additional study arms (placebo: 3 PF-06882961 arms with 4-week 
titration steps) to characterize the tolerability and efficacy profile of 4-week dose titration 
steps, with placebo included to maintain the double-blind aspect.
Randomization is stratified according to biological gender (female versus male), as both
tolerability and efficacy may be different between men and women. This stratification is 
intended to balance the numbers of participants of either gender across treatment arms.  In 
addition, no more than approximately 70% of the trial population will consist of 1 gender, in 
order to permit adequate representation of both men and women in the trial population.  
Number of Participants
There will be total of approximately 581 participants across all 3 cohorts of this study.
Combining Cohorts 1 and 2, there were a total of approximately 469 participants randomized 
(approximately 67 in the placebo, approximately 60 in each of the 5 PF-06882961 arms with 
1-week titration steps and approximately 34 in each of the 3 PF-06882961 arms with 2-week 
titration steps). In Cohort 3, approximately 112 participants will be randomized to 
4 additional study arms (approximately 16 in the placebo and approximately 32 in each of 
3 PF-06882961 arms with 4-week titration steps).  
Intervention Groups and Duration
For the purposes of this protocol, study intervention refers to PF-06882961 and matching 
placebo. Blinded study intervention will be provided as tablets for oral administration, with 
the placebo run-in being single blinded (participant only) and the randomized treatment 
period being double-blinded. Participants in Cohorts 1 and 2 are instructed to take 4 tablets 
of study intervention in the morning with food and 4 tablets of study intervention in the 
evening with food, for a total of 8 tablets daily. Participants in Cohort 3 are instructed to take 
2 tablets of study intervention in the morning with food and 2 tablets of study intervention in 
the evening with food, for a total of 4 tablets daily. The morning and evening doses should 
be taken approximately 10-12 hours apart and at approximately the same time each day.
All dosing regimens for all cohorts include dose titration to enhance tolerability of 
PF-06882961, where the dose level is increased at set intervals of 1, 2 or 4 weeks until a 
target dose is achieved. For Cohort 1, participants were randomized into 9 arms in a 
3:3:3:3:3:3:1:1:1 ratio (placebo: 5 PF-06882961 arms with 1-week titration steps: 




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Target Doses for Randomized Regimens for Cohort 3
Regimen Description
(dosed twice daily)
Total 
Number 
of 
Tablets
per dose
Placebo
PF-06882961 – 80 mg (4-week titration steps)
PF-06882961 – 140 mg (4-week titration steps)
PF-06882961 – 200 mg (4-week titration steps)
Data Monitoring Committee or Other Independent Oversight Committee: Yes
This study will use an IRC, an external DMC will not be utilized.  The IRC is independent of 
the study team and includes only internal (ie, Pfizer colleague) members.  The IRC charter 
describes the role of the IRC in more detail.
Statistical Methods
Detailed methodology for summary and statistical analyses of the data collected in this study 
is further detailed in a SAP, which will be maintained by the sponsor.  Data from participants 
enrolled into the original cohort (Cohort 1) and Cohort 2 will be combined for reporting,
where data from the placebo and 2-week titration arms will be combined from the 2 cohorts 
and analyzed together. Data from participants enrolled into Cohort 3 will be analyzed 
separately unless otherwise specified.
The primary estimand (Estimand 1) will be the population average treatment effect on the 
percent CFB in body weight at End of Treatment of PF-06882961 compared to placebo in all 
evaluable participants while on treatment. 
For Cohorts 1 and 2, End of Treatment is defined as Week 26. For Cohort 3, End of 
Treatment is defined as Week 32. Measurements after discontinuation of study intervention 
will be censored and treated as missing data.  Missing data due to censoring, study 
withdrawal or other reasons will have data imputed based on a MAR assumption.  The 
population-based treatment effect will be percent CFB in each PF-06882961 arm compared 
to placebo.
A secondary estimand will be the population odds ratio of the treatment effect of achieving a 
body weight loss ≥5% from baseline at End of Treatment of PF-06882961 compared to 
placebo in all evaluable participants while on treatment. All other key secondary continuous 
clinical endpoints will be analyzed using a similar estimand to the primary estimand 
described above.
CCI
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The primary analysis of the primary endpoint will be conducted using a MMRM analysis of 
the CFB in body weight through End of Treatment, and Cohorts 1 and 2 will be analyzed 
separately to Cohort 3. MMRM models will be fitted to the CFB of loge-transformed values. 
The model for Cohorts 1 and 2 will include Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26. The 
model for Cohort 3 will include Weeks 4, 8, 12, 16, 20, 24, 28 and 32.
The primary analysis will include all participants randomly assigned to study intervention 
and who take at least 1 dose of randomized study intervention.  The MMRM models will 
include treatment, time, strata (females versus males) and treatment-by-time interaction as 
fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a 
repeated effect and participant as a random effect.  Baseline body weight will be included on 
the loge scale.  An unstructured correlation matrix will be used, and the Kenward-Roger 
approximation will be used for estimating degrees of freedom for the model parameters.  
Missing values will be imputed as part of the MMRM model assumptions and no adjustments 
will be made for multiplicity.  The modelled mean loge-differences and 90% CIs for the 
loge-differences at End of Treatment will be extracted from the model and exponentiated to 
provide estimates of the relative difference in each PF-06882961 treatment arm reported 
separately, compared to placebo.
1.2. Schema
Figure 1.
Overall Study Schema for Cohorts 1 and 2
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a.
End of Treatment: Defined as Week 26.
b.
Study part and Follow-up: In Part A (Weeks 1-16) participants will be randomized and dosed with double-blinded study intervention on Day 1 and dosing will continue 
through 16 weeks. In Part B (Weeks 17-26) participants in Part A will continue dosing, according to randomization from Part A.
c.
Early termination/discontinuation: This visit applies only to participants who are enrolled/randomized and then are prematurely withdrawn from the study, ie, permanently 
discontinued both from the study intervention and from the study.  Note: discontinuation of study intervention does not represent withdrawal from the study.  If only study 
intervention is discontinued, the participant will remain in the study and continue with all visits and assessments (except for dosing activities and assessment of PK).  See 
Section 7 for further details.
d.
Days relative to Dosing on Day 1:  Dosing occurs on Day 1 and timing of subsequent visits is determined by adding the number of days noted to Day 1. For example, V4 is 
Day 1+14 days (±3 days), V5 is Day 1+28 days (±3 days), etc.
e.
Follow-up V15: Visit may be a phone call.
f.
Site based PROs: Completed at the site on an electronic tablet.  Participants at ex-US sites will only complete the SF-36v2®.  Participants at US sites will complete all PRO 
assessments (SF-36v2®, PGI-S, PGI-C, PROMIS® Fatigue, PROMIS® Physical Function, IWQOL-Lite-CT©).  See Section 8.1.3 for more details.
g.
Physical examination: Complete physical examination performed according to the SoA, with height measured at V1 only.  A limited physical examination is performed at 
follow-up V14 and may be performed at non-specified visits if there are findings during the previous exam or new/open AEs, if appropriate and at investigator discretion.
h.
Body weight: The second weight measurement should be obtained at least 1-2 minutes apart from the first weight measurement.
i.
Supine vital signs (BP and pulse rate): At V3, V7, V10 and V13, triplicate vital signs will be measured pre-dose and triplicate vital signs will be measured 1 time within the 
window of approximately 2-6 hours post-dose (around the same time as post-dose PK samples are collected and according to the chronology in Appendix 9).  
j.
Eating-Related Factors Daily Diary: Only participants at selected US sites will complete this PRO diary, which will be done daily at home on a handheld device. 
k.
Study intervention: For V2 only, study intervention reflects single blinded placebo.  For V3 through V12, study intervention is dispensed via IRT and reflects double-blinded
randomized PF-06882961 or placebo.
l.
Dispensation of study intervention at V10-V12 (Weeks 16-22): For V10-12 only, study intervention dispensation via IRT will be permitted only after formal agreement 
with regulatory authorities and IRBs/ECs as described in “b” above.  
m.
PK sampling: At V3, V7, V10 and V13, PK samples will be collected pre-dose and one time within the window of approximately 2-6 hours post-dose (around the same time 
as post-dose vital sign measurements and according to the chronology in Appendix 9).
n.
Banked biospecimen Prep D1: If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in 
conjunction with a participant visit.
o.
Pregnancy tests: Serum and urine pregnancy tests are required for all females regardless of childbearing potential.  For the on-site urine pregnancy tests performed at each 
visit V2 through V14, the test result must be negative in order to continue participation in the study.








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m.
PK sampling: At V3, V7, V11, V15 and V19, PK samples will be collected pre-dose and 1 time within the window of approximately 2-6 hours post-dose (around the same 
time as post-dose vital sign measurements and according to the chronology in Appendix 9).
n.
Banked biospecimen Prep D1: If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in 
conjunction with a participant visit.


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2. INTRODUCTION
GLP-1 is a neuroendocrine hormone that is predominantly released from the small intestine 
in response to food intake.1  GLP-1 activation of the GLP-1R stimulates insulin release, 
inhibits glucagon secretion in a glucose-dependent manner, and delays gastric emptying.2,3  
In addition, GLP-1 has been shown to increase satiety and suppress food intake.4  
PF-06882961 is an orally administered, small molecule GLP-1R agonist that has been 
demonstrated, in nonclinical models, to stimulate glucose-dependent insulin release and 
suppress food intake with equivalent efficacy to an injectable peptide GLP-1R agonist 
approved for the treatment of T2DM.
PF-06882961 is an oral, small molecule GLP-1R agonist that is currently being investigated
for the treatment of T2DM, and also as an adjunct to diet and exercise for weight loss in adult
participants with obesity.
2.1. Study Rationale 
This multicenter, Phase 2b, randomized, double-blind, placebo-controlled, parallel group, 
dose-ranging study is being conducted in adults with obesity.  There are 3 Cohorts included 
in the study: Cohort 1 under the original protocol, Cohort 2 added under Amendment 1, and 
Cohort 3 added under Amendment 2, as described in Section 4.
This study will assess the efficacy, safety, tolerability and PK of PF-06882961 in adults with 
obesity and is intended to enable selection of efficacious doses for future clinical 
development of PF-06882961 for weight loss in adults with obesity.
2.2. Background 
Obesity is a chronic disease that is associated with serious co-morbidities, including T2DM, 
dyslipidemia, hypertension, atherosclerosis, obstructive sleep apnea and certain cancers,5 and 
is also associated with increased all-cause mortality.6  The global burden of obesity is high 
with more than 600 million adults estimated to have obesity worldwide. In addition, the 
prevalence of obesity has doubled in more than 70 countries since 1980 and poses a major 
public health challenge.7,8  First line treatment for obesity is lifestyle intervention including 
diet, exercise and behavioral therapy.  While effective in many patients, lifestyle intervention 
is often not sustainable, and many patients regain weight after initial weight loss.9  
Pharmacotherapy has been approved for the long-term treatment of obesity and can be a 
useful adjunct to lifestyle intervention to augment and maintain weight loss.
Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and cardiovascular safety, with more than one marketed agent demonstrating 
cardiovascular benefit.10  Based on the clinical history of injectable GLP-1R agonists, an 
oral, small molecule GLP-1R agonist is expected to decrease appetite and food intake, 
resulting in weight loss in patients with obesity, while avoiding the subcutaneous injection 
required by currently available peptidic GLP-1R agonists.








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2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably expected AEs of PF-06882961 may be 
found in the IB, which is SRSD for this study.
2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) PF-06882961
Thyroid C-cell tumors
The potential risks are based on product labeling for peptidic 
marketed GLP-1R agonists (ie, semaglutide, 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 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 peptidic
GLP-1R agonists (ie, semaglutide, 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 pancreatitis are not 
eligible for study entry.  Serum amylase and lipase 
are monitored during the clinical studies.  
Hypoglycemia
Clinical trials with peptidic GLP-1R agonists have not demonstrated 
an increased risk for hypoglycemia.  However, when administered in 
combination with anti-diabetic agents that are known to have an 
increased risk of hypoglycemia (such as insulin or sulfonylureas), an 
increased risk for hypoglycemia was observed. 
Participants with obesity who do not have co-existing T2DM would 
not be taking anti-diabetic agents and therefore would not be 
expected to have an increased risk for hypoglycemia.  
A low overall incidence of generally mild hypoglycemia has been 
reported in the PF-06882961 clinical development program to date.
Anti-diabetic medications are prohibited in this 
study, and blood glucose is monitored via central 
lab assessments at every clinical visit in this study. 
Participants are informed about the signs and 
symptoms of hypoglycemia, and are monitoring for 
these symptoms at clinical study visits.




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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Increase in HR
The potential risk is based on the product labeling for the injectable 
GLP 1R agonists liraglutide and semaglutide for T2DM and for 
obesity.  
Increases in HR have been noted in the clinical program with 
PF-06882961 with most values within the normal range. While there 
have been isolated vital sign values outside the reference ranges 
observed, in these cases the values were not considered clinically 
significant and there were no clinically significant adverse trends
observed across dose levels, to date. 
Vital signs, including HR and BP, and ECGs are 
assessed at all onsite study visits in all participants.
Acute gallbladder disease
Substantial or rapid weight loss can increase the risk of cholelithiasis.
The potential risk is based on the product labeling for the injectable 
GLP 1R agonist liraglutide for obesity and also exenatide.  
In the completed clinical studies with PF-06882961, no 
treatment-emergent events of cholelithiasis have been observed.
Participants with symptomatic gallbladder disease 
are excluded from this clinical study. Participants 
are monitored at clinical visits for AEs and 
laboratory tests that may suggest development of 
acute gallbladder disease.
Study Procedures
Use of a placebo arm
Participants randomized to placebo may not experience weight loss 
efficacy. 
A majority of the randomized study population will 
receive PF-06882961, and all participants will 
receive lifestyle counseling, which is standard of 
care for management of obesity.


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2.3.2. Benefit Assessment
Based on the clinical history of injectable GLP-1R agonists, participants with obesity 
randomized to PF-06882961 may have diminished food intake and decreased body weight.  
Other potential benefits for all participants in this study may include receiving lifestyle 
counseling, receiving medical evaluations/assessments associated with clinical study visits 
(eg, physical examinations, ECGs, labs), and contributing to the process of developing a 
potential new therapy for weight loss.
2.3.3. Overall Benefit/Risk Conclusion
Considering all available clinical and nonclinical data, the benefit-risk profile of 
PF-06882961 supports continued clinical development in participants with obesity.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on body weight in participants 
with obesity
•
Estimand 1: This estimand is 
intended to provide a population 
level estimate of the mean 
treatment effect (PF-06882961 
versus placebo) on a continuous 
endpoint in all evaluable 
participants while on treatment.
•
Percent CFB in body weight at End 
of Treatment.a
Secondary: 
Secondary:
Secondary: 
•
To characterize the safety and 
tolerability of multiple dose 
levels of PF-06882961 
administered to participants 
with obesity.
•
There are no defined estimands 
for these endpoints and they will 
be analyzed using Pfizer data 
standards as applicable.
•
Incidence of treatment emergent AEs 
[AEs and SAEs], and clinically 
significant abnormal laboratory, vital 
signs and ECG parameters.
•
Assessment of mental health as 
determined by C-SSRS and PHQ-9.
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on additional parameters of 
body weight in participants 
with obesity.
•
Estimand 2: This estimand is 
intended to provide a population 
level estimate of the odds ratio 
treatment effect (PF-06882961 
versus placebo) on a binary 
endpoint in all evaluable 
participants while on treatment.
•
Response as defined by a body 
weight loss of ≥5% from baseline at 
End of Treatment.a
•
Estimand 1 as above.
•
Cohorts 1 and 2: Percent CFB in 
body weight at Weeks 2, 4, 6, 8, 10, 
12, 16, 18 and 22.
•
Cohort 3: Percent CFB in body 
weight at Weeks 4, 8, 12, 16, 20, 24 
and 28.
•
Estimand 3: This estimand is 
intended to provide a population 
level estimate of the mean 
treatment effect (PF-06882961 
versus placebo) on a continuous 
•
Absolute CFB in waist 
circumference at End of Treatment.a


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Objectives
Estimands
Endpoints
endpoint in all evaluable 
participants while on treatment.
•
Estimand 4: This estimand will 
be similar to 3 above.
•
Absolute CFB in waist-to-hip ratio at 
End of Treatment.a
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on glycemic parameters in 
participants with obesity.
•
Estimand 5: This estimand will 
be similar to 3 above.
•
Cohorts 1 and 2: Absolute CFB in 
HbA1c at Weeks 16 and 26.
•
Cohort 3: Absolute CFB in HbA1c 
at Weeks 16, 24 and 32.
•
Estimand 6: This estimand will 
be similar to 3 above.
•
Absolute CFB in FPG at each 
planned in-clinic study visit up 
through the End of Treatment visit.b
Tertiary/Exploratory: 
Tertiary/Exploratory:
Tertiary/Exploratory: 
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on body weight in participants 
with obesity who do not have 
major protocol deviations.
•
Estimand 7: This estimand is 
intended to provide a population 
level estimate of the mean 
treatment effect (PF-06882961
versus placebo) on a continuous 
endpoint in evaluable 
participants with no major 
protocol deviations and while on 
treatment.  
•
Percent CFB in body weight at each 
planned in-clinic study visit up 
through the End of Treatment visit.b
•
To characterize the PK of 
PF-06882961 in participants 
with obesity.
•
There is no defined estimand for 
this endpoint and this will be 
analyzed using Pfizer data 
standards as applicable.
•
Trough plasma concentrations of 
PF-06882961 at time points specified 
in the SoA for the applicable cohort 
(see SoA for Cohorts 1 and 2, and 
SoA for Cohort 3).
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on markers of insulin 
resistance in participants with 
obesity.
•
There are no defined estimands 
for these endpoints and they will 
be analyzed using Pfizer data 
standards as applicable.
•
Cohorts 1 and 2: CFB in fasting 
plasma insulin, HOMA-IR and 
HOMA-B at Weeks 4, 8, 12, 16, 22 
and 26.
•
Cohort 3: CFB in fasting plasma 
insulin, HOMA-IR and HOMA-B at 
Weeks 4, 8, 12, 16, 20, 24, 28 and 
32.
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on additional parameters of 
body weight in participants 
with obesity.
•
Estimand 3: This estimand is 
defined above.
•
Cohorts 1 and 2: Absolute CFB  in 
waist circumference at Weeks 2, 4, 6, 
8, 10, 12, 16, 18 and 22.
•
Cohort 3: Percent CFB in body 
weight at Weeks 4, 8, 12, 16, 20, 24 
and 28.
•
Estimand 4: This estimand will 
be similar to 3 above.
•
Cohorts 1 and 2: Absolute CFB in 
waist-to-hip ratio at Weeks 2, 4, 6, 8, 
10, 12, 16, 18 and 22.
•
Cohort 3: Percent CFB in body 
weight at Weeks 4, 8, 12, 16, 20, 24 
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Objectives
Estimands
Endpoints
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on glycemic category in 
participants with obesity.
•
There are no defined estimands 
for these endpoints and they will 
be analyzed using Pfizer data 
standards as applicable.
•
Shift from baseline in glycemic 
category (normoglycemia, 
pre-diabetes, or T2DM) at End of 
Treatment.a
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on BP and lipid levels in 
participants with obesity.
•
There are no defined estimands 
for these endpoints and they will 
be analyzed using Pfizer data 
standards as applicable.
•
CFB in systolic and diastolic BP at 
each planned in-clinic study visit up 
through the End of Treatment visit.
•
Cohorts 1 and 2: CFB in lipid 
parameters at Weeks 4, 8, 12, 16, 22 
and 26.
•
Cohort 3: CFB in lipid parameters at 
Weeks 4, 8, 12, 16, 20, 24, 28 and 
32.
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on PCOAs in participants with 
obesity.
•
There are no defined estimands 
for these endpoints and they will 
be analyzed using Pfizer data 
standards as applicable.
•
Cohorts 1 and 2: CFB in SF-36v2®
subscales and summary scores at 
Weeks 16 and 26.
•
Cohort 3: CFB in SF-36v2®
subscales and summary scores at 
Weeks 16, 24 and 32.
•
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on PCOAs in participants with 
obesity (US sites only).
•
There are no defined estimands 
for these endpoints and they will 
be analyzed using Pfizer data 
standards as applicable.
•
Cohorts 1 and 2: CFB in 
Eating-Related Factors Daily Diary 
at Weeks 4, 8, 12, 16, 22 and 26.
•
Cohort 3: CFB in Eating-Related 
Factors Daily Diary at Weeks 4, 8, 
12, 16, 20, 24, 28 and 32.
•
CFB in PGI-S at each planned in-
clinic study visit up through the End 
of Treatment visit.b
•
Cohorts 1 and 2: CFB in PROMIS®
Fatigue at Weeks 16 and 26.
•
Cohort 3: CFB in PROMIS® Fatigue 
at Weeks 16, 24 and 32.
•
Cohorts 1 and 2: CFB in PROMIS®
Physical Function at Weeks 16 and 
26.
•
Cohort 3: CFB in PROMIS®
Physical Function at Weeks 16, 24 
and 32.
•
Cohorts 1 and 2: CFB in 
IWQOL-Lite-CT© at Weeks 16 and 
26.
•
Cohort 3: CFB in IWQOL Lite-CT©
at Weeks 16, 24  and 32.
•
Cohorts 1 and 2: PGI-C at Weeks 4, 
16 and 26.
•
Cohort 3: PGI-C at Weeks 4, 16, 24 
and 32.
Note: For all endpoints, baseline is defined as the result closest prior to dosing at V3 (Day 1).
See Section 9.1 for additional details regarding Estimands.


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Objectives
Estimands
Endpoints
a.
End of Treatment defined as Week 26 for Cohorts 1 and 2, and as Week 32 for Cohort 3. 
b.
For Cohorts 1 and 2, this includes Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26; for Cohort 3, this includes 
Weeks 4, 8, 12, 16, 20, 24, 28 and 32. 
4. STUDY DESIGN
4.1. Overall Design
This Phase 2b, multicenter, randomized, double-blind, placebo-controlled,  parallel group, 
study will assess efficacy, safety, tolerability and PK of twice daily oral administration of 
PF-06882961 in adult participants with obesity. There are 3 Cohorts included in the study: 
Cohort 1 under the original protocol, Cohort 2 added under Amendment 1, and Cohort 3 
added under Amendment 2, as described below. 
For all cohorts, following the initial screening period to confirm eligibility (up to 4 weeks), 
screening continues with a 2-week placebo run-in period which will be single-blinded 
(participant).  Eligible participants who maintain acceptable compliance during the run-in 
period are randomized on Day 1 to double-blinded study intervention.  
This study was initially designed with a 2-part double-blinded treatment phase, as the 
16-week dosing duration of Part A was supported by the nonclinical toxicology data 
available at the time of the original protocol finalization, and dosing in Part B over 
Weeks 17-26 was contingent on availability of supportive nonclinical data from a 9-month 
toxicology study in monkeys (Study 
) that was ongoing at that time, and is now 
completed.  For Cohort 1, participants were randomized into 9 arms: a placebo arm, 5 arms 
with 1-week titration steps (also referred to as standard titration in previous protocol 
versions), and 3 arms with 2-week titration steps (also referred to as slow titration in previous 
protocol versions). Protocol Amendment 1 added Cohort 2 where additional participants 
were randomized to the placebo and the 3 arms with 2-week titration steps. All SoA
activities are the same for Cohort 2 as for the original cohort (Cohort 1) of randomized 
participants. Part B was approved before any participant reached the end of Part A, and 
participants in both Cohorts 1 and 2 were able to proceed directly from Part A to Part B.  
Accordingly, the primary endpoint for Cohorts 1 and 2 is based on End of Treatment defined 
as Week 26. For participants in Cohorts 1 and 2, the total duration of dosing with 
double-blinded study intervention is 26 weeks, followed by an approximate 4-week 
follow-up.  The total duration of participation in this study for the participants in Cohorts 1 
and 2 is approximately 32 weeks, including the 2-week single-blind run-in period, but
excluding the initial screening period.
For Cohort 3, added under protocol Amendment 2, participants will be randomized to 
placebo or 1 of 3 PF-06882961 arms with 4-week dose titration steps.  The overall approach 
to study procedures is similar to the previous cohorts, however, the double-blinded treatment 
phase is not presented as 2-parts (as there is now supportive data for the full dosing duration 
as described above) and the visit schedule for Cohort 3 is adjusted to correspond to the 
4-week dose titration intervals. The double-blinded treatment phase for Cohort 3 is extended 
to 32 weeks compared to 26 weeks for Cohorts 1 and 2 in order to allow for sufficient steady 
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state dosing given the longer titration intervals, and to generate additional efficacy data over 
a longer treatment period. Accordingly, the primary endpoint for Cohort 3 is based on End 
of Treatment defined as Week 32. For Cohort 3, the total duration of dosing with 
double-blinded study intervention is 32 weeks, followed by an approximate 4-week 
follow-up.  The total duration of study participation for participants in Cohort 3 is 
approximately 38 weeks, including the 2-week single-blind run-in period, but excluding the 
initial screening period.
All dosing regimens for all cohorts include dose titration to enhance tolerability of 
PF-06882961, where the dose level is increased at set intervals of 1, 2 or 4 weeks until a 
target dose is achieved (see Table 1 for Cohorts 1 and 2, and Table 2 for Cohort 3). For all 
cohorts, dosing is to occur with food twice daily. For the 5 1-week titration PF-06882961 
groups in Cohort 1, the target dose levels for each of the arms are 40 mg BID, 80 mg BID, 
120 mg BID, 160 mg BID, and 200 mg BID, with titration from a starting dose of 
mg BID, and up to 
weeks of the dosing duration used for titration. For the 3 2-week
titration PF-06882961 groups in Cohorts 1 and 2, target dose levels for each of the arms are 
120 mg BID, 160 mg BID, and 200 mg BID, with titration from a starting dose of 
mg BID, and up to 
weeks used for titration. Both Cohorts 1 and 2 also include a 
placebo arm. For Cohort 3, participants will be enrolled into 4 study arms, and target dose 
levels are placebo and PF-06882961 doses of 80 mg BID, 140 mg BID, and 200 mg BID. 
For Cohort 3, titration will occur at 4-week intervals from a starting dose of 
 mg BID, and 
up to 
 weeks will be used for titration to reach the target dose. Additional details regarding 
dose titration are provided in Section 6.1 and in the IP Manual.
There will be total of approximately 581 participants across all 3 cohorts of this study. In 
Cohort 1, approximately 420 participants (approximately 60 in each of the placebo and 
5 1-week titration PF-06882961 arms and approximately 20 in each of the 3 2-week titration
PF-06882961 arms) were randomized. All dosing arms, including placebo, were enrolled 
simultaneously in Cohort 1. Subsequently, in Cohort 2, approximately 49 additional 
participants were randomized to the placebo and 2-week titration arms (approximately 7 in 
the placebo and approximately 14 in each of the 3 2-week titration arms.).  Combining 
Cohorts 1 and 2, there were a total of approximately 469 participants randomized 
(approximately 67 in the placebo, approximately 60 in each of the 5 1-week titration arms 
and approximately 34 in each of the 3 2-week titration arms).  In Cohort 3, approximately 
112 participants will be randomized to 4 additional study arms (approximately 16 in the 
placebo and approximately 32 in each of 3 PF-06882961 arms with 4-week titration steps).  
Randomization is stratified according to biological gender (female versus male), as both 
tolerability and efficacy may be different between men and women.11  This stratification is 
intended to balance the numbers of participants of either gender across treatment arms.  In 
addition, no more than approximately 70% of the trial population will consist of 1 gender, in 
order to permit adequate representation of both men and women in the trial population.
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4.1.1. Assessment of Safety and Tolerability While Study is Ongoing
In accordance with the sponsor’s standard practices, emerging safety data are reviewed 
periodically in a blinded manner by the sponsor’s clinical team on an ongoing basis during 
study conduct. An interim analysis of the unblinded safety data by the IRC will occur at least 
once annually while the study is ongoing, as described in Section 9.5. In addition, during 
study conduct for Cohorts 1 and 2, there were 3 blinded safety reviews performed by selected 
members of the sponsor’s study team; each of these blinded safety reviews was separated by 
at least 1 month from the previous review.
4.2. Scientific Rationale for Study Design
This study is designed to assess the efficacy and safety of PF-06882961 in adult participants 
with obesity. After completing initial screening activities in V1, a placebo run-in period 
(ie, V2 to V3) is included in this study to familiarize participants with the study treatment 
regimens and to exclude those who are not compliant with single-blinded placebo dosing 
prior to randomization.  Clinical laboratory tests, assessments of vital signs and 12-lead 
ECGs, physical examinations, measurement of body weight, waist and hip circumference,
AE monitoring, and collection of blood for PK samples will provide data to evaluate the 
efficacy, safety, tolerability and PK of PF-06882961. In order to reduce variability in the 
assessment of the primary endpoint, body weight, all body weight measurements will be 
collected in duplicate. Waist and hip circumference12,13 will be measured in triplicate, as 
additional parameters of body weight. Similarly, in an effort to reduce variability and better 
quantitate potential changes in BP and pulse rate during the study, all measurements of BP 
and pulse rate will be collected in triplicate and the mean systolic and diastolic BP and mean 
pulse rate will be reported at each time point.
As part of the clinical safety laboratory tests, calcitonin, amylase, and lipase will be assessed, 
as these laboratory parameters have been shown to increase with marketed GLP-1R 
agonists.14-17  In addition, TSH, FT4, lipids, coagulation profile and TBA will be assessed, 
based on non-adverse findings in the nonclinical studies with PF-06882961. Assessment of 
suicidal ideation and behavior by the C-SSRS18 and PHQ-919 will also be performed based on 
the potential risk related to the product labeling for the injectable GLP-1R agonist liraglutide 
for obesity.17 The collection of blood samples, specifically HbA1c, FPG, and FPI will be 
used to assess changes in glycemic parameters and insulin resistance in this study population.  
FPG and FPI levels will be used to calculate HOMA-IR and HOMA-B.20
There are 3 cohorts included in this study: Cohort 1 under the original protocol, Cohort 2 
added under Amendment 1 and Cohort 3 added under Amendment 2.  Cohort 1 included 
placebo, 5 PF-06882961 arms with 1-week titration steps, and 3 PF-06882961 arms with 
2-week titration steps. For Cohort 2, additional participants were randomized to the placebo 
and 3 arms with 2-week titration steps.  This cohort was added to better characterize the 
tolerability and efficacy profile of the 2-week titration schemes, relative to the 1-week 
titration schemes, with placebo included to maintain the double-blind study design. The 
study design for Cohorts 1 and 2 was chosen to permit sufficient efficacy21 and tolerability 
assessment of both arms with 1-week titration steps and arms with 2-week steps. The target 


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doses and titration schemes initially utilized in this study were informed by the doses 
administered and tolerability data from the C3421002 study. Cohort 3 is being added under 
Amendment 2, and includes 4 arms, which are placebo and 3 PF-06882961 arms with 4-week 
dose titration steps.  This cohort is added to characterize the tolerability and efficacy profile 
of 4-week titration steps, with placebo included to maintain the double-blind aspect. In this 
study, the total duration of dosing with randomized double-blinded study intervention is
26 weeks for participants in Cohorts 1 and 2, and 32 weeks for participants in Cohort 3. The 
duration of double-blinded treatment for Cohort 3 is extended to 32 weeks in order to allow 
for sufficient steady state dosing given the longer titration intervals, and to generate 
additional efficacy data over a longer treatment period. Downward titration of dosing is not 
permitted during the study; participants who do not tolerate the titration scheme and/or 
assigned dose may be required to discontinue dosing of study intervention.  
In accordance with guidelines for the management for obesity,22 all participants will receive 
dietary and physical activity counseling.  
GLP-1R agonists typically are not associated with hypoglycemia unless co-administered with 
anti-diabetic agents that can cause hypoglycemia (such as insulin or sulfonylureas), which 
are prohibited in this study. Blood glucose concentrations will be monitored throughout the 
study as part of the safety laboratory measurements.  In addition, all participants will be 
instructed at placebo run-in and randomization regarding the symptoms associated with, and 
management of, hypoglycemia, which will permit the monitoring of symptomatic HAEs.
PCOAs have been included to understand how the study intervention affects eating-related 
factors such as appetite, hunger and food-cravings. Recognizing the wider impact of obesity 
on patients, additional PRO measures for fatigue, physical function and health-related quality 
of life have also been included.23,24
An interim analysis of the unblinded safety data by the IRC will be performed at least once 
annually while the study is ongoing, and dose level(s) may be dropped if deemed necessary.  
See Section 4.1.1 and Section 9.5 for additional information regarding the interim analysis.  
Females of childbearing potential may be enrolled into this study given the availability of 
embryo fetal developmental toxicity studies with PF-06882961.  However, as marketed 
GLP-1R agonists are listed as contraindicated in pregnancy, the use of a highly effective 
method of contraception is required and measures will be taken to limit the risk of pregnancy 
in the female population enrolled [see SoA for the applicable cohort (SoA for Cohorts 1 and 
2, and SoA for Cohort 3) and Appendix 4].
The potential risk of exposure to PF-06882961 in a sexual partner of a male participant in 
this study via ejaculate is low, and therefore no contraception (condom) use in male 
participants is warranted.  The calculated safety margin is 
 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 
 is based on 
applying a 10-fold safety factor for interspecies extrapolation and a 10-fold safety factor for 
susceptible populations.25
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The dose range selected for PF-06882961 across all cohorts of this study has been 
demonstrated to be safe with no clinically relevant dose-related adverse trends identified in 
previous clinical studies and a tolerability profile in line with the mechanism of action 
(Section 2.2.2.1). The expected PF-06882961 exposure at the highest 200 mg BID dose is 
approximately 
-fold and 
-fold lower (for Cmax and AUC24, respectively) than the 
exposure observed at the NOAEL in the pivotal 9-month toxicology study in monkeys, after 
accounting for differences in plasma protein binding between species. Based on the above, 
PF-06882961 doses up to 200 mg BID are viewed as appropriate for assessment in this study 
with an expected acceptable safety and tolerability profile. 
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 last follow-up visit, approximately 28 to 35 days post last dose of 
study intervention.
The end of the study is defined as the date of the last visit of the last participant in the study
across all sites globally.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 (or the minimum country-specific 
age of consent if >18) and 75 years, inclusive, at V1.
•
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.
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Type of Participant and Disease Characteristics:
2. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, 
lifestyle considerations, and other study procedures.
Body Mass Index (BMI) and Weight:
3. Participants with obesity, defined as a BMI ≥30.0 kg/m2 at V1.
4. Stable body weight, defined as <5 kg change (per participant report) for 90 days 
before V1. 
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. Known intolerance or hypersensitivity to GLP-1R agonists.
2. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or 
pancreatic insufficiency).
3. Current or prior diagnosis of T1DM or T2DM or secondary forms of diabetes. 
Note: women with medical history of gestational diabetes that resolved upon delivery 
are eligible if they meet the other eligibility criteria.
4. 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 prior to V1.
5. Any malignancy not considered cured (except focal, treated basal cell carcinoma and 
squamous cell carcinoma of the skin); a participant is considered cured if there has 
been no evidence of cancer recurrence in the previous 5 years.
6. Personal or family history of medullary thyroid carcinoma or Multiple Endocrine 
Neoplasia syndrome type 2, or participants with suspected medullary thyroid 
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20. At V1, V2 or V3 prior to randomization, supine BP ≥160 mmHg (systolic) or 
≥100 mmHg (diastolic), following at least 5 minutes of supine rest.  BP should be 
measured in triplicate and the average of the 3 BP values should be used to determine 
the participant’s eligibility.  
21. At V1, V2 or V3 prior to randomization, 12-lead ECG that demonstrates clinically 
relevant abnormalities that may affect participant safety or interpretation of study 
results (eg, QTcF interval >450 msec, complete LBBB, signs of an acute or 
indeterminate-age myocardial infarction, ST-T interval changes suggestive of
myocardial ischemia, second- or third-degree AV block, or serious bradyarrhythmias 
or tachyarrhythmias).  If the QTcF exceeds 450 msec, or QRS exceeds 120 msec, the 
ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values 
should be used to determine the participant’s eligibility.  Computer-interpreted ECGs 
should be overread by a physician experienced in reading ECGs before excluding 
participants.
22. A positive urine drug screen at V1 that is consistent with illicit drug use.  Note:
Participants who have been medically prescribed medications including but not 
limited to, opiates/opioids or benzodiazepines and report the use of these drugs to the 
investigator at V1 may be allowed to participate with notification to the sponsor.  
23. Participants with ANY of the following abnormalities in clinical laboratory tests at 
V1, as assessed by the study specific laboratory and confirmed by a single repeat test, 
if deemed necessary:
•
HbA1c ≥6.5%;
•
AST or ALT level ≥2 times ULN;
•
TBili level ≥1.5 times ULN;
•
Fasting C-peptide <0.8 ng/mL;
•
TSH >1.5 times ULN or < LLN;
•
Serum calcitonin > ULN;
•
Amylase or lipase > ULN;
•
FPG ≥126 mg/dL (7 mmol/L);
•
eGFR <60 mL/min/1.73 m2 as calculated by the CKD-EPI equation.


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Other Exclusions:
24. Compliance of <89% (based on tablet count) during the 2-week placebo run-in 
period, as assessed prior to randomization on Day 1 (see Section 6.4).
25. Participation in a formal weight reduction program (eg, Weight Watchers) within 
90 days prior to V1.
26. History of regular alcohol consumption exceeding 7 drinks/week for female 
participants or 14 drinks/week for male participants (1 drink = 5 ounces [150 mL] of 
wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 
6 months prior to V1.
27. Known or suspected illicit drug use.
28. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to randomization (Day 1).
29. Unwilling or unable to comply with the Lifestyle Considerations section of the 
protocol (see Section 5.3).
30. Living in the same household as a participant who is currently in screening or in the 
randomized treatment phase of the study. Note: participants can be enrolled in the 
study if another member of their household has already screen failed or is in the 
follow-up phase of the study.
31. Body weight exceeds the maximum capacity of the site’s scale, preventing accurate 
assessment of body weight.
32. 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 sections describe guidelines for diet, physical activity, alcohol, caffeine and 
tobacco use and contraception requirements that are to be followed throughout the study.
5.3.1. Dietary Restrictions
•
Participants must abstain from all food and drink (except water) for at least 
8 (preferably 10) hours prior to any body weight, waist and hip measurements, and 
blood sample collections, except for post-dose PK collections.
•
Water may be consumed as desired (ad libitum).
•
Study intervention must be administered BID in the morning and evening with food, 
approximately 10-12 hours apart. 


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•
On scheduled visits to the site, in the morning, from start of run-in (V2) through the 
last visit in the treatment phase for the respective cohort (see SoA for Cohorts 1 and 
2, and SoA for Cohort 3), participants should be instructed to arrive fasting for at 
least 8 hours (without having food/breakfast) and without self-administration of study 
intervention. Note: Participants may take their morning dose of antihypertensive 
medication and/or lipid modifying medication before their visit per their usual 
routine, if applicable.
•
On the mornings of the above visits, the study intervention will be administered at the 
site with food.  
•
Participants will be counseled on appropriate dietary and physical activity guidelines, 
as described in Section 5.3.2 and Section 5.3.3, for obesity at the times listed in the 
SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3)
and asked to maintain these guidelines throughout participation in the study.  Note:
Participation in formal weight loss programs should be avoided during participation 
in this study.
5.3.2. Dietary Counseling
At times listed in the SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA 
for Cohort 3), participants will receive dietary counseling by appropriate site staff with 
instruction to induce an energy deficit of ≥500 kcal/day from the participant’s estimated total 
energy expenditure (TEE), in accordance with guidelines,22 using the formula below:
•
TEE = Resting energy expenditure (REE) x activity factor.
For all participants, an activity factor of 1.3 (to match a sedentary activity level) will be used.  
The REE for each participant will be calculated with the Harris Benedict formula for men 
and women, using the participant’s body weight, height, and age obtained at V1, as listed 
below:28
•
For women: REE (kcal/d) = 655 + 9.5 (weight in kg) + 1.9 (height in cm) – 4.7 (age 
in years).
•
For men: REE (kcal/d) = 66 + 13.8 (weight in kg) + 5.0 (height in cm) – 6.8 (age in 
years).
5.3.3. Physical Activity Counseling
At times listed in the SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA 
for Cohort 3), participants will be instructed to maintain physical activity for ≥150 minutes 
per week (≥30 minutes per day most days of the week) in accordance with guidelines.22  
Prior to clinical study visits, participants will be instructed not to perform physically 
strenuous exercise (for example: heavy lifting, weight training, calisthenics and aerobics) 
within 48 hours prior to blood sample collections; walking at a normal pace is permitted.


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5.3.4. Alcohol, Caffeine, and Tobacco
•
Intake of alcohol is permitted in moderation (see exclusion criterion 26 for acceptable 
amount of alcohol consumption).
•
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.
•
Use of nicotine-containing products is permitted in this study with the following 
restrictions: nicotine-containing products may not be used within 1 hour prior to 
measuring vital signs and ECGs.
5.3.5. 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 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 for the applicable cohort (see SoA for Cohorts 1 and 2, and 
SoA for Cohort 3), 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 randomly assigned to study intervention. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE.
A participant who qualified for this study but did not enroll within the protocol prescribed 
screening period may be re-screened.  All screening procedures must be repeated, and the 
participant assigned a new 8-digit SSID number. 
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.


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For the purposes of this protocol, study intervention refers to PF-06882961 and matching 
placebo tablets. All tablets (across unit dose strengths and placebo) are identical in 
appearance and are to be taken orally.
6.1. Study Intervention(s) Administered
Intervention Name
PF-06882961
Placebo for PF-06882961
ARM Name
(group of patients receiving 
a specific treatment or no 
treatment)
Active
Placebo
Type
Drug
Drug
Dose Formulation
Tablet
Tablet
Unit Dose Strength(s)
Not applicable
Target Dosage Level(s)
(achieved upon titration)
Cohort 1 and Cohort 2: 40 mg BID, 
80 mg BID, 120 mg BID, 
160 mg BID, 200 mg BID
Cohort 3: 80 mg BID, 140 mg BID, 
200 mg BID
0 mg BID
Route of Administration
Oral
Oral
Use
Experimental
Placebo
IMP or NIMP
IMP 
IMP 
Sourcing
Provided centrally by the sponsor. 
Refer to the IP Manual.
Provided centrally by the 
sponsor. Refer to the IP Manual.
Packaging and Labeling
Cohort 1 and Cohort 2: Study 
intervention will be provided in blister 
packs. Each blister pack will be 
labeled as required per country 
requirement.
Cohort 3: Study intervention will be 
provided in bottles.
Blinded labels will be utilized for
placebo run-in, titration and stable 
dosing blister packs, and bottles.
Cohort 1 and Cohort 2: Study 
intervention will be provided in 
blister packs.  Each blister pack 
will be labeled as required per 
country requirement.
Cohort 3: Study intervention will 
be provided in bottles.
Blinded labels will be utilized 
for placebo run-in, titration and 
stable dosing blister packs, and 
bottles.
6.1.1. Administration
Participants will be provided with blinded study intervention, consisting of identical tablets, 
packaged in blister packs for Cohorts 1 and 2, and in bottles for Cohort 3. The same dosing 
paradigm will be used for the single-blind placebo run-in and the randomized double-blind 
study intervention administered in the study.  
CCI


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Participants in Cohorts 1 and 2 are instructed to take 4 tablets of study intervention 
(PF-06882961 or matching placebo) in the morning with food and 4 tablets of study 
intervention in the evening with food, for a total of 8 tablets of study intervention daily.  
Participants in Cohort 3 are instructed to take 2 tablets of study intervention (PF-06882961 or 
matching placebo) in the morning with food and 2 tablets of study intervention in the evening 
with food, for a total of 4 tablets of study intervention daily.  All participants are instructed to 
swallow the study intervention whole, and not crush, chew, break or dissolve the study 
intervention prior to swallowing.  
The morning and evening doses should be taken approximately 10-12 hours apart and at 
approximately the same time each day.  Participants should be instructed that if they forget to 
take a dose at their usual time, they should take that dose as soon as possible (with food), 
ensuring that there is at least an 8 hour interval between that dose and the next dose.  If the 
interval to the next dose is less than 8 hours, then the forgotten dose should not be 
administered.
Dosing and administration instructions along with a dosing diary, will be provided to 
participants to support at home dosing of the study intervention. When participants 
self-administer the study intervention at home, they will record each dose in the diary.  
Morning dosing will occur at the site with food at V2-V13 for Cohorts 1 and 2 (see SoA for 
Cohorts 1 and 2), and at scheduled in-clinic study visits for Cohort 3 (see SoA for Cohort 3).
Participants will be instructed to arrive at the site in the fasted state for each of these visits. 
Participants will be instructed to bring their study intervention supply and dosing diary with 
them, and to delay self-administration of study intervention until directed to dose during their 
visit.  When participants dose at the site, they will self-administer the study intervention 
under supervision by site staff. Onsite dosing will be administered from newly dispensed 
study intervention, with the exception of the End of Treatment visit (ie, the last dose), which 
will be administered from study intervention supply brought back to the site by the 
participant, as no new study intervention is dispensed at the End of Treatment visit. The date 
and time of each dose administered at the site will be recorded in the site source documents,
in the diary and in the CRF.  Additionally, the date and time of the previous 2 doses of 
double-blinded study intervention prior to each of the pre-dose PK blood collections (ie, the 
2 most recent doses prior to the visit as noted in the diary) will be entered in the CRF.
The actual titration schemes for PF-06882961 to be used in this study are provided in Table 1
for Cohorts 1 and 2, and Table 2 for Cohort 3.  Details regarding dose titration are provided 
in the IP Manual.






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6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken.  The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible.  Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  Specific details regarding the definition of an excursion
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
7. 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.  All study intervention that is 
taken home by the participant, both used and unused, must be returned to the 
investigator by the participant.  Returned study intervention must not be redispensed 
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8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented.  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
A qualified staff member will dispense the study intervention using the IRT system via 
unique container numbers on the blister cards or bottles provided, in quantities appropriate 
according to the SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for 
Cohort 3).  The participant should be instructed to maintain the product in the original 
containers provided throughout the course of dosing and bring the original containers to the 
site at the next study visit.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Assignment of placebo in the run-in period and allocation of participants to treatment groups 
for the double-blind treatment period will proceed through the use of an IRT system (IWR).
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s ID and password, the protocol number, 
and the participant number.  For the placebo run-in, the site personnel will then be provided 
with a DU or container number; for the double-blind treatment period, the site personnel will 
then be provided with a randomization number, and DU or container number(s). The IRT 
system will provide a confirmation report containing the participant number, randomization 
number, and DU or container number(s) assigned.  The confirmation report must be stored in 
the site’s files. 
For Cohort 1, a randomization code using the method of random permuted blocks will be 
utilized to randomize eligible participants in 3:3:3:3:3:3:1:1:1 (placebo: 5 1-week titration
PF-06882961 arms: 3 2-week titration PF-06882961 arms) prior to the first dose of 
double-blinded study intervention.  For the additional participants enrolled as part of 
Cohort 2, a randomization code using the method of random permuted blocks will be utilized 
to randomize eligible participants in 1:2:2:2 (placebo: 3 2-week titration PF-06882961 arms) 
prior to the first dose of double-blinded study intervention. For Cohort 3, a randomization 
code using the method of random permuted blocks will be utilized to randomize eligible 
participants in 1:2:2:2 (placebo: 3 4-week titration PF-06882961 arms) prior to the first dose 
of double blinded study intervention. Participants will be randomized to 1 of the blinded 
study intervention regimens described in Table 3 for Cohorts 1 and 2, and Table 4 for 
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6.3.2. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant. If a participant’s treatment assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Study Intervention Compliance
Compliance with study intervention will be assessed at each site visit by counting returned 
tablets and this will be documented in the source documents and CRF. Deviation(s) from the 
prescribed dosage regimen should be recorded in the CRF.
A record of the number of study intervention tablets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records.
Compliance (as assessed by tablet count) will be defined as self-administration, by the 
participants, of:
•
≥89% of the study-supplied placebo administered during the placebo run-in period.
Based on the visit window, for a run-in that is 11-13 days, 2 missed doses (or fewer)
are allowed, and for a run-in that is 14-17 days, 3 missed doses (or fewer) are 
allowed. Participants who do not meet this compliance threshold are not eligible to 
be randomized into the study (see Section 5.2).
•
≥80% of the study supplied from Day 1 through End of Treatment, inclusive.  
Investigators must closely follow non-compliant, randomized, participants in order to 
enhance their adherence to treatment.  Any participant who fails to meet the criterion 
of ≥80% compliance will be re-educated by the site staff on the importance of 
compliance with study intervention.
6.5. Concomitant Therapy
Participants in this study will be allowed to be on certain concomitant medications that have 
been prescribed.  Attempts should be made not to alter the doses and regimens of the 
background medications after randomization and for the duration of participation in this 
study, except in circumstances where a change in dose is deemed medically necessary.  Any 
changes must be captured in the CRF.  Additionally, many over-the-counter medications are 


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also permitted during this study unless specified as prohibited in Appendix 8, eg, appetite 
suppressants.  
Treatments taken within 28 days before the first dose of randomized study intervention on 
Day 1 will be documented as prior treatment.  Treatments taken after the first dose of 
randomized study treatment will be documented as concomitant treatment.  
All concomitant treatments, both prescription and over-the-counter 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. 
See Appendix 8 for details regarding prohibited concomitant medications, as well as 
medications with timeframes for restriction prior to V1 or prior to first dose of study 
intervention.  Sites are encouraged to contact the sponsor should there be questions as to 
whether a medication is permitted or prohibited.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
6.5.1. Antihypertensive Medications
The use of background antihypertensive agent(s) is permitted unless otherwise noted in 
Appendix 8.  Doses of antihypertensive agent(s) must be stable for at least 4 weeks prior to 
screening and throughout the study, except in circumstances where a change in dose is 
deemed medically necessary.  Any changes in doses of these medications must be captured in 
the CRF. 
6.5.2. Lipid Modifying Medications
The use of background lipid modifying agents is permitted unless otherwise noted in
Appendix 8.  Doses of such lipid modifying agents must be stable for at least 4 weeks prior 
to screening and throughout the study, except in circumstances where a change in dose is 
deemed medically necessary.  Any changes in doses of these medications must be captured in 
the CRF.
6.5.3. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with PF-06882961; standard medical 
supportive care should be provided to manage the AEs.
6.6. Dose Modification
6.6.1. Dose Titration
Dose titration schemes are utilized for each study intervention dosing arm in this study as 
described in Section 6.1.1.  Dose adjustment, either during dose titration or steady state 
dosing, will not be permitted per protocol. Separate materials on participant education and
approaches to manage temporary mechanism of action based gastrointestinal-related AEs
will be provided by the sponsor prior to initiation of dosing for Cohort 3.


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6.6.2. Considerations for Pausing or Stopping Active Dose(s) Based on Observed Safety
The decision to stop dosing for 1 or more active dose(s) of PF-06882961 may be considered 
based on recommendations from the IRC according to their review of unblinded, study-level 
emerging, observed safety data (see Section 9.5), for reasons such as the following:
•
More than 50% of participants develop a moderate or severe AE in the 
gastrointestinal SOC not responsive to symptomatic management.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following:
•
Criteria for a potential Hy’s law case are met (see Appendix 6);
•
Intent to become pregnant or pregnancy confirmed by β-hCG testing;
•
Safety or tolerability concern arises, in particular if not responsive to symptomatic 
management, dosing with double-blind study intervention may be stopped in an 
individual participant at the discretion of the investigator;
•
Based on mental health assessment as outlined in Section 8.2.6, should be
discontinued from dosing at the discretion of the investigator.
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 for obesity, and will be expected to continue with all study visits and 
assessments as outlined in the SoA for the applicable cohort (see SoA for Cohorts 1 and 2,
and SoA for Cohort 3), with the exception of dosing activities and assessment of PK. See the 
SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3) 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.


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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:
•
Refused further follow-up;
•
Lost to follow-up;
•
Death;
•
Study terminated by sponsor;
•
Safety or behavioral reasons at the discretion of the investigator, including reasons 
related to mental health assessments as described in Section 8.2.6.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA 
for Cohort 3) for assessments to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study.  Participants should be questioned regarding 
their reason for withdrawal.  The participant will be permanently discontinued both from the 
study intervention and from the study at that time.
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 


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withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for/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 for the applicable cohort (see 
SoA for Cohorts 1 and 2, and SoA for Cohort 3). 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 for the 
applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3), is essential and 
required for study conduct.


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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.
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.
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 who complete the study is 
approximately 280 mL. The actual collection times of blood sampling may change.  
Additional blood samples may be taken for safety assessments at times specified by the 
sponsor, provided the total volume taken during the study does not exceed 550 mL during 
any period of 60 consecutive days.
8.1. Efficacy Assessments
Efficacy assessments for this study include measurements of body weight, waist 
circumference, and waist-to-hip ratio (calculated from waist and hip circumference 
measurements). In addition, PCOAs will be completed to assess how the participants feel 
and function.
8.1.1. Primary Efficacy Parameter: Body Weight
Body weight is the primary efficacy assessment for this study.  Body weight will be 
measured in duplicate as indicated in the SoA for the applicable cohort (see SoA for 
Cohorts 1 and 2, and SoA for Cohort 3). The second weight measurement should be 
obtained at least 1-2 minutes apart from the first weight measurement.
Weight will be recorded using a calibrated scale (with the same scale used as much as 
practically 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). Calibration of 
the scale must occur within 3 months prior to study initiation at the site and at least every 
6 months during study conduct. The scale must be placed on a stable, flat surface.
Weight measurement should be taken under the following conditions:


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•
Participant is in a fasted state (see Section 5.3.1);
•
After the participant has been asked to void of urine (ie, forced void);
•
After the participant has removed shoes and bulky layers of clothing and jackets so 
that only light clothing (with empty pockets) or a hospital gown remains; 
•
With the participant standing still while on the scale.
8.1.2. Secondary Efficacy Parameters: Waist and Hip Circumference
Waist and hip circumference will be measured at the times specified in the SoA for the 
applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3) and will be used to 
calculate the waist-to-hip ratio.  The waist circumference is defined as the abdominal 
circumference located at the approximate midpoint between the lower margin of the last 
palpable rib and the top of the iliac crest.  The hip circumference is defined as the 
circumference around the widest portion of the buttocks.12,13
Waist and hip measurements should be taken under the following conditions:
•
Participant is in a fasted state (see Section 5.3.1);
•
After the participant has been asked to void of urine (ie, forced void);
•
With the participant wearing light clothing or a hospital gown that allows access for 
the measurements to be taken with the tape touching the skin (not clothing) for waist 
measurements, and the tape touching the skin if possible for hip measurements;
•
While the  participant is standing with their feet close together, their weight equally 
distributed to each leg, and arms at their side but with waist and hips accessible;
•
After the participant has been asked to breathe normally; the reading of the 
measurement should be taken at the end of a normal exhalation.
These measurements will be obtained using an anthropometric tape (stretch-resistant). The 
tape should be snug around the body, but not pulled so tight that it is constricting.  The tape 
should be in the horizontal all around the body, parallel to the floor at the level at which the 
measurement is made and avoiding twists in the tape. The waist and hip circumference will 
be measured in triplicate,12 with a brief interval (at least 1-2 minutes) between successive 
measurements. All 3 measurements will be recorded in inches or cm, rounded to the nearest 
1/16th inch or 0.1 cm.  




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Measure
Frequency 
Number of 
Questions
Estimated
Completion 
Time
US Sites Onlya
Ex-US 
Sitesb
IWQOL-Lite-CT©
Cohorts 1 and 2:
V2 (Pbo run-in)
V3 (Day 1)
V10 (Week 16)
V13 (Week 26)
Cohort 3:
V2 (Pbo run-in)
V3 (Day 1)
V11 (Week 16)
V15 (Week 24)
V19 (Week 32)
20
SF-36v2®
Cohorts 1 and 2:
V2 (Pbo run-in)
V3 (Day 1)
V10 (Week 16)
V13 (Week 26)
Cohort 3:
V2 (Pbo run-in)
V3 (Day 1)
V11 (Week 16)
V15 (Week 24)
V19 (Week 32)
36
9 minutes
At the clinic 
(electronic 
tablet)
At the clinic
(electronic 
tablet)
a.
Participants from US sites will complete all PRO assessments. 
b.
Participants from ex-US sites will complete only the SF-36v2®. 
c.
Participants from selected US sites will complete the Eating-Related Factors Daily Diary.
Every effort should be made to have the participant complete all PRO assessments as per the 
SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3).
Site-based PRO assessments should be completed by the participant at the beginning of the 
visit before any medical procedures or interactions with the medical staff (as much as 
practically possible) take place.
Additional details regarding the process of administration of the PROs will be provided in a 
study-specific user manual supplied by the sponsor.
8.1.3.1. Eating-Related Factors Daily Diary
The Eating-Related Factors Daily Diary is a daily, self-administered questionnaire that 
measures eating-related factors. The diary consists of 5 items that ask participants to 
evaluate their hunger, appetite, fullness, and cravings in the past 24 hours.
8.1.3.2. Patient’s Global Impression of Severity (PGI-S)
The PGI-S is a supportive item recommended by FDA for use as an anchor measure to 
generate an appropriate threshold that represents meaningful within-patient change in the 
target patient population. There are 4 PGI-S items that ask participants to evaluate the 
severity of their hunger, appetite, fullness, and cravings in the past 7 days.


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8.1.3.3. Patient’s Global Impression of Change (PGI-C)
The PGI-C is a supportive item recommended by FDA for use as an anchor measure to 
generate an appropriate threshold that represents meaningful within-patient change in the 
target patient population.  There are 4 PGI-C items that ask participants to rate the overall 
change in their hunger, appetite, fullness, and cravings since they started taking the study 
medication.
8.1.3.4. PROMIS® Fatigue Custom 9-item Version
The PROMIS® Fatigue29 Custom 9-item Version is a self-reported measure that assesses a 
range of symptoms in the past 7 days from mild subjective feelings of tiredness to an 
overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one’s 
ability to execute daily activities and function normally in family or social roles. A global 
raw score ranging from 9 to 45 is calculated and can be translated into a T-score 
(Mean=50, SD=10) using the applicable score conversion table or online HealthMeasures 
Scoring Service,30 where full derivation details will be provided in the SAP. 
8.1.3.5. PROMIS® Physical Function Custom 13-item Version
The PROMIS® Physical Function31 Custom 13-item Version is a self-reported measure that 
assesses capability rather than actual performance of physical activities. It includes 
assessment of one’s ability to walk, climb stairs, run/jog, exercise as well as instrumental 
activities of daily living.  A global raw score ranging from 13 to 65 is calculated and can be 
translated into a T-score (Mean=50, SD=10) using the applicable score conversion table or 
online HealthMeasures Scoring Service,30 where full derivation details will be provided in 
the SAP.
8.1.3.6. Impact of Weight on Quality of Life–Lite (IWQOL-Lite) Clinical Trials Version
The IWQOL-Lite-CT©32 was developed for use in the context of clinical trials for 
obesity, with 20 items addressing concerns that are specifically relevant to the study 
population.
8.1.3.7. SF-36v2® Health Survey
The SF-36v2®33 is a 36-item questionnaire that measures functional health and well-being 
from a patient’s perspective. It is a generic questionnaire and can be used across age (adults), 
disease, and treatment groups.  The questionnaire consists of 8 health domain scales: physical 
functioning (10 items), role-physical (4 items), bodily pain (2 items), general health 
(5 items), vitality (4 items), social functioning (2 items), role-emotional (3 items), mental 
health (5 items), reported health transition (1 item) and 2, physical and mental component 
summary scores.  Each health domain scale raw score is transformed to 0-100 scale which 
can then be converted to norm-based T scores (Mean=50, SD=10) using scoring software 
provided by the developer, where full derivation details will be provided in the SAP.


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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA for the applicable 
cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3).  Unscheduled clinical laboratory 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
8.2.1. Physical Examinations
Physical examinations are performed as indicated in the SoA for the applicable cohort (see 
SoA for Cohorts 1 and 2, and SoA for Cohort 3). 
Physical examinations may be conducted by a physician, trained physician’s assistant or 
nurse practitioner as acceptable and according to local regulation.  A complete physical 
examination will include, at a minimum, assessments of the participant’s general appearance, 
head, ears, eyes, nose, mouth, throat, neck (including thyroid examination), skin, heart and 
lung examinations, lymph nodes, as well as gastrointestinal, musculoskeletal and 
neurological systems.
Height will be measured after the participant has removed their shoes and will be collected at 
V1 only.  
A limited physical examination is performed at the in-clinic follow-up visit and may be 
performed at non-specified visits if there are findings during the previous physical 
examination or new/open AEs, if appropriate and at investigator discretion.  The limited 
physical examination will be focused on general appearance, lungs, heart, and participant 
reported symptoms.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2. Vital Signs
8.2.2.1. Blood Pressure and Pulse Rate
In this study, assessment of vital signs (systolic BP, diastolic BP, and pulse rate) will occur at 
the nominal time points specified in the SoA for the applicable cohort (see SoA for Cohorts 1 
and 2, and SoA for Cohort 3) per the following specifications:
•
At V1, the participant’s arm circumference should be measured (eg, using an
anthropometric tape) at the midpoint of the length of the upper arm and the 
appropriate cuff selected and used throughout the study. 
•
BP and pulse rate will be measured via an automated device using an oscillometric 
method (not auscultation).


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•
Assessment of BP and pulse rate can be manual (rather than using an automated 
device), only if an automated device is not available; however, when done 
manually pulse rate must be measured in the brachial/radial artery for at least 
30 seconds.
•
Supine BP and pulse rate will be measured with the participant’s arm supported at the 
level of the heart, following a rest of at least 5 minutes and BP will be recorded to the 
nearest mm Hg. Triplicate assessments will be measured, with an interval of at least 
1-2 minutes between each measurement, and these will be performed pre-dose (as 
applicable) at each planned in-clinic study visit. For visits with post-dose PK 
collections as specified in the SoA for the applicable cohort (see SoA for Cohorts 1 
and 2, and SoA for Cohort 3), these triplicate assessments will also be performed 
1 time within the window of approximately 2-6 hours post-dose (around the same 
time as post-dose PK samples are collected and according to the chronology in 
Appendix 9). Each triplicate reading will be recorded, and the average of the 
3 measurements at V3 (Day 1) will serve as the participant’s baseline.  
•
Same arm (preferably the dominant arm) will be used for BP and pulse rate
assessments throughout the study, whenever possible.
•
Participants should be instructed not to speak during BP and pulse rate measurements.
•
See Appendix 9 for proposed chronology of procedures for nominal time points when 
vital sign assessments coincide with other procedures. 
Additional collection times, or changes to collection times of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
8.2.3. Electrocardiograms
Standard 12-lead ECGs should be collected at times specified in the SoA section of this 
protocol for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3) using 
an ECG machine that automatically calculates the HR and measures PR, QT, and QTcF
intervals and QRS complex. All scheduled ECGs should be performed after the participant 
has rested quietly for at least 10 minutes in a supine position, and prior to dosing (as 
applicable), according to the chronology in Appendix 9. 
If a) a post-dose QTcF interval remains ≥30 msec from the baseline and is >450 msec; or 
b) an absolute QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours 
(or sooner, at the discretion of the investigator); or c) QTcF intervals get progressively 
longer, the participant should undergo continuous ECG monitoring (eg, cardiac telemetry or 
frequent ECG ascertainment as per investigator’s medical judgment).  A cardiologist should 
be consulted if QTcF intervals do not return to less than the criteria listed above after 8 hours 
of monitoring (or sooner, at the discretion of the investigator).


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In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3) 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 for the applicable cohort 
(see SoA for Cohorts 1 and 2, and SoA for Cohort 3). 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 to 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
DILI.
8.2.5. Management of Hypoglycemia
While hypoglycemia is not expected in the study participants, FPG will be measured at each 
clinic visit via the central lab. In addition, as a precaution, participants will be instructed to 
recognize the signs and symptoms associated with hypoglycemia. 
Any episode of hypoglycemia must be captured on the AE CRF with specific details captured 
on the HAE Form CRF.  For the definition of a hypoglycemic episode and severity 
categorization see Section 8.2.5.1 below.


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8.2.5.1. Definition and Severity of Hypoglycemic Adverse Event (HAE)
The investigator must assess the glucose values reported by the central laboratory, as well as 
any signs or symptoms reported by the study participant.
HAE is defined as one of the following:34
a.
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a glucose value of <70 mg/dL (3.9 mmol/L) using either glucometer 
(fingerstick blood glucose) at the study site or sponsor-identified central laboratory 
(plasma glucose).
b. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose value of <70 mg/dL (3.9 mmol/L), using 
glucometer at the study site or sponsor identified central 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 1 of the following neurological symptoms:
•
Memory loss;
•
Confusion;
•
Uncontrolled behavior;
•
Irrational behavior;
•
Unusual difficulty in awakening;
•
Suspected seizure;
•
Seizure;
•
Loss of consciousness.


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3. Either:
•
If blood glucose was measured and was ≤54 mg/dL (2.7 mmol/L) using 
glucometer (or central laboratory); or
•
If blood glucose was not measured, the clinical manifestations were reversed by 
oral carbohydrates, subcutaneous glucagon, or IV glucose.
Events that do not meet all the criteria above for severe HAE are characterized as mild or 
moderate in severity.
8.2.6. Mental Health Questionnaires 
8.2.6.1. Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behavior.18  The “baseline/screening” version of the C-SSRS will be administered at 
V1.  The “since last visit” version of the C-SSRS will be administered at the other visits 
specified in the SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for 
Cohort 3).  The C-SSRS will be administered by study site staff who have completed training 
in its administration. Participants who respond “yes” to questions 4 or 5 (indicating suicidal 
ideation), or to any suicidal behavioral question on the C-SSRS at V1, V2 or V3 will not be 
permitted in the study (see Section 5.2).
8.2.6.1.1. 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 will be outlined in a 
guidance document provided to each participating site.  The level of experience with the 
target population (or equivalent), specific scale experience (or equivalent), and certification 
required (if applicable) will be listed and used to determine whether a rater is approved for a 
given assessment.  The rater must become certified to perform selected study assessments 
before he or she can participate in the conduct of the study.  For specifically defined 
assessments, rater training and standardization exercises may be conducted, and written and 
signed documentation will be provided by the site for each rater’s certification.  In return, 
each site will be provided written and signed documentation outlining each rater’s 
certification for specific study assessments.  Recertification may be required at periodic 
intervals during the study.  The raters who administer specific study assessments will be 
documented in a centralized location and all site staff who administer ratings will be verified 
in the site study documentation during the conduct of the study.
8.2.6.2. Patient Health Questionnaire-9 (PHQ-9)
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms.19  The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in the SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA 
for Cohort 3).  A PHQ-9 score of ≥15 at V1, V2 or V3 indicates clinically significant 
depression and serves as an exclusion criterion for this study (see Section 5.2).


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8.2.6.3. Referral to a Mental Health Professional
A participant should be referred to a MHP for any of 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.
8.2.7. Pregnancy Testing 
Pregnancy tests will be both urine and serum, and must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in all females at the times listed in the SoA
for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3).  Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and a second negative pregnancy test result will be required at the baseline visit prior the 
participant’s receiving the study intervention.  Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected) and at the end of the study.  Pregnancy tests may also be repeated if 
requested by IRBs/ECs or if required by local regulations.  
8.3. 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 


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event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
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 after the last administration of the study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.


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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1 will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.


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An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 
•
A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.
•
A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.
•
A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP: 
•
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.
•
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then 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 calendar 
days after the last administration of IP.
•
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.


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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
•
Spontaneous abortion including miscarriage and missed abortion;
•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 
•
A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.
•
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.  


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The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease Related Events and/or Disease Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.


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8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:
•
Medication errors involving participant exposure to the study intervention;
•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 
tablets for Cohorts 1 and 2, or
tablets for Cohort 3, within a 24-hour time period will be considered an overdose.
There is no specific antidote for overdose with PF-06882961.  Treatment of overdose should 
consist of general supportive measures.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.
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2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-06882961 (whichever 
is longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 2 days 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 of approximately 3 mL each, to provide sufficient plasma for PK analysis, 
will be collected into appropriately labeled tubes containing K2EDTA, at times defined in the 
SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3) and 
according to the chronology in Appendix 9, with collections occurring prior to dosing with 
study intervention on the given scheduled visit, and also 1 time within the window of 
approximately 2 to 6 hours post-dose at specific visits noted in the SoA (ie, also collected 
post-dose for Cohorts 1 and 2 at V3, V7, V10 and V13, and for Cohort 3 at V3, V7, V11, 
V15 and V19).  The date/time of the blood collections related to PK (both pre- and post-dose 
samples) should be noted in source documents and captured in the CRF.  
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual.  To maintain sample integrity:
•
Any deviations from the PK sample handling procedures (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 scheduled pre-dose collection (ie, trough concentration) obtained post dose or 
any post dose samples not collected within the approximately 2-6 hours post dose 
interval, will be captured as a protocol deviation even if results are deemed evaluable.
As part of understanding the PK of the study intervention, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method, as well as for other 
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Samples will be analyzed using a validated analytical method in compliance with Pfizer
SOPs. 
8.6. Pharmacodynamics
PD parameters evaluated in this study include HbA1c, FPG, FPI, HOMA-IR, and HOMA-B,
and will be collected according to the SoA for the applicable cohort (see SoA for Cohorts 1 
and 2, and SoA for Cohort 3).  The PD parameters will be assessed by the Central Laboratory 
as part of the clinical laboratory assessments (see Appendix 2).  
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected as local 
regulations and IRBs/ECs allow.
Banked Biospecimens may be used for research related to the study intervention(s)  and 
adults with obesity.  Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may 
be studied using the banked samples. 
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in the laboratory manual.
8.8. Biomarkers
8.8.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.8.2. Specified Protein Research 
Specified protein research is not included in this study.
8.8.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.8.4. Banked Biospecimens for Biomarkers
Additional Banked Biospecimens in this study are as follows and will be collected at the 
timepoints outlined in the SoA for the applicable cohort (see SoA for Cohorts 1 and 2, and 
SoA for Cohort 3):
•
10-mL whole blood (Prep B2 optimized for serum); 
•
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Banked Biospecimens will be collected as local regulations and IRB/ECs allow.  
Banked Biospecimens may be used for research related to the study intervention(s)  and 
adults with obesity.  Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may 
be studied using the banked samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual. 
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.  Data from participants enrolled into the original cohort (Cohort 1) and 
Cohort 2 will be combined for reporting, where data from the placebo and 2-week titration 
arms will be combined from the 2 cohorts and analyzed together. Data from participants 
enrolled into Cohort 3 will be analyzed separately unless otherwise specified.
9.1. Estimands and Statistical Hypotheses
Estimands related to percent CFB in body weight:
The primary estimand (Estimand 1) will be the population average treatment effect on the 
percent CFB in body weight at End of Treatment of PF-06882961 compared to placebo in all 
evaluable participants while on treatment. For Cohorts 1 and 2, End of Treatment is defined 
as Week 26. For Cohort 3, End of Treatment is defined as Week 32. This reflects a 
combination of the ‘Hypothetical’ and ‘While on treatment’ strategies as outlined in the 
ICH-E9 (R1) guidance.35
Measurements after discontinuation of study intervention will be censored and treated as 
missing data.  Missing data due to censoring, study withdrawal or other reasons  will have 
data imputed based on a MAR assumption.  The population-based treatment effect will be the 
mean percent CFB in each PF-06882961 arm compared to placebo.  This estimand will 
similarly be applied to the percent changes from baseline in body weight at all time points 
through to End of Treatment. For all cohorts, all randomized participants  who take at least 
1 dose of study intervention will be included. 


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An additional exploratory estimand (Estimand 7) will be analyzed, which will be the 
population average treatment effect on the percent CFB in body weight at End of Treatment
of PF-06882961 compared to placebo in evaluable participants with no major protocol 
deviations and while on treatment. This reflects a combination of the ‘Hypothetical’, ‘While 
on treatment’ and ‘Principal stratum’ strategies as outlined in the ICH-E9 (R1) guidance.35
This is the same as Estimand 1 except that participants with major protocol deviations 
(eg, inadequate study intervention compliance, use of prohibited medication, etc.) will be 
excluded from this analysis. Major protocol deviations will be reviewed prior to database 
lock to identify such participants, with further details included in the SAP. 
Estimands related to achieving body weight loss ≥5% at End of Treatment:
A secondary estimand (Estimand 2) will be the population odds ratio of the treatment effect 
of achieving a body weight loss ≥5% from baseline at End of Treatment of PF-06882961 
compared to placebo in all evaluable participants while on treatment.  This reflects a 
combination of the ‘Hypothetical’ and ‘While on treatment’ strategies as outlined in the 
ICH-E9 (R1) guidance.35
Measurements after discontinuation of study intervention will be censored and treated as 
missing data.  Missing data due to censoring, study withdrawal, or other reasons 
(eg, laboratory failure) may be imputed as outlined in the SAP.  The population-based 
treatment effect will be the odds of achieving a body weight loss ≥5% from baseline at End 
of Treatment on PF-06882961 compared to the odds of achieving this on placebo (ie, odds 
ratio).
Estimands related to other endpoints:
Estimand 3 is similar to Estimand 1, except the population average treatment effect is on the 
absolute CFB in waist circumference at End of Treatment. The population based treatment 
effect will be the mean CFB in each PF-06882961 arm compared to placebo. 
Estimands 4, 5 and 6 will utilize the same approach as Estimand 3 for the associated 
endpoint(s).
Tertiary endpoints may be analyzed using similar estimands or analyzed in a descriptive 
manner without reference to an estimand.  Other supporting estimands may be used for some 
of the primary and secondary endpoints as a means to examine the robustness of results, 
compare to available literature and/or be used for future study planning as needed.  Details of 
these estimands and analyses will be presented in the SAP. 
9.2. Sample Size Determination
For Cohort 1, the sample size was based on the need to have an adequately sized safety 
database of participants on PF-06882961 in an obese population up to 26 weeks of dosing 
following Phase 2 clinical development. Approximately 420 participants (approximately
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approximately 20 in each of the 3 PF-06882961 arms with 2-week titration steps) were to be 
randomized in the original cohort (Cohort 1).  The sample size of Cohort 1 also provided
acceptable operating characteristics for decision making based on the primary endpoint, the 
percent CFB at End of Treatment in body weight.  
For Cohort 1, assuming a 25% drop-out rate there would be expected to be approximately
315 completed participants, with approximately 45 completed participants per arm for each 
of the placebo and 1-week titration PF-06882961 arms.  For End of Treatment defined as 
Week 26, this yields 80% power to detect a placebo-adjusted reduction in body weight of 
% (comparing PF-06882961 to placebo), using a 1-sided t-test at a 5% level and assuming 
a conservative SD on the loge-scale of 
for body weight change at Week 26, based on 
historical internal studies.
For Cohort 2, approximately 49 additional participants were to be randomized to the placebo 
and 2-week titration PF-06882961 arms (approximately 7 in the placebo and approximately 
14 in each of the 3 2-week titration arms). This sample size was selected to provide 
additional tolerability data on the 2-week titration arms and provide improved operating 
characteristics of the primary endpoint.
Assuming a 25% drop-out rate, with the combination of placebo and the 2-week titration 
arms from both Cohorts 1 and 2 (approximately 67 participants randomized to placebo and 
approximately 34 participants in each of the 2-week titration arms in total) there would be 
expected to be approximately 50 completed placebo participants and approximately 
25 completed participants in each of the 2-week titration arms. For End of Treatment defined 
as Week 26, this yields 80% power to detect a placebo-adjusted reduction in body weight of 
% (comparing a 2-week titration arm of PF-06882961 to placebo), using a 1-sided t-test at 
a 5% level, and assuming a conservative SD on the loge-scale of 
 for body weight 
change at Week 26, based on historical internal studies.
For Cohort 3, approximately 112 additional participants will be randomized (approximately 
16 in the placebo and approximately 32 in each of the 3 PF-06882961 arms with 4-week 
titration steps). This sample size was selected to provide additional tolerability data using 
4-week titration steps and provide acceptable operating characteristics for the primary 
endpoint. Assuming a discontinuation rate of 25%, it is expected that approximately 84 of 
these participants will complete the study, with approximately 12 completing the placebo 
arm and approximately 24 completing each of the PF-06882961 arms. For End of Treatment 
defined as Week 32, this yields 80% power to detect a placebo-adjusted reduction in body 
weight of
% (comparing PF-06882961 to placebo) at Week 32, using a 1-sided t-test at a 
5% level and assuming a conservative SD on the loge-scale of 
for body weight change at
Week 32, based on historical internal studies. If judged necessary by the sponsor to meet 
study objectives (for example, if the rate of discontinuation or rate of non-compliance is 
higher than anticipated), then up to approximately 140 participants may be randomized into 
Cohort 3, to ensure a sufficient number of completing participants.  
Participants who withdraw from the study will not be replaced.  Evaluable participants are 
defined as in Section 9.3.
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9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined for the combined Cohorts 1 
and 2, and separately for Cohort 3:
Participant Analysis Set
Description
Enrolled
"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.
Randomly assigned to study 
intervention
All participants randomly assigned to study intervention 
regardless of whether or not study intervention was 
administered.
Evaluable
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention.  
Participants will be analyzed according to the randomized 
study intervention.
Safety
All participants randomly assigned to study intervention
and who take at least 1 dose of study intervention.  
Participants will be analyzed according to the study 
intervention they actually received.
Defined Analysis Set
Description
Estimand Set 1 (related to 
estimands 1, 2, 3, 4, 5 and 
6)
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  For participants 
who discontinue study intervention, all subsequent values will 
be censored.
Estimand Set 2 (related to 
estimand 7)
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and do not have 
major protocol deviations. Major protocol deviations will be 
reviewed prior to database lock to identify such participants, 
with further details included in the SAP. For participants who 
discontinue study intervention, all subsequent values will be 
censored. 


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PK Concentration Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of PF-06882961 and in whom at least 
1 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
Cohorts 1 and 2 will generally be analyzed separately from Cohort 3, with all treatment arms 
of PF-06882961 and placebo analyzed separately. For Cohorts 1 and 2, reporting of the 
placebo and the 2-week titration PF-06882961 arms will be based on the combined set of 
participants from both cohorts, ie, the original cohort (Cohort 1) and Cohort 2.
For Cohorts 1 and 2, End of Treatment is defined as Week 26. For Cohort 3, End of 
Treatment is defined as Week 32.
9.4.1.1. Analyses for Continuous Endpoints
The MMRM model(s) will include treatment, time, strata (females versus males) and 
treatment-by-time interaction as fixed effects, baseline as a covariate and the 
baseline-by-time interaction with time fitted as a repeated effect and participant as a random 
effect. An unstructured correlation matrix will be used, and the Kenward-Roger 
approximation will be used for estimating degrees of freedom for the model parameters.
Missing values will be imputed as part of the MMRM model assumptions.
9.4.1.2. Analyses for Categorical Endpoints
The logistic regression model(s) will include a term for treatment, strata (females versus 
males), and baseline will be included as a covariate.  
Missing values will be imputed using multiple imputation where the model will include 
treatment, baseline and strata (females vs. males) and will include all time course data up to 
Week 26 or Week 32, depending on the cohort. The logistic regression model will be applied 
to each imputed dataset and the parameter estimates will be combined using standard 
multiple imputation techniques. Further details will be described in the SAP.
9.4.2. Primary Endpoint(s)
A MMRM analysis (as per Section 9.4.1) of the percent CFB in body weight through End of 
Treatment will be used to estimate the treatment effect related to the primary Estimand 1.
MMRM models will be fitted to the combined Cohorts 1 and 2 data and separately to the 
Cohort 3 data. Baseline body weight will be included on the loge-scale. The MMRM models


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will be fitted to the CFB of loge-transformed values to Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 
and 26 for Cohorts 1 and 2 or Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for Cohort 3 from the 
Estimand Set 1. The modelled mean loge-differences and 90% CIs for the loge-differences at
the End of Treatment timepoint will be extracted from the model and exponentiated to 
provide estimates of the relative difference in each PF-06882961 treatment arm reported 
separately, compared to placebo.
No adjustments will be made for multiplicity.
9.4.3. Secondary Endpoint(s)
For the secondary endpoints described below in the table, models will be fitted to the 
combined Cohorts 1 and 2 data, and separately to the Cohort 3 data.
Endpoint
Statistical Analysis Methods
Secondary: 
Response as defined 
by a body weight 
loss ≥5% at End of 
Treatment.
A logistic regression analysis utilizing multiple imputation for 
missing values (as per Section 9.4.1.2) of participants who achieved 
a body weight loss ≥5% at the End of Treatment timepoint and 
those that didn’t will be used to estimate the treatment effect related 
to the secondary estimand 2. Baseline body weight will be included 
in the logistic regression and multiple imputation analyses.
The logistic regression model will be fitted to the End of Treatment
timepoint only after multiple imputation has been applied to 
Estimand Set 1.  No adjustments will be made for multiplicity.
Secondary: Percent 
CFB in body weight 
at Weeks 2, 4, 6, 8, 
10, 12, 16, 18 and 
22 for Cohorts 1 and 
2, and at Weeks 4, 
8, 12, 16, 20, 24 and 
28 for Cohort 3
Results related to this endpoint will be obtained from the Primary 
Analysis model.
No adjustments will be made for multiplicity.
This analysis will estimate the treatment effect related to 
Estimand 1.
Secondary: 
Absolute CFB in 
waist circumference 
at End of Treatment
Absolute CFB in waist circumference at each planned in-clinic 
study visit up through the End of Visit Treatment visit will be 
analyzed using an MMRM model (as per Section 9.4.1.1). Baseline 
waist circumference will be included as a covariate in the model. 
No adjustments will be made for multiplicity. Results at the End of 
Treatment timepoint will be extracted from the model. 
This analysis will be applied to Estimand Set 1 to estimate the 
treatment effect related to Estimand 3.


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Endpoint
Statistical Analysis Methods
Secondary: 
Absolute CFB in 
waist-to-hip ratio at 
End of Treatment
Absolute CFB in waist-to-hip ratio at each planned in-clinic study 
visit up through the End of Visit Treatment visit will be analyzed 
using an MMRM model (as per Section 9.4.1.1). Baseline waist-to-
hip ratio will be included as a covariate in the model. No 
adjustments will be made for multiplicity. Results at the End of 
Treatment timepoint will be extracted from the model.
This analysis will be applied to Estimand Set 1 to estimate the 
treatment effect related to Estimand 4.
Secondary: CFB in 
HbA1c at Weeks 16
and 26 for Cohorts 1 
and 2, and Weeks 
16, 24 and 32 for 
Cohort 3
CFB in HbA1c at Weeks 16 and 26 for Cohorts 1 and 2, and Weeks 
16, 24 and 32 for Cohort 3, will be analyzed using an MMRM 
model (as per Section 9.4.1.1).  Baseline HbA1c will be included as 
a covariate in the selected model. No adjustments will be made for 
multiplicity.
This analysis will be applied to Estimand Set 1 to estimate the 
treatment effect related to Estimand 5.
Secondary: CFB in 
FPG at each planned 
in-clinic study visit 
up through the End 
of Treatment
CFB in FPG at each planned in-clinic study visit up through the End 
of Treatment will be analyzed using an MMRM model (as per 
Section 9.4.1.1). Baseline FPG will be included as a covariate in 
the model.  No adjustments will be made for multiplicity.
This analysis will be applied to Estimand Set 1 to estimate the 
treatment effect related to Estimand 6.
9.4.4. Tertiary/Exploratory Endpoint(s)
For the purposes of reporting the shift in glycemic categories,34 the following definitions will 
be used:
•
Normoglycemia: FPG <100 mg/dL and HbA1c <5.7%;
•
Pre-diabetes: FPG 100-125 mg/dL (both inclusive) or HbA1c 5.7-6.4% (both 
inclusive);
•
T2DM: FPG ≥126 mg/dL or HbA1c ≥6.5%.
For discordant results between FPG and HbA1c with respect to the glycemic category 
criteria, the higher category will be used (eg, a participant with FPG of 124 mg/dL and 
HbA1c of 6.6% would be classified as T2DM).  
Further details on the definitions and analyses of this and other Tertiary/Exploratory 
endpoints will be described in the SAP.


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9.4.5. Other Safety Analyses
The safety data will be summarized in accordance with Pfizer Data Standards.  All 
participants who receive study intervention (safety population) will be included in the safety 
analyses.  All safety data will be summarized descriptively through appropriate data 
tabulation, descriptive statistics, categorical summaries, and graphical presentations.  Safety 
endpoints for the study are referenced in Section 8.2.
Results may also be reported by strata (females versus males), where details will be 
described in the SAP.
9.4.5.1. Electrocardiogram Interval Analyses
CFB for the ECG parameters QT interval, HR, QTcF interval, PR interval, and QRS complex
will be summarized by treatment and time.
The number (%) of participants with maximum post dose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
9.4.6. Other Analyse(s)
Tertiary/Exploratory analyses not included in the efficacy or safety analyses outlined above 
will be documented in the SAP and may not be reported in the CSR. 
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during or 
after the trial and retained for future analyses; the results of such analyses are not planned to 
be included in the CSR.
9.5. Interim Analyses
An interim analysis will be performed at least once annually while the study is ongoing, after 
at least 25% of participants (ie, approximately 105) are randomized, with further details 
provided in the IRC charter.  This interim analysis will assess, at a minimum, unblinded
safety of the randomized participants. Additional interim analyses for safety and/or efficacy 
may be performed if needed. Further details will be provided in the IRC charter.  
Interim analysis results may be used for internal business decisions including, but not limited 
to: stopping a dose level, future study planning, stopping for futility, stopping for early 
success, conducting a sample size re-estimation, or adapting the study after the interim 
analysis.  Before any interim analysis is instigated, the details of the objectives, decision 
criteria, information dissemination plan, and method of maintaining the study blind as per 
Pfizer’s SOPs will be documented and approved in an IRC charter.  In addition, the analysis 
details must be documented and approved in an interim analysis SAP or final SAP.


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9.5.1. PK/PD Unblinding Plan
A limited number of individuals not on the study team will be unblinded according to 
sponsor SOPs with the purpose of composing PK/PD analysis sets and conducting PK/PD 
analysis that will be made available to the study team following database lock.  These data 
are expected to include PK, body weight, vitals and potentially other PD markers.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC. The IRC is independent of the study team and includes only 
internal (ie, Pfizer colleague) members.  The IRC charter describes the role of the IRC in 
more detail.  The IRC will be responsible for ongoing monitoring of the safety and/or 
efficacy of participants in the study according to the charter.  The recommendations made by 
the IRC to alter the conduct of the study will be forwarded to the appropriate Pfizer personnel 
for final decision.  Pfizer will forward such decisions, which may include summaries of 
aggregate analyses of safety data, to regulatory authorities, as appropriate. 
This study will not use a DMC.


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


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10.1.2. Financial Disclosure
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.
Participants who are rescreened are required to sign a new ICD.


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Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples.  The investigator 
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a participant's agreement to allow specimens to be 
used for additional research. Participants who decline to participate in this optional 
additional research will not provide this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.  In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods.  Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data.  Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make 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.


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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.
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.
)


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:
•
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;


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•
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.
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.


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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 system.  
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.  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 laboratory tests will be performed at times defined in the SoA section of this 
protocol for the applicable cohort (see SoA for Cohorts 1 and 2, and SoA for Cohort 3).  
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 6.
Protocol Required Laboratory Assessments
Hematology
Chemistry
Urine Testing
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN 
Creatinine
eGFR
Plasma Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST
ALT
TBili
GGT
Alkaline phosphatase
Uric acid
Albumin
Total protein
Urinalysis:
•
pH
•
Glucose (qual)
•
Protein (qual)
•
Blood (qual)
•
Ketones
•
Nitrites
•
Leukocyte esterase
•
Urobilinogen
•
Urine bilirubin
•
Microscopya
Urine pregnancy test
HbA1c
Plasma insulin (fasting)
Serum pregnancy test 
(β hCG)
Lipid panel:
•
Total cholesterol
•
Direct LDL-C
•
HDL-C
•
Triglycerides
TSH
Free T4
Calcitonin
Amylase
Lipase
Total bile acids
PT/INR/aPTT
At V1 only:
FSHb
C-peptide (fasting)
Urine drug screen
Additional Tests (Needed 
for Hy’s Law)
AST, ALT (repeat)
TBili (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
CK
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or 
protein adduct levels
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For female participants to confirm post-menopausal status only.


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Investigators must document their review of each laboratory safety report.
After randomization, the sponsor study team and site will be blinded to HbA1c, FPG, and 
FPI measured by the central laboratory, unless the FPG meets the criterion for hypoglycemia 
as listed in Section 8.2.5.1, or indicates hyperglycemia with an FPG ≥270 mg/dL 
(15.0 mmol/L).






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serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
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.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or non-pathogenic, is considered serious.
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:
•
Medical or scientific judgment should be exercised 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.










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•
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 
 between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:
•
Is not a WOCBP (see definitions below in Section 10.4.3).
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure
rate of <1% per year), preferably with low user dependency, as described below
during the intervention period and for at least 28 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any reproductive 
safety risk of the study intervention(s). The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention.
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with high user dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention,
which corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s).  In addition, a second effective method of contraception, as 
described below, must be used.  The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
CCI


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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 of age and not using hormonal 
contraception or HRT. 
•
Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they 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. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.


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4. Bilateral tubal occlusion.
5. Vasectomized partner.
•
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:
•
Oral;
•
Intravaginal;
•
Transdermal.
2. Progestogen-only hormone contraception associated with inhibition of ovulation:
•
Oral;
•
Injectable.
3. 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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10.5. Appendix 5: Genetics
Use/Analysis of DNA
•
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.
•
The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.
•
The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.
•
The results of genetic analyses may be reported in CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.
•
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
•
The samples will be retained as indicated:
•
Samples for banking will be stored indefinitely or for another period as per local 
requirements.
•
Participants may withdraw their consent for the storage and/or use of their Banked 
Biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.
•
Banked Biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.


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


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






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10.8. Appendix 8: Prohibited Prior/Concomitant Medications
The medications listed in Table 7 may interact (at the PK level) with PF-06882961 and thus 
are prohibited for the provided timeframe of restriction (Table 7) and until the first follow-up 
visit. Additionally, the medications listed in Table 8 are also prohibited for the provided 
timeframe of restriction (Table 8) and until the first follow-up visit. 
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgment on the ongoing 
participation of any participant with prohibited medication use during the study.
Prohibited medications and timeframe of restriction may be revised during the course of the 
study with written notification from sponsor, to include or exclude specific drugs or drug 
categories for various reasons (eg, emerging DDI results for the investigational products, 
availability of new information in literature on the DDI potential of other drugs).  
These are not all-inclusive lists. Site staff should consult with the sponsor or designee 
with any questions as to whether a medication is permitted or prohibited and questions 
regarding potential DDI.
Investigators should consult the product label for any other medication used during the study
for information regarding medication that is prohibited for concomitant use.
Table 7.
Prohibited medications that may interact (at the PK level) with PF-06882961
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Table 8.
Other Prohibited Medications
Drug Classes and/or Drugs
Timeframe of Restriction
Thiazolidinediones such as pioglitazone and rosiglitazone.
90 days prior to V1
Subcutaneously administered agents for glycemic control (eg, insulin, 
exenatide, liraglutide, dulaglutide, semaglutide, tirzepatide, pramlintide).  
Note: Short-term (ie, ≤7 days) of insulin administration is permitted if 
participant is hospitalized.
90 days prior to V1
Pharmacological agents with approved indication for weight loss such as 
liraglutide, semaglutide, orlistat and sibutramine.
90 days prior to V1
Oral anti-diabetic medications, including:
Metformin
Sulfonylureas such as acetohexamide, chlorpropamide, tolazamide, 
tolbutamide, glimepiride, glipizide, glyburide. 
Meglitinide analogues such as repaglinide, nateglinide.
60 days prior to V1
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Drug Classes and/or Drugs
Timeframe of Restriction
DPP-4 inhibitors such as sitagliptin, saxagliptin, linagliptin, vildagliptin.
α-glucosidase inhibitors such as acarbose, miglitol.
SGLT2 inhibitors such as canagliflozin, empagliflozin, dapagliflozin, 
ertugliflozin.  
Anti-hyperglycemic medications, including bromocriptine and colesevelam
Oral GLP-1 receptor agonists (oral semaglutide).
Systemic glucocorticoids such as prednisone, dexamethasone, triamcinolone, 
budesonide, betamethasone.  Note: As an exception, steroid-containing 
inhalers, nasal sprays and topical formulations are permitted.  
Note: Intercurrent treatment with systemic corticosteroids during 
participation in the study may be permitted if treatment does/will not exceed 
7 days.
60 days prior to V1
Immunosuppressants such as cyclosporine and tacrolimus.
60 days prior to V1
Appetite or weight modifying medications, including nonprescription or 
herbals and medical grade marijuana.
60 days prior to V1
Anti-psychotic medications such as olanzapine, risperidone.
60 days prior to V1
Coumarin type anticoagulants or other anticoagulants (eg, dabigatran, 
apixaban, edoxaban, fondaparinux, rivaroxaban).
60 days prior to V1
Anticonvulsants if prescribed for seizure disorder.
60 days prior to V1
Antiarrhythmic medications whose primary mechanism of action is sodium 
or potassium channel blockade (eg, procainamide, phenytoin, quinidine, 
propafenone; as well as amiodarone, dofetilide, sotalol).
Note: β-adrenergic receptor blocking agents (eg, atenolol, metoprolol) and 
calcium channel blockers (eg, diltiazem, amlodipine, nifedipine) are 
permitted.
60 days prior to V1
Sympathomimetic agents.
Note: Inhaled β-adrenergic receptor agonists (eg albuterol) are permitted.
Methylphenidate and amphetamine medications for ADHD that are at a stable 
dose for at least 90 days prior to V1 are permitted.
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10.9. Appendix 9: 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:
•
Site-based PRO assessments: should be completed by the participant at the beginning 
of the visit before any medical procedures or interactions with the medical staff (as 
much as practically possible) take place (see Section 8.1.3);
•
12-lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing (as applicable) (see Section 8.2.3); 
•
Vital Signs (BP, pulse rate): 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); 
•
Measurement of body weight, waist and hip circumference:  obtain prior to dosing 
and food consumption (see Section 8.1.1 and Section 8.1.2);
•
Fasting blood samples [for safety (see Section 8.2.4), PK (see Section 8.5), and 
banked biospecimens (see Section 8.7.2 and Section 8.8.4)]: after assessment of 
12-lead ECG and vital signs but prior to dosing (as applicable for pre-dose 
collection); 
•
Dosing: must occur in the morning with food, and where applicable, after any 
pre-dose blood sample collection(s); 
•
For the random, post-dose PK blood collection to occur approximately 2 to 6 hours 
post dose (see Section 8.5): these blood samples should be collected after vital signs 
are measured; if collection time coincides with time of a meal/snack, these blood 
samples should be collected just prior to the meal/snack.


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10.10. Appendix 10: Protocol Amendment History
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below:
Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 1
16 December 2021
Rationale: The protocol was amended to 
add Cohort 2 where approximately 
49 additional participants will be 
randomized in a 1:2:2:2 ratio to the placebo 
(Arm 1, Figure 2) and 3 slow titration arms 
(Arms 7, 8, 9, Figure 2).  This cohort was 
added to better characterize the tolerability 
and efficacy profile of the 2-week titration 
schemes, relative to the 1-week titration 
schemes, and to maintain the double-blind 
study design.  All SoA activities will be the 
same for Cohort 2 as for the original 
Cohort of randomized participants.  The 
following sections were revised as part of 
this rationale: 
Section 1.1 Synopsis, Overall Design: 
Added wording to reflect the addition of 
Cohort 2, including that the additional 
participants will be randomized to blinded 
study intervention in 1 of 4 arms in a 
1:2:2:2 ratio (placebo: 3 slow titration 
arms). 
Section 1.1 Synopsis, Number of 
Participants: Added the number of 
participants in Cohort 2, specifying that 
approximately 49 additional participants 
will be randomized to the placebo and slow 
titration arms (approximately 7 in the 
placebo and approximately 14 in each of 
the 3 slow titration arms).


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Section 1.2 Schema, Figure 2 Titration 
Schema: Revised the “n” in the figure for 
the placebo and 3 slow titration arms to 
reflect the total number of participants in 
those arms, including the original Cohort 
plus Cohort 2.  Added a footnote to explain 
this.
Section 4.1 Overall Design: Revised the 
wording to reflect the addition of Cohort 2, 
including the subsequent enrollment into 4 
of the 9 study arms (placebo and the 3 slow 
titration arms), and the number of 
participants being added as approximately 
49.
Section 6.3.1 Allocation to Study 
Intervention: Added wording to reflect the 
randomization for Cohort 2 is 1:2:2:2 
(placebo: 3 slow titration arms).
Section 9 Statistical Considerations: Added 
wording to reflect that the data from both 
cohorts (the original Cohort and Cohort 2) 
will be combined for final reporting.
Section 9.2 Sample Size Determination: 
provided updated sample size for Cohort 2 
including rationale.
Section 9.4.1 General Considerations: 
Added wording to reflect that the data from 
both cohorts (the original Cohort and 
Cohort 2) will be combined for final 
reporting.
Rationale: updated the nonclinical safety 
section with the most recent toxicology 
information, available after the original 
protocol.
Section 2.2.1.2 Nonclinical Safety: Added 
that data from the 9-month toxicology 
study in cynomolgus monkeys (Study 
) demonstrated no test 
article-related mortality, use of palliative 
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23 November 2020) change to clarify that 
continuous ECG monitoring for the 
referenced scenario may be either cardiac 
telemetry or frequent ECG ascertainment as 
per investigator’s medical judgment for 
sites that do not have access to cardiac 
telemetry. 
Section 8.2.3 Electrocardiograms: added 
wording after continuous ECG monitoring 
to reflect this could be cardiac telemetry or 
frequent ECG ascertainment as per 
investigator’s medical judgment.
Rationale: incorporated Protocol 
Administrative Clarification Letter (dated 
23 November 2020) change to clarify more 
precisely the timing following screening 
that blinding of the specified laboratory 
results will begin after randomization.
Section 10.2, Appendix 2: Clinical 
Laboratory Tests: changed wording for 
blinding of the specified labs to be “after 
randomization” rather than “following 
screening”.
Rationale: incorporated Protocol 
Administrative Clarification Letter #2 
(dated 21 January 2021) change to clarify 
that the unblinding criteria for FPG include 
parameters for hyperglycemia as well as 
hypoglycemia, and to specify the level of 
FPG required for unblinding. 
Section 10.2, Appendix 2: Clinical 
Laboratory Tests; added wording for 
unblinding for FPG that indicates 
hyperglycemia with an FPG ≥270 mg/dL 
(15.0 mmol/L).
Rationale: incorporated changes from 
Protocol Administrative Clarification Letter 
#2 (dated 21 January 2021) and #3 (dated 
01 Feb 2021) to clarify that the standard 
30 day washout for investigational drug use 


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should be interpreted to include 
investigational vaccines.  Per FDA 
guidance FDA does not consider receipt 
under an Emergency Use Authorization as 
receipt of an investigational product. 
Section 5.2. Exclusion Criteria, criterion 
#16: revised wording to investigational 
product (eg, drug or vaccine).
Rationale: clarified that serum and urine 
pregnancy tests are required for all females 
regardless of childbearing potential.
Section 1.3 Schedule of Activities (SoA): 
in SoA table, for Pregnancy test row and 
Urine on-site pregnancy test row changed 
parenthetical content from “females only” 
to “all females”. Revised table footnote “o” 
to include that serum and urine pregnancy 
tests are required for all females regardless 
of childbearing potential.
Rationale: clarified that the post-dose vital 
sign measurements are done in triplicate.
Section 1.3 Schedule of Activities (SoA): 
revised the wording of table footnote “i” to 
clarify post dose vital signs will be 
measured in triplicate. 
Section 8.2.2.1 Blood Pressure and Pulse 
Rate: in the bullet point that addresses post-
dose BP and pulse rate measurements 
clarified that these are triplicate 
assessments.
Rationale: clarified that methylphenidate 
and amphetamine medications for ADHD 
that are at a stable dose for at least 90 days 
prior to V1 are permitted.
Section 10.8 Appendix 8: Prohibited 
Prior/Concomitant Medications: Added a 
note to the sympathomimetic agents 
category to clarify that methylphenidate 


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and amphetamine medications for ADHD 
that are at a stable dose for at least 90 days 
prior to V1 are permitted.
Rationale: clarified that MHP referral 
should be done for any of the reasons 
listed.
Section 8.2.6.3 Referral to a Mental Health 
Professional: added “any of” before the list 
of reasons for MHP referral.
Rationale: incorporated administrative 
revisions consistent with the updated 
Clinical Protocol Template Phase 1 2 3 4 
(01 March 2021).
Title page: changed to new Pfizer logo.
Sections: 7.1, 8.3.1, 10.3.2, 10.3.3 and 
10.4.4: editorial revisions.
Rationale: entered study intervention name.
Title page: entered Danuglipron in Study 
Intervention Name row.
Original protocol
14 September 2020 
N/A


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10.11. Appendix 11: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Term
%CV
percent coefficient of variation
Abs
absolute
ADHD
Attention Deficit Hyperactivity Disorder
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve 
AUC24
area under the concentration-time curve from time 0 to 24 hours 
AUCinf
area under the concentration-time curve from time 0 to infinity
AV
atrioventricular
β-hCG
β-human chorionic gonadotropin 
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
C-SSRS
Columbia-Suicide Severity Rating Scale
cAMP
cyclic adenosine monophosphate
CFB
change from baseline
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 
Cmax
maximum observed concentration 
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
DCT
data collection tool
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
CCI
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Term
DNA
deoxyribonucleic acid
DPP 4
dipeptidyl peptidase 4 
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EoT
End of Treatment
ePRO
electronic patient-reported outcome
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FPG
fasting plasma glucose 
FSH
follicle-stimulating hormone
FPI
fasting plasma insulin 
FT4
free thyroxine
FU
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
HAE
hypoglycemic adverse event
HbA1c
hemoglobin A1c
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HOMA-B
homeostatic model assessment of beta-cell function
HOMA-IR
homeostatic model assessment of insulin resistance
HR
heart rate
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ICH E9 (R1)
ICH Harmonised Guideline E9 (R1)
ID
identification
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP manual
investigational product manual


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Term
IPAL
Investigational Product Accountability Log
IR
immediate release
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ISO
International Organization for Standardization
IV
intravenous
IVGTT
intravenous glucose tolerance test 
IWQOL-Lite-CT©
Impact of Weight on Quality of Life – Lite Clinical Trials Version
IWR
interactive Web-based response
K2EDTA
dipotassium edetic acid (ethylenediaminetetraacetic acid)
LBBB
left bundle branch block
LFT
liver function test
LLN
lower limit of normal
loge
natural logarithm
MAR
missing at random
MATE
multidrug and toxin extrusion protein 
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR1
multidrug resistance mutation 
MHP
mental health professional
MMRM
mixed model repeated measures
N/A
not applicable
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
OCT
organic cation transporter 
Pbo
placebo
PCOA
patient centered outcome assessment
PD
pharmacodynamic(s)
PGI-C
patient’s global impression of change 
PGI-S
patient’s global impression of severity 
PHQ-9
Patient Health Questionnaire-9
PI
principal investigator
PK
pharmacokinetic(s)
PRO
patient-reported outcome
PROMIS®
Patient-Reported Outcomes Measurements Information System
PT
prothrombin time
PVC
premature ventricular contraction/complex
QTcF
corrected QT (Fridericia method)
qual
qualitative
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Term
Rac
accumulation ratio based on AUC 
RBC
red blood cell
REE
resting energy expenditure
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SF-36v2®
Short Form-36 Health Survey
SGLT2
sodium glucose cotransporter 2 
SoA
schedule of activities
SOC
system organ class 
SOP
standard operating procedure
SRSD
single reference safety document
SSID
study-specific subject identification 
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
T
telephone 
t½
terminal phase half-life 
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
TBA
total bile acids
TBili
total bilirubin
TEAEs
treatment emergent adverse events 
TEE
total energy expenditure
Tmax
time to first occurrence of Cmax
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
V
visit
WBC
white blood cell
Wk
week
WOCBP
woman of childbearing potential
CCI


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11. REFERENCES
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Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
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Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin 
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Franz MJ, VanWormer JJ, Crain AL, et al. Weight-loss outcomes: a systematic review 
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Diet Assoc 2007;107(10):1755-67.
22.
American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines, Obesity Expert Panel, 2013. Expert Panel Report: guidelines (2013) for the 
management of overweight and obesity in adults. Obesity (Silver Spring) 2014;22: 
Suppl 2:S41-410.
23.
Di Benedetti D, Harris N, Rozjabek HM, et al. Assessing factors influencing eating in 
overweight and obese individuals.  Poster presented at Endo 2019; 23-26 March 2019; 
New Orleans, LA.
24.
Tronieri JS, Wadden TA, Walsh O, et al. Effects of liraglutide on appetite, food 
preoccupation, and food liking: results of a randomized controlled trial. Int J Obes 
(Lond) 2020;44(2):353-61.


PF-06882961
Protocol C3421019
Final Protocol Amendment 2, 16 September 2022
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 135
25.
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.
26.
O’Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide 
compared with liraglutide and placebo for weight loss in patients with obesity: a 
randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial.  
Lancet 2018;392(10148):637-49.
27.
Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 
2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102. 
28.
Lin PH, Proschan MA, Bray GA, et al. Estimation of energy requirements in a 
controlled feeding trial.  Am J Clin Nutr 2003;77:639–45.
29.
Patient Reported Outcomes Measurements Information System, FATIGUE: A brief 
guide to the PROMIS® Fatigue instruments; Feb 28, 2019.
30.
HealthMeasures. http://www.healthmeasures.net/score-and-interpret/calculate-
scores/scoring-instructions.  2020.
31.
Patient-Reported Outcomes Measurements Information System, PHYSICAL 
FUNCTION, A brief guide to the PROMIS® Physical Function instruments; 
July 18, 2019.
32.
Kolotkin RL,  Williams VSL, Ervin CM, et al. Validation of a new measure of quality 
of life in obesity trials: Impact of Weight on Quality of Life-Lite Clinical Trials 
Version. Clin Obes 2019;9:e12310.
33.
Ware J, Kosinski M, Bjorner J, et al. Development. User's Manual for the SF-36v2®
Health Survey. Lincoln (RI): QualityMetric Incorporated;2007.
34.
American Diabetes Association. Standards of medical care in diabetes -2019. Diabetes 
Care 2019;42(Suppl 1):S1-S193.
35.
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use. ICH Harmonised Guideline: Addendum on estimands 
and sensitivity analysis in clinical trials to the guideline on statistical principles for 
clinical trials: ICH E9 (R1); 2019.

SAP_001.pdf: 
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Protocol C3421019
A PHASE 2B, RANDOMIZED, DOUBLE-BLIND,
PLACEBO-CONTROLLED, PARALLEL GROUP, DOSE-RANGING STUDY TO
EVALUATE THE EFFICACY AND SAFETY OF PF-06882961 ADMINISTRATION
IN ADULTS WITH OBESITY
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date:
25 Oct 2023


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TABLE OF CONTENTS
LIST OF TABLES..................................................................................................................5
LIST OF FIGURES................................................................................................................5
APPENDICES.......................................................................................................................5
1. VERSION HISTORY .........................................................................................................6
2. INTRODUCTION...............................................................................................................8
2.1. Modifications to the Analysis Plan Described in the Protocol.................................8
2.2. Study Objectives, Endpoints, and Estimands ........................................................8
2.2.1. Primary Estimand(s) ...............................................................................11
2.2.2. Secondary Estimand(s)...........................................................................11
2.2.2.1. Estimand related to achieving Body Weight loss ≥5% at 
End of Treatment............................................................................11
2.2.2.2. Estimands related to Waist Circumference at End of 
Treatment.......................................................................................12
2.2.2.3. Estimands related to Waist-to-hip ratio, HbA1c and 
Fasting Plasma Glucose.................................................................12
2.2.3. Additional Estimand(s) ............................................................................12
2.3. Study Design.......................................................................................................12
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS ........15
3.1. Primary Endpoint(s) ............................................................................................15
3.2. Secondary Endpoint(s)........................................................................................16
3.2.1. Efficacy Endpoint(s)................................................................................16
3.2.2. Safety Endpoint(s) ..................................................................................17
3.2.2.1. Adverse Event........................................................................17
3.2.2.2. Hypoglycemic Monitoring .......................................................18
3.2.2.3. Laboratory Data .....................................................................18
3.2.2.1. Vital Signs..............................................................................20
3.2.2.2. Electrocardiogram (ECG).......................................................20
3.2.2.3. Assessment of Mental Health as determined by 
Columbia-Suicide Severity Rating Scale (C-SSRS) and Patient 
Health Questionnaire-9 (PHQ-9). ...................................................21
3.3. Other Safety Endpoint(s).....................................................................................21
3.4. Other Endpoint(s) (or, Exploratory Endpoints).....................................................21
3.5. Baseline Variables ..............................................................................................24


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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) .....................................................25
4.1. Identifying Major Protocol Deviations ..................................................................26
4.2. Strata Misallocations ...........................................................................................26
5. GENERAL METHODOLOGY AND CONVENTIONS.......................................................26
5.1. Hypotheses and Decision Rules..........................................................................26
5.2. General Methods.................................................................................................26
5.2.1. Analyses for Continuous Endpoints.........................................................27
5.2.2. Analyses for Categorical Endpoints.........................................................27
5.2.3. Mixed Model Repeated Measures (MMRM) ............................................27
5.2.4. Logistic Regression.................................................................................28
5.2.5. Emax Model............................................................................................28
5.2.6. Emax Model (baseline interaction) ..........................................................29
5.2.7. Cumulative Incidence Plots.....................................................................29
5.3. Methods to Manage Missing Data.......................................................................30
5.3.1. Multiple Imputation..................................................................................30
6. ANALYSES AND SUMMARIES ......................................................................................30
6.1. Primary Endpoint(s) ............................................................................................31
6.1.1. Percent Change from Baseline in Body Weight at End of Treatment.......31
6.1.1.1. Main Analysis.........................................................................31
6.1.1.2. Sensitivity/Supplementary Analyses.......................................32
6.2. Secondary Endpoint(s)........................................................................................33
6.2.1. Response as defined by a body weight loss of ≥5% from baseline at 
End of Treatment .........................................................................................33
6.2.2. Percent CFB in Body Weight over time...................................................33
6.2.3. Absolute CFB in waist circumference at End of Treatment......................33
6.2.4. Absolute CFB in waist-to-hip ratio at End of Treatment...........................34
6.2.5. Absolute CFB in HbA1c ..........................................................................34
6.2.6. Absolute CFB in FPG over time ..............................................................34
6.3. Other Safety Summaries and Analyses Endpoint(s)............................................35
6.3.1. Adverse Events.......................................................................................35
6.3.1.1. Forest plots on the Incidence of adverse events of 
interest ...........................................................................................36
6.3.1.2. Incidence of first occurrence of adverse events of interest 
by week..........................................................................................36
6.3.1.3. Prevalence of adverse events of interest by week..................36


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6.3.1.4. Time to First Occurrence/Recurrence of AEs of Interest.........37
6.3.1.5. Time to discontinuation from IP due to Gastrointestinal 
Disorders AEs ................................................................................37
6.3.1.6. Subset Reporting Interval.......................................................37
6.3.1.7. Hypoglycemic Adverse Events...............................................37
6.3.2. Laboratory Data ......................................................................................37
6.3.2.1. Focused Laboratory Summaries on Endpoints of Interest ......37
6.3.2.2. Clinical Laboratory Parameters of Interest..............................38
6.3.3. Vital Signs...............................................................................................38
6.3.4. Electrocardiograms.................................................................................39
6.3.5. Assessment of mental health as determined by C-SSRS and PHQ-
9...................................................................................................................40
6.4. Other Endpoint(s) (or, Exploratory Endpoint[s])...................................................40
6.4.1. Trough plasma concentrations of danuglipron at time points 
specified in the SoA .....................................................................................40
6.4.2. CFB in fasting plasma insulin, HOMA-IR and HOMA-B at Weeks 4, 
8, 12, 16, 22 and 26 .....................................................................................41
6.4.3. Absolute CFB in waist circumference over time. .....................................41
6.4.4. Absolute CFB in waist-to-hip ratio over time............................................41
6.4.5. Shift from baseline in glycemic category (normoglycemia, pre-
diabetes, or T2DM) at End of Treatment ......................................................41
6.4.6. CFB in systolic and diastolic BP over time ..............................................41
6.4.7. CFB in lipid parameters over time ...........................................................42
6.4.8. CFB in SF-36v2® subscales and summary scores .................................42
6.4.9. CFB in Eating-Related Factors Daily Diary..............................................42
6.4.10. CFB in PGI-S at each planned clinic visit up through End of 
Treatment visit .............................................................................................42
6.4.11. CFB in PROMIS® Fatigue ....................................................................42
6.4.12. CFB in PROMIS® Physical Function.....................................................42
6.4.13. CFB in IWQOL-Lite-CT©.......................................................................43
6.4.14. PGI-C....................................................................................................43
6.5. Subset Analyses .................................................................................................43
6.6. Baseline and Other Summaries and Analyses ....................................................43
6.6.1. Baseline Summaries ...............................................................................43
6.6.2. Study Conduct and Participant Disposition..............................................43
6.6.3. Study Treatment Exposure .....................................................................43


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6.6.4. Concomitant Medications and Nondrug Treatments................................43
6.6.1. Treatment Compliance............................................................................44
6.6.2. Discontinuations......................................................................................44
7. INTERIM ANALYSES......................................................................................................44
7.1. Introduction .........................................................................................................44
7.2. Interim Analyses and Summaries........................................................................44
8. REFERENCES................................................................................................................45
LIST OF TABLES
Table 1.
Summary of Changes..............................................................................6
Table 2.
C-SSRS Mapped to C-CASA (Suicidality Events and Codes) ...............55
LIST OF FIGURES
Figure 1: Overall Study Schema for Cohorts 1 and 2...........................................................14
Figure 2: Overall Study Schema for Cohort 3......................................................................14
Figure 3: Titration Schema for Cohorts 1 and 2...................................................................15
Figure 4: Titration Schema for Cohort 3...............................................................................15
APPENDICES
Appendix 1. Summary of Efficacy Analyses ........................................................................47
Appendix 2. Bayesian Statistical Methodology Details.........................................................49
Appendix 3. Traditional Statistical Methodology Details.......................................................51
Appendix 4. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....54
Appendix 5. C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events and 
Codes ...................................................................................................55
Appendix 6. PROMIS-Fatigue .............................................................................................55
Appendix 7. PROMIS-Physical Function .............................................................................56
Appendix 8. IwQOL-Lite CT.................................................................................................58
Appendix 9. List of Abbreviations ........................................................................................59


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
2
25Oct2023
Amendment 
2
16Sept2022
Updates made 
based on 
addition of 
Cohorts 2 and 3
and Blinded 
Data Reviews
Rationale: The protocol was amended to 
add cohorts 2 and 3 of approximately 49 
and 112 additional participants, 
respectively. The following sections were 
revised as part of this rationale:
!
Section 1.2: Endpoint column 
updated to reflect new timepoint 
schedule in Cohort 3. Text updated 
to reflect change of treatment 
duration for Cohort 3.
!
Section 1.3: added text verbatim 
and updated study design figures 
from the protocol amendment to 
reflect the changes to the protocol.
!
Section 2: Change in definition of 
end of treatment for Cohort 3. 
Update to text to reflect different 
timepoints for Cohort 3. 
!
Section 4.2: Labels for titration 
arms updated and new titration 
arms for Cohort 3 added. 
!
Sections 4.2 and 5: clarified that 
data from participants in the Cohort 
1 and Cohort 2 will be combined 
and reported together unless 
otherwise stated and that Cohort 3 
would be reported separately also 
unless otherwise stated.
!
Section 5.7.1: added text verbatim 
from the protocol amendment to 
specify that two separate baseline 
summary tables will be produced; 
one for Cohorts 1 & 2 and one for 
Cohort 3
Rationale: Changes to reflect updates 
based on ongoing blinded review of tables, 
to also provide consistency with 
other C342 studies. The following sections 
were revised as part of this rationale:
!
Section 2.3: t-scores based on SF-
36 results won't be calculated using 


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Optum scoring solution software, 
but internal code based on 
publications per internal approach.
!
Section 2.3.2.4: added text to 
specify that both pre- and post-
dose populations will be from the 
safety analysis set.
!
Section 4.3: added text to specify 
that for the analysis of safety 
endpoints, the sponsor data 
standard rules for imputation of 
BLQ values will be applied.
!
Section 5.4.1.3: added wording to 
include discontinuation from IP as 
well as from study in exclusion from 
the denominator for the percentage 
of TEAEs of interest by week.
Rationale: additional outputs needed for 
reporting. The following sections were 
revised as part of this rationale:
!
Sections 2.3.2.3.1 & 5.4.2.1: Bile 
acids and GGT have been included 
in the list of liver function tests for 
which the change from baseline is 
a safety laboratory endpoint of 
interest.
!
Section 5.1.1.1: added text to 
specify that absolute changes from 
baseline in body weight should be 
summarized as part of the main 
analysis.
!
Section 5.7.1: hip circumference 
has been added to be summarized 
at baseline.
!
Section 5.7.2: added text to 
specify that an additional table 
summarizing participant 
discontinuations due to adverse 
events for each system class and 
preferred term will be produced by 
treatment group and overall.
!
Sections 5.7.1, 5.4.2, 5.4.2.2, 5.4.3 
& 5.4.4: additionally summarising 
parameters by overall
Rationale: erroneously missed endpoints 
in version 1 of SAP. The following sections 
were revised as part of this rationale:


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!
Section 5.4.1: added text that the 
number of participants who met the 
criteria for referral to a mental 
health professional will be listed 
and summarized by treatment 
group and time point.
Minor formatting errors were also 
addressed (e.g. changing “Danuglipron” to 
“danuglipron” when included in middle of 
sentence).
1
10 Feb 2021
Original 
14 Sep 2020
N/A
N/A
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3421019. 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. Modifications to the Analysis Plan Described in the Protocol
None.
2.2. Study Objectives, Endpoints, and Estimands
Type
Objective
Endpoint
Estimand
Primary 
Efficacy
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on body weight in participants 
with obesity.
Percent CFB in body weight at 
End of Treatment.a
Estimand 1: This estimand is 
intended to provide a 
population level estimate of 
the mean treatment effect 
(PF-06882961 versus 
placebo) on a continuous 
endpoint in all evaluable 
participants while on 
treatment
Secondar
y (Safety)
To characterize the safety and 
tolerability of multiple dose 
levels of PF-06882961 
administered to participants 
with obesity.
!
Incidence of treatment 
emergent AEs [AEs and 
SAEs], and clinically 
significant abnormal 
laboratory, vital signs and 
ECG parameters. 
Assessment of mental health 
as determined by C-SSRS 
and PHQ-9.
There are no defined 
estimands for these endpoints 
and they will be analyzed 
using Pfizer data standards as 
applicable.
Secondar
y
(Efficacy)
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on additional parameters of 
body weight in participants 
with obesity.
!
Response as defined by a 
body weight loss of ≥5% 
from baseline at End of 
Treatment.a
Estimand 2: This estimand is 
intended to provide a 
population level estimate of 
the odds ratio treatment effect 
(PF-06882961 versus 
placebo) on a binary endpoint 
in all evaluable participants 
while on treatment.


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!
Cohorts 1 and 2: Percent 
CFB in body weight at 
Weeks 2, 4, 6, 8, 10, 12, 
16, 18 and 22.
!
Cohort 3: Percent CFB in 
body weight at Weeks 4, 8, 
12, 16, 20, 24 and 28.
Estimand 1 as above.
!
Absolute CFB in waist 
circumference at End of 
Treatment.a
Estimand 3: This estimand is 
intended to provide a 
population level estimate of 
the mean treatment effect 
(PF-06882961 versus 
placebo) on a continuous 
endpoint in all evaluable 
participants while on 
treatment.
!
Absolute CFB in waist-to-
hip ratio at End of 
Treatment.a
Estimand 4: This estimand will 
be similar to 3 above.
Secondar
y 
(Efficacy)
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on glycemic parameters in 
participants with obesity.
!
Cohorts 1 and 2: Absolute 
CFB in HbA1c at 
Weeks 16 and 26.
!
Cohort 3: Absolute CFB in 
HbA1c at Weeks 16, 24 
and 32.
Estimand 5: This estimand will 
be similar to 3 above.
!
Absolute CFB in FPG at 
each planned in-clinic study 
visit up through the End of 
Treatment visit.b
Estimand 6: This estimand will 
be similar to 3 above.
Tertiary/
Explorato
ry
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on body weight in participants 
with obesity who do not have 
major protocol deviations.
!
Percent CFB in body 
weight at each planned in-
clinic study visit up through 
the End of Treatment visit.b
Estimand 7: This estimand is 
intended to provide a 
population level estimate of 
the mean treatment effect 
(PF-06882961 versus 
placebo) on a continuous 
endpoint in evaluable 
participants with no major 
protocol deviations and while 
on treatment.  
Tertiary/
Explorato
ry
To characterize the PK of 
PF-06882961 in participants 
with obesity.
!
Trough plasma 
concentrations of 
PF-06882961 at time points 
specified in the SoA for the 
applicable cohort (see SoA 
for Cohorts 1 and 2, and 
SoA for Cohort 3).
There is no defined estimand 
for this endpoint and this will 
be analyzed using Pfizer data 
standards as applicable.
Tertiary/
Explorato
ry
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on markers of insulin 
resistance in participants with 
obesity.
!
Cohorts 1 and 2: CFB in 
fasting plasma insulin, 
HOMA-IR and HOMA-B at 
Weeks 4, 8, 12, 16, 22 and 
26.
!
Cohort 3: CFB in fasting 
plasma insulin, HOMA IR 
and HOMA-B at Weeks 4, 
8, 12, 16, 20, 24, 28 and 
32.
There are no defined 
estimands for these endpoints 
and they will be analyzed 
using Pfizer data standards as 
applicable.
Tertiary/
To compare the effect of 
multiple dose levels of 
!
Cohorts 1 and 2: Absolute 
CFB in waist circumference 
Estimand 3: This estimand is 
defined above.


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Explorato
ry
PF-06882961 versus placebo 
on additional parameters of 
body weight in participants 
with obesity.
at Weeks 2, 4, 6, 8, 10, 12, 
16, 18 and 22.
!
Cohort 3: Percent CFB in 
body weight at Weeks 4, 8, 
12, 16, 20, 24 and 28.
!
Cohorts 1 and 2: Absolute 
CFB in waist-to-hip ratio at 
Weeks 2, 4, 6, 8, 10, 12, 
16, 18 and 22.
!
Cohort 3: Percent CFB in 
body weight at Weeks 4, 8, 
12, 16, 20, 24 and 28.
Estimand 4: This estimand will 
be similar to 3 above.
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on glycemic category in 
participants with obesity.
!
Shift from baseline in 
glycemic category 
(normoglycemia, 
pre-diabetes, or T2DM) at 
End of Treatment.a
There are no defined 
estimands for these endpoints 
and they will be analyzed 
using Pfizer data standards as 
applicable.
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on blood pressure (BP) and 
lipid levels in participants with 
obesity.
!
CFB in systolic and 
diastolic BP at each 
planned in-clinic study visit 
up through the End of 
Treatment visit.
!
Cohorts 1 and 2: CFB in 
lipid parameters at 
Weeks 4, 8, 12, 16, 22 and 
26.
!
Cohort 3: CFB in lipid 
parameters at Weeks 4, 8, 
12, 16, 20, 24, 28 and 32.
There are no defined 
estimands for these endpoints 
and they will be analyzed 
using Pfizer data standards as 
applicable.
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on PCOAs in participants with 
obesity.
!
Cohorts 1 and 2: CFB in 
SF-36v2® subscales and 
summary scores at Weeks 
16 and 26.
!
Cohort 3: CFB in SF-
36v2® subscales and 
summary scores at Weeks 
16, 24 and 32.
There are no defined 
estimands for these endpoints 
and they will be analyzed 
using Pfizer data standards as 
applicable.
To compare the effect of 
multiple dose levels of 
PF-06882961 versus placebo 
on PCOAs in participants with 
obesity (US sites only).
!
Cohorts 1 and 2: CFB in 
Eating-Related Factors 
Daily Diary at Weeks 4, 8, 
12, 16, 22 and 26.
!
Cohort 3:  CFB in 
Eating-Related Factors 
Daily Diary at Weeks 4, 8, 
12, 16, 20, 24, 28 and 32.
!
CFB in PGI-S at each 
planned in-clinic study visit 
up through the End of 
Treatment visit.b
!
Cohorts 1 and 2: CFB in 
PROMIS® Fatigue at 
Weeks 16 and 26.
!
Cohort 3: CFB in 
PROMIS® Fatigue at 
Weeks 16, 24 and 32.
!
Cohorts 1 and 2: CFB in 
PROMIS® Physical 
There are no defined 
estimands for these endpoints 
and they will be analyzed 
using Pfizer data standards as 
applicable.


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Function at Weeks 16 and 
26.
!
Cohort 3: CFB in 
PROMIS® Physical 
Function at Weeks 16, 24 
and 32.
!
Cohorts 1 and 2: CFB in 
IWQOL-Lite-CT© at 
Weeks 16 and 26.
!
Cohort 3:  CFB in IWQOL 
Lite-CT© at Weeks 16, 24 
and 32.
!
Cohorts 1 and 2: PGI-C at 
Weeks 4, 16 and 26.
!
Cohort 3: PGI-C at Weeks 
4, 16, 24 and 32.
Note: For all endpoints, baseline is defined as the result closest prior to dosing at V3 (Day 1).
a.
End of Treatment defined as Week 26 for Cohorts 1 and 2, and as Week 32 for Cohort 3. 
b.
For Cohorts 1 and 2, this includes Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26; for Cohort 3, 
this includes Weeks 4, 8, 12, 16, 20, 24, 28 and 32.
2.2.1. Primary Estimand(s)
The primary estimand (Estimand 1) will be the population average treatment effect on the 
percent change from baseline (CFB) in body weight at End of Treatment of PF-06882961 
(danuglipron) compared to placebo in all evaluable participants while on treatment. For 
Cohorts 1 and 2, End of Treatment is defined as Week 26. For Cohort 3, End of Treatment 
is defined as Week 32. This reflects a combination of the ‘Hypothetical’ and ‘While on 
treatment’ strategies as outlined in the ICH-E9 (R1) guidance.1 It includes the following 4 
attributes:
!
Population: Defined by the inclusion and exclusion criteria to reflect participants with 
obesity
!
Variable: Percent change from baseline in body weight at End of Treatment 
!
Intercurrent events: All data after an intercurrent event of discontinuation of 
investigational product (IP) will be censored
!
Population-level summary: Mean percent change from baseline in each danuglipron arm 
compared to placebo
2.2.2. Secondary Estimand(s)
2.2.2.1. Estimand related to achieving Body Weight loss ≥5% at End of Treatment
A secondary estimand (Estimand 2) will be the population odds ratio of the treatment effect
of achieving a body weight loss ≥5% from baseline at End of Treatment of PF-06882961
(danuglipron) compared to placebo in all evaluable participants while on treatment. This 
reflects a combination of the ‘Hypothetical’ and ‘While on treatment’ strategies as outlined in 
the ICH-E9 (R1) guidance.1 It includes the following 4 attributes:
!
Population: Defined by the inclusion and exclusion criteria to reflect participants with 
obesity


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!
Variable: Response as defined by a body weight loss of ≥5% from baseline at End of 
Treatment 
!
Intercurrent events: All data after an intercurrent event of discontinuation of 
investigational product (IP) will be censored. Missing or censored values at End of 
Treatment will be imputed (assuming missing at random [MAR]) to determine a 
response classification.
!
Population-level summary: Odds ratio for a response between danuglipron (each 
arm considered separately) and placebo
2.2.2.2. Estimands related to Waist Circumference at End of Treatment
Estimand 3 is similar to Estimand 1, except the population average treatment effect is on the 
absolute CFB in waist circumference at End of Treatment.  The population based treatment 
effect will be the mean CFB in each PF-06882961 (danuglipron) arm compared to placebo. 
2.2.2.3. Estimands related to Waist-to-hip ratio, HbA1c and Fasting Plasma Glucose
Estimands 4, 5 and 6 will utilize the same approach as Estimand 3 (Section 2.2.2.2) for 
the associated endpoint(s).
2.2.3. Additional Estimand(s)
An additional exploratory estimand (Estimand 7) will be analyzed, which will be the 
population average treatment effect on the percent CFB in body weight at End of Treatment 
of PF-06882961 (danuglipron) compared to placebo in evaluable participants with no major 
protocol deviations and while on treatment.  This reflects a combination of the ‘Hypothetical’, 
‘While on treatment’ and ‘Principal stratum’ strategies as outlined in the ICH-E9 (R1) 
guidance.1
It includes the following 4 attributes:
!
Population: Defined by the inclusion and exclusion criteria to reflect participants with 
obesity who do not have major protocol deviations
!
Variable: Percent change from baseline in body weight at End of Treatment 
!
Intercurrent events: All data after an intercurrent event of discontinuation of 
investigational product (IP) will be censored
!
Population-level summary: Mean percent change from baseline in each danuglipron
arm compared to placebo
2.3. Study Design
This is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel 
group, study to assess efficacy, safety, tolerability and PK of twice daily oral administration 
of PF-06882961 (danuglipron) in adult participants with obesity. There are 3 Cohorts 
included in the study: Cohort 1 under the original protocol, Cohort 2 added under 
Amendment 1, and Cohort 3 added under Amendment 2.


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For all cohorts, following the initial screening period to confirm eligibility (up to 4 weeks), 
screening continues with a 2-week placebo run-in period which will be single-blinded 
(participant).  Eligible participants who maintain acceptable compliance during the run-in 
period are randomized on Day 1 to double-blinded study intervention.  
For participants in Cohorts 1 and 2, the total duration of dosing with double-blinded study 
intervention is 26 weeks, followed by an approximate 4-week follow-up. The total duration of 
participation in this study for the participants in Cohorts 1 and 2 is approximately 32 weeks, 
including the 2-week single-blind run-in period, but excluding the initial screening period.
For Cohort 3, added under protocol Amendment 2, participants will be randomized to 
placebo or 1 of 3 PF-06882961 (danuglipron) arms with 4-week dose titration steps. The 
total duration of dosing with double-blinded study intervention is 32 weeks, followed by an 
approximate 4-week follow-up.  The total duration of study participation for participants in 
Cohort 3 is approximately 38 weeks, including the 2-week single-blind run-in period, but 
excluding the initial screening period.
All dosing regimens for all cohorts include dose titration to enhance tolerability of PF-
06882961 (danuglipron), where the dose level is increased at set intervals of 1, 2 or 4 weeks 
until a target dose is achieved. For all cohorts, dosing is to occur with food twice daily. For 
the 5 1-week titration PF-06882961 (danuglipron) groups in Cohort 1, the target dose levels 
for each of the arms are 40 mg BID, 80 mg BID, 120 mg BID, 160 mg BID, and 200 mg BID, 
with titration from a starting dose of 10 mg BID, and up to 10 weeks of the dosing duration 
used for titration. For the 3 2-week titration PF-06882961 (danuglipron) groups in Cohorts 1 
and 2, target dose levels for each of the arms are 120 mg BID, 160 mg BID, and 200 mg 
BID, with titration from a starting dose of 10 mg BID, and up to 20 weeks used for titration. 
Both Cohorts 1 and 2 also include a placebo arm. For Cohort 3, participants will be enrolled 
into 4 study arms, and target dose levels are placebo and PF-06882961 (danuglipron) doses 
of 80 mg BID, 140 mg BID, and 200 mg BID. For Cohort 3, titration will occur at 4-week 
intervals from a starting dose of 10 mg BID, and up to 20 weeks will be used for titration to 
reach the target dose.
There will be total of approximately 581 participants across all 3 cohorts of this study. In 
Cohort 1, approximately 420 participants (approximately 60 in each of the placebo and 
5 1-week titration PF-06882961 (danuglipron) arms and approximately 20 participants in 
each of the 3 2-week titration arms) were randomized. All dosing arms, including placebo, 
were enrolled simultaneously in Cohort 1. Subsequently, in Cohort 2, approximately 
49 additional participants were randomized to the placebo and 2-week titration arms 
(approximately 7 in the placebo and approximately 14 in each of the 3 2-week titration 
arms).  Combining Cohorts 1 and 2, there are a total of approximately 469 participants 
randomized (approximately 67 in the placebo, approximately 60 each of the 5 1-week 
titration arms and approximately 34 in each of the 3 2-week titration arms).  In Cohort 3, 
approximately 112 participants will be randomized to 4 additional study arms (approximately 
16 in the placebo and approximately 32 in each of 3 PF-06882961 (danuglipron) arms with 
4-week titration steps).  
Eligible participants in the Cohort 1 will be randomized to double-blinded study intervention 
in 1 of 9 arms in a 3:3:3:3:3:3:1:1:1 ratio (placebo: 5 standard titration danuglipron arms: 3 
2-week titration arms). Eligible participants in Cohort 2 will be randomized to double-blinded 
study intervention in 1 of 4 arms in a 1:2:2:2 ratio (1 placebo: 3 2-week titration arms).   
Similarly for Cohort 3, eligible participants will be randomized to double-blinded study 


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intervention in 1 of 4 arms in a 1:2:2:2 ratio (1 placebo: 3 4-week titration arms). 
Randomization is stratified according to biological gender (female versus male), as both 
tolerability and efficacy may be different between men and women.  This stratification is 
intended to balance the numbers of participants of either gender across treatment arms.  In 
addition, no more than approximately 70% of the trial population will consist of 1 gender, in 
order to permit adequate representation of both men and women in the trial population.
Figure 1: Overall Study Schema for Cohorts 1 and 2
Figure 2: Overall Study Schema for Cohort 3


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Figure 3: Titration Schema for Cohorts 1 and 2
Figure 4: Titration Schema for Cohort 3
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS
For all endpoints, unless otherwise specified below, baseline is defined as the result closest 
prior to dosing at V3 (Day 1).
The “End of Treatment” definition is applied at the endpoint level (not the subject-level) and 
is defined for relevant endpoints as Week 26 for Cohorts 1 & 2, and as Week 32 for 
Cohort 3.
3.1. Primary Endpoint(s)
!
Percent change from baseline in body weight at End of Treatment.
The average of the duplicate body weight readings collected at each assessment time will 
be calculated prior to summaries/analysis. If one of the two duplicates are missing, the non-


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missing value will be used, and missing values will not be imputed. Both the absolute 
change and percent change from baseline in body weight will be calculated. 
For the MMRM model, all body weight values (including baseline) will be loge-transformed 
prior to analysis (i.e. the outcome in the model will be the difference of the loge absolute 
value at the time point of interest minus the loge baseline). All LSMeans and LSMean 
differences (including confidence intervals) will be back-transformed to obtain the ratio to 
baseline or placebo (as applicable). The percent change from baseline or percent difference 
to placebo (as applicable) will then be calculated as follows: 
Percent change = 100*(back-transformed LSMean – 1) 
For descriptive summaries, percentage change from baseline will be calculated as the End 
of Treatment measurement minus the baseline value divided by the baseline value 
multiplied by 100.
The absolute change from baseline in body weight at End of Treatment will also be 
calculated for additional reporting.
3.2. Secondary Endpoint(s)
3.2.1. Efficacy Endpoint(s)
!
Response as defined by a body weight loss of ≥5% from baseline at End of 
Treatment
This endpoint will have two levels: ‘Response’ and ‘Non-response’. The former will be based 
on participants having a body weight loss of ≥5% from baseline at End of Treatment, 
otherwise participants with a loss of <5% will be classed as having a ‘Non-response’. 
Participants with an intercurrent event of discontinuation of IP prior to, or on, the End of 
Treatment week will have their End of Treatment value censored (if not missing). Missing or 
censored values at End of Treatment will be imputed as described in Section 5.3. Percent 
change will be calculated as described in Section 3.1 (based on the descriptive summaries 
approach).
!
Percent CFB in body weight at:
o
Weeks 2, 4, 6, 8, 10, 12, 16, 18 and 22 for Cohorts 1 and 2
o
Weeks 4, 8, 12, 16, 20, 24 and 28 for Cohort 3.
Data will be analysed on the natural log scale and the percent change from baseline will be 
calculated as described in Section 3.1.
!
Absolute CFB in waist circumference at End of Treatment.
The average of the triplicate waist measurements collected at each assessment time will be 
calculated prior to summaries/analysis. If any of the triplicates are missing, the non-missing 
value(s) will be used, and missing values will not be imputed.
!
Absolute CFB in waist-to-hip ratio at End of Treatment.


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The average of the triplicate waist and hip measurements collected at each assessment 
time will be calculated prior to calculating the waist-to-hip ratio at each assessment time. If 
any of the triplicates are missing, the non-missing value(s) will be used, and missing values 
will not be imputed.
!
Absolute CFB in HbA1c at:
o
Weeks 16 and 26 for Cohorts 1 and 2.
o
Weeks 16, 24 and 32 for Cohort 3.
!
Absolute CFB in Fasting Plasma Glucose (FPG) at each planned in-clinic study visit 
up through the End of Treatment visit
3.2.2. Safety Endpoint(s)
3.2.2.1. Adverse Event
If an adverse event has a start time of 00:00 and a start date that is equal to the date of first 
administration of IP, the adverse event start time will be imputed with the time of the first 
dose of administration of IP. 
If an adverse event has an end time of 00:00 then the end time will be imputed as 23:59.
An adverse event is considered treatment emergent (TEAE) relative to a given treatment if
the event starts during the effective duration of treatment (i.e. starting on or after the first 
dose but before the last dose plus lag time).
The effective duration of treatment is determined by the lag time. Any event occurring within 
the lag time, whether this occurs during a break in treatment or at the end of treatment, is 
attributed to the corresponding treatment period. The lag time is defined by the Pfizer 
Standard of 365 days post last dose of IP.
Adverse events occurring during the placebo run-in period (i.e. starting from Day -14, 
inclusive, up to and before the first dose of active treatment on Day 1) will be considered 
non-treatment emergent.
A 3-tier approach will be used to summarize TEAEs. Under this approach, TEAEs are 
classified into 1 of 3 tiers. Different analyses will be performed for different tiers (see 
Section 6.3.1.
Tier 1 events: These are prespecified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan.
Tier 2 events: These are events that are not tier 1 but are “common.” A Medical Dictionary 
for Regulatory Activities (MedDRA) preferred term (PT) is defined as a Tier 2 event if there 
are at least 5% of participants reporting the event in any of the standard titration or placebo 
groups or at least 2 participants reporting the event in any of the slow titration groups.
Tier 3 events: These are events that are neither Tier 1 nor Tier 2 events.


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3.2.2.1.1. Adverse events of interest
The TEAEs of interest for additional reporting are: nausea, vomiting and diarrhoea (as 
defined based on preferred term). Based on emerging blinded data reviews, other AEs of 
interest may be added to this list, which would be documented with a SAP amendment or 
documented in the changes to planned analysis section in the CSR.
3.2.2.1.2. Subset Reporting Interval 
A summary of adverse events occurring during a subset of the main reporting interval will be 
based on a shorter reporting window. This interval will include all TEAEs (reported 
separately) if:
!
the event starts after or on the first dose, but doesn’t start more than two days after 
the last dose of IP (defined as either completing the 26 weeks or 32 weeks 
(depending on cohort) of treatment or discontinuing from IP earlier).
3.2.2.2. Hypoglycemic Monitoring
Hypoglycemia AEs will be recorded in the AE Case Report Form (CRF) with details of the 
event captured on the Hypoglycemic Event Details CRF. Details of when these will be 
recorded are given in the protocol Section 8.2.5.
For programming purposes, the hypoglycemic AE categories are based on the following:
!
Severe Hypoglycemia: Severe is checked in the severity criteria of the CRF. This 
assessment will be made by the PI based on the protocol definition.
!
Documented Symptomatic Hypoglycemia: If (1 – Did the participant have symptoms 
of hypoglycemia?) Yes and (2 – Was the blood glucose measured?) Yes and result 
<70 mg/dL on the CRF, but hypoglycemia is not classified as severe.
!
Asymptomatic Hypoglycemia: If (1) No and (2) Yes and result <70 mg/dL on the 
CRF, but hypoglycemia is not classified as severe.
!
Probable Symptomatic Hypoglycemia: If (1) Yes and (2) No and (2b – If blood 
glucose was not measured, did symptoms resolve when treated with carbohydrate or 
glucagon?) Yes on the CRF, but hypoglycemia is not classified as severe.
3.2.2.3. Laboratory Data
Safety laboratory tests (hematology, chemistry, urine testing and other clinical laboratory 
tests) will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the safety tests 
will be assessed against the criteria specified in the sponsor reporting standards. The 
assessment will take into account whether each participant’s baseline test result is within or 
outside the laboratory reference range for the particular laboratory parameter.
Baseline for all laboratory measurements will be defined as the result closest prior to dosing 
at Visit 3 (Day 1).


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3.2.2.3.1. Change from Baseline Summaries
Focused change from baseline summaries (including both absolute changes from baseline 
and percent change from baseline, calculated separately) of the following safety laboratory 
endpoints will be assessed:
!
Change from baseline in calcitonin to all post-dose time points as per the SOA
!
Change from baseline in amylase to all post-dose time points as per the SOA
!
Change from baseline in lipase to all post-dose time points as per the SOA
!
Change from baseline in thyroid stimulating hormone (TSH) to all post-dose time 
points as per the SOA
!
Change from baseline in free thyroxine (free T4) to all post-dose time points as per 
the SOA
!
Change from baseline in lipid profile (total cholesterol, direct LDL cholesterol, HDL 
cholesterol and triglycerides) to all post-dose time points as per the SOA
!
Change from baseline in liver function tests (alanine transaminase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase, total bilirubin, bile acids and gamma-
glutamyl tranferase [GGT]) to all post-dose time points as per the SOA
!
Change from baseline in estimated glomerular filtration rate (eGFR) to all post-dose 
time points as per the SOA
3.2.2.3.2. Clinical Laboratory Parameters of Interest
For the specific laboratory parameters listed in the table below, the following endpoints will 
be derived:
•
Abnormalities defined as either a “Flag Level” or “Alert Level” as in the table below
Parameter
Flag Level
Alert Level
Conventional Units
Amylase
> ULN
Pfizer standard 
flag for PCC
U/L
Calcitonin
> ULN
Pfizer standard 
flag for PCC 
ng/L
Lipase
> ULN
Pfizer standard 
flag for PCC
U/L
HbA1c
-
>10
%
Fasting Plasma Glucose
-
< 54
mg/dL
-
> 240
Alanine aminotransferase
> ULN
> 2x ULN
> 3x ULN
> 5x ULN
> 5x ULN
> 5x ULN
-
-
-
>8x ULN
>10x ULN
>20x ULN


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Aspartate Aminotransferase
> ULN
≥ 2x ULN
≥ 3x ULN
≥ 5x ULN
≥ 5x ULN
≥ 5x ULN
-
-
-
> 8x ULN
> 10x ULN
> 20x ULN
U/L
Alkaline Phosphatase
≥ 2x ULN
≥ 3x ULN
≥ 5x ULN
Pfizer standard 
flag for PCC
U/L
Creatinine
≥0.3 
relative to 
baseline
≥0.4 relative to 
baseline
mg/dL
Gamma Glutamyl Transferase
≥ ULN
Pfizer standard 
flag for PCC
U/L
Total Bilirubin
> 1.5 ULN
Pfizer standard 
flag for PCC
mg/dL
Serum Total Bile Acids
> ULN
Pfizer standard 
flag for PCC
μmol/L
Direct and Indirect Bilirubin
> ULN
-
mg/dL
PCC – potential clinical concern
ULN – upper limit of normal as determined by the central laboratory
These endpoints will be derived using both pre- and post-dose data separately. Post-dose 
will include all post-baseline data including unplanned readings and pre-dose will include all 
data from the placebo run-in defined by including all values from Visit 2 to pre-dose, 
including the baseline measurement and unplanned readings. Note, both pre- and post-dose 
populations will be from the safety analysis set (defined in Section 4).
3.2.2.1. Vital Signs
Vital sign measurements (blood pressure and pulse rate) will be taken as detailed in the 
Schedule of Activities given in the protocol. The average of the triplicate measurements 
collected at each appropriate assessment time will be calculated for each vital sign
parameter.
Baseline will be defined as the average of the triplicate measurements at the visit closest 
prior to dosing at Visit 3 (Day 1).
Changes from baseline for supine systolic and diastolic blood pressure and pulse rate will 
be calculated for each post baseline measurement.
3.2.2.2. Electrocardiogram (ECG)
Standard 12-lead ECG (including heart rate, QT, QTcF, PR and QRS interval) will be 
obtained at times detailed in the Schedule of Activities given in the protocol.
Baseline will be defined as the measurement at the visit closest prior to dosing at Visit 3 
(Day 1).
Change from baseline for heart rate, QT, QTcF, PR and QRS interval will be calculated for 
each post baseline measurement.


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3.2.2.3. Assessment of Mental Health as determined by Columbia-Suicide Severity 
Rating Scale (C-SSRS) and Patient Health Questionnaire-9 (PHQ-9).
The C-SSRS is a validated tool to evaluate suicidal ideation and behaviour. Data relevant to 
the assessment of suicidality will be mapped to the Columbia-Classification Algorithm of 
Suicide Assessment (C-CASA) codes as given in Appendix 5. 
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. Baseline is defined as the last 
pre-dose measurement.
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in the schedule of activities.
The PHQ-9 total score will be derived for each time point separately by summing the 
responses to the 9 questions.
3.3. Other Safety Endpoint(s)
Not applicable.
3.4. Other Endpoint(s) (or, Exploratory Endpoints)
!
Trough plasma concentrations of danuglipron at time points specified in the SoA.
!
CFB in fasting plasma insulin, homeostatic model assessment of insulin resistance 
(HOMA-IR) and homeostatic model assessment of beta-cell function (HOMA-B) at:
o
Weeks 4, 8, 12, 16, 22 and 26 for Cohorts 1 and 2.
o
Weeks 4, 8, 16, 20, 24, 28 and 32 for Cohort 3.
HOMA-IR is calculated as: (fasting plasma insulin [FPI] × fasting plasma glucose [FPG])/405
HOMA-B is calculated as: (360 × FPI) / (FPG – 63) 
In both cases above, FPI concentration is in mΙU/L and the FPG concentration is in mg/dL.
!
Absolute CFB in waist circumference at:
o
Weeks 2, 4, 6, 8, 10, 12, 16, 18 and 22 for Cohorts 1 and 2.
o
Weeks 4, 8, 12, 16, 20, 24 and 28 for Cohort 3.
The average of the triplicate waist measurements collected at each assessment time will be 
calculated prior to summaries/analysis. If any of the triplicates are missing, the non-missing 
value(s) will be used, and missing values will not be imputed.
!
Absolute CFB in waist-to-hip ratio at:
o
Weeks 2, 4, 6, 8, 10, 12, 16, 18 and 22 for Cohorts 1 and 2.


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o
Weeks 4, 8, 12, 16, 20, 24 and 28 for Cohort 3.
The average of the triplicate waist and hip measurements collected at each assessment 
time will be calculated prior to calculating the waist-to-hip ratio at each assessment time. If 
any of the triplicates are missing, the non-missing value(s) will be used, and missing values 
will not be imputed.
!
Shift from baseline in glycemic category (normoglycemia, pre-diabetes, or T2DM) at 
End of Treatment
For the purposes of reporting the shift in glycemic categories2, the following definitions will 
be used:
Normoglycemia: FPG < 100 mg/dL and HbA1c < 5.7%;
Pre-diabetes: FPG 100-125 mg/dL (both inclusive) or HbA1c 5.7-6.4% (both 
inclusive);
T2DM: FPG ≥126 mg/dL or HbA1c ≥6.5%.
For discordant results between FPG and HbA1c with respect to the glycemic category
criteria, the higher category will be used (eg, a participant with FPG of 124 mg/dL and
HbA1c of 6.6% would be classified as T2DM).
!
CFB in systolic and diastolic BP at each planned in-clinic study visit up through the 
End of Treatment visit.
!
CFB in lipid parameters at:
o
Weeks 4, 8, 12, 16, 22 and 26 for Cohorts 1 and 2.
o
Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for Cohort 3.
!
CFB in SF-36v2® subscales and summary scores at:
o
Weeks 16 and 26 at Weeks 16 and 26 for Cohorts 1 and 2.
o
Weeks 16, 24 and 32 for Cohort 3.
The SF-36v2®3,4 is a 36-item questionnaire that measures functional health and well-being
from a patient’s perspective. It is a generic questionnaire and can be used across age
(adults), disease, and treatment groups. The questionnaire consists of 8 health domain
scales: physical functioning (10 items), role-physical (4 items), bodily pain (2 items), general 
health (5 items), vitality (4 items), social functioning (2 items), role-emotional (3 items), 
mental health (5 items), reported health transition (1 item) and 2, physical and mental 
component summary scores. Each health domain scale raw score is transformed to 0-100 
scale which can then be converted to norm-based T-scores (Mean=50, SD=10).
The following transformed norm-based T-scores will be derived: physical functioning (PF); 
role-physical (RP); bodily pain (BP); general health (GH); vitality (VT); social functioning 
(SF); role-emotional (RE); mental health (MH); reported health transition; physical 
component summary (PCS); and mental component summary scores (MCS).


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!
CFB in Eating-Related Factors Daily Diary at:
o
Weeks 4, 8, 12, 16, 22 and 26 for Cohorts 1 and 2.
o
Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for Cohort 3.
The Eating-Related Factors Daily Diary is a daily, self-administered questionnaire that 
measures eating-related factors. The diary consists of 5 items that ask participants to 
evaluate their hunger, appetite, fullness, and cravings in the past 24 hours.
At baseline and at the timepoints listed above, the 7-day average score will be calculated 
separately for each item. This average score will be based on the 7 days leading up to the 
respective week (i.e. for Week 4 it would be Day 22 up to Day 28) and will be considered 
missing when 4 or more days are missing in a 7 day period. Baseline is defined as the 7 
days leading up to dosing on Day 1 (i.e. Day -7 up to and including Day -1). The change 
from baseline for each post-dose time point will then be calculated for each of the 5 items 
separately.
!
CFB in PGI-S at each planned in-clinic study visit up through the End of Treatment 
visit.
The PGI-S is a supportive item recommended by FDA for use as an anchor measure to 
generate an appropriate threshold that represents meaningful within-patient change in the
target patient population. There are 4 PGI-S items that ask participants to evaluate the
severity of their hunger, appetite, fullness, and cravings in the past 7 days.
The PGI-S should be converted to a numeric scale using the following mapping:
Response
Numeric value
None
0
Mild
1
Moderate
2
Severe
3
The change from baseline to each post-dose time point will then be calculated.
!
CFB in PROMIS® Fatigue at:
o
Weeks 16 and 26 for Cohorts 1 and 2.
o
Weeks 16, 24 and 32 for Cohort 3.
The PROMIS® Fatigue5 Custom 9-item Version is a self-reported measure that assesses a 
range of symptoms in the past 7 days from mild subjective feelings of tiredness to an 
overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one’s 
ability to execute daily activities and function normally in family or social roles. A global raw 
score ranging from 9 to 45 is calculated and can be translated into a T-score (Mean=50, 
SD=10) using the applicable score conversion table.
See Appendix 6 for derivation of the PROMIS Fatigue T-scores.


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!
CFB in PROMIS® Physical Function at:
o
Weeks 16 and 26 for Cohorts 1 and 2.
o
Weeks 16, 24 and 32 for Cohort 3.
The PROMIS® Physical Function6 Custom 13-item Version is a self-reported measure that
assesses capability rather than actual performance of physical activities. It includes
assessment of one’s ability to walk, climb stairs, run/jog, exercise as well as instrumental
activities of daily living. A global raw score ranging from 13 to 65 is calculated and can be
translated into a T-score (Mean=50, SD=10) using the applicable score conversion table.
See Appendix 7 for derivation of the PROMIS Physical Function T-scores.
!
CFB in IWQOL-Lite-CT© at:
o
Weeks 16 and 26 for Cohorts 1 and 2.
o
Weeks 16, 24 and 32 for Cohort 3.
The IWQOL-Lite-CT©7 was developed for use in the context of clinical trials for obesity, with 
20 items addressing concerns that are specifically relevant to the study population.
The responses to the 20 items will be summarised at each visit using the following 3 scores: 
physical composite score; physical function score; and psychosocial composite score. 
These are derived as outlined in Appendix 8. The change from baseline for each post-dose 
time point (as applicable) will then be calculated for each of the 3 scores.
!
PGI-C at:
o
Weeks 4, 16 and 26 for Cohorts 1 and 2.
o
Weeks 4, 16, 24 and 32 for Cohort 3.
The PGI-C is a supportive item recommended by FDA for use as an anchor measure to
generate an appropriate threshold that represents meaningful within-patient change in the
target patient population. There are 4 PGI-C items that ask participants to rate the overall
change in their hunger, appetite, fullness, and cravings since they started taking the study
medication.
3.5. Baseline Variables
Baseline measures will be included as a covariate in all applicable statistical models along 
with the stratification variable of biological gender (female versus male) at screening.
The statistician may conduct further exploratory analyses into the effect of covariates and 
factors (such as age and strata) on the efficacy endpoints. If conducted, and considered 
relevant to the clinical study report (CSR), the methods will be fully justified and discussed 
within the report.


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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
Participant Analysis 
Set
Description
Enrolled
"Enrolled" means a participant's 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 participate in the study, are not considered enrolled, 
unless otherwise specified by the protocol.
Randomly assigned to 
study intervention
All participants randomly assigned to study intervention 
regardless of whether or not study intervention was 
administered.
Evaluable
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention. 
Participants will be analyzed according to the randomized 
study intervention.
Safety
All participants randomly assigned to study intervention
and who take at least 1 dose of study intervention. 
Participants will be analyzed according to the study 
intervention they actually received. 
Defined Analysis Set
Description
Estimand Set 1
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention.For 
participants who discontinue study intervention, all 
subsequent values will be censored.
Estimand Set 2
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention and do 
not have major protocol deviations. Major protocol 
deviations will be reviewed prior to database lock to 
identify such participants (described in Section 4.1). For 
participants who discontinue study intervention, all 
subsequent values will be censored. 
PK Concentration Set
All participants randomly assigned to study intervention 
and who take at least 1 dose of PF-06882961 
(danuglipron) and in whom at least 1 concentration value 
is reported. 


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4.1. Identifying Major Protocol Deviations
Major protocol deviations will be identified by review of each protocol deviation on a case-
by-case basis to determine whether the associated subject should be excluded from the 
Estimand Set 2. The list of potential deviations that could be classified as major are: falsely 
enrolled into study despite violating inclusion/exclusion criteria; non-compliance with study 
medication; and use of prohibited medications. Other deviations that are identified during the 
study based on emerging data that are deemed to qualify as major may also be considered. 
The project statistician will ensure that the list of subjects and the reason for exclusion is 
clearly documented and provided to programming prior to unblinding and releasing the 
database.
4.2. Strata Misallocations
Participants who are randomized to the wrong stratum (male/female), in error, will have the 
incorrect stratum assignment remain in IMPALA but the clinical database will include the 
correct stratum. The latter will subsequently be used for all relevant analyses.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
The null hypothesis that there is no difference between danuglipron and placebo will be 
tested for the primary endpoint and efficacy related secondary and tertiary endpoints. The 
alternative hypothesis is that danuglipron is superior (i.e. greater reduction) to placebo on 
the primary endpoint.
Statistical inference will be based on the primary endpoint: percent change from baseline in 
body weight at End of Treatment. 
The Type I error rate (∀-level) used for the statistical inference will be 5% (1-sided).
Each treatment group of danuglipron will be tested separately compared to placebo. The 
slow titration arms will be considered separate treatment groups, to the standard titration 
arms.
No adjustment for multiple comparisons will be made.
For all other endpoints there will be no formal hypothesis testing.
5.2. General Methods
The analyses related to the primary, secondary and exploratory endpoints will be based on 
the appropriate population for analysis (see Section 4).
Unless otherwise stated, all summaries, analyses and plots will be presented by treatment 
group with separate tables for Cohorts 1 & 2 combined and Cohort 3. The following 
treatment group labels (or similar) will be used:
Cohorts 1 & 2
Placebo
PF-06882961 40mg BID (1-week titration)


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PF-06882961 80mg BID (1-week titration)
PF-06882961 120mg BID (1-week titration)
PF-06882961 160mg BID (1-week titration)
PF-06882961 200mg BID (1-week titration)
PF-06882961 120mg BID (2-week titration)
PF-06882961 160mg BID (2-week titration)
PF-06882961 200mg BID (2-week titration)
Cohort 3
Placebo
PF-06882961 80mg BID (4-week titration)
PF-06882961 140mg BID (4-week titration)
PF-06882961 200mg BID (4-week titration)
5.2.1. Analyses for Continuous Endpoints
Continuous variables will be presented using summary statistics: number of observations, 
arithmetic mean, standard deviation, median and range (minimum and maximum) values.
For endpoints to be analysed on the natural loge scale, the geometric mean and geometric 
coefficient of variation will additionally be calculated (excluding change from baseline 
summaries).
5.2.2. Analyses for Categorical Endpoints
Categorical variables will be presented using summary statistics: number of observations, 
counts and percentages.
5.2.3. Mixed Model Repeated Measures (MMRM)
The MMRM model(s) will include treatment, time, strata (females versus males) and
treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-
time interaction with time fitted as a repeated effect and participant as a random effect. 
An unstructured covariance matrix will be used to estimate the variances and covariance 
within participant across time points. If convergence is not obtained or model fit is not 
adequate, then other covariance structures will be investigated as necessary. The Kenward-
Roger approximation will be used for estimating degrees of freedom for the model 
parameters.
Missing values (e.g. due to censoring) will be implicitly imputed as part of the MMRM model 
fitting. 
The Least Squares Means (LSMeans) together with 90% confidence intervals, standard 
errors and p-values (2-sided) will be obtained for each treatment group at each time point. 
Differences in LSMeans between each treatment group of danuglipron relative to placebo at 
each time point, together with 90% confidence intervals, standard errors and p-values 
(2-sided), will also be obtained. 
Example SAS code is provided in Appendix 3.


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5.2.4. Logistic Regression
The logistic regression model(s) will include a term for treatment, strata (females versus
males), and baseline will be included as a covariate. 
Missing values (e.g. due to censoring) will be imputed for missing data using a multiple 
imputation method as described in Section 5.3. 
The odds ratio for each treatment group of danuglipron relative to placebo and 
corresponding 90% confidence interval will be obtained.
Example SAS code is provided in Appendix 3. 
5.2.5. Emax Model
The 4-parameter dose-response Emax model will be used to characterize the percent 
change from baseline (%CFB) dose-response relationships with dose included as a 
continuous variable.
The model structure will take the form:
	
 = () + () × 

 + 
E0 is the placebo effect, dose is the target randomized dose, Emax is the maximum effect, 
ED50 is the dose producing 50% of the maximum effect and Hill is the slope parameter. 
The model will be applied to the raw LSMean results (i.e. on the loge-scale) from the primary 
MMRM model (Section 5.2.3) utilizing a Bayesian methodology approach with weakly 
informative priors as described in Appendix 2. Only the raw LSMean results from the 
placebo (combined Cohorts 1 & 2 only) and 1-week titration treatment groups (from Cohort 
1) will be included in the model, i.e. the results from the 2-week and 4-week titration 
treatment groups and placebo from Cohort 3 will not be included.
Estimates of the model parameters of E0, Emax, ED50 and Hill and their 95% credible intervals 
will be produced.
The posterior medians and 90% credible intervals (5th and 95th percentiles of the relevant 
posterior distribution) will be reported for each target randomized dose (including Placebo) 
and their differences relative to placebo. These will all be presented on the %scale by back 
transforming modelled results. Both will be reported in tables and plotted in separate figures.
If convergence cannot be obtained or visual inspection of the data does not support a 
dose-response Emax relationship the following options will be considered in order: (1) 
assume the hill parameter is 1 and remove from the model (giving a 3-parameter dose-
response Emax model); (2) utilize alternative priors to those provided in the appendix 2; (3) 
otherwise this Emax model will not be reported and alternative model structures may be 
investigated and the subsequent analyses may be included in the CSR with rationale for the 
eventual model selected.


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5.2.6. Emax Model (baseline interaction)
An additional 4-parameter dose-response Emax model will be used to characterize percent 
change from baseline dose-response relationships, assuming an interaction between 
baseline body weight and dose.
The model structure will be the same as Section 5.2.5. 
The model will be applied to the raw LSMean results (i.e: on the loge-scale) from individual 
MMRM models that have been applied to each treatment group separately. The MMRM 
models will include time, strata, baseline (on the loge-scale) as a covariate and the baseline-
by-time interaction with time fitted as a repeated effect and participant as a random effect.
Only the raw LSMean results from placebo (combined Cohorts 1 & 2 only) and 1-week 
titration treatment groups (from Cohort 1) will be included in the model, i.e. the results from 
the 2-week and 4-week titration treatment groups and placebo from Cohort 3 will not be 
included. 
An unstructured covariance matrix will be used to estimate the variances and covariance 
within participant across time points for each separate MMRM. If convergence is not 
obtained or model fit is not adequate, then other covariance structures will be investigated 
as necessary. The Kenward-Roger approximation will be used for estimating degrees of 
freedom for the model parameters. 
The raw LSMean results from the separate MMRM models (placebo and standard titration 
treatment groups only, as above) will be calculated for the average baseline body weight 
(i.e. across all participants in the Estimand Set 1A) and then fitted with the Emax model 
above utilizing a Bayesian methodology approach with weakly informative priors as 
described in Appendix 2
Estimates of the model parameters of E0, Emax, ED50 and Hill and their 95% credible intervals 
will be produced.
The posterior medians and 90% credible intervals (5th and 95th percentiles of the relevant 
posterior distribution) will be reported for each target randomized dose (including Placebo) 
and their differences relative to placebo. These will all be presented on the %scale by back 
transforming modelled results.  Both will be reported in tables and plotted in separate 
figures.
If convergence cannot be obtained or visual inspection of the data does not support a 
dose-response Emax relationship the following options will be considered in order: (1) 
assume the hill parameter is 1 and remove from the model (giving a 3-parameter dose-
response Emax model); (2) utilize alternative priors to those provided in the appendix 2; (3) 
otherwise an Emax model (with a baseline interaction) will not be reported.
5.2.7. Cumulative Incidence Plots
Cumulative Incidence Plots will be produced based on the time to the event of interest 
(starting from the time of start of dosing on Day 1) for each treatment group separately and 
will be plotted on the same graph. This will be based on plotting the cumulative incidence 
function (with no competing risks), which will be presented as a % on the y-axis. No 
statistical testing for differences between treatment groups will be considered.


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Details of censoring are included in Section 6 and example SAS code is provided in
Appendix 3.
5.3. Methods to Manage Missing Data
Details of efficacy data to be censored is described in Section 3.2.
For applicable continuous endpoints modelled with an MMRM, missing/censored values will 
be imputed as part of the analysis method. 
For the analysis of safety endpoints, the sponsor data standard rules for imputation of BLQ 
values will be applied. 
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. In listings BLQ values will be reported as “<LLQ”, where LLQ will 
be replaced with the value for the lower limit of quantification (LLQ).
Where a dose has been administered on site and actual dose, frequency, planned dose, 
planned dose frequency, end date time and start date time are missing, these missing 
values will be imputed with the details of the dose planned as per the protocol. 
5.3.1. Multiple Imputation
For summarizing the proportion of responses in body weight, all data from Estimand Set 1 
will be included (i.e. all time points up to and including End of Treatment). A multiple 
imputation (MI) method will be implemented, using a multivariate imputation method by 
chained equations, which is still valid with an arbitrary missing data pattern. The model will 
include: treatment, baseline body weight and strata. Twenty sets of imputations of each 
missing value will be constructed from the MI method and the proportion of responses by 
treatment group will be determined with associated standard errors utilizing a normal 
approximation and will be combined using standard multiple imputation techniques 
proposed by Rubin8 to yield overall estimates. If there is more missing data in the study than 
anticipated, the number of imputation sets may be increased as required.
For logistic regression of body weight, all data from Estimand Set 1 will be included (i.e. all 
time points up to and including End of Treatment). The same imputed datasets as produced 
for the proportion of responses above will be utilized, where a Logistic Regression model (as 
described in Section 5.2.4) will be applied to each of the 20 imputed datasets separately. 
Parameter estimates of the log odds ratios for each treatment group relative to placebo will 
be combined using standard multiple imputation techniques proposed by Rubin8 to yield 
overall estimates of the log odds ratios and their associated standard errors will be used to 
create 90% confidence intervals on the log-odds scale. The log odds ratios and log odds 
90% confidence intervals will be back transformed into odds ratios and associated 90% 
confidence intervals for final reporting.
6. ANALYSES AND SUMMARIES
Data collected before baseline will only be listed, unless otherwise stated. 
For all endpoints, baseline is defined in Section 3.


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For Cohorts 1 and 2, End of Treatment is defined as Week 26.  For Cohort 3, End of
Treatment is defined as Week 32.
Data from participants enrolled into the original cohort (Cohort 1) and Cohort 2 will be 
combined for reporting, where data from the placebo and 2-week titration arms will be 
combined from the 2 cohorts and analyzed together. Data from participants enrolled into 
Cohort 3 will be analyzed and reported separately unless otherwise specified.
6.1. Primary Endpoint(s)
6.1.1. Percent Change from Baseline in Body Weight at End of Treatment
6.1.1.1. Main Analysis
In all cases the Estimand Set 1, as specified in Section 2.2.1 will be utilised.
Absolute changes from baseline and percent changes from baseline in body weight will be 
summarised descriptively by treatment group and time point as described in Section 5.2.1, 
which will be presented separately for the combined Cohorts 1 & 2 and Cohort 3. Tables will 
present all data from the screening (visit 1, absolute tables only), beginning of the placebo 
run-un (visit 2, absolute tables only), baseline and post-baseline time points (including 
follow-up, which will be restricted to participants who completed treatment up to and 
including the End of Treatment visit). 
The primary analysis will be an MMRM (as described in Section 5.2.3) applied to the 
changes from baseline in body weight on the natural log scale at Weeks 2, 4, 6, 8, 10, 12, 
16, 18, 22 and 26 for Cohorts 1 & 2, and at Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for Cohort 
3, that will be used to estimate the treatment effect related to the primary Estimand 1 (as 
described in Section 2.2.1). The MMRM results will be back-transformed as described in 
Section 3.1 for presentations.
The following results from the above primary analysis will be plotted separately for the 
combined Cohorts 1 & 2 and Cohort 3 and for Cohorts 1, 2 and 3 combined. The plots for 
Cohort 1 & 2 and Cohort 3 separately will not be included in the CSR.
!
Profile plots of the back-transformed LSMeans (including 90% confidence intervals) 
representing percent change from baseline over time, with a separate line for each 
treatment group
!
Profile plots of the back-transformed LSMean differences to Placebo (including 90% 
confidence intervals), representing percent change to Placebo over time, with a 
separate line for each treatment group of danuglipron
!
Plot of the back-transformed LSMeans (including 90% confidence intervals) 
representing percent change from baseline at End of Treatment versus treatment 
group on the x-axis (applicable to analyses related to body weight only)
!
Plot of the back-transformed LSMean differences to Placebo (including 90% 
confidence intervals) representing percent change to Placebo at End of Treatment, 
with a separate point for each treatment group of danuglipron (applicable to analyses 
related to body weight only)
)


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Standard SAS output will be provided to support the main statistical summary table for the 
primary analysis model but will not be included in the CSR.
Statistical Model Diagnostics
The presence of outliers will be investigated for this analysis. An outlier will be defined as 
any response data value with a studentized (conditional) residual greater than 3, or less 
than -3. A listing will be presented of any participants meeting these criteria and will be 
included with standard SAS outputs. The assumptions of normality will be verified 
graphically using residual plots. For each fitted model, a set of conditional studentized 
residual plots will be produced, including residual plot, histogram of normality, QQ plot and 
summary of fit statistics. The residual plots will not be included in the clinical study report.
If there are outliers or major deviations from normality, then the effect of these on the 
conclusions may be investigated through alternative transformations and/or analyses 
excluding outliers. Justification for any alternative to the planned analysis will be given in the 
report of the study.
6.1.1.2. Sensitivity/Supplementary Analyses
For all of the following analyses, standard SAS output will be provided to support the 
statistical summaries produced but will not be included in the CSR.
The following supplementary analyses to the primary endpoint will be carried out:
!
To assume a dose-response relationship with body weight (without a baseline 
interaction) an Emax model will be applied to the raw LSMeans at End of Treatment 
from the main MMRM analysis as described in Section 5.2.5. Final results from the 
Emax model will be back transformed using the same formula as provided in 3.1. 
This will only be applied in reference to percent change from baseline in body weight 
for Cohorts 1 & 2.
!
To assume a dose-response relationship with body weight, including an interaction 
between baseline body weight and dose, an Emax model will be applied to the raw 
LSMeans at End of Treatment from separate MMRM models at the overall baseline 
body weight as described in Section 5.2.6. Final results from the Emax model will be 
back transformed using the same formula as provided in 3.1. This will only be 
applied in reference to percent change from baseline in body weight for Cohorts 1 &
2.
!
To model absolute changes from baseline in body weight, a separate MMRM model
(as described in Section 5.2.3) will be applied to the absolute change from baseline 
in body weight at Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26 for Cohorts 1 & 2, and 
at Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for Cohort 3 separately, where baseline 
absolute body weight will be the baseline term. Similar outputs to Section 6.1.1.1 will 
be reported from the MMRM model where back-transformation of LSMeans and 
LSMean differences will not be applicable, along with standard SAS output (which 
will not be included in the CSR).
The additional exploratory estimand to the primary endpoint will be carried out:


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An additional exploratory analysis that assesses the primary endpoint in evaluable 
participants with no major protocol deviations while on treatment (Section 2.2.3) will be 
performed to estimate the treatment effect related to the exploratory Estimand 7 (as 
described in Section 2.2.3). The same summary and analysis output as the main analysis
(Section 6.1.1.1) will be performed and reported but applied to the Estimand Set 2 (as 
described in Section 4).
6.2. Secondary Endpoint(s)
6.2.1. Response as defined by a body weight loss of ≥5% from baseline at End of 
Treatment
In all cases the Estimand Set 1 as specified in Section 4 will be utilised.
The proportion of responses at End of Treatment will be summarised descriptively by 
treatment group as described in Section 5.2.2, where no imputation for missing values will 
be conducted. The proportion of responses at End of Treatment will also be reported after 
multiple imputation for missing values as per Section 5.3.
A logistic regression model (as described in Section 5.2.4) will be applied to the response at 
End of Treatment that will be used to estimate the treatment effect related to the secondary 
Estimand 2 (as described in Section 2.2.2.1), where missing values will be imputed using 
multiple imputation as per Section 5.3. Baseline body weight and strata will be included in 
the model.
In addition, standard SAS output will be provided to support the main statistical summary 
table for the logistic regression model and multiple imputation approach but will not be 
included in the CSR.
6.2.2. Percent CFB in Body Weight over time
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Percent CFB in body weight will be summarized at Weeks 2, 4, 6, 8, 10, 12, 16, 18 and 22 
for Cohorts 1 & 2 and for Weeks 4, 8, 12, 16, 20, 24 and 28 for Cohort 3.  Summaries and 
analysis results will be reported as part of the main analysis approach for the primary 
endpoint (Section 6.1.1.1).
6.2.3. Absolute CFB in waist circumference at End of Treatment
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute changes from baseline in waist circumference will be summarised and analysed 
similar to body weight in Section 6.1.1.1, including follow-up.
An MMRM (as described in Section 5.2.3) will be applied to the absolute change from 
baseline at Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26 for Cohorts 1 & 2 and at Weeks 4, 8, 
12, 16, 20, 24, 28 and 32 for Cohort 3 separately, where baseline waist circumference will 
be the baseline term. Results similar to body weight in Section 6.1.1.1, where back-
transformation of LSMeans and LSMean differences will not be applicable, will be reported 
along with standard SAS output (where the figures and standard SAS output will not be 
included in the CSR).


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The MMRM results from the End of Treatment visit will be extracted in order to estimate the 
treatment effect related to Estimand 3.
6.2.4. Absolute CFB in waist-to-hip ratio at End of Treatment
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute changes from baseline in waist-to-hip ratio will be summarised and analysed 
similar to body weight in Section 6.1.1.1, including follow-up.
An MMRM (as described in Section 5.2.3) will be applied to the absolute change from 
baseline at Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26 for Cohorts 1 & 2 and at Weeks 4, 8, 
12, 16, 20, 24, 28 and 32 for Cohort 3 separately, where baseline waist-to-hip ratio will be 
the baseline term. Results similar to body weight in Section 6.1.1.1, where back-
transformation of LSMeans and LSMean differences will not be applicable, will be reported 
along with standard SAS output (where figures and standard SAS output will not be included 
in the CSR).
The MMRM results from the End of Treatment visit will be extracted in order to estimate the 
treatment effect related to Estimand 4.
6.2.5. Absolute CFB in HbA1c 
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute changes from baseline in HbA1c will be summarised and analysed similar to body 
weight (Weeks 16 and 26 for Cohorts 1 & 2 and Weeks 16, 24 and 32 for Cohort 3) in 
Section 6.1.1.1, including follow-up.
An MMRM (as described in Section 5.2.3) will be applied to the absolute change from 
baseline at the time points specified above where baseline HbA1c will be the baseline term. 
Results similar to body weight in Section 6.1.1.1, where back-transformation of LSMeans 
and LSMean differences will not be applicable, will be reported along with standard SAS 
output (where figures and standard SAS output will not be included in the CSR).
The MMRM results will be extracted in order to estimate the treatment effect related to 
Estimand 5.
6.2.6. Absolute CFB in FPG over time
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute changes from baseline in FPG will be summarised and analysed similar to body 
weight in Section 6.1.1.1, including follow-up.
An MMRM (as described in Section 5.2.3) will be applied to the absolute change from 
baseline at Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26 for Cohorts 1 & 2 and separately, at 
Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for Cohort 3, where baseline FPG will be the baseline 
term. Results similar to body weight in Section 6.1.1.1, where back-transformation of 
LSMeans and LSMean differences will not be applicable, will be reported along with 
standard SAS output (where figures and standard SAS output will not be included in the 
CSR).


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The MMRM results will be extracted in order to estimate the treatment effect related to 
Estimand 6.
6.3. Other Safety Summaries and Analyses Endpoint(s)
The AEs of interest are defined in Section 3.2.2.1.1. Figures described in this section may 
not be included in the CSR.
6.3.1. Adverse Events
Adverse events (Tier 1, 2 and 3 AEs as described in Section 3.2.2.1) will be summarized by 
treatment group and overall and in accordance with sponsor reporting standards using the 
safety analysis set defined in Section 4. The adverse events (AEs) will be sorted in 
descending frequency within a system organ class.
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. 
The following tables and figures related to TEAEs classed as Tier 1 or 2 will be ordered in 
descending point estimate of risk difference within System Organ Class. If two or more 
events have the same frequency, they will be sorted alphabetically by preferred term. 
TEAEs classed as Tier 1 events will be tabulated by treatment group. Number of 
participants and percent will be presented, along with the risk difference between each 
treatment group of danuglipron and placebo. 95% confidence intervals and p-values will also 
be presented for the comparison. No adjustment for multiplicity will be used. 
Tier 1 TEAEs will also be presented graphically. The TEAEs will be presented in a two-panel 
plot, the left panel will give the proportions of TEAEs observed in a treatment group of 
danuglipron and separately placebo while the right panel will display the 95% confidence 
interval for the risk differences for each TEAE. A vertical line corresponding to the value of 
0 will be added to the right-hand plot. For the graphical display for tier 1 events, a column 
containing the p-value for each event will be added to the right-hand side of the forest plot in 
the right panel. Each panel will be paged by treatment group of danuglipron. 
TEAEs classed as Tier 2 events will be summarised and graphically presented similar to 
Tier 1 events, but no p-values will be presented. No adjustments for multiplicity will also be 
used.
For Tier 1 and Tier 2 outputs, footnotes will be included on the tables to provide proper 
interpretation of p-values (Tier 1 only) and confidence intervals and to describe how the 
comparison was conducted, e.g. “P-values and confidence intervals are not adjusted for 
multiplicity and should be used for screening purpose only. 95% Confidence intervals are 
provided to help gauge the precision of the estimates for Risk Difference. Risk Difference is 
computed as danuglipron versus placebo.”
The incidence of TEAEs by preferred term with more than 5% occurrences by preferred term 
will be presented. The TEAEs to include in tables will be based on those occurring in more 
than 5% of participants in either (1) Cohorts 1 and 2 combined; or (2) more than 5% of 
participants in Cohort 3.


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TEAEs with more than 5% occurrences in any treatment arm will additionally be presented, 
split by the titration step at the time of TEAE onset.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group 
of adverse events. Except for select events in unique situations, studies do not employ 
formal adjudication procedures for the purpose of event classification. As such, safety 
analysis is generally considered as an exploratory analysis and its purpose is to generate 
hypotheses for further investigation. The 3-tier approach facilitates this exploratory analysis.
6.3.1.1. Forest plots on the Incidence of adverse events of interest
Forest plots displaying the incidence of TEAEs of interest (“All Causality” only) by treatment 
group will be produced separately by AE. Each forest plot will present all treatment groups 
separately and will include 95% confidence intervals (calculated using the Blyth-Still-Casella 
method9).
6.3.1.2. Incidence of first occurrence of adverse events of interest by week
The number and percentage of participants who experience the first occurrence of a TEAE 
of interest each week (up to and including the follow-up visit) will be tabulated by treatment 
group and week, where percentage will be defined in two ways. These will be included in the 
same table and produced separately for each TEAE of interest.
To calculate the percentage each week, the numerator will be the total number of 
participants with the TEAE of interest that was also their first post-dose occurrence of the 
event during that respective week. The two approaches for the denominator are: (1) the total 
overall number of evaluable participants in the Safety Analysis Set for the respective 
treatment group; and (2) the total number of participants who had not discontinued from the 
study prior to that respective week will be the denominator (note if a participant did 
discontinue from the study during that respective week they would be included in the 
denominator).
A figure of the percentage per week will also be produced, with week on the x-axis and a 
separate line for each treatment group. The percentage will represent the above definition 
(2) of the denominator but based on blinded data reviews this figure may be adapted or 
additionally produced based on definition (1). These figures will be produced separately for 
each TEAE of interest.
6.3.1.3. Prevalence of adverse events of interest by week
The number and percentage of participants who are experiencing a TEAE of interest (either 
onset or ongoing) each week (up to and including the follow-up visit, with week as 
appropriate based on the End of Treatment definition) will be tabulated by treatment group 
and week. A separate table representing the number and percentage by severity (mild, 
moderate or severe) will also be produced. These tables will be produced separately for 
each TEAE of interest.
To calculate the percentage each week, the total number of participants who experience the 
TEAE of interest at any time during the respective week will be the numerator and the total 
number of participants who had not discontinued from IP and/or the study prior to that 


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respective week will be the denominator (note if a participant did discontinue from IP and/or 
the study during that respective week they would be included in the denominator).
A figure of the overall percentage (i.e. not by severity) per week will be produced, with week 
on the x-axis and a separate line for each treatment group. A separate figure of the 
percentage per week will also be produced, with week on the x-axis and a separate line for 
each severity, paged by treatment group. These figures will be produced separately for each 
TEAE of interest.
6.3.1.4. Time to First Occurrence/Recurrence of AEs of Interest
Exploratory summaries on the time to the first occurrence of AEs of interest will be produced 
in Cumulative Incidence Plots as described in Section 5.2.7. Participants who discontinue 
from the study or discontinue from IP prior to the start of the AE event of interest will be 
censored at the discontinuation/initiation date.
A separate plot for each AE of interest will be produced separately.
The above will also be produced separately for the time to the first recurrence of the AEs of 
interest.
6.3.1.5. Time to discontinuation from IP due to Gastrointestinal Disorders AEs
Exploratory summaries on the time to discontinuation from IP (regardless of study 
discontinuation or continuation) due to Gastrointestinal Disorders AEs (defined as based on 
System Organ Class) will be produced with a Cumulative Incidence Plot as described in 
Section 5.2.7. Participants who discontinue will be censored at the associated 
discontinuation date.
6.3.1.6. Subset Reporting Interval
The subset adverse events, described in Section 3.2.2.1.2, will be summarised as above 
(excluding the 3-tier reporting system) where standard tables and incidence tables will be 
produced for both ‘All causality’ and ‘Treatment related’.
6.3.1.7. Hypoglycemic Adverse Events
The hypoglycemic AEs will be listed in a separate table and summarized categorically by 
treatment group and overall as per Section 5.2.1.
6.3.2. Laboratory Data
Laboratory data from will be listed and summarized by treatment group and overall, in 
accordance with the sponsor reporting standards. 
6.3.2.1. Focused Laboratory Summaries on Endpoints of Interest 
Absolute values, changes from baseline and percent changes from baseline in calcitonin, 
amylase, lipase, TSH, free T4, lipid profile, liver function tests and eGFR (as outlined in 
Section 3.2.2.3) will be summarized by treatment group and time point as per Section 5.2.1
(unplanned readings will not be included in these summaries). Follow-up data will be 
including in the summaries with data from all participants in the safety analysis set. Tables 
will be paged by parameter.


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The following box and whisker plots for each parameter will be produced: 
!
Absolute values over time by treatment group 
!
Change from baseline over time by treatment group
!
Percentage change from baseline over time by treatment group.
Spaghetti plots for individual data versus time, by treatment, will be produced for ALT, ALP, 
AST and total bilirubin:
Plots of absolute values of ALT and AST versus change from baseline in weight by 
treatment will also be produced.
MMRM models (as described in Section 5.2.3) will be applied to the change from baseline at 
Weeks 4, 8, 12, 16, 22 and 26 (as applicable) for Cohorts 1 & 2 and at Weeks 4, 8, 12, 16, 
20, 24, 28 and 32 for Cohort 3 separately and for each parameter separately using the 
safety analysis set (as defined in Section 4). For ALT, AST, alkaline phosphatase and GGT, 
the MMRM models will instead be applied to the change from baseline on the natural log 
scale and the MMRM results will be back-transformed for reporting, similar to the primary 
endpoint as described in Section 6.1.1.1.
From each model, the LSMeans together with 90% confidence intervals, standard errors 
and p-values will be obtained for each treatment group at each time point. Differences in 
LSMeans between each treatment group of danuglipron relative to placebo at each time 
point, together with 90% confidence intervals, standard errors and 2-sided p-values will also 
be obtained. A plot of the LSMean differences to Placebo (including 90% confidence 
intervals) over time, with a separate line for each treatment group of danuglipron will be 
produced separately for each parameter. Standard SAS outputs will be provided to support 
the main statistical summary tables but will not be included in the CSR. 
6.3.2.2. Clinical Laboratory Parameters of Interest
An additional summary table of the number of participants (from the Safety Analysis Set as 
defined in Section 4) with “Flag Level” or “Alert Level” abnormalities for each of the clinical 
laboratory parameters of interest as specified in Section 3.2.2.4 will be produced. This table 
will summarise the number of participants with “Flag level” or “Alert level” abnormalities 
separately and by treatment group and placebo run-in and overall as per Section 5.2.2.
6.3.3. Vital Signs
Average of the triplicate measurements (where applicable) will be used in analyses.
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarized by treatment group and time point, according to sponsor 
reporting standards. Tables will be paged by parameter.
Mean changes from baseline for systolic and diastolic blood pressure and pulse rate will be 
plotted against time point. On each plot there will be 1 line for each treatment group with all 
groups on the same plot including placebo.


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MMRM models (as described in Section 5.2.3) will be applied to the change from baseline
for supine systolic and diastolic blood pressure and pulse rate separately using the safety 
analysis set (as defined in Section 4). For Cohorts 1 & 2, Weeks 0 (i.e. 2-6H post-dose 
only), 2, 4, 6, 8 (0 and 2-6H separately), 10, 12, 16 (0 and 2-6H separately), 18, 22 and 26 
(0 and 2-6H separately) assessments will be included in the model.  For Cohort 3, Weeks 0 
(0 and 2-6H separately), 4, 8 (0 and 2-6H separately), 12, 16 (0 and 2-6H separately), 20, 
24 (0 and 2-6H separately), 28 and 32 (0 and 2-6H separately) assessments will be 
included. From each model, the LSMeans together with 90% confidence intervals, standard 
errors and p-values will be obtained for each treatment group at each time point. Differences 
in LSMeans between each treatment group of danuglipron relative to placebo at each time 
point, together with 90% confidence intervals, standard errors and 2-sided p-values will also 
be obtained. A plot of the LSMean differences to Placebo (including 90% confidence 
intervals) over time, with a separate line for each treatment group of danuglipron will be 
produced separately for each parameter. Standard SAS outputs will be provided to support 
the main statistical summary tables but will not be included in the CSR.
Maximum absolute values and maximum changes from baseline for vital signs, over all 
measurements taken post-dose will also be tabulated by treatment group and overall using 
categories as defined in the Appendix 4. Numbers and percentages of participants meeting 
the categorical criteria will be provided. All planned and unplanned post-dose time points will 
be counted in these categorical summaries. All values meeting the criteria of potential 
clinical concern will be listed. 
Maximum decrease and increase from baseline for supine systolic and diastolic blood 
pressures, and maximum increase from baseline for supine pulse rate will be summarized 
by treatment group, according to sponsor reporting standards. 
6.3.4. Electrocardiograms
Average of the triplicate measurements (where applicable) will be used in analyses. 
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment group and time point using sponsor reporting standards. Tables 
will be paged by parameter.
Mean changes from baseline in QT, heart rate and QTcF will be plotted against time 
point. On each plot there will be 1 line for each treatment group with all treatments included 
on the same plot including placebo. 
MMRM models (as described in Section 5.2.3) will be applied to the change from baseline at 
Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26 for Cohorts 1 & 2 and at Weeks 4, 8, 12, 16, 20, 
24, 28 and 32 for Cohort 3 separately, for QT, heart rate and QTcF separately using the 
safety analysis set (as defined in Section 4). From each model, the LSMeans together with 
90% confidence intervals, standard errors and p-values will be obtained for each treatment 
group at each time point. Differences in LSMeans between each treatment group of 
danuglipron relative to placebo at each time point, together with 90% confidence intervals, 
standard errors and 2-sided p-values will also be obtained. A plot of the LSMean differences 
to Placebo (including 90% confidence intervals) over time, with a separate line for each 
treatment group of danuglipron will be produced separately for each parameter. Standard 
SAS outputs will be provided to support the main statistical summary tables but will not be 
included in the CSR. 


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ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by treatment group and overall using categories as defined in the Appendix 4
(for QTc these correspond to the Pfizer Guidance10). Numbers and percentages of 
participants meeting the categorical criteria will be provided. All planned and unplanned 
post-dose time points will be counted in these categorical summaries. All values meeting 
the criteria of potential clinical concern will be listed. 
Maximum absolute value (post-dose) and the maximum increase from baseline for QTcF, 
PR and QRS will be summarized by treatment group according to sponsor reporting 
standards.
Listings of participants with any single post-dose value > 500 msec will also be produced for 
QTcF.
6.3.5. Assessment of mental health as determined by C-SSRS and PHQ-9.
Screening, baseline and post-baseline C-SSRS data (mapped to C-CASA scores as 
described in Section3.2.2.3) using the safety population defined in Section 4, will be 
separately summarized categorically by treatment group and time point as outlined in 
Section 5.2.2.
Baseline and post-baseline PHQ-9 data (responses to each of the 9 items) using the safety 
population defined in Section 4 will be summarized categorically for each question 
separately by treatment group and time point as outlined in Section 5.2.2. The PHQ-9 total 
score as defined in Section 3.2.4 will additionally be summarized descriptively by treatment 
group and time point as outlined in Section 5.2.1.
The number of participants who met the criteria for referral to a mental health professional 
will be listed and summarized by treatment group and time point as outlined in Section 5.2.2.
6.4. Other Endpoint(s) (or, Exploratory Endpoint[s])
6.4.1. Trough plasma concentrations of danuglipron at time points specified in the 
SoA
Danuglipron concentrations will be characterized by Ctrough and will be summarized by 
treatment group and by time point using the following descriptive statistics: number of 
participants contributing at each time point, arithmetic mean, median, minimum, maximum, 
Q1, Q3, standard deviation, geometric mean, and geometric CV (%).
Median Ctrough versus time point will be plotted by treatment group including error bars 
representing the inter-quartile range (i.e. Q1 to Q3).
Ctrough values from PK samples that were collected after discontinuation of investigational 
product will be listed but excluded from summarization.
The post-dose random plasma concentration data will only be listed (and not summarized); 
these data are noted for use in supplemental population-PK analyses.
In addition, as permitted by data and determined by the sponsor, PK-PD relationship 
between plasma concentrations of danuglipron and effect on primary, secondary and tertiary 
endpoints may be characterized using a population PK-PD approach. The objective of such 


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an analysis, if conducted, would aim to explore potential demographic determinants (eg, 
age, gender, and weight) influencing the observed PK or PD variability in response to 
danuglipron. The population PK-PD analysis, if conducted, will be reported separately from 
the main CSR.
6.4.2. CFB in fasting plasma insulin, HOMA-IR and HOMA-B at Weeks 4, 8, 12, 16, 22 
and 26
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute changes from baseline in fasting plasma insulin, HOMA-IR and HOMA-B will be 
summarised and analysed separately similar to body weight in Section 6.1.1.1, including 
follow-up, where HOMA-IR and HOMA-B are as defined in Section 3.2.2.
MMRM models (as described in Section 5.2.3) will be applied to each parameter separately, 
where each will include the absolute change from baseline at Weeks 4, 8, 12, 16, 22 and 26 
for Cohorts 1 & 2 and at Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for Cohort 3 separately, and 
the baseline term will be the baseline for the associated parameter. Results similar to body 
weight in Section 6.1.1.1, where back-transformation of LSMeans and LSMean differences 
will not be applicable, will be reported separately along with standard SAS output (where the 
latter will not be included in the CSR).
6.4.3. Absolute CFB in waist circumference over time.
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
CFB in waist circumference will be summarized at Weeks 2, 4, 6, 8, 10, 12, 16, 18 and 22 
for Cohorts 1 & 2, and at Weeks 4, 8, 12, 16, 20, 24 and 28 for Cohort 3 separately.  
Summary and analysis results will be reported as described in Section 6.2.3.
6.4.4. Absolute CFB in waist-to-hip ratio over time
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
CFB in waist-to-hip ratio will be summarized at Weeks 2, 4, 6, 8, 10, 12, 16, 18 and 22 for 
Cohorts 1 & 2 and at Weeks 4, 8, 12, 16, 20, 24 and 28 for Cohort 3 separately.  Summary 
and analysis results will be reported as described in Section 6.2.4.
6.4.5. Shift from baseline in glycemic category (normoglycemia, pre-diabetes, or 
T2DM) at End of Treatment
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
A shift table for the baseline glycemic category to the End of Treatment glycemic category 
will be presented by treatment group.
6.4.6. CFB in systolic and diastolic BP over time
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute and change from baseline in systolic and diastolic blood pressure will be 
summarised descriptively and analyzed as described in Section 6.3.3 at Weeks 2, 4, 6, 8, 


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10, 12, 16, 18, 22 and 26 for Cohorts 1 & 2 and at Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for 
Cohort 3 separately.
6.4.7. CFB in lipid parameters over time
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute and change from baseline in lipid parameters will be summarised descriptively and 
analyzed as described in Section 6.3.2.1 at Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26 for 
Cohorts 1 & 2 and at Weeks 4, 8, 12, 16, 20, 24, 28 and 32 for Cohort 3 separately.
6.4.8. CFB in SF-36v2® subscales and summary scores 
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute and change from baseline in the 11 SF-36v2 transformed norm-based T-scores
(covering 8 domains, health transition and 2 components) will be summarised descriptively 
by treatment group and time point as described in Section 5.2.1, at Weeks 16 and 26 for 
Cohorts 1 & 2 and at Weeks 16, 24 and 32 at Cohort 3 separately.
6.4.9. CFB in Eating-Related Factors Daily Diary 
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute and change from baseline in the 7-day average scores for each of the 5 individual 
items from the Eating-Related Factors Daily Diary will be summarized descriptively by 
treatment group and time point for each item separately as described in Section 5.2.1, at 
Weeks 4, 8, 12, 16, 22 and 26 for Cohorts 1 & 2 and at Weeks 4, 8,12, 16, 20, 24, 28 and 
32 at Cohort 3 separately. 
6.4.10. CFB in PGI-S at each planned clinic visit up through End of Treatment visit
In all cases a dataset similar to Estimand Set 1 as specified in Section 4will be utilised.
PGI-S will be summarized categorically by treatment group and time point for each item as 
described in Section 5.2.2. Shift tables will also be produced to summarise the categorical 
changes for each item at each post-dose time-point separately.
6.4.11. CFB in PROMIS® Fatigue 
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute and change from baseline in the PROMIS® Fatigue T-scores will be summarized 
descriptively by treatment group and time point as described in Section 5.2.1, at Weeks 16 
and 26 for Cohorts 1 & 2 and at Weeks 16, 24 and 32 for Cohort 3 separately. 
6.4.12. CFB in PROMIS® Physical Function 
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute and change from baseline in the PROMIS® Physical Function T-scores will be 
summarized descriptively by treatment group and time point as described in Section 5.2.1, 
at Weeks 16 and 26 for Cohorts 1 & 2 and at Weeks 16, 24 and 32 for Cohort 3 separately. 


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6.4.13. CFB in IWQOL-Lite-CT© 
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
Absolute and change from baseline for each of the 3 composite scores from the 
IWQOL-Lite-CT© will be separately summarized descriptively by treatment group and time 
point as described in Section 5.2.1, at Weeks 16 and 26 for Cohorts 1 & 2 and at Weeks 16, 
24 and 32 for Cohort 3 separately. 
6.4.14. PGI-C 
In all cases a dataset similar to Estimand Set 1 as specified in Section 4 will be utilised.
PGI-C data will be summarized categorically by treatment group and time point for each item 
as described in Section 5.2.2, at Weeks 4, 16 and 26 for Cohorts 1 & 2 and at Weeks 4, 16, 
24 and 32 for Cohort 3 separately.
6.5. Subset Analyses
Absolute values, percentage changes from baseline and absolute changes from baseline in 
body weight will be summarised descriptively by treatment group, time point and biological 
sex as described in Section 5.2.1. The tables will present time points as described in 
Section 6.1.1.1 and baseline is as defined in Section 3.
6.6. Baseline and Other Summaries and Analyses
6.6.1. Baseline Summaries
Baseline tables summarizing the following will be produced by treatment group and overall: 
age; gender; race; ethnicity; height; body weight; body mass index; waist circumference; 
waist-to-hip ratio; hip circumference; country; HbA1c; fasting plasma glucose; systolic blood 
pressure; diastolic blood pressure; pulse rate; total cholesterol; direct LDL cholesterol; HDL 
cholesterol and triglycerides. The tables should be produced separately for: (1) Cohorts 1 &
2, and (2) Cohort 3.
6.6.2. Study Conduct and Participant Disposition
Participant evaluation groups will show participant disposition for each phase of the study 
(screening, double blind treatment and follow-up) and will additionally show which 
participants were analyzed for efficacy (Estimand Set 1 and 2) as well as for safety. 
Frequency counts and percentages will be supplied for participant discontinuation(s) by 
treatment group and overall for: (1) Cohorts 1 & 2, and (2) Cohort 3 data, which will be 
reported in accordance with the sponsor reporting standards.
6.6.3. Study Treatment Exposure
Banked biospecimens will be collected and retained for future analyses, but will not be 
analyzed specifically for this study and will not be included in the CSR.
6.6.4. Concomitant Medications and Nondrug Treatments
All prior and concomitant medication(s) as well as non-drug treatment(s) will be reported 
according to current sponsor reporting standards.
)


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6.6.1. Treatment Compliance
Treatment compliance (in %) will be summarised descriptively by treatment group and 
overall, at time point as described in Section 5.2.1. The time points will be: the Placebo run-
in phase; Weeks 2, 4, 6, 8, 10, 12, 16, 18, 22 and 26 for Cohorts 1 & 2 and at Weeks 4, 8, 
12, 16, 20, 24, 28 and 32 for Cohort 3 separately.
Treatment compliance is defined for each time point separately as: (actual number of IP 
tablets / planned number of IP tablets) × 100%.
Missing information pertaining to doses administered on site will be imputed as per Section
5.3. 
6.6.2. Discontinuations
Participant discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarised by treatment group and overall.
Data will be reported in accordance with the sponsor reporting standards, where an 
additional table summarizing participant discontinuations of IP due to adverse events for 
each system organ class and preferred term will be produced by treatment group and 
overall also.
Exploratory summaries on the time to discontinuation from the study and time to 
discontinuation of IP (regardless of study discontinuation or continuation) will be produced 
separately using Cumulative Incidence Plots as described in Section 5.2.7. For both, 
participants who discontinue from the study/IP will be censored at the associated 
discontinuation date.
7. INTERIM ANALYSES
7.1. Introduction
An interim analysis will be performed at least once annually while the study is ongoing, after 
at least 25% of participants are randomized, with further details provided in the IRC charter. 
This interim analysis will assess, at a minimum, unblinded safety of the randomized 
participants. Additional interim analyses for safety and/or efficacy may be performed if 
needed. Further details will be provided in the IRC charter.
Interim analysis results may be used for internal business decisions including, but not limited
to: stopping a dose level, future study planning, stopping for futility, stopping for early
success, conducting a sample size re-estimation, or adapting the study after the interim
analysis. Before any interim analysis is instigated, the details of the objectives, decision
criteria, information dissemination plan, and method of maintaining the study blind as per
Pfizer’s SOPs will be documented and approved in an IRC charter. In addition, the analysis 
details must be documented and approved in an interim analysis SAP or final SAP.
7.2. Interim Analyses and Summaries
The interim analyses will be performed using the methodology specified in this SAP and will 
be outlined in this SAP (with an amendment) or an interim analysis SAP. Any substantial 
deviations from the SAP’s methodology will be fully justified and outlined. Details of the 
ongoing unblinded safety reviews will be provided in the IRC Charter and/or the interim 
analysis SAP.


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8. REFERENCES
1. ICH Harmonised Guideline E9 (R1); Estimands and Sensitivity Analysis in Clinical 
Trials; 16 June 2017.
2. American Diabetes Association. Standards of medical care in diabetes – 2019. 
Diabetes Care 2019;42(Suppl 1):S1-S193.
3. Ware J, Kosinski M, Bjorner J, et al. Development. User's Manual for the SF-36v2® 
Health Survey. Lincoln (RI): QualityMetric Incorporated; 2007.
4. Ware J, Kosinski M, Bjorner J, et al. SF-36v2® Health Survey: Administration guide 
for clinical trial investigators: Lincoln (RI): QualityMetric Incorporated; 2008.
5. Patient Reported Outcomes Measurements Information System, FATIGUE: A brief
guide to the PROMIS® Fatigue instruments; Feb 28, 2019.
6. Patient-Reported Outcomes Measurements Information System, PHYSICAL 
FUNCTION, A brief guide to the PROMIS® Physical Function instruments; July 18, 
2019.
7. Kolotkin RL, Williams VSL, Ervin CM, et al. Validation of a new measure of quality of 
life in obesity trials: Impact of Weight on Quality of Life-Lite Clinical Trials Version. 
Clin Obes 2019;9:e12310.
8. Rubin DB. Multiple Imputation for Nonresponse in Surveys. 1987; Wiley, New York.
9. Blyth CR, Still HA. Binomial confidence intervals. Journal of the American 
Statististical Association. 78:108-116, 1983, & Casella G. Refining binomial 
confidence intervals. The Canadian Journal of Statistics, 14:113-129, 1986 
10. 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.
11. Thomas, N. and Wu, J. (2019). clinDR: Simulation and Analysis Tools for Clinical
Dose Response Modeling. R package version 1.9. https://CRAN.R-
project.org/package=clinDR
12. Wu, J,  Banerjee, A., Jin, B., Menon, S., Martin, S., and Heatherington, A., (2017), 
Clinical dose-response for a broad set of biological products: A model-based meta-
analysis, Statistical Methods in Medical Research, Vol. 7, No. 9, 2694-2721.
13. Thomas, N., and Roy, D. (2017).  Analysis of clinical dose-response in small-
molecule drug development:  2009-2014. Statistics in Biopharmaceutical Research,  
Vol. 9, No. 2, 137-146.
14. Thomas, N., Sweeney, K., and Somayaji, V. (2014).  Meta-analysis of clinical dose 
response in a large drug development portfolio, Statistics in Biopharmaceutical 
Research, Vol. 6, No.4, 302-317.


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15. HealthMeasures. http://www.healthmeasures.net/score-and-
interpret/calculatescores/scoring-instructions. 2020. 


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Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and Rules for Handling 
Intercurrent Events and Missing Data 
Analysis Model
Percent change from 
baseline in body weight
at End of Treatment 
(and also at Weeks 2, 
4, 6, 8, 10, 12, 16, 18 
and 22 for Cohorts 1 & 
2 and at Weeks 4, 8, 
12, 16, 20, 24 and 28 
for Cohort 3.)
Summary
Estimand Set 1
DFI: Censor all values post discontinuation
MV: Not imputed
N/A
Primary analysis
MMRM
Supplementary analyses
Emax (x 2)
Exploratory analysis 
(summary)
Estimand Set 2
MPD: Remove participants
DFI: Censor all values post discontinuation
MV: Not imputed
N/A
Exploratory analysis
MMRM
Response as defined 
by a body weight loss 
of ≥5% from baseline 
at End of Treatment
Summary
Estimand Set 1
DFI: Censor all values post discontinuation
MV: Not imputed
N/A
Summary
DFI: Censor all values post discontinuation
MV: Imputed using multiple imputation
N/A
Secondary analysis
Logistic 
regression
Absolute change from 
baseline in waist 
circumference at End 
of Treatment (and at 
Weeks 2, 4, 6, 8, 10, 
12, 16, 18 and 22 for 
Cohorts 1 & 2 and at 
Weeks 4, 8, 12, 16, 20, 
24 and 28 for Cohort 
3.)
Summary
Estimand Set 1
DFI: Censor all values post discontinuation
MV: Not imputed
N/A
Secondary analysis
MMRM
Absolute change from 
baseline in waist-to-hip 
ratio at End of 
Treatment (and at 
Weeks 2, 4, 6, 8, 10, 
12, 16, 18 and 22 for 
Cohorts 1 & 2 and at 
Summary
Estimand Set 1
DFI: Censor all values post discontinuation
MV: Not imputed
N/A
Secondary analysis
MMRM


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Weeks 4, 8, 12, 16, 20, 
24 and 28 for Cohort 
3.)
Absolute change from 
baseline in HbA1c at 
Weeks 16 and 26 for 
Cohorts 1 & 2 and at 
Weeks 16, 24 and 32 
for Cohort 3.
Summary
Estimand Set 1
DFI: Censor all values post discontinuation
MV: Not imputed
N/A
Secondary analysis
MMRM
Absolute change from 
baseline in FPG at 
Weeks 2, 4, 6, 8, 10, 
12, 16, 18, 22 and 26 
for Cohorts 1 & 2 and 
at Weeks 4, 8, 12, 16, 
20, 24, 28 and 32 for 
Cohort 3.
Summary
Estimand Set 1
DFI: Censor all values post discontinuation
MV: Not imputed
N/A
Secondary analysis
MMRM
CFB in fasting plasma 
insulin, HOMA-IR and 
HOMA-B at Weeks 4, 
8, 12, 16, 22 and 26 for 
Cohort 1 & 2 and at 
Weeks 4, 8, 12, 15, 20, 
24 and 28 for Cohort 3.
Summary
Estimand Set 1
DFI: Censor all values post discontinuation
MV: Not imputed
N/A
Exploratory analysis
MMRM
Abbreviations: DFI = discontinuation from IP; MPD = major protocol deviations; MV = missing values (note this includes missing 
values produced through censoring).
End of Treatment is defined as Week 26 for Cohorts 1 and 2 and as Week 32 for Cohort 3. 


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Appendix 2. Bayesian Statistical Methodology Details
Emax model without baseline interaction (Section 5.2.5)
A dataset (either .txt or .csv) of the following format should be produced by programming for 
use in R by the reporting statistician and QC statistician. Note, column headers should be 
labelled as specified below (including capitalization), as R is case sensitive:
Dose
Mean SE
0
0
0.3
40 
-0.01
0.4
80
-0.02
0.5
120
-0.03
0.3
160
-0.05
0.4
200
-0.1
0.5
Note the danuglipron dose groups refers to the results from the 1-week titration arms only,
from the model described in Section 6.1.1.1. The Placebo group is the combined data from 
Cohorts 1 & 2. The residual standard deviation at End of Treatment from the unstructured 
covariance matrix from the associated MMRM will also be provided to the statisticians. The 
4-parameter Emax model will be fit using the latest version (currently v2.1) of the clinDR 
package.11 This analysis will be conducted by the study statistician. A different statistician 
will conduct QC of the analysis. The outputs of the analysis will be provided as .txt files to 
the programming team for inclusion in the final CSR table and figure formats.
Compound-specific information will be used to specify independent prior distributions for the 
placebo response (E0), and the difference in response between the highest dose 
(dTarget=200 mg) and placebo, denoted by difTarget, based on data from the C3421002 
study.  Non-informative priors will be used for these parameters.  Note that the Emax
parameter is derived from the other parameters and is thus not explicitly supplied.  The 
residual standard deviation, sigma, is assigned a uniform prior distribution over a range we 
are confident will include the population value.
Parameter
Prior
E0
Normal(Mean = 0, SD = 6.8)
difTarget
Normal(Mean = -0.067, SD = 6.8)
sigma
Uniform(lb = 0.017, ub = 0.272)
In addition, the projected ED50 is P50 = ~6mg based on data from the C3421002 study.  It will 
be combined with the predictive prior distribution for the log(ED50/P50), obtained from meta-
data on approximately 225 compounds (from 3 references12,13,14), to specify an informative 
prior distribution for the ED50.  The distribution of the Hill parameter is the predictive 
distribution from the meta-data.  The current distributions are listed below.  They are the 
default distributions in clinDR.  These default distributions will be updated if the meta-data 
and their analysis are updated before the completion of the current study.
Parameter
Prior
log(Hill)
t(Mean = 0, SD = 0.84, df = 5)
log(ED50)
log(P50) + t(Mean = 0, SD = 1.74, df = 5)


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The bivariate predictive distribution of these parameters also includes a prior correlation, 
which is currently -0.43 based on the analysis of the meta-data, which also would be 
updated if the historical analysis is updated.
The default burn-in and number of samples will be utilized along with thinning of 20, which 
will include 3 chains to assess convergence. Model diagnostics will be examined including 
trace and auto-correlations plots. If these raise concerns over model convergence, 
additional burn-ins, samples and thinning will be attempted to improve convergence. 
Changes to the priors above may also be considered (e.g. increase precision of E0 and
difTarget) to improve convergence if deemed necessary. The final diagnostic plots will not 
be included in the clinical study report.
The following R code is included as an example that will be used as a basis for the analysis:
library(clinDR)
compileStanModels()
mmrmRes <- read.csv(“LSmeans.csv",header=T,stringsAsFactors=F)
# Determine 'effective' subject numbers based on MMRM SD at End of Treatment:
mmrm_sd <- 0.068 # Provided by programming
mmrmRes$N <- trunc((mmrm_sd/mmrmRes$StdErr)^2,0)
# Set-up priors and MCMC options:
prior_mmrm <- emaxPrior.control(epmu=0, epsca=6.8, difTargetmu=-0.067, difTargetsca=6.8,
dTarget=200, effDF=9999, p50=6, sigmalow=0.017, sigmaup=0.272)
mcmc_mmrm <- mcmc.control(chains=3,thin=20,seed=169)
### Run Emax model: ###
emaxMMRM <-
fitEmaxB(mmrmRes$Estimate,mmrmRes$dose,prior_mmrm,modType=4,count=mmrmRes$N,msSat
=mmrm_sd^2,mcmc=mcmc_mmrm)
# Diagnostics and output:
stan_trace(emaxMMRM$estanfit) # Look at trace
stan_dens(emaxMMRM$estanfit) # Look at densities
stan_ac(emaxMMRM$estanfit) # Look at autocorrelation
summary(emaxMMRM) # Summary of model parameters
plot(emaxMMRM) # Look at fitted vs. observed data
emaxMMRMout <- predict(emaxMMRM,dosevec=mmrmRes$dose,clev=0.90) # Get dose predictions
Model parameters, posterior medians and 90%/95% credible intervals as specified in 
Section 5.2.5 will be output and provided back to the programming team after QC is 
complete.
Emax model with baseline interaction (Section 5.2.6)
A dataset of the same format to above should be produced by programming for use in R by 
the reporting statistician and QC statistician. Note, column headers should be labelled as 
specified (including capitalization), as R is case sensitive.
The residual standard deviations at End of Treatment from the unstructured covariance 
matrices from each of the associated MMRM models will also be provided to the 
statisticians.


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The same process for priors, model fitting, checking of model convergence and QC as 
above will be implemented for this model along with similar R code as to above. The only 
major difference in R code is the requirement to take the average of the residual standard 
deviations from the separate MMRM outputs which will be used as the global standard 
deviation in model fitting:
mmrmDoseRes <- read.csv(Dose_LSmeans.csv",header=T,stringsAsFactors=F)
# Covariance matrix:
mmrmDoseCov <- read.csv(Dose_CovParams.csv",header=T,stringsAsFactors=F)
# Calculate global SD:
mmrm_global_sd <- mean(mmrmDoseCov$SD)
# Merge datasets:
mmrmDoseRes <- merge(mmrmDoseRes,mmrmDoseCov,by="dose")
mmrmDoseRes$N1 <- trunc((mmrmDoseRes$SD/mmrmDoseRes$StdErr)^2,0)
mmrmDoseRes$Glob_SD <- mmrm_global_sd
mmrmDoseRes$N <- trunc((mmrmDoseRes$Glob_SD/mmrmDoseRes$StdErr)^2,0)
…
emaxMMRM_Int <-
fitEmaxB(mmrmDoseRes$Estimate,mmrmDoseRes$dose,prior_mmrm,modType=4,count=mmrmDos
eRes$N,msSat=mmrm_global_sd^2,mcmc=mcmc_mmrm)
Model parameters, posterior medians and 90%/95% credible intervals as specified in 
Section 5.2.6 will be output and provided back to the programming team after QC is 
complete.
Appendix 3. Traditional Statistical Methodology Details
The following SAS code is to be used as a guide for implementation.
Example SAS code for MMRM Model (strata included):
proc mixed data = dataset method=reml;
class subject treatment time strata;
model cfb = treatment base time base* time time *treatment strata/ddfm=kr residual 
outp=resid_out;
repeated time /subject=subjid type = un;
lsmeans treatment*time/diff cl alpha=0.1;
ods output lsmeans=lsmeans_out;
ods output diffs=diffs_out;
ods output CovParms=CovParms_out;
run;
Example SAS code for Cumulative Incidence Plots:
proc lifetest data = dataset method=km plots=cif(test) outcif=cifatrisk intervals=0 to 20 by 2; 
strata treatment;
time day*censor(1)/eventcode=0;
run; 
NOTE: the censor variable has a value = 1 when the related time is censored and has a 
value = 0 when the event of interest occurs. There should be no other values available for 
this censored variable in this dataset (including missing values). If required, missing 
observations should be removed prior to analysis.


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Example SAS code for Proportion of Responses (with multiple imputation):
Assume the SAS dataset is in a long format. The variable ‘treatment’ should be coded 
similar to ‘Placebo’, ‘Danuglipron 40 mg BID’, ‘Danuglipron 80 mg BID’,… ‘Danuglipron 200 
mg BID’, ‘Danuglipron 120 mg BID (2-week titration)’, ‘Danuglipron 160 mg BID (2-week 
titration)’ and ‘Danuglipron 200 mg BID (2-week titration)’ so that when sorted in descending 
order ‘Placebo’ comes first.
proc sort data=analysis out= analysisl;
by subjid time treatment strata;
run;
* Create wide dataset for multiple imputation;
proc transpose data= analysisl out=analysisw  prefix=week;
by subjid treatment strata;
id time;
var cfb_log;
run;
* Perform multiple imputation;
proc mi data=analysisw seed=169 nimpute=20 out= analysis_mi;
class treatment strata;
fcs nbiter=10 reg(/details);
var base treatment strata week2 week4 week6 week8 week10 week12 week16 week18 
week22 week26;
run;
* Determine responders and non-responders at End of Treatment for all imputed datasets;
data analysis_mi_26;
set analysis_mi;
value = week26;
if value < log(0.95) and week26 ne . then resp = 1;
if value >= log(0.95) and week26 ne . then resp = 0;
run;
* Create datasets and combine proportions;
proc freq data=analysis_mi_26;
tables _imputation_*dose*resp/out=prop_mi outpct;
run;
data prop_mi_0;
set prop_mi;
if resp=0;
keep _imputation_ treatment count;
rename count=count_0;
run;
data prop_mi_1;
set prop_mi;
if resp=1;
keep _imputation_ treatment count;
rename count=count_1;
run;
data prop_mi_combined;


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merge prop_mi_0 prop_mi_1;
by _imputation_ treatment;
total = count_0 + count_1;
p = count_1/total;
q = count_0/total;
se_p = sqrt((p*q)/total);
run;
proc sort data=prop_mi_combined;
by treatment _imputation_;
proc mianalyze data=prop_mi_combined  alpha=0.1;
      by treatment;
      modeleffects p;
      stderr se_p;
      ods output parameterestimates=prop_mi_out;
run;
Example SAS code for Logistic Regression Model (with multiple imputation):
The same imputed datasets as produced above for the ‘Proportion of Responses’ will be 
utilized. Note: the imputed dataset should be ordered so that the group ‘Placebo’ and 
‘Resp’=1 comes first to ensure that the reference group is Placebo and the odds ratios are 
for a response = 1.
* Fit logistic regressions to each imputed dataset and combine results;
proc sort data=analysis_mi_26;
by _imputation_ descending treatment descending resp;
proc logistic data = analysis_mi_26 order=data;
by _imputation_;
class resp treatment strata;
model resp = treatment strata base/alpha=0.1;
oddsratio dose/diff=all;
ods output OddsRatiosWald=OddsRatiosWald_mi;
run;
data OddsRatiosWald_mi;
set OddsRatiosWald_mi;
if effect = . then delete;
estimate = log(OddsRatioEst);
SE = (log(UpperCL) - log(LowerCL))/(2*QUANTILE('NORMAL',0.95));
run;
proc sort data=OddsRatiosWald_mi;
by effect _imputation_;
proc mianalyze data=OddsRatiosWald_mi  alpha=0.1;
      by effect;
      modeleffects estimate;
      stderr SE;
      ods output parameterestimates=OddsRatiosWald_mi_out;
run;


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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
Supine Systolic BP (mm Hg)
min. <90
Supine Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Supine Diastolic BP (mm Hg)
min. <50
Supine Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120


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Appendix 5. C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events and 
Codes
Table 2.
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 plan1
“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?”
1According 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.
Appendix 6. PROMIS-Fatigue
The raw score for each patient should be translated into a T-Score using the table below 
(i.e. 9 would be 29.1 on the T-Score scale), which was provided by the Health Measures 
Scoring Service15:
Raw
Scale
9
29.1
10
32.8
11
36
12
38.3
13
40.3
14
42
15
43.7
16
45.1
17
46.4


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18
47.6
19
48.8
20
50
21
51.1
22
52.2
23
53.3
24
54.4
25
55.5
26
56.6
27
57.6
28
58.7
29
59.8
30
60.9
31
62
32
63.1
33
64.2
34
65.3
35
66.4
36
67.6
37
68.8
38
70.1
39
71.4
40
72.8
41
74.3
42
76
43
78
44
80.3
45
83
Appendix 7. PROMIS-Physical Function
The raw score for each patient should be translated into a T-Score using the table below 
(i.e. 13 would be 21.5 on the T-Score scale), which was provided by the Health Measures 
Scoring Service15:
Raw
Scale
13
21.5
14
25.1
15
26.8
16
28.1
17
29.1
18
30
19
30.7


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20
31.4
21
32.1
22
32.7
23
33.3
24
33.8
25
34.3
26
34.8
27
35.3
28
35.8
29
36.3
30
36.8
31
37.2
32
37.7
33
38.1
34
38.6
35
39
36
39.5
37
39.9
38
40.4
39
40.8
40
41.3
41
41.8
42
42.2
43
42.7
44
43.2
45
43.7
46
44.2
47
44.7
48
45.2
49
45.7
50
46.3
51
46.9
52
47.5
53
48.1
54
48.8
55
49.5
56
50.3
57
51.1
58
52
59
53
60
54.1
61
55.4


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62
56.8
63
58.7
64
61
65
66
Appendix 8. IwQOL-Lite CT
The Physical composite score comprises Items 1-5, 16, and 17. The Physical Function 
composite comprises Items 1-3, 16, and 17, with Item 4 (“Uncomfortable in small seats”) and 
Item 5 (“Bodily pain”) excluded. The Psychosocial composite comprises Items 6-8, 9-15, 18, 
19, and 20.
Each response is assigned a score as follows: 1= “Never” or “Not at all true”; 2= “Rarely” or 
“A little true”; 3= “Sometimes” or “Moderately true”; 4= “Usually” or “Mostly true”; 5= “Always” 
or “Completely true”.
The scoring algorithm is as follows:
!
Scores for each composite should only be compared if a minimum of 50% of the 
iterms for that composite are non-missing, for the IWQOL-Lite-CT total score if a 
minimum of 75% of all items are non-missing. Psychosocial 7 of 13; Physical 4 of 7; 
Physical Function 3 of 5; Total 15 of 20).
!
If the minimum number of items is answered for a composite, the composite score is 
calculated by transforming the composite item average to the worst (0) to 100 (best) 
metric using the following formula for every patient at each time point:
100 × (Smax −Cavg )/(Smax −Smin )
where
!
Cavg is the raw average score of all non-missing item responses in the composite; 
this average must be a number between 1 and 5, inclusive
!
Smax is the maximum possible raw score value, i.e., 5
!
Smin is the minimum possible raw score value, i.e., 1
!
Inserting the maximum and minimum possible score values, the formula is reduced 
to 100 x (5-Cavg)/4.


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Appendix 9. List of Abbreviations
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase
AST
aspartate aminotransferase
BID
twice daily
BLQ
below the limit of quantitation
BP
blood pressure/ bodily pain
C-CASA
Columbia Classification Algorithm of Suicide Assessment
CFB
Change from baseline
CRF
case report form
CSR
clinical study report
C-SSRS
Columbia-suicide severity rating scale
Ctrough
Lowest concentration
CV
coefficient of variation
DFI
discontinuation from IP
dL
Deciliter
ECG
electrocardiogram
E0
Placebo effect
ED50
Dose producing 50% of Emax
eGFR
estimated glomerular flitration rate 
Emax
Maximum response
FDA
Food and Drug Administration (United States)
FPG
Fasting Plasma Glucose
FPI
Fasting Plasma Insulin
GGT
Gamma-glutamyl transpeptidase
GH
Growth hormone
H
hours
HbA1c
Hemoglobin A1c
HOMA-B
Homeostatis model assessment of β-cell function
HOMA-IR
Homeostatis model assessment -insulin resistance
ICH
International Council for Harmonisation
IRC
internal review committee
IP
Investigational Product
IWQOL Lite-CT
Impact of Weight on Quality of Life – Lite Clinical Trials 
Version
L
liter


Protocol C3421019 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
DMB02-GSOP-RF02 8.0 Statistical Analysis Plan Template
TMF Doc ID: 98.03
Page 60 of 61
LDL
low-density lipoprotein
LLQ
lower limit of quantitation
LS
least-squares
MAR
Missing at random
MCS
mental component summary scores
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MH
mental health
MI
multiple imputation
mIU
milli-international units
MMRM
mixed-effects model with repeated measures
#mol
micromol
MPD
major protocol deviations
msec
millisecond
MV
Missing values
N/A
not applicable
PCC
potential clinical concern
PCOA
patient centered outcome assessment
PCS
physical component summary
PD
protocol deviation
PF
physical functioning
PGI-C
Patient’s global impression of change
PGI-S
Patient’s global impression of severity
PHQ-9
Patient health questionnaire-9
PK
Pharmacokinetic
PROMIS
Patient-reported outcomes measurements information system
PT
preferred term
Q1
First quartile
Q3
Third quartile
QC
Quality control
QQ
quantile-quantile
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
RE
role-emotional
RP
role-physical
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation


Protocol C3421019 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
DMB02-GSOP-RF02 8.0 Statistical Analysis Plan Template
TMF Doc ID: 98.03
Page 61 of 61
SF
social functioning
SF-36
Short Form-36 Health Survey
SoA
schedule of activities
SOP
standard operating procedure
T2DM
Type 2 diabetes mellitus
T4
thyroxine
TEAE
treatment emergent adverse event
TSH
thyroid stimulating hormone
U
Units
ULN
upper limit of normal
US
United States
VT
vitality