A 12-WEEK, PHASE 2A, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO ASSESS THE SAFETY, TOLERABILITY, AND PHARMACODYNAMICS OF PF-06882961 TITRATION IN ADULTS WITH TYPE 2 DIABETES MELLITUS TREATED WITH METFORMIN AND IN NON-DIABETIC ADULTS WITH OBESITY
Phase: PHASE2
Conditions: Diabetes, Obesity
Sponsor: Pfizer

PF-06882961
Protocol C3421008
Final Protocol Amendment 2, 23 September 2020
PFIZER CONFIDENTIAL
Page 1
A 12-WEEK, PHASE 2A, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO ASSESS THE 
SAFETY, TOLERABILITY, AND PHARMACODYNAMICS OF PF-06882961 
TITRATION IN ADULTS WITH TYPE 2 DIABETES MELLITUS TREATED WITH 
METFORMIN AND IN NON-DIABETIC ADULTS WITH OBESITY
Investigational Product Number:
PF-06882961
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
C3421008
Phase:
2a
Short Title: A 12-Week Titration Study to Evaluate Safety, Tolerability, and 
Pharmacodynamics of PF-06882961 in Adults with Type 2 Diabetes Mellitus and in 
Non-Diabetic 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.
CCI

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Protocol C3421008
Final Protocol Amendment 2, 23 September 2020
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 2
23 Sep 2020
Title page: Updates made to reflect addition of 
non-diabetic adults with obesity.
Rationale: This study population has been updated 
with Amendment 2.
Section 1.2, Schema: updated to indicate that
participant-provided metformin is in participants with 
T2DM.
Rationale: Requirement for background metformin 
use is only applicable to T2DM participants.
Section 1.3, Schedule of Activities: footnote “b” added 
to table to indicate that regular fingersticks are not 
required in participants with obesity without T2DM but 
the glucometer and supplies should be dispensed as a 
backup in case they have signs or symptoms of 
hypoglycemia.  Added mental health questionnaires 
(C-SSRS and PHQ-9) due to inclusion of participants
with obesity.  
Rationale: Safety monitoring approach has been 
updated due to addition of non-diabetic participants 
with obesity.
Section 2, Introduction: updated to indicate that clinical 
development in obesity is also planned.
Rationale: Update provides context for updated 
study population.
Section 2.1, Study Rationale: updated to reflect 
inclusion and rationale for participants with obesity and 
without T2DM, in addition to the addition of the higher 
target dose of 200 mg BID in 2 study arms. 
Rationale: Updates provide rationale for updated 
study population and higher dose in 2 study arms.
Section 2.2.1, Nonclinical Safety: updated to include 

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Final Protocol Amendment 2, 23 September 2020
PFIZER CONFIDENTIAL
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exposure margins to the updated highest planned dose in 
this study of PF-06882961 200 mg BID.
Rationale: Updates align with higher dose in 2 study 
arms.
Section 2.2.2.2, Clinical Pharmacokinetics: updated to 
provide additional PK exposure information in 
participants without T2DM compared with participants 
with T2DM.
Rationale: Updates align with updated study 
population.
Section 3, Objectives and Endpoints: updated to reflect 
inclusion of participants with obesity and without 
T2DM.
Rationale: Updates align with updated study 
population.
Section 4.1, Overall Design and Figure 1: updated to 
reflect the following changes: 
1. inclusion and rationale for participants with obesity 
and without T2DM; 
2. Addition of Arm 5 (target dose of PF-06882961 
200 mg BID) which will be administered to participants 
with T2DM and participants with obesity and without 
T2DM; 
3. Increase in sample size for placebo arm and total 
study population.
Rationale: Updates provide rationale for updated 
study population and sample size, addition of 2 study 
arms and higher dose in 2 study arms.
Section 4.2, Scientific Rationale for Study Design and 
Section 4.3, Justification for Dose: updated to include 
rationale for inclusion of participants with obesity and 
without T2DM and rationale for addition of Arms 6 and 
7 with target dose of PF-06882961 200 mg BID.
Rationale: Updates align with updated study 
population and higher dose in 2 study arms.
Section 5.1, Inclusion Criteria: updated to specify 

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inclusion criteria for all participants, criteria for 
participants with T2DM only and criteria for 
participants with obesity without T2DM. Also, 
minimum BMI for participants with T2DM has been 
increased to 27 kg/m2 (with no upper limit for BMI), to
provide a closer range to participants with obesity 
without T2DM. 
Rationale: Updates align with updated study 
population.
Section 5.2.2. Exclusion Criteria All Participants: 
Added criteria numbers – 12. History of major 
depressive disorder or history of other severe psychiatric 
disorders (eg, schizophrenia or bipolar disorder) within 
the last 2 years; and criteria number 13. Any lifetime 
history of a suicide attempt. 17. A PHQ 9 score 
≥15 obtained at V1, V2 or V3. 18.Response of “yes” 
to question 4 or 5, or on any behavioral question on the 
C-SSRS at V1, V2 or V3. These updates have been 
made based on the potential risk related to the product 
labeling for the injectable GLP-1R agonist liraglutide 
for obesity.
Rationale: Updates align with updated study 
population.
Section 5.3.1, Dietary Restrictions: updated to separate 
dietary guidelines for participants with and without 
T2DM.
Rationale: Updates align with updated study 
population.
Sections 6.1.1, Administration and 6.3.1 Allocation to 
Investigational Product: updated to indicate that with 
addition of Arm 6 and 7, Week 9 will also require 
4 tablets BID to maintain the double blind across 
treatment arms. Table 2 was also updated to include 
titration scheme for Arm 6 and 7. 
Rationale: Updates align with titration schemes 
required for the higher dose in the 2 additional study 
arms.
Section 6.6, Dose Modification: wording updated to 

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clarify that scheduled dose titration is used in active
dosing regimens.
Rationale: Update clarifies that while doses are 
titrated over the study duration in the active arms,
modification of the blinded dosing regimen is not 
permitted per protocol.
Section 8.2.4.1, Home Glucose Monitoring: updated to 
indicate that regular fingersticks are not required in 
participants with obesity without T2DM unless they 
have signs or symptoms of hypoglycemia.
Rationale: Updates align with updated study 
population.
Section 8.2.7, Mental Health Questionnaires and 
associated sub-sections have been added under Safety 
Assessments.  Related sub-sections include: 8.2.7.1, 
Columbia Suicide Severity Rating Scale (C-SSRS), 
8.2.7.1.1, Rater Qualifications, 8.2.7.2, Patient Health 
Questionnaire – 9 (PHQ-9) and 8.2.7.3, Referral to a 
Mental Health Professional.
Rationale: Updates to safety monitoring align with 
updated study population.
Section 9.1.1, Estimands, Section 9.3, Populations for 
Analysis and Section 9.4.1 Pharmacodynamic Analyses, 
updated wording.
Rationale: Updates clarify estimands and analyses 
pertaining to participants with T2DM and those 
pertaining to participants with obesity without 
T2DM.
Section 9.2, Sample Size Determination, increase in 
sample size for placebo arm and total study population.
Rationales: Updates reflect the changes in the study 
design.
Amendment 1
08 June 2020
Title page: EudraCT number in the original protocol 
was not correct and has been updated to Not Applicable, 
as this study will take place in the United States only.

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Final Protocol Amendment 2, 23 September 2020
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Section 1.3. (Schedule of Activities), 8.7.2 (Banked 
biospecimens) and 8.8.2 (Biomarkers) change have been 
revised to incorporate Protocol Administrative 
Clarification Letter (dated 08 Oct 2019) to update the 
types of Biobank Samples collected.
Section 1.3, (Schedule of Activities) has been updated to 
add collection of banked biospecimens Prep B1.5 and 
B2.5 at the early termination visit.
Rationale: Collection of banked biospecimens at the 
early termination visit to allow for additional research in 
cases of early termination if applicable.
Section 2.2.1, Nonclinical Safety has been added to 
provide the most recent toxicology information. This 
section also includes the embryo-fetal toxicology data, 
which was previously in Section 4.2.
Rationale: Updates align with recently updated 
Investigator Brochure and all of the toxicology data are 
presented in the same section.
Sections 2.2.2 (Clinical Overview), 2.2.2.1 (Clinical 
Safety) and 2.2.2.2 (Clinical Pharmacokinetics) have 
been updated to reflect the completed C3421002 study.  
Rationale: Updates align with the most recent clinical 
safety and pharmacokinetics information. 
Section 4.2 and Appendix 8 (Prohibited 
Prior/Concomitant Medication) have been revised to list 
the exclusion of sulfasalazine, simplification regarding 
the use of potent CYP3A4 inhibitors and extension of 
timeframe prohibiting use of weight loss drugs.  
Rationale: 
 
 
  Weight loss drug extension is to align with 
liraglutide restriction for glycemic control.
Section 4.3, Justification for Dose has been revised to 
reflect that study C3421002 has completed and data are 
no longer preliminary.
Rationale: C3421002 was completed after initial 
CCI

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protocol finalization.
Section 5.2, Exclusion Criteria, criterion #15 has been 
revised to lower the systolic and diastolic blood pressure 
eligibility criteria.  
Rationale: The cut off for blood pressure has been 
lowered to a more conservative level to optimize blood 
pressure control prior to study entry.
Section 5.3.1, Dietary Restrictions has been revised to 
clarify that fasting is required prior to body weight (also 
a revision to Section 8.6.1 and Appendix 9) but is not 
required prior to post dose PK sample collection.  
Additionally, the requirement to withhold blood 
pressure and lipid modifying medications prior to site 
has been removed.
Rationale: Aligns with updates to Section 8.6.1 and 
Appendix 9, as body weight must be obtained under 
standardized conditions. Clarification that fasting is not 
required prior to post dose PK sample collection has 
been included given PF-06882961 is dosed with food.  
Blood pressure and lipid modifying medications may be 
taken prior to site visits to ensure blood pressure and 
lipid management is maintained in participants requiring 
these medications.  
Section 6.4, Study Intervention Compliance has been 
updated to provide an example of how many doses may 
be missed for the placebo run-in duration, depending on 
differences in visit windows.
Rationale: Clarifies the compliance requirement for 
eligibility.  
Section 6.5.4, Antihypertensive Medications has been 
revised to remove language regarding handling of 
participants who enter the study with a blood pressure of 
≥160/100.
Rationale: This language is no longer applicable given 
the revision to exclusion criterion #15.
Section 8.2.2.1, Blood Pressure and Pulse Rate has been 
revised to allow for manual assessment of BP and PR 

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only if an automated instrument is not available and also 
to clarify that the same arm for BP and PR should be 
used throughout the study, when possible.
Rationale: These revisions are made for clarification.
Section 8.3: (1) 8.3.1 Time Period and Frequency for 
Collection AE and SAE Information has been revised to 
remove the requirement for medical occurrences that 
begin before the start of study intervention but after 
obtaining informed consent to be recorded on the 
Medical History/Current Medical Conditions section of 
the CRF; (2) 8.3.1.2 Recording Nonserious AEs and 
SAEs on the CRF has been updated to reflect current 
sponsor language.
Rationale: This revision aligns with the requirement to 
collect and record all AEs and SAEs from the time 
informed consent is provided. It also aligns with current 
sponsor language regarding the recording of AEs and 
SAEs on the CRF.
Section 9.4.2.1, Electrocardiogram Analyses, has been 
revised to remove summarization of the number of 
participants with uncorrected QT values >500 msec.
Rationale: Safety analyses and summaries will be based 
on QTcF intervals, not QT intervals.
Section 9.4.3, Other Analyses has been revised to clarify 
that results from any future analyses from 
pharmacogenomic or biomarker data from banked 
biospecimens are not planned to be included in the CSR.
Rationale: These results are not routinely included in 
CSRs.
Protocol Appendix 4, Section 10.4.2, Female Participant 
Reproductive Inclusion Criteria the requirement of 
females to not donate eggs has been removed.
Rationale: This revision is made as PF-06882961 does 
not have risk of genotoxicity; as such the requirement of 
females to not donate eggs has been removed.
Original 
27 September 
N/A

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Final Protocol Amendment 2, 23 September 2020
PFIZER CONFIDENTIAL
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protocol
2019
This amendment incorporates all revisions to date, including Protocol Administrative 
Clarification letters (PACLs), and amendments made at the request of country health 
authorities and IRBs/ECs.

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Protocol C3421008
Final Protocol Amendment 2, 23 September 2020
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................14
LIST OF FIGURES .................................................................................................................14
1. PROTOCOL SUMMARY...................................................................................................15
1.1. Synopsis ..................................................................................................................15
1.2. Schema ....................................................................................................................15
1.3. Schedule of Activities (SoA)...................................................................................16
2. INTRODUCTION ...............................................................................................................18
2.1. Study Rationale .......................................................................................................18
2.2. Background .............................................................................................................18
2.2.1. Nonclinical Safety ......................................................................................19
2.2.2. Clinical Overview.......................................................................................20
2.2.2.1. Clinical Safety...........................................................................20
2.2.2.2. Clinical Pharmacokinetics.........................................................21
2.3. Benefit/Risk Assessment.........................................................................................22
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................23
4. STUDY DESIGN.................................................................................................................24
4.1. Overall Design.........................................................................................................24
4.2. Scientific Rationale for Study Design.....................................................................26
4.3. Justification for Dose ..............................................................................................28
4.4. End of Study Definition ..........................................................................................29
5. STUDY POPULATION......................................................................................................29
5.1. Inclusion Criteria.....................................................................................................29
5.1.1. Inclusion Criteria for All Participants.........................................................29
5.1.2. Additional Inclusion Criteria Only for Participants with T2DM................30
5.1.3. Additional Inclusion Criteria Only for Participants with Obesity 
without T2DM .................................................................................................30
5.2. Exclusion Criteria....................................................................................................30
5.2.1. Exclusion Criteria for Only Participants with Obesity without T2DM......30
5.2.2. Exclusion Criteria for All Participants .......................................................30
5.3. Lifestyle Considerations..........................................................................................33
5.3.1. Dietary Restrictions ....................................................................................33

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5.3.2. Alcohol, Caffeine, and Tobacco .................................................................34
5.3.3. Physical Activity.........................................................................................34
5.3.4. Contraception..............................................................................................34
5.4. Screen Failures ........................................................................................................35
6. STUDY INTERVENTION..................................................................................................35
6.1. Study Intervention(s) Administered........................................................................36
6.1.1. Administration............................................................................................36
6.2. Preparation/Handling/Storage/Accountability ........................................................38
6.2.1. Preparation and Dispensing........................................................................39
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................39
6.3.1. Allocation to Investigational Product .........................................................39
6.3.2. Breaking the Blind......................................................................................40
6.4. Study Intervention Compliance...............................................................................40
6.5. Concomitant Therapy..............................................................................................41
6.5.1. Metformin...................................................................................................41
6.5.2. Medications for Glycemic Control.............................................................41
6.5.3. Glycemic Rescue Medicine........................................................................42
6.5.4. Antihypertensive Medications....................................................................42
6.5.5. Lipid Modifying Medications.....................................................................42
6.6. Dose Modification...................................................................................................42
6.7. Intervention After the End of the Study..................................................................43
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................43
7.1. Discontinuation of Study Intervention ....................................................................43
7.1.1. Criteria for Discontinuation........................................................................43
7.2. Participant Discontinuation/Withdrawal From the Study.......................................43
7.3. Lost to Follow-up....................................................................................................44
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................45
8.1. Efficacy Assessments..............................................................................................46
8.2. Safety Assessments .................................................................................................46
8.2.1. Physical Examinations................................................................................46
8.2.2. Vital Signs ..................................................................................................47

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8.2.2.1. Blood Pressure and Pulse Rate..................................................47
8.2.3. Electrocardiograms.....................................................................................48
8.2.4. Management of Glycemic Control .............................................................48
8.2.4.1. Home Glucose Monitoring........................................................48
8.2.4.2. Management of Hypoglycemia .................................................49
8.2.4.3. Management of Hyperglycemia................................................51
8.2.5. Clinical Safety Laboratory Assessments ....................................................51
8.2.6. Pregnancy Testing ......................................................................................52
8.2.7. Mental Health Questionnaires ....................................................................52
8.2.7.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................52
8.2.7.2. Patient Health Questionnaire-9 (PHQ-9) ..................................53
8.2.7.3. Referral to a Mental Health Professional ..................................53
8.3. Adverse Events and Serious Adverse Events..........................................................53
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......54
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................54
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................54
8.3.2. Method of Detecting AEs and SAEs ..........................................................54
8.3.3. Follow-up of AEs and SAEs.......................................................................55
8.3.4. Regulatory Reporting Requirements for SAEs...........................................55
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................55
8.3.5.1. Exposure During Pregnancy......................................................56
8.3.5.2. Exposure During Breastfeeding ................................................56
8.3.5.3. Occupational Exposure .............................................................56
8.3.6. Medication Errors .......................................................................................56
8.4. Treatment of Overdose............................................................................................57
8.5. Pharmacokinetics ....................................................................................................58
8.6. Pharmacodynamics..................................................................................................58
8.6.1. Body Weight...............................................................................................59
8.7. Genetics...................................................................................................................59
8.7.1. Specified Genetics ......................................................................................59
8.7.2. Banked Biospecimens for Genetics............................................................59

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8.8. Biomarkers ..............................................................................................................60
8.8.1. Specified Metabolomic Research ...............................................................60
8.8.2. Banked Biospecimens for Biomarkers .......................................................60
8.9. Health Economics ...................................................................................................60
9. STATISTICAL CONSIDERATIONS ................................................................................61
9.1. Estimands and Statistical Hypotheses.....................................................................61
9.1.1. Estimands....................................................................................................61
9.2. Sample Size Determination.....................................................................................63
9.3. Populations for Analysis .........................................................................................63
9.4. Statistical Analyses .................................................................................................64
9.4.1. Pharmacodynamic Analyses.......................................................................64
9.4.2. Safety Analyses ..........................................................................................65
9.4.2.1. Electrocardiogram Analyses......................................................66
9.4.3. Other Analyses............................................................................................66
9.5. Interim Analyses .....................................................................................................66
9.5.1. Data Monitoring Committee.......................................................................66
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................67
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............67
10.1.1. Regulatory and Ethical Considerations ....................................................67
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................67
10.1.2. Financial Disclosure .................................................................................68
10.1.3. Informed Consent Process ........................................................................68
10.1.4. Data Protection .........................................................................................69
10.1.5. Dissemination of Clinical Study Data ......................................................69
10.1.6. Data Quality Assurance ............................................................................71
10.1.7. Source Documents....................................................................................72
10.1.8. Study and Site Closure..............................................................................72
10.1.9. Publication Policy.....................................................................................73
10.1.10. Sponsor’s Qualified Medical Personnel .................................................74
10.2. Appendix 2: Clinical Laboratory Tests .................................................................75

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................78
10.3.1. Definition of AE .......................................................................................78
10.3.2. Definition of SAE.....................................................................................79
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................80
10.3.4. Reporting of SAEs....................................................................................83
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................85
10.4.1. Male Participant Reproductive Inclusion Criteria....................................85
10.4.2. Female Participant Reproductive Inclusion Criteria.................................85
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................85
10.4.4. Contraception Methods.............................................................................86
10.5. Appendix 5: Genetics............................................................................................89
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........90
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................92
10.8. Appendix 8: Prohibited Prior/Concomitant Medications......................................94
10.9. Appendix 9: Proposed Chronology of Procedures................................................96
10.10. Appendix 10: Abbreviations ...............................................................................97
11. REFERENCES ................................................................................................................101
LIST OF TABLES
Table 1.
Summary of Treatment-Emergent Adverse Events in C3421002 ............21
Table 2.
Titration Schemes.....................................................................................37
Table 3.
Protocol-Required Safety Laboratory Assessments .................................76
LIST OF FIGURES
Figure 1.
Dose Titration Schemes............................................................................25

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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Not Applicable (N/A).
1.2. Schema

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1.3. Schedule of Activities (SoA)
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES Section 8 of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, to conduct evaluations or 
assessments required to protect the well-being of the participant. 
Protocol Phase (for abbreviations refer to Appendix 10)
Screen Run-
in
Treatment Phase
Follow-Up
Early 
Term
Weeks Relative to Dosing on Day 1
-6 to -3
-2
0
2
4
6
8
10
12
13-14
16-17
ET
Days Relative to Dosing on Day 1
-42 to
-15
-14±3
1
14±3
28±3
42±3
56±3
70±3
84±3
91-98
112-119a
--
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
ET
Informed consent & demography
x
Review of eligibility criteria
x
x
x
Open-ended inquiry for adverse events
x









x
x
Medical history (update only at V2 and V3)
x
x
x
Review prior or concomitant treatments
x
x
x
x
x
x
x
x
x
x
x
x
Review drug, alcohol/tobacco use
x
x
x
x
x
x
x
x
x
x
x
x
Review contraception use (females only)
x
x
x
x
x
x
x
x
x
x
x
x
Counseling on diet/exercise guidelines
x
Dispense glucometer, supplies, diary, and provide training
x
Review drug diary, glucometer & glucose logb
x
x
x
x
x
x
x
x
x
Glucose measurement (fasting, via glucometer, on site)
x
x
x
x
x
x
x
x
x
Mental health questionnaires (C-SSRS, PHQ-9)
x
x
x
x
x
x
x
x
x
x
x
Physical examination (height at Screen only)c
x
x
x
xc
x
Body weight (in duplicate)
x
x
x
x
x
x
x
x
x
x
x
Supine vital signs assessment
xd
x
xd
x
x
xd
x
x
xd
x
x
Supine 12-lead ECG
x
xd
x
x
xd
x
x
xd
x
x
Registration in trial (via IRT)
x
Randomization in trial (via IRT)
x
Dispensation of IRT
xe
xf
xf
xf
xf
xf
xf
Witnessed dosing on site of IP (AM dose) – with food
x
x
x
x
x
x
x
x
Compliance via pill count on site of returned IP
x
x
x
x
x
x
x
x
Blood Sampling for:
-Fasting plasma glucose and HbA1c
x
x
x
x
x
x
x
x
x
x
x
-Hematology, chemistry (including eGFR) 
x
x
x
x
x
x
x
x
x
x

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Protocol Phase (for abbreviations refer to Appendix 10)
Screen Run-
in
Treatment Phase
Follow-Up
Early 
Term
Weeks Relative to Dosing on Day 1
-6 to -3
-2
0
2
4
6
8
10
12
13-14
16-17
ET
Days Relative to Dosing on Day 1
-42 to
-15
-14±3
1
14±3
28±3
42±3
56±3
70±3
84±3
91-98
112-119a
--
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
ET
-FSH (females only), C-peptide
x
-Pregnancy test (females only)
x
x
x
x
x
x
x
x
x
x
x
Lipids, TSH, free T4, calcitonin, amylase, lipase, TBA, 
PT/INR/aPTT
x
x
x
x
x
x
x
-PF-06882961 PK (pre-dose unless noted)
xg
x
x
xg
x
x
xg
x
-Banked biospecimen: Prep B1.5 & B2.5
x
x
x
x
-Banked biospecimen: Prep D1 (only Day 1)h
x
Urine Sampling for:
-Urine drug test
x
Urinalysis (and microscopy, reflexive)
x
x
x
x
x
x
-On-site urine pregnancy test (females only)i
x
x
x
x
x
x
x
x
x
x
x
a.
May be a telephone contact, or a visit to the clinic if deemed necessary by the investigator.
b.
For participants with obesity only, the review of the glucometer and glucose log should be completed if participants have signs or symptoms of 
hypoglycemia. Otherwise, regular glucometer monitoring at home is not required.
c.
Full physical examination performed according to the SoA.  A limited physical examination is performed at the follow-up visit 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. 
d.
Triplicate assessments (see Section 8.2.2) will be measured at screening, and pre- and post-dose times at Visit 3, Visit 6 and Visit 9, when both pre-dose and 
post-dose PK measurements are obtained.
e.
On V2 only, IP reflects single-blind placebo; it is dispensed via IRT.
f.
For V3 through V8, IP is dispensed via IRT and reflects double-blind randomized PF-06882961 or placebo.
g.
PK samples collected pre-dose and within the window approximately 2-6 hours post dose.
h.
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.
i.
For V3 through V9, the test result must be reviewed and deemed acceptable (ie, negative), to continue participation in the study.

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2. INTRODUCTION
Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone that is predominantly 
released from the small intestine in response to food intake.1  GLP-1 activation of the GLP-1 
receptor (GLP-1R) stimulates insulin release, inhibits glucagon secretion in a 
glucose-dependent manner, and delays gastric emptying.2,3  In addition, GLP-1 has been 
shown to increase satiety and suppress food intake.4  PF-06882961 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 type 2 diabetes 
mellitus (T2DM). PF-06882961 is in Phase 2 development for the treatment of adults with 
T2DM.  Investigation of the efficacy, safety, and tolerability of PF-06882961 for weight loss 
in adults with obesity is also being evaluated.
2.1. Study Rationale 
The purpose of this multicenter, Phase 2a, randomized, double-blind, sponsor-open,
placebo-controlled, parallel-group study is to assess the tolerability, safety, and 
pharmacodynamic (PD) data for PF-06882961 in participants with T2DM treated with 
metformin and in participants with obesity, without T2DM. Five different titration schemes 
of PF-06882961, including one titration scheme to the target dose of 200 mg BID, will be 
investigated in participants with T2DM, who comprise a majority of the study population. 
One titration scheme of PF-06882961 to the target dose of 200 mg BID will be investigated 
in participants with obesity, without T2DM. Differences in tolerability, safety and 
pharmacokinetics will be explored between participants with T2DM and participants without 
T2DM, supporting the clinical development of both T2DM and of obesity.
2.2. Background 
The increase in the global prevalence of T2DM is largely attributed to rising rates of excess 
body weight and obesity.5 T2DM is estimated to affect more than 424 million people 
worldwide,6 and the prevalence of T2DM within the United States (US) is estimated to range 
from 12 to 14%.7 T2DM is characterized by insulin resistance, a disorder in which cells do
not respond effectively to insulin, resulting in higher blood glucose levels.  Elevated blood 
glucose levels and increasing severity of insulin resistance result in the need for more insulin 
over time, eventually resulting in progressive pancreatic -cell failure.8  Patients with poorly 
controlled T2DM have an increased risk of developing complications associated with both 
microvascular and macrovascular disease, including nephropathy, neuropathy, retinopathy, 
cardiovascular disease and stroke; and are at 2 to 4 times increased risk of mortality than 
adults who do not have diabetes.9  While existing pharmacological options for the treatment 
of diabetes may provide satisfactory glycemic control for some patients, there remains a large 
number of patients who do not achieve target glycated hemoglobin (HbA1c) levels, 
suggesting a need for additional therapeutic options.

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Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and cardiovascular safety, with some agents demonstrating cardiovascular benefit.10  
Based on the clinical history of injectable GLP-1R agonists, an oral GLP-1R agonist is 
expected to improve glucose control and reduce HbA1c levels in patients with T2DM, while 
decreasing food intake and body weight and avoiding the subcutaneous injection required by 
currently available peptidic GLP-1R agonists.
2.2.1. Nonclinical Safety
General toxicology studies have been completed in cynomolgus monkeys up to 6 months in 
duration (with a 3-week lead-in and 1-month recovery) and in rats up to 6 months in duration 
(with a 1-month recovery).  The exposure limits for plasma concentrations of PF-06882961 
for clinical studies are based on the exposure at the no observed adverse effect level 
(NOAEL) dose of 250 mg/kg/day in the 6-month with 1-month recovery toxicology study in 
rats, 
 
  In the 6-month toxicity study in rats 
with 1-month recovery, the NOAEL was 250 mg/kg/day 
 
 The exposure margins at 250 mg/kg/day were 27-fold (Cmax, free) and 14-fold 
(AUC24, free), to the predicted human exposures at the highest projected mean exposure of 
PF-06882961 in this study (200 mg BID in T2DM participants).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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At the NOAEL dose of 150 mg/kg/day in the 13-week study with 3-week lead-in, exposure 
margins were 6.2- and 4.5-fold for Cmax (free) in males and females, respectively, and were 
5.1- and 4.7-fold for AUC24 (free) in males and females, respectively, at the highest projected 
mean exposure of PF-06882961 in this study (200 mg BID in T2DM participants).
Embryo-fetal developmental studies were completed in rats and rabbits.  Based on the lack of 
maternal toxicity or adverse effects on embryo-fetal development, the NOAEL for maternal 
and developmental toxicity in rats was 500 mg/kg/day (highest dose evaluated). 
 
 
In embryo-fetal studies conducted in rabbits, the NOAEL for maternal and developmental 
toxicity was 250 mg/kg/day.
 
PF-06882961 was negative in genetic toxicity testing and photosafety endpoints.  A risk 
assessment of the target organ toxicities noted in the repeat-dose toxicity studies is provided 
in the Investigator Brochure (IB).  
Refer to the IB for more details on the nonclinical safety of PF-06882961.
2.2.2. Clinical Overview
To date, 3 clinical studies, C3421001, C3421002 and C3421003 have been completed with 
PF-06882961. In C3421001 and C3421003, healthy participants were randomized to receive 
single oral doses of PF-06882961 (or matching placebo).  In C3421002, adult participants 
with T2DM were randomized to receive oral doses of PF-06882961 (or matching placebo) 
for 28 days, and safety results from this study are provided in Section 2.2.2.1.  Refer to the 
investigator’s brochure (IB) for more details on these studies and the known drug class 
effects on marketed injectable GLP-1R agonists.
2.2.2.1. Clinical Safety
Clinical data from the completed C3421001, C3421002 and C3421003 studies are provided 
in the IB for PF-06882961.
In the C3421002 study, PF-06882961 doses ranging from 10 mg BID to 120 mg BID were
generally safe and well tolerated. A total of 98 participants with T2DM on a background of 
metformin were randomized to receive PF-06882961 or matching placebo in a 
3:1 randomization ratio for 28 days, and 92 participants completed the study. Six (6) 
participants discontinued from the study, of which 2 withdrew from the study due to adverse 
events and 4 withdrew during the treatment or follow up period for non-treatment related 
reasons.  
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A total of 319 all-causality treatment-emergent adverse events (TEAEs) were reported in 
these participants, of which a majority (294 or 92%) were mild in intensity, 23 (or 7%) were 
moderate, and 2 (or 1%) were severe in intensity.  A summary of adverse events (AEs) by
randomized treatment is presented in the table below.
Table 1.
Summary of Treatment-Emergent Adverse Events in C3421002
Placebo
PF-06882961 Dosea
10 mg 
BID
15 mg 
BIDb
50 mg 
BIDb
70 mg 
BID
120 mg 
BID
120 mg 
BID ST
120 mg 
QD
200 mg 
CR QD
Number of participants 
evaluable for TEAEs
25
9
9
10
9
9
9
8
10
Number of Participants 
with TEAEs
17
6
8
10
8
8
9
8
9
Number of Adverse Events
44
8
16
45
31
43
50
35
47
ST= slow titration; CR= controlled release formulation; BID = twice daily; QD = daily.
a.
PF-06882961 dose reflects the randomized target dose for the group.  Note that some participants in the 
50 mg BID, 120 mg BID and 120 mg BID ST groups include subject(s) that, due to tolerability, did not 
remain on the target dose.
b.
Neither the PF-06882961 15 mg BID nor the 50 mg BID dose groups received titration.
The most frequently reported TEAEs were nausea (49.0%), dyspepsia (32.7%),
vomiting (26.5%), diarrhea (24.5%), headache (23.5%), and constipation (20.4%).  In 
addition, there was 1 symptomatic hypoglycemic adverse event (AE) that was reported in 
1 subject in the 120 mg BID group. This AE was non-fasting, mild in severity and of limited 
duration.
No deaths occurred in the C3421002 study.  Two (2) participants experienced 2 severe 
TEAEs during the study, 1 of which occurred in the dosing period and was considered 
treatment related, and the other occurred during the follow-up period and was not considered 
treatment related.  The latter participant experienced 2 non-treatment-related serious adverse 
events (SAEs), 1 of which occurred in the follow-up period and was a TEAE of severe 
intensity, and the other SAE occurred outside of the study reporting period.
While there were isolated values for laboratory tests, vital signs and electrocardiogram 
(ECG) intervals outside of the reference ranges, no clear adverse trends were apparent in 
these parameters.  As has been reported for marketed GLP-1R agonists,10,11 increases in heart 
rate have been observed, with mean increases ranging from 5 to 15 beats per minute (bpm)
across doses administered to date, and most heart rate values within the normal range.
2.2.2.2. Clinical Pharmacokinetics
The clinical pharmacokinetics (PK) of PF-06882961 in adult participants has been evaluated 
in three completed studies: C3421001, C3421002, and C3421003.  The results of these 
completed studies are summarized in the PF-06882961 IB.  

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2.3. Benefit/Risk Assessment
Based on the clinical history of injectable GLP-1R agonists, an oral GLP-1R agonist is 
expected to improve glucose control, reduce HbA1c levels, diminish food intake, and 
decrease body weight in patients with T2DM, while avoiding the requirement for 
subcutaneous injections that accompanies currently available peptidic GLP-1R agonists.
In line with the clinical profile of marketed GLP-1R agonists,12,17,18 the most frequently 
reported AEs with PF-06882961 administration have been nausea, diarrhea, dyspepsia, 
headache, and vomiting. In addition, as has been reported for marketed GLP-1R agonists, 
increases in heart rate have been observed with PF-06882961 administration, with most heart 
rate values within the normal range.
Considering all available clinical and nonclinical data, the benefit-risk profile of 
PF-06882961 is favorable and supports continued clinical development in patients with 
T2DM.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06882961 may be found in the IB which is the single reference safety 
document (SRSD) for this study. 
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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 

To evaluate the tolerability of 
different titration schemes of 
PF-06882961 administered for 
12 weeks to participants with 
T2DM and the tolerability of a 
single titration scheme in non-
diabetic participants with obesity.

Incidence and severity of 
treatment emergent AEs.

There are no defined estimands 
for these endpoints and they will 
be analyzed using Pfizer data 
standards as applicable.
Secondary: 
Secondary:
Secondary: 

To evaluate the safety of 
different titration schemes of 
PF-06882961 administered for 
12 weeks to participants with 
T2DM and the safety of a single 
titration scheme in non-diabetic 
participants with obesity.

Incidence of clinical 
laboratory abnormalities, 
vital signs (blood pressure 
and pulse rate) and ECG 
parameters (heart rate, 
QT, QTcF, PR and QRS 
intervals).

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.

To evaluate the effect on fasting 
plasma glucose of different 
titration schemes of PF-06882961 
administered for 12 weeks to 
participants with T2DM.

Change from baseline in 
fasting plasma glucose at 
Weeks 2, 4, 6, 8, 10 
and 12.

Estimand 1A: This estimand is 
intended to provide a population 
level estimate of the mean 
treatment effect (PF-06882961 
versus placebo) on a continuous 
endpoint in participants with 
T2DM on stable doses of 
metformin without the benefit of 
glycemic rescue medication while 
on treatment.

To evaluate the effect on HbA1c 
of different titration schemes of 
PF-06882961 administered for 
12 weeks to participants with 
T2DM.

Change from baseline in 
HbA1c at Weeks 2, 4, 6, 
8, 10 and 12.

Estimand 2A: This estimand will 
be the same as 1A.

To evaluate the effect on body 
weight of different titration 
schemes of PF-06882961 
administered for 12 weeks to 
participants with T2DM.

Change from baseline in 
body weight at Weeks 2, 
4, 6 8, 10 and 12.

Estimand 3A: This estimand will 
be the same as 1A.

To evaluate the effect on body 
weight of a single titration 
scheme of PF-06882961 
administered for 12 weeks to 
non-diabetic participants with 
obesity.

Change from baseline in 
body weight at Weeks 2, 
4, 6 8, 10 and 12.

Estimand 3B: This estimand will 
be the same as 1B.

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Objectives
Endpoints
Estimands
Tertiary/Exploratory: 
Tertiary/Exploratory:
Tertiary/Exploratory: 

To evaluate the effect on fasting 
plasma glucose of a single 
titration scheme of PF-06882961 
administered for 12 weeks to 
non-diabetic participants with 
obesity.

Change from baseline in 
fasting plasma glucose at 
Weeks 2, 4, 6, 8, 10 
and 12.

Estimand 1B: This estimand is 
intended to provide a population 
level estimate of the mean 
treatment effect (PF-06882961 
versus placebo) on a continuous 
endpoint in non-diabetic obese 
participants with obesity while on 
treatment.

To evaluate the effect on HbA1c 
of a single titration scheme of 
PF-06882961 administered for 
12 weeks to non-diabetic 
participants with obesity.

Change from baseline in 
HbA1c at Weeks 2, 4, 6, 
8, 10 and 12.

Estimand 2B: This estimand will 
be the same as 1B.

To summarize the 
pharmacokinetics of 
PF-06882961 in participants with 
T2DM and in non-diabetic 
participants with obesity.

Pre-dose plasma 
concentration of 
PF-06882961 on 
Days, 14, 28, 42, 56, 70, 
84 and at 2-6 hours 
post-dose on Days 1, 42, 
84.

There are no defined estimands for 
these endpoints and they will be 
analyzed using Pfizer data 
standards as applicable.

To enable exploratory research 
through collection of banked 
biospecimens, unless prohibited 
by local regulations or ethics 
committee decision.  

Potential results from 
exploratory analysis of 
banked biospecimens 
(these results may or may 
not be generated in the 
context of the present 
study).
For all endpoints, baseline is defined as the result closest prior to dosing at Visit 3 (Day 1).
4. STUDY DESIGN
4.1. Overall Design
This Phase 2a, multicenter, randomized, double-blind, sponsor-open, placebo-controlled, 
parallel-group, study will assess tolerability, safety, and pharmacodynamics (PD) of BID 
administration of PF-06882961 in adult participants with T2DM who are treated with 
metformin. In addition, participants with obesity, without T2DM, will be enrolled to explore 
differences in tolerability, safety, pharmacokinetics and pharmacodynamics between 
participants with T2DM and participants without T2DM and to support clinical development 
in both T2DM and obesity.
For participants with T2DM, the metformin dose (at least 500 mg/day) must have been stable 
for at least 60 days prior to the screening visit (Visit 1) and should remain the same until the 
first follow-up visit (ie, Visit 10, Week 13-14), except in circumstances where a dose change 
is deemed medically necessary.

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Following the screening period to confirm eligibility (up to 4 weeks), the study will consist 
of a 2-week single-blind placebo run-in period, prior to randomization on Day 1.  Following 
randomization, participants with T2DM will be assigned to either the placebo arm or 1 of the 
5 active treatment arms with PF-06882961.  PF-06882961 doses will be titrated to a target 
dose of 80 mg BID in 2 arms, 120 mg BID in 2 arms, and 200 mg BID in 1 arm.  
Following randomization, participants with obesity will be assigned to either the placebo arm 
or an active treatment arm with PF-06882961 with a target dose of 200 mg BID.  
The treatment period will be 12 weeks, followed by an approximate 4-week follow-up.  The 
total duration of participation in this study is approximately 18 weeks, not including the 
screening period.  Dosing with PF-06882961 or placebo will occur BID with food in the 
morning and evening.  Refer to Figure 1 for details of dose titration schemes per study arm, 
in which the doses depicted in Arms 1 to 7 are administered BID.  
Figure 1.
Dose Titration Schemes
Assuming a 25% drop-out rate, approximately 140 participants will be randomly assigned to 
IP such that approximately 105 evaluable participants complete the study.  Of these 
approximately 140 randomized participants, approximately 115 participants will have T2DM
and approximately 25 will have obesity without T2DM. For participants with T2DM, 
approximately 20 participants will be allocated to each of the 5 active arms and 
approximately 15 participants to the placebo arm.  For participants with obesity without 
T2DM, approximately 20 participants will be allocated to Arm 7 and approximately 
5 participants to the placebo arm. To ensure balance between the groups, randomization will 
be stratified based on biological sex (men vs. women).  There are no plans to replace 
withdrawn participants.  

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4.2. Scientific Rationale for Study Design
This study is designed to assess the tolerability, safety, and PD of PF-06882961 in 
participants with T2DM and in non-diabetic participants with obesity over 12 weeks of 
dosing.  A single-blind placebo-run-in period (Visit 2 to Visit 3) is included in this study to 
familiarize participants with the study treatment regimens and to exclude those who are not 
compliant with blinded placebo dosing prior to randomization.  Study intervention 
compliance is described in Section 6.4.  Clinical laboratory tests, assessment of vital signs 
and 12-lead ECGs, physical examination, and AE monitoring will provide data to evaluate 
the tolerability, safety, and PD of PF-06882961.
This study will assess tolerability of PF-06882961 at different starting doses (5 mg BID vs 
10 mg BID), as well as tolerability of PF-06882961 at different duration of each titration step 
(1 week vs. 2 weeks), and the tolerability of different target doses (80 mg BID, 120 mg BID 
and 200 mg BID).  The placebo arm is added to facilitate blinding to active treatment and to 
mitigate bias in reporting of AEs.  
 
 
 
  Therefore, to compare tolerability, 
safety and PK exposures directly in this study, the study population includes participants with 
obesity without T2DM, to target a similar BMI range as patients with T2DM and to support 
clinical development in T2DM and obesity.  
Published data from marketed GLP-1R agonists suggests that gastrointestinal (GI) 
tolerability may be different between men and women, therefore randomization will be 
stratified based on biological sex.
 
 
  
 
 
  
 
 
 
 
 
 
  
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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.12 In addition, thyroid stimulating hormone (TSH), free thyroxine (FT4), lipids, 
coagulation profile and total bile acids (TBA) will be assessed, based on non-adverse 
findings in the nonclinical studies with PF-06882961. Assessment of suicidal ideation and 
behavior by the C-SSRS19 and PHQ-920 will also be performed based on the potential risk 
related to the product labeling for the injectable GLP1R agonist liraglutide for obesity.21
While GLP-1R agonists typically are not associated with hypoglycemia unless 
co-administered with anti-diabetic agents that can cause hypoglycemia (such as insulin or 
sulfonylureas), blood glucose concentrations will be monitored throughout the study via 
glucometer, and monitoring of symptomatic hypoglycemic AEs (HAEs) will be performed.  
Body weight will be measured in duplicate at all study visits, except Visit 11, as GLP-1R
agonists have been shown to decrease food intake and body weight. The collection of blood 
samples, specifically fasting plasma glucose (FPG) and HbA1c will assist in the time- and 
dose-related PD response.  
Both females of childbearing potential, as well as those who are of non-childbearing 
potential, will be enrolled given the availability of embryo fetal developmental (EFD) 
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 Schedule of Activities and Appendix 4 re: contraception) for additional 
information regarding contraception use and monitoring.
The potential risk of exposure to PF-06882961 in a sexual partner of a male participant in 
this study via ejaculate is low, and therefore no contraception (condom) use in male 
participants is warranted.  The calculated safety margin is ≥100-fold between the estimated 
partner exposure due to seminal transfer and the no-observed-adverse-effect level (NOAEL)
for serious manifestations of developmental toxicity in nonclinical studies.  The safety 
margin of 100-fold is based on applying a 10-fold safety factor for interspecies extrapolation 
and a 10-fold safety factor for susceptible populations.11
Banked biospecimens will be collected for exploratory pharmacogenomic/genomic/
biomarker analyses and retained in the Biospecimen Banking System (BBS), which makes it 
possible to better understand the investigational product’s mechanism of action and to seek 
explanations for differences in, for example, exposure, tolerability, safety, and/or efficacy not 
anticipated prior to the beginning of the study.
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4.3. Justification for Dose
The target doses (planned dose at end of study) in the C3421008 study of 80 mg BID 
(Arms 3 and 4)and 120 mg BID (Arms 1 and 2) represent the 2 top doses being assessed in 
the Phase 2b dose ranging study in T2DM with PF-06882961.  As described in 
Section 2.2.2.1, more AEs were observed in the 120 mg BID cohort in study C3421002, 
relative to the 70 mg BID cohort.  However, it is not known if tolerability at higher dose 
levels would be different using titration schemes that take longer than 4 weeks.  Based on 
data from the C3421002 study, the glucose lowering effect of PF-06882961 is expected to be 
similar to that of marketed GLP-1R agonists.  
 
 
Although doses of >120 mg BID are not anticipated to be needed for glycemic efficacy in 
T2DM participants, based on experience from marketed GLP-1 agonists, doses needed to 
maximize weight loss are generally higher than what are needed for glycemic efficacy.  For 
this reason, a higher dose of PF-06882961 is being assessed in this study (200 mg BID, 
Arm 6) to assess the tolerability of this dose following an extended titration scheme of 
10 weeks. The starting dose and titration scheme for Arms 6 and 7 is similar to Arm 2 
(Figure 1), but the titration scheme continues at a 1-week interval over a longer duration to 
achieve a higher target dose.  This additional 200 mg BID arm in T2DM may facilitate 
development of PF-06882961 for treatment of obesity in participants with T2DM.
Although the steady-state exposures of PF-06882961 at 200 mg BID in T2DM participants 
are expected to be higher than that encountered in previous clinical studies (120 mg BID in 
C3421002), reasonable tolerability of this dose may be expected based on the extended 
12-week titration scheme.  Moreover, the predicted exposure at 200 mg BID in participants 
with obesity and without T2DM is expected to have a 27- and 14-fold margin under the 
unbound NOAEL for the 6 month rat toxicology study for Cmax and AUC, respectively 
(Section 2.2.2.2).  
 
 
  Inclusion of a cohort of participants 
with obesity and not T2DM has been included at the highest dose (200 mg BID) to compare 
PK, PD and tolerability between the 2 populations.
As the duration in the multiple ascending dose study C3421002 was limited to 4 weeks, the 
time course of titration in this study was less than 4 weeks.  In the current study, the doses 
will be titrated to the highest doses over a 10-week duration, which is expected to improve 
the tolerability of PF-06882961, and therefore doses of up to 200 mg BID are viewed as
appropriate for assessment in this study.  
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This study will also assess the appropriate starting dose for titration of PF-06882961.  While 
10 mg BID of PF-06882961 was generally well tolerated in C3421002, a lower dose of 
5 mg BID might be better tolerated than 10 mg BID and improve tolerability of subsequent 
titration steps. 
While this study is designed with target doses of ≥80 mg BID, intermediate doses of 10 to 
60 mg will also be assessed in this study, with tolerability of titration schemes leading to
these intermediate doses.  
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the follow-up visit (Visit 11), approximately 28 to 35 days post last dose 
of double-blind investigator product (IP).
The end of the study is defined as the date of the follow-up last visit (Visit 11) of the last 
participant in the study. 
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
5.1.1. Inclusion Criteria for All Participants
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 and 75 years, inclusive, at 
Visit 1 (screening).

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures, including 
the ability to perform self-monitoring blood glucose at a frequency deemed 
appropriate by the investigator.

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Informed Consent:
3. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.1.2. Additional Inclusion Criteria Only for Participants with T2DM
1. Participants with T2DM who are treated with metformin.  Metformin dose (at least 
500 mg/day) must have been stable for at least 60 days prior to the screening visit 
(Visit 1).
2. HbA1c ≥7.0% and ≤10.5% at screening (Visit 1) as assessed by the study specific 
central laboratory.  A single repeat is allowed, if deemed necessary.
3. Body mass index (BMI) ≥27 kg/m2; and a total body weight >50 kg (110 lbs).  Body 
weight must have been stable (<5% change) for at least 90 days prior to screening
(Visit 1) as per participant self-report.
5.1.3. Additional Inclusion Criteria Only for Participants with Obesity without T2DM
1. BMI ≥30 kg/m2; and a total body weight >50 kg (110 lbs).  Body weight must have 
been stable (<5% change) for at least 90 days prior to screening (Visit 1) as per 
participant self-report.
2. HbA1c <6.5% at screening (Visit 1) as assessed by the study specific central 
laboratory.  A single repeat is allowed, if deemed necessary.
3. FPG <126 mg/dL at screening (Visit 1) as assessed by the study specific central 
laboratory.  A single repeat is allowed, if deemed necessary.
5.2. Exclusion Criteria
5.2.1. Exclusion Criteria for Only Participants with Obesity without T2DM
1. Diagnosis of T2DM.
5.2.2. Exclusion Criteria for All Participants
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or IP administration or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study.

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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. Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes.
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 of screening (Visit 1).
5. Any malignancy not considered cured (except 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 (MTC) or multiple 
endocrine neoplasia syndrome type 2 (MEN2), or participants with suspected MTC 
per the investigator’s judgement.
7. Acute pancreatitis or history of chronic pancreatitis.
8. Symptomatic gallbladder disease. 
9. Participants with a known medical history of active proliferative retinopathy and/or 
macular edema.
10. Participants with a known medical history of active liver disease (other than 
non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, or primary 
biliary cirrhosis.
11. Participants with known history of human immunodeficiency virus (HIV).
12. History of major depressive disorder or history of other severe psychiatric disorders 
(eg, schizophrenia or bipolar disorder) within the last 2 years.
13. Any lifetime history of a suicide attempt. 
Prior/Concomitant Therapy:
14. See Appendix 8 for details regarding prohibited prior/concomitant medication.
Prior/Concurrent Clinical Study Experience:
15. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of IP used in this 
study (whichever is longer). 

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16. Known prior participation in a trial involving PF-06882961 or known intolerance or 
hypersensitivity to a GLP-1R agonist.
Diagnostic Assessments:
17. A PHQ-9 score ≥15 obtained at V1, V2 or V3.
18. Response of “yes” to question 4 or 5, or on any behavioral question on the C-SSRS at 
V1, V2 or V3.
19. Screening (Visit 1) supine blood pressure (BP) ≥160 mm Hg (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. Note: Participants with an arm circumference greater 
than the largest cuff size or those with a mid-arm circumference >52 cm are not 
eligible.
20. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, baseline corrected QT 
interval [QTcF] >450 msec, complete left bundle branch block [LBBB], signs of an 
acute or indeterminate-age myocardial infarction, ST-T interval changes suggestive of 
myocardial ischemia, second- or third-degree atrioventricular [AV] block, or serious
bradyarrhythmias or tachyarrhythmias).  

If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be 
repeated 2 more times and the average of the 3 QTcF or QRS values should be 
used to determine the participant’s eligibility.  
21. A positive urine drug test at screening.

Note: Participants who have been prescribed opiates/opioids or benzodiazepine 
and report the use of these drugs to the investigator at screening (Visit 1) may be 
allowed to participate with notification to the sponsor.  
22. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study specific central laboratory and confirmed by a 
single repeat test, if deemed necessary:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
≥2 x upper limit of normal (ULN).

Total bilirubin level ≥1.5 x ULN.

Fasting C-peptide <0.8 ng/mL.

TSH >1.5 x ULN.

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
Serum calcitonin > ULN.

Amylase or lipase > ULN.

Fasting plasma glucose >270 mg/dL (15 mmol/L) at screening visit (Visit 1) or 
single-blind placebo run-in (Visit 2).

Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 as calculated by 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.14
Other Exclusions:
23. Compliance of <89% (based on pill count) during the 2-week run in period, as 
assessed prior to randomization on Day 1 (Visit 3).
24. 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 before screening (Visit 1).
25. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
26. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
Section 5.3 of the protocol.
27. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study. 
5.3. Lifestyle Considerations
5.3.1. Dietary Restrictions
1. Participants must abstain from all food and drink (except water) for at least 
8 (preferably 10) hours prior to any body weight and blood sample collection(except 
post-dose PK samples).
2. IP must be administered BID with food, approximately 10 to 12 hours apart.
3. On scheduled morning visits to the site, from Visit 2 through Visit 9, participants 
should be instructed to arrive without having morning meal/breakfast, 
self-administration of IP, and for participants with T2DM only, morning dose of 
metformin for the given day. The above-mentioned medications will be administered 
with food at the site.  Note: Participants may take their morning dose of 

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antihypertensive and/or lipid modifying medication per their usual routine, if 
applicable.
4. Participants will be counseled on appropriate dietary and lifestyle guidelines at Visit 2 
and asked to maintain these guidelines throughout participation in the study.  

For participants with T2DM, counseling on dietary guidelines should be in 
accordance with local medical standards of care for patients with T2DM.  

For participants with obesity without T2DM, counseling on dietary guidelines 
should be in accordance with local medical standards of care for patients with 
obesity.

Note: Participation in formal weight loss programs should be avoided during 
participation in this study.
5.3.2. Alcohol, Caffeine, and Tobacco

Intake of alcohol is permitted in moderation (refer to exclusion criterion 24 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.
5.3.3. Physical Activity
Participants will not be permitted to perform physically strenuous exercise (for example: 
heavy lifting, weight training, calisthenics and aerobics) within 48 hours prior to blood 
sample collections; walking at normal pace is permitted.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the female participants have selected an appropriate method of contraception from the 
permitted list of contraception methods (see Appendix 4 Section 10.4.4) and will confirm 
that the participant has been instructed in its consistent and correct use.  At time points 
indicated in the SoA, the investigator or designee will inform the participant of the need to 
use highly effective contraception consistently and correctly and document the conversation 
and the participant’s affirmation in the participant’s chart (participants need to affirm their 
consistent and correct use of at least 1 of the selected methods of contraception).  In addition, 
the investigator or designee will instruct the participant to call immediately if the selected 

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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 IP at Visit 3.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (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 study-specific subject identification (SSID) number. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.  
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term IP may be used synonymously with study 
intervention.  For this study, the IP is PF-06882961 and matching placebo tablets; and will be 
administered orally, BID, with food.
Treatment phase IP will be packaged in blister cards containing blinded PF-06882961 or 
matching placebo for oral administration.  Treatment assignment will be blinded, and blister 
cards will be labeled according to local regulatory requirements.  For single-blind placebo 
run-in, tablets will be packaged in blinded-label blister cards according to local regulatory 
requirements.
Participants will continue taking their own metformin medication at the same total daily dose 
that was prescribed prior to study entry, except in circumstances where a dose change is 
deemed medically necessary.  

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6.1. Study Intervention(s) Administered
Intervention Name
PF-06882961
Placebo for PF-06882961
ARM Name
Active
Placebo
Type
Drug
Drug
Dose Formulation
Tablet
Tablet
Unit Dose Strength(s)
2.5 mg, 10 mg, 40 mg, and 100 mg
0 mg
Dosage Level(s)
Dose amount and frequency – refer to 
Figure 1
0 mg BID
Route of Administration
Oral
Oral
Investigational Medicinal 
Product (IMP) and 
Noninvestigational 
Medicinal Product (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
Study intervention will be provided in 
blister packs.  Each blister pack will be 
labeled as required per country 
requirement.
Blinded labels will be utilized for blister 
packs.
Study intervention will be 
provided in blister packs.  Each 
blister pack will be labeled as 
required per country 
requirement.
Blinded labels will be utilized 
for blister packs.
6.1.1. Administration
All doses will be blinded and consist of 3 to 4 tablets administered BID via a blister pack.
Four (4) tablets BID will be administered during the 2-week single-blind placebo run-in and 
after randomization, during Weeks 1, 2 and 9 of dosing.  Three (3) tablets will be 
administered BID during Weeks 3 to 8 and weeks 10 to 12 of dosing.  Single-blinded blister 
cards will be used for the placebo run-in period.  The dosing regimens after randomization 
will look the same across arms for each dosing window.  Blister cards will look the same 
across all study arms and will contain the same number of tablets for the same time point in 
treatment.  
After randomization during Weeks 1, 2 and 9 of dosing, participants will take 4 tablets of IP 
(PF-06882961 or matching placebo) in the morning with food and 4 tablets of IP in the 
evening with food, approximately 10 to 12 hours apart and at approximately the same time 
each day.  Participants will take a total of 8 tablets of IP daily.  The same dosing paradigm 
will be used during the single-blind placebo run-in period.

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During Weeks 3 to 8 and Weeks 10 to 12 of dosing, participants will take 3 tablets of IP (in 
the morning with food and 3 tablets of IP with the evening with food approximately 10 to 
12 hours apart and at approximately the same time each day.  Participants will take a total of 
6 tablets of IP (PF-06882961 or matching placebo) daily.  
Participants will swallow the IP whole, and will not manipulate or chew the IP prior to 
swallowing.  To maximize tolerability of PF-06882961 dose will be titrated over a period of 
6 to 10 weeks.
The actual titration schemes for PF-06882961 to be used in this study are provided in Table 2
below.  The regimen for Arm 5 (the placebo arm) will be placebo tablets administered BID 
with food in the morning and evening. Arms 1 to 7 are also depicted in Figure 1.
Table 2.
Titration Schemes
Week of Study
Arm 1
Arm 2
Arm 3
Arm 4
Arms 6 and 7
1
5 mg BID
10 mg BID
5 mg BID
10 mg BID
10 mg BID
2
10 mg BID
20 mg BID
5 mg BID
10 mg BID
20 mg BID
3
20 mg BID
40 mg BID
10 mg BID
20 mg BID
40 mg BID
4
40 mg BID
60 mg BID
10 mg BID
20 mg BID
60 mg BID
5
60 mg BID
80 mg BID
20 mg BID
40 mg BID
80 mg BID
6
80 mg BID
100 mg BID
20 mg BID
40 mg BID
100 mg BID
7
100 mg BID
120 mg BID
40 mg BID
60 mg BID
120 mg BID
8
120 mg BID
120 mg BID
40 mg BID
60 mg BID
140 mg BID
9
120 mg BID
120 mg BID
60 mg BID
80 mg BID
160 mg BID
10
120 mg BID
120 mg BID
60 mg BID
80 mg BID
180 mg BID
11
120 mg BID
120 mg BID
80 mg BID
80 mg BID
200 mg BID
12
120 mg BID
120 mg BID
80 mg BID
80 mg BID
200 mg BID
Morning dosing will occur with the food at the site at Visit 2 through Visit 9.  Participants 
will be instructed to arrive at the site in the fasted state, bring their IP with them and to delay 
self-administration of IP and concomitant medications, if appropriate (as described in 
Section 5.3.1), on scheduled visit days until they arrive for their outpatient clinic visit.
Participants should be instructed that if they forget to take their morning dose at their usual 
time, they should take the missed dose as soon as possible (with food) on the day it was 
missed; however, there must be at least an 8-hour interval between the missed dose and the 
next dose.  If a dose is missed and the interval to the next dose is less than 8 hours, the 
missed dose should not be administered.
Dosing and administration instructions along with the dosing diary, will be provided to 
participants to support at-home dosing of IP.

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If participants schedule a visit prior to the protocol specified visit day they should be 
instructed by the investigator or site staff to continue dosing from the blister card they were 
dispensed previously.
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, as 
applicable for temperature-monitored shipments. 
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 temperature since previously documented for all 
site storage locations upon return to business.
3. 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).  All study 
interventions will be accounted for using an IP accountability form/record.  All IP 
that it taken home by the participant, both used and unused, must be returned to the 
investigator by the participant.
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the investigational product (IP) manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels. 
7. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention. 
8. 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.  It will not be considered a protocol deviation if Pfizer 
approves the use of the study intervention after the temperature excursion. Use of the 

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study intervention prior to Pfizer approval will be considered a protocol deviation. 
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 investigational 
product (IP manual).
9. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  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, and all destruction must be adequately 
documented.
Additional details about accountability, storage, destruction, and excursion reporting can be 
found in the IP manual.
6.2.1. Preparation and Dispensing
The 2-week single-blind placebo run-in tablets will be dispensed at Visit 1 using an 
interactive response technology (IRT) drug management system.  The same IRT drug 
management system will be used to dispense the IP from Visit 2 to Visit 8.  A qualified staff 
member will dispense the IP via unique container numbers in the blister cards provided, in 
quantities appropriate for the study visit schedule.  The participant should be instructed to 
maintain the product in the blister cards provided throughout the course of dosing and return 
the blister cards to the site at the next study visit.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
Allocation of participants to treatment groups will proceed through the use of an IRT) system 
(interactive Web-based response [IWR]).  
A randomization code using the method of random permuted blocks will be utilized to 
randomize eligible participants with T2DM treated with metformin in a 4:4:4:4:4:3 ratio (1 of 
5 active dosing regimens of PF-06882961 or placebo) and non-diabetic participants with 
obesity in a 4:1 ratio (1 active dosing regimen of PF-06882961 or placebo) prior to the first 
dose of IP.  
Participants will be stratified at randomization (Day 1) by population (T2DM vs. 
non-diabetic) and by biological sex (men vs. women).
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the participant number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when IP is being supplied via the IRT system.  The IRT system will provide a confirmation 
report containing the participant number, randomization number, and DU or container 
number assigned.  The confirmation report must be stored in the site’s files. 

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IP will be dispensed at the study visits summarized in the SoA. 
Returned IP must not be re-dispensed to the participants.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.3.2. 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 case report form (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
Participant compliance with IP will be assessed at each visit as noted in the SoA.  
Compliance will be assessed by counting returned tablets.  Through Visit 8, which occurs 
during the first 10 weeks of dosing when participants may be receiving titrated doses as part 
of their blinded regimen, sites should assess the blister cards for compliance; however, the 
cards should remain in the possession of the participant.  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 single-blind placebo 
run-in period.  Based on the visit window, for a placebo run-in that is 11-13 days, up 
to 2 missed doses are allowed, and for a placebo run-in that is 14-17 days, up to 
3 missed doses 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 IP from Day 1 (Visit 3) through Week 12 (Visit 9), 
inclusive.  Investigators must closely follow non-compliant, randomized, participants 
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 IP.
Deviation(s) from the prescribed dosage regimen should be recorded in the CRF.

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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 metformin 
or any concomitant 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 also permitted during this study.  
Treatments taken within 28 days before the first dose of randomized IP on Day 1 will be 
documented as prior treatment.  Treatments taken after the first dose of randomized IP 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.  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 women of childbearing potential (WOCBP) (see Appendix 4).
6.5.1. Metformin
All participants with T2DM are required to be taking metformin monotherapy prior to 
inclusion in this study as listed in Section 5.1.  Participants must have been taking a stable 
dose of metformin (≥500 mg/day) for at least 60 days prior to the screening visit (Visit 1).  
Participants will continue taking their own metformin at the same total daily dose that was 
prescribed prior to study entry through the first follow-up visit (ie, Visit 10, Week 13-14), 
except in circumstances where a change in dose is deemed medically necessary.  For study 
visit days, participants should be instructed to refrain from taking morning doses at home and 
to bring the metformin to the site for dosing at the same time as their blinded IP.  For 
participants taking metformin more than once a day, the timing should be approximately the 
same on each day.
6.5.2. Medications for Glycemic Control
Aside from metformin, the use of other medications for glycemic control is not permitted in 
this study unless the participant meets the protocol defined glycemic rescue criteria (see 
Section 8.2.4.3).

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6.5.3. Glycemic Rescue Medicine
Participants with hyperglycemia as defined in Section 8.2.4.3 should be offered glycemic 
rescue medication as an add on to their randomized treatment.
Glycemic rescue medication should be prescribed according to local label and obtained 
locally.  The following glycemic rescue medications may be used: sulfonylureas, or sodium 
glucose co-transporter 2 (SGLT2) inhibitors.  For participants who were taking a dose of 
metformin lower than the approved dose, increasing the metformin dose may be instituted as 
glycemic rescue medication, as long as the dose does not exceed the highest approved dose in 
the country of participation.
The following medication are NOT permitted as glycemic rescue medications: GLP-1R 
agonists, DPP-4 inhibitors, amylin analogues, thiazolediediones (TZDs) or insulin.
The date of glycemic rescue medication administration as well as the name and dosage 
regimen of the glycemic rescue medication must be recorded on the CRF.
Participants receiving glycemic rescue medication should continue to follow all protocol 
specified visits and procedures according to the SoA.
There is no rescue therapy to reverse the AEs observed with PF-06882961.  Standard medical 
supportive care must be provided to manage the AEs, including administration of 
carbohydrates to treat HAEs (see Section 8.2.4.2.1).
6.5.4. 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. 
6.5.5. Lipid Modifying Medications
The use of background lipid modifying agents is permitted unless otherwise noted in 
Appendix 8.  Doses of 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.
6.6. Dose Modification 
Dose titration schemes are utilized for each study intervention dosing arm in this study as 
described in Section 6.1.1.  However, each dosing regimen will be provided in blister packs, 
and dose adjustment will not be permitted per protocol.

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6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue IP.  If a 
safety or tolerability concern arises, in particular if not responsive to symptomatic 
management, dosing with double-blinded IP may be stopped in an individual participant at 
investigator discretion.  
If IP is permanently discontinued, the participant remains in the study and continues to
follow all protocol specified visits and procedures according to the SoA. 
The site should notify the Sponsor Medical Monitor or Sponsor Clinician if the below criteria 
for permanent discontinuation are met.
Note that discontinuation of IP does not represent withdrawal from the study.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.1.1. Criteria for Discontinuation
Discontinuation of IP must occur for a participant meeting any of the following conditions: 

Criteria for a potential Hy’s law case are met (see Appendix 6).

Intent to become pregnant or pregnancy confirmed by serum beta human chorionic 
gonadotropin (-hCG) testing.  

Based on mental health assessment as outlined in Section 8.2.7, should be 
discontinued from dosing at the discretion of the investigator.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.
At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted.  See the SoA for assessments to be collected at the time of early termination and 
follow-up and for any further evaluations that need to be completed. 

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The early termination visit applies only to participants who are 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, but data already generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.
If the participant withdraws from the study and also withdraws consent (see below) 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.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the Clinical Trial (CT) SAE Report.
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.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of IP or also from study procedures and/or 
post-treatment 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 a required 
study visit:

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
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. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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.

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For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
276 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
8.1. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
8.2.1. Physical Examinations
Physical examinations are performed as indicated in the SoA.
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 head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal and 
neurological systems.  
Height will be measured at screening only.
A limited physical examination is performed at the 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, cardiovascular system, and 
participant reported symptoms.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

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8.2.2. Vital Signs
8.2.2.1. Blood Pressure and Pulse Rate
In this study, assessment of vital signs (systolic blood pressure (BP), diastolic BP, and pulse 
rate) will occur at the nominal time points specified in the SoA per the following 
specifications:

At screening, the participant’s arm circumference should be measured (eg, using a 
flexible anthropometric tape) at the midpoint of the length of the upper arm and the 
appropriate cuff selected and used throughout the study. 

Note: Participants with arm circumference greater than the largest cuff size 
available at the site or >52 cm are not eligible.  

BP and pulse rate will be measured via an automated device using an oscillometric 
method (not auscultation).

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, and recorded to the nearest mm Hg, following a rest of at least 
5 minutes.  The assessment at Visit 3 (Day 1) will serve as the participant’s baseline.  
Triplicate assessments will be measured at screening, and pre- and post-dose times at 
Visit 3, Visit 6 and Visit 9 with a brief interval (eg, 2-4 minutes) between successive 
triplicate assessments.

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.

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8.2.3. Electrocardiograms
Standard 12-Lead ECGs should be collected at times specified in the SoA section of this
protocol using an ECG machine that automatically calculates the heart rate and measures 
pulse rate (PR), QT, and QTc 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. 
Triplicate ECGs will be collected at pre- and post-dose times at Visit 3, Visit 6, and Visit 9 as 
specified in the SoA.
If a postdose QTc interval remains ≥30 msec from the baseline and is >450 msec; or an 
absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner,
at the discretion of the investigator), or QTc intervals get progressively longer, the participant
should undergo continuous ECG monitoring.  A cardiologist should be consulted if QTc 
intervals do not return to less than the criterion listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time to achieve precise ECG recordings.  If a machine-read QTc value is 
prolonged, as defined above, repeat measurements may not be necessary if a qualified 
medical provider’s interpretation determines that the QTc values are in the acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. Management of Glycemic Control
HAEs and fasting plasma glucose will be routinely monitored during participation in the 
study.
Based on this information, as well as review of the results reported by the central laboratory, 
an assessment of any symptomatic and asymptomatic occurrence of hypo- or hyper-glycemia 
must be undertaken.
8.2.4.1. Home Glucose Monitoring

All participants will be provided home glucose monitoring supplies including a 
Sponsor-provided glucometer, instructions on the use of the glucometer and 
accompanying supplies.

Home glucose monitoring logs will be provided to participants for completion at 
home and brought to each outpatient visit to the site along with the glucometers.  

For participants with T2DM, investigators must review the home glucose monitoring 
logs completed by the participants and the readings stored in the glucometer device at 
each visit to the site after the single-blind placebo run-in visit (Visit 2).

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
For participants with obesity only, the review of the glucometer and glucose log 
should be completed if participants have signs or symptoms of hypoglycemia. 
Otherwise, regular glucometer monitoring at home is not required.

Participants with T2DM must perform home glucose monitoring at least 3 times 
weekly following at least an 8- (preferably 10-) hour fast (except water).  However, 
the investigator may recommend more frequent home glucose monitoring if needed.

Less frequent glucose monitoring in participants with T2DM will NOT be considered 
a protocol deviation unless the participant fails to monitor his/her glucose for 3 or 
more days per week.

If a participant experiences symptoms of hypoglycemia, home glucose monitoring 
should be performed, and these symptoms, along with the glucometer measurement, 
should be captured on the home glucose monitoring log.

If a participant uses his/her own glucometer, and not one provided by the Sponsor, a 
protocol deviation will NOT be recorded provided the investigator is still able to 
monitor the participant’s daily glucose values according to the criteria stated above. 
8.2.4.2. Management of Hypoglycemia
Any episode of hypoglycemia must be captured on the Adverse Event CRF with specific 
details captured on the hypoglycemia Adverse Event (HAE) Form CRF.  For the definition of 
a hypoglycemic episode and severity categorization see Section 8.2.4.2.1 below.
Participants noted to have a fasting glucose value (during home glucose monitoring) meeting 
the definition of hypoglycemia must be instructed to repeat the measurement the next day 
(following at least an 8- [preferably 10-] hour fast, except water).  If the second measurement 
also meets the below definition, participants must be asked to return to the site within 
1 to 3 days (following at least an 8- [preferably 10-] hour fast, except water) and have blood 
collected and sent to the central laboratory for analysis of fasting plasma glucose.
8.2.4.2.1. Definition and Severity of Categorization of Hypoglycemic Adverse Event 
(HAE)
Based on review of the participant completed home glucose monitoring log at each site visit, 
as well as results reported by the central laboratory, the investigator must assess the glucose 
values as well as any symptoms documented.
HAE is defined as 1 of the following:
1. Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a blood  glucose value of <70 mg/dL (3.9 mmoL/L) using either glucometer 
(fingerstick blood glucose) or sponsor-identified central laboratory (plasma glucose).

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2. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a blood glucose value of <70 mg/dL (3.9 mmol/L) 
using glucometer (fingerstick blood glucose) or sponsor-identified central laboratory
(plasma glucose) and the clinical picture includes prompt resolution with food intake, 
subcutaneous glucagon, or intravenous (IV) glucose.
3. Probable symptomatic hypoglycemia: An event during which symptoms of HAE 
are not accompanied by a glucose determination but was presumably caused by a 
blood 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.  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 participants exhibit at least one of the following neurological symptoms:

Memory loss;

Confusion;

Uncontrolled behavior;

Irrational behavior;

Unusual difficulty in awakening;

Suspected seizure;

Seizure;

Loss of consciousness.
3. Either:

If blood glucose was measured and was ≤54 mg/dL (2.7 mmol/L) using 
glucometer (or central laboratory); or

If blood glucose was not measured, the clinical manifestations were reversed by 
oral carbohydrates, subcutaneous glucagon, or intravenous glucose.
Events that do not meet all criteria above for severe HAE are characterized as mild or 
moderate in severity.

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Any episode of HAE must be captured on the HAE CRF.
8.2.4.3. Management of Hyperglycemia
Hyperglycemia is defined as the following:

Fasting blood glucose ≥270 mg/dL (15.0 mmol/L) using glucometer (or central
laboratory).
After randomization, participants noted to have a fasting blood glucose value (during home 
glucose monitoring) meeting the above definition of hyperglycemia must be instructed to 
repeat the measurement the next day (following at least an 8- (preferably 10-) hour fast, 
except water).  If the second measurement also meets the above definition, participants must 
be asked to return to the site a day later (following at least an 8- (preferably 10-) hour fast, 
except water) and have blood collected for fasting plasma glucose (and shipped to the central 
laboratory for analysis).
The investigator should determine if the participant collected the samples after an adequate 
fasting period; and if the participant is following recommended dietary guidelines.  Proper 
dietary and collected procedures should be reinforced with the participant.
If the results from the central laboratory confirm the readings using glucometer, the 
participant should receive glycemic rescue medication at the discretion of the investigator 
(see Section 6.5.3).
8.2.5. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.
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.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.

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If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.6. Pregnancy Testing
Pregnancy tests will be both urine and serum tests, and must have a sensitivity of at least 
25 mIU/mL.  Serum pregnancy test will be required for eCRF collection.  Urine pregnancy 
test will be used for site reference until serum pregnancy result becomes available.  
Pregnancy tests will be performed in all females at the times listed in the SoA.  Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and a second negative pregnancy test result will be required at the baseline visit prior the 
participant’s receiving the IP.  Pregnancy tests will also be done whenever one 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 
institutional review boards (IRBs)/ethics committees (ECs) or if required by local 
regulations.  
8.2.7. Mental Health Questionnaires
8.2.7.1. Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behavior.19  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.  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.
8.2.7.1.1. 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.

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8.2.7.2. Patient Health Questionnaire-9 (PHQ-9)
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms.  The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in the SoA.  A PHQ-9 score of ≥15 at V1, V2 or V3 indicates clinically 
significant depression and serves as an exclusion criterion for this study.
8.2.7.3. Referral to a Mental Health Professional
A participant should be referred to a MHP for the following reasons:

Response of “yes” to question 4 or 5, or on any behavioral question on the C-SSRS;

A score of ≥15 on the PHQ-9;

In the investigator’s judgment a risk assessment or exclusion is required.
A clinically-qualified MHP is a MHP with appropriate training in the assessment of suicide 
risk, according to local clinical practice standards and regulations, who would normally 
evaluate the risk for suicidal ideation and behavior in a patient.
Participants who have recurrent suicidal ideation or behavior during the study should be 
discontinued from the study and treated appropriately. If a study participant endorses a 4 or 
5 on the ideation subscale or any behavioral item of the C-SSRS on 2 or more occasions and 
is confirmed to have active suicidal ideation or behavior on both occasions by a risk 
assessment conducted by a qualified MHP, then the participant should be discontinued from 
the study and treated appropriately.
Participants who meet criteria for referral to a MHP, but refuse evaluation and/or treatment 
by a MHP, must be assessed by the investigator to determine if the participant should be 
discontinued from dosing or from the study. 
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 it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study intervention (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.

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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 IP), through and including a minimum of 
28 calendar days, except as indicated below, after the last administration of the IP.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately 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.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to IP must be 
reported to Pfizer Safety.
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.

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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, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure 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 IP under study during pregnancy or breastfeeding and occupational exposure 
are reportable to Pfizer Safety within 24 hours of investigator awareness.

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8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 28 calendar days after the last administration of IP.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  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’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information 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. Medication Errors
Medication errors may result from the administration or consumption of the IP by the wrong 
participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the IP 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

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Medication errors include:

Medication errors involving participant exposure to the IP;

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 an 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 IP greater than 16 blinded tablets of PF-06882961 within a 
24-hour time period ±2 hours 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 PF-06882961 should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-06882961 (whichever 
is longer).
3. 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).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to the Sponsor only when associated with an SAE.  Refer to 
Section 8.3.4 for regulatory reporting requirements. 

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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
In this study, blood samples (approximately 3 mL, each) to provide sufficient plasma for PK 
analysis will be collected into appropriately labeled tubes containing dipotassium edetic acid 
(ethylenediaminetetraacetic acid) - K2 EDTA, at times defined in the SoA – with collections 
occurring prior to dosing with IP on the given scheduled visit and between 2 and 6 hours 
post dose on 3 different visits: Visit 3, Visit 6 and Visit 9.  The date/time of the blood 
collection and the date/time of the previous 2 doses of blinded IP prior to each of the blood 
collections related to PK (both pre- and post- dose samples) should be noted in a dosing diary 
(or similar) by the participants and captured in the CRF.  

The PK samples must be processed and shipped as indicated in the study-specific 
laboratory manual provided to the investigator site, prior to initiation of study, to 
maintain sample integrity:

Any deviations from the PK sample handling procedure (eg, sample collection 
and processing steps, interim storage or shipping conditions), including any 
actions taken, must be documented and reported to the sponsor. On a
case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample 
handling procedure resulting in compromised sample integrity will be considered 
a protocol deviation;

Any scheduled pre-dose collection [ie, trough concentration (Ctrough)] obtained 
post dose or any post dose samples not collected within the 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 IP, samples may be used for metabolite 
identification and/or evaluation of the bioanalytical method, as well as for other 
internal exploratory purposes.  These data may not be included in the clinical report.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.
8.6. Pharmacodynamics
PD parameters evaluated in this study include fasting plasma glucose, HbA1c and body 
weight and will be collected according to the SoA.  The PD parameters of fasting plasma
glucose and HbA1c will be assessed by the Central Laboratory as part of the clinical 
laboratory assessments (see Appendix 2), and body weight will be assessed as described in 
Section 8.6.1.  

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As part of understanding the PD of the IP, samples may be used for evaluation of the 
bioanalytical method, as well as for other internal exploratory purposes. These data will not 
be included in the clinical study report. 
The PD samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PD sample 
handling procedure (eg, sample collection and processing steps, interim storage, or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
8.6.1. Body Weight
Body weight will be measured in duplicate as indicated in the SoA.  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 if possible for the 
duration of the study) reporting weight in either pounds (lb) or kilograms (kg), and accuracy 
to the nearest 0.2 lb (or 0.1 kg); ie, the device must be able to distinguish a difference 
between 150.4 lb (68.4 kg) versus 150.2 lb (68.3 kg).  The scale must be placed on a stable, 
flat surface.
Weight measurement should be taken under the following conditions:

Participant is in a fasted state (see Section 5.3.1);

After void of urine;

After removal of shoes, bulky layers of clothing and jackets so that only light clothing 
remains;

While remaining still during the measurement.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
An approximately 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 drug response, T2DM and obesity. 
Genes and other analytes (eg, proteins, ribonucleic acid [RNA], nondrug metabolites) may be 
studied using the banked samples. 

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Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked biospecimens to also 
be used to design and conduct research to gain a further understanding of other diseases and 
to advance science, including development of other medicines for patients.  This component 
of the sampling banking is optional for participants; they may still participate in the study 
even if they do not agree to the additional research on their banked biospecimens.  The 
optional additional research does not require the collection of any further 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
Biomarkers are not evaluated in this study.
8.8.1. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.8.2. Banked Biospecimens for Biomarkers
Serum (Prep B2.5) and plasma (Prep B1.5) samples of approximately 6-mL each will be 
collected according to the SoA and as local regulations and IRB/ECs allow. 
Banked biospecimens may be used for research related to drug response, T2DM, and obesity.  
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
banked samples. 
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked samples to also be 
used to design and conduct research to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.  This component of 
the sampling banking is optional for participants; they may still participate in the study even 
if they do not agree to the additional research on their banked samples.  The optional 
additional research does not require the collection of any further 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. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.

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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 statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
There are no estimands related to the primary objective and endpoint as outlined in Section 3.
A summary of estimands is provided in the table below and described in detail thereafter:
Variable
Estimand
Population
Intercurrent Event
Population-level 
Summary
International 
Council for 
Harmonisation 
(ICH)-E9(R1) 
Strategy(ies)
Fasting 
Plasma 
Glucose 
(continuous 
endpoint)
1A
T2DM on 
background
of metformin
Absence of glycemic 
rescue medication and 
discontinuation of 
study IP
Mean difference 
(PF-06882961 
versus Placebo)
Hypothetical
While on
treatment
1B
Non-diabetic 
with obesity
Discontinuation of 
study IP
Mean difference 
(PF-06882961 
versus Placebo)
Hypothetical
While on 
treatment
HbA1c 
(continuous 
endpoint)
2A
T2DM on 
background
of metformin
Absence of glycemic 
rescue medication and 
discontinuation of 
study IP
Mean difference 
(PF-06882961 
versus Placebo)
Hypothetical
While on 
treatment
2B
Non-diabetic 
with obesity
Discontinuation of 
study IP
Mean difference 
(PF-06882961 
versus Placebo)
Hypothetical
While on 
treatment
Body 
Weight 
(continuous 
endpoint)
3A
T2DM on 
background 
of metformin
Absence of glycemic 
rescue medication and 
discontinuation of 
study IP
Mean difference 
(PF-06882961 
versus Placebo)
Hypothetical
While on 
treatment
3B
Non-diabetic 
with obesity
Discontinuation of 
study IP
Mean difference 
(PF-06882961 
versus Placebo)
Hypothetical
While on 
treatment

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Estimand 1A will be the population average treatment effect on the change from baseline in 
FPG of PF-06882961 compared to placebo in participants with T2DM in the absence of 
glycemic rescue medication while on treatment and stable doses of background metformin.  
This reflects a combination of the ‘Hypothetical’ and ‘While on treatment’ strategies as 
outlined in the ICH-E9 (R1) draft guidance.16
Measurements after initiation of glycemic rescue medication or discontinuation of IP will be 
censored and treated as missing data.  Missing data due to censoring, study withdrawal or 
other reasons (eg, laboratory failure) will have data imputed based on a missing at random 
(MAR) assumption. Participants with inadequate compliance will have their fasting plasma 
glucose values used as-is in the analysis. The population-based treatment effect will be the 
difference in the mean change from baseline in each PF-06882961 arm compared to placebo.  
This estimand will be applied to the changes from baseline in FPG at Weeks 2, 4, 6, 8, 10 
and 12.
Estimand 1B will be the population average treatment effect on the change from baseline in 
FPG of PF-06882961 compared to placebo in non-diabetic participants with obesity, while 
on treatment.  This reflects a combination of the ‘Hypothetical’ and ‘While on treatment’ 
strategies as outlined in the ICH-E9 (R1) draft guidance.16
Measurements after discontinuation of IP will be censored and treated as missing data.  
Missing data due to censoring, study withdrawal or other reasons (eg, laboratory failure) will 
have data imputed based on a missing at random (MAR) assumption. Participants with 
inadequate compliance will have their fasting plasma glucose values used as-is in the 
analysis. The population-based treatment effect will be the difference in the mean change 
from baseline in each PF-06882961 arm compared to placebo.  This estimand will be applied 
to the changes from baseline in FPG at Weeks 2, 4, 6, 8, 10 and 12.
Estimands related to other endpoints:
Estimands 2A and 3A will utilize the same approach as Estimand 1A for the associated
endpoints. Similarly, Estimands 2B and 3B will utilize the same approach as Estimand 1B
for the associated endpoints.
Other exploratory/tertiary analyses may or may not be analyzed using these estimands and 
may be analyzed in a descriptive manner without reference to an estimand. Other 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.

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9.2. Sample Size Determination
A sufficient number of participants will be screened to achieve approximately
140 participants randomly assigned to IP (approximately 120 participants in a PF-06882961 
arm and approximately 20 evaluable participants in the placebo arm). For participants with 
T2DM, approximately 20 participants will be allocated to each of the 5 PF-06882961 arms
and approximately 15 participants will be allocated to the placebo arm.  For non-diabetic 
participants with obesity, approximately 20 participants will be allocated to a PF-06882961
arm (Arm 7) and approximately 5 participants to the placebo arm. Assuming a 25% drop-out 
rate for the entire study population, approximately 140 participants will be randomly 
assigned to IP such that approximately 105 evaluable participants complete the study.
Once approximately 140 participants have been randomized into the study, enrollment will 
be halted and any participants who have signed the ICD and initiated screening procedures at 
this stage may be permitted to continue the study process to completion/withdrawal.
The number of participants was selected empirically to provide a sufficient number of 
participants to assess and characterize the safety and tolerability of various titration schemes 
and target doses of PF-06882961 across the 2 populations.
9.3. Populations for Analysis
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICD.
Randomly assigned to IP
All participants randomly assigned to IP regardless of whether
or not IP was administered.
Evaluable
All participants randomly assigned to IP and who take at least
1 dose of IP. Participants will be analyzed according to the
randomized intervention.
Safety
All participants randomly assigned to IP and who take at least 
1 dose of IP.  Participants will be analyzed according to the
product they actually received.

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Defined Population for 
Analysis
Description
Estimand Set 1A (related 
to estimands 1A, 2A & 
3A)
All evaluable participants with T2DM randomly assigned to IP 
and who take at least 1 dose of IP. For participants who 
discontinue IP and/or receive glycemic rescue medication, all 
subsequent values will be censored.
Estimand Set 1B (related 
to estimands 1B, 2B & 
3B)
All evaluable non-diabetic participants with obesity randomly 
assigned to IP and who take at least 1 dose of IP. For 
participants who discontinue IP, all subsequent values will be 
censored.
PK Concentration Set
All participants randomly assigned to IP 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 database lock and will describe the 
participant populations to be included in 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. Pharmacodynamic Analyses
Endpoint
Statistical Analysis Methods
Secondary: Change 
from baseline in 
fasting plasma 
glucose at Weeks 2, 
4, 6, 8, 10 and 12
A mixed model repeated measures (MMRM) analysis will be fitted 
to the change from baseline in fasting plasma glucose at Weeks 2, 
4, 6, 8, 10 and 12 from the Estimand Set 1A to estimate the 
treatment effect related to the Estimand 1A.
The MMRM will include treatment, time, strata (male versus 
female) 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.
No adjustments will be made for multiplicity.
The above analysis will also be applied separately to the Estimand 
Set 1B to estimate the treatment effect related to the Estimand 1B.

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Secondary: Change 
from baseline in 
HbA1c at Weeks 2, 
4, 6, 8, 10 and 12
Changes from baseline in HbA1c will be analyzed using a similar 
MMRM model to that used for fasting plasma glucose above.  
Baseline HbA1c will be included as a covariate in the model, rather 
than baseline fasting plasma glucose.  No adjustments will be made 
for multiplicity.
This analysis will be applied to the Estimand Set 1A to estimate the 
treatment effect related to Estimand 2A. It will also be applied 
separately to the Estimand Set 1B to estimate the treatment effect 
related to the Estimand 2B.
Secondary: Change 
from baseline in 
body weight at 
Weeks 2, 4, 6, 8, 10 
and 12
Changes from baseline in body weight will be analyzed using a 
similar MMRM model to that used for fasting plasma glucose 
above.  Baseline body weight will be included as a covariate in the 
model, rather than baseline fasting plasma glucose.  No adjustments 
will be made for multiplicity.
This analysis will be applied to the Estimand Set 1A to estimate the 
treatment effect related to Estimand 3A. It will also be applied 
separately to the Estimand Set 1B to estimate the treatment effect 
related to the Estimand 3B.
Tertiary/Exploratory
Will be described in the SAP finalized before database lock.
9.4.2. Safety Analyses
All safety analyses will be performed on the safety population.
All safety analyses will primarily report results by treatment arm, where Arms 6 and 7 will 
be reported as 2 separate groups (T2DM and non-diabetic participants with obesity) and 
Arm 5 will be reported as 2 separate groups (ie, Placebo will be reported separately across 
the 2 populations).  
The safety data will be summarized in accordance with Pfizer Data Standards.  All 
participants who receive IP (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.
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint will be analyzed in accordance with Pfizer Data 
Standards as above.
The primary analyses will be on the incidence and severity of all treatment 
emergent adverse events (TEAE), that will be reported by treatment arm.  
The number of participants and percent will be presented.
Secondary
Secondary safety endpoints will also be analyzed in accordance with Pfizer 
Data Standards as above for the endpoints referenced in Section 3.

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Additional exploratory safety analyses such as time to the first occurrence of AEs of interest 
(eg. diarrhea, nausea and vomiting, analyzed separately) and incidence of AEs of interest 
over time may also be performed (reported by treatment arm) where full details will be 
described in the SAP.
Results may also be reported by pooling the placebo groups or by strata (males vs. female), 
where details will be described in the SAP.
9.4.2.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS complex will be summarized by treatment arm (as defined above in 
Section 9.4.2) and time.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment
Degree of 
Prolongation
Mild (msec)
Moderate (msec)
Severe 
(msec)
Absolute value
>450-480
>480-500
>500
Increase from 
baseline
30-60
>60
9.4.3. Other Analyses 
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
No formal interim analysis will be conducted for this study. However, as this is a 
sponsor-open study, the sponsor may conduct unblinded reviews of the data during the 
course of the study for the purpose of safety assessment, facilitating PK/PD modeling, and/or 
supporting clinical development. If such an unblinded review is deemed necessary, the 
decision for the sponsor to conduct the review will be documented along with details on 
plans to control dissemination.
9.5.1. Data Monitoring Committee 
This study will not use a data monitoring committee (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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, investigator’s brochure (IB), 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 Code of Federal Regulations (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 IP, Pfizer 
should be informed immediately. 

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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative defined as legal guardian will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, 
where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative 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 or his or her legally 
authorized representative 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.

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Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICD.
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each participant the objectives of the exploratory 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 any remaining specimens to be used for exploratory 
research.  Participants who decline to participate in this optional 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 shall 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 natural persons 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.  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 European Clinical Trials 
Database (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 standard operating procedures (SOPs).

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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic 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.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
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 US Basic Results document is 
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 European Medicines Agency (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.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
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.

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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed 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 (SMP).
10.1.8. Study and Site Closure
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.

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The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
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 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 study team on demand (SToD) 
system. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and IP 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 safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory; or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety concerns.

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Table 3.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN 
Creatinine
eGFR
Plasma glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST
ALT
Total bilirubin
GGT
Alkaline phosphatase
Uric acid
Albumin
Total protein
Urinalysis:

pH

Glucose (qual)

Protein (qual)

Blood (qual)

Ketones

Nitrites

Leukocyte 
esterase

Urobilinogen

Urine bilirubin

Microscopya
Urine pregnancy test
HbA1c
Serum pregnancy test 
(-hCG)b
Lipid panel:

Total cholesterol

Direct LDL-C

HDL-C

Triglycerides
TSH
Free T4
Calcitonin
Amylase
Lipase
Serum total bile acids
PT/INR/aPTT
Screening only:
FSHc
Urine drug screening
C-peptide
Additional Tests 
(Needed for Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
For all female participants.
c.
For all female participants to confirm post-menopausal status only.
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin 
time; AST = aspartate aminotransferase; -hCG = beta human chorionic gonadotropin; BUN = blood urea 
nitrogen; CO2 = carbon dioxide; eGFR = estimated glomerular filtration rate; FSH = follicle stimulating 
hormone; GGT = gamma-glutamyl transferase; HbA1c = glycated hemoglobin; HDL-C = high density 
lipoprotein cholesterol; INR = international normalized ratio; LDL-C = low density lipoprotein cholesterol; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; PT = prothrombin time; qual = qualitative; RBC = red blood cell; 
TSH = thyroid stimulating hormone; WBC = white blood cell.

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Investigators must document their review of each laboratory safety report.
Following screening, the sponsor study team and site will be blinded to HbA1c and fasting 
plasma glucose, measured by the central laboratory, unless the fasting plasma glucose meets 
the criteria for hypo-or hyper-glycemia as listed in Section 8.2.4.2 and Section 8.2.4.3.

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

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

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

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study during pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the IP under 
study during pregnancy 
or breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and exposure during 
pregnancy [EDP] 
supplemental form for 
EDP)  
Note: Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.

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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities.  An AE that is assessed 
as severe should not be confused with an SAE.  Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 

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information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the IP caused the event, then the 
event will be handled as “related to IP” for reporting purposes, as defined by the 
sponsor.  In addition, if the investigator determines that an SAE is associated with 
study procedures, the investigator must record this causal relationship in the source 
documents and CRF, and report such an assessment in the dedicated section of the 
CT SAE Report Form and in accordance with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 

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

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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below,
during the intervention period and for at least 28 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any study 
intervention(s).
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 (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

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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 age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females 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
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
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.

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Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

oral;

intravaginal;

transdermal;

injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

oral;

injectable.
8. 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.
Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the IP; or the female 
becomes or is found to be pregnant after discontinuing and/or being exposed to the 
IP;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
IP prior to or around the time of conception and/or is exposed during his partner’s 
pregnancy.

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If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the IP, 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.  In addition, the investigator must submit information regarding 
environmental exposure to a Pfizer product in a pregnant woman (eg, a participant reports 
that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) to 
Pfizer Safety using the EDP supplemental form.  This must be done irrespective of whether 
an AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
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).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes 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 IP. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.

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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.

Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome 
(as appropriate).

The samples may be analyzed as part of a multi study assessment of genetic factors 
involved in the response to PF-06882961 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 the clinical study report (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 specified genetic analysis (see Section 8.6.1 and Section 8.8.2) will 
be stored indefinitely or other 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 drug-induced 
liver injury (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 aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (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, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (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 (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 sample for acetaminophen 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 liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.

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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (AEs)

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate:
ie, rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ duration.

Frequent premature ventricular contractions/complexes (PVCs), triplets, or short 
intervals (<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (SAEs)

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free patients with atrial fibrillation and bradycardia with 
1 or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40 bpm < x bpm <100 bpm), and 

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

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10.8. Appendix 8: Prohibited Prior/Concomitant Medications
The following medications are prohibited until the first follow-up visit (ie, Visit 10, 
Week 13-14), unless stated otherwise.  If a participant receives a prohibited medication, the 
investigator should contact the Sponsor Clinician or Sponsor Medical Monitor to determine if 
the participant may remain in the study.  
Drug Classes and/or Drugs 
Timeframe of Restriction 
Prior to Screening Visit
Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone.
90 days
Subcutaneously administered agents for glycemic control (eg, insulin, 
exenatide, liraglutide, dulaglutide, semaglutide, pramlintide).  Note: Short-term 
(ie, ≤7 days) of insulin administration is permitted if participant is hospitalized.
90 days
Pharmacological agents with approved indication for weight loss such as 
liraglutide, orlistat and sibutramine.
90 days
Oral anti-diabetic medications, including:
Sulfonylureas such as acetohexamide, chlorpropamide, tolazamide, 
tolbutamine, glimepiride, glipizide, glyburide. Note: These may be used as 
glycemic rescue medications (See Section 6.5.3).
Meglitinide analogues such as repaglinide, nateglinide.
Dipeptidyl peptidase 4 inhibitors (DPP 4i) such as sitagliptin, saxagliptin, 
linagliptin, vildagliptin.
glucosidase inhibitors such as acarbose, miglitol.
Sodium glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin, 
empagliflozin, dapagliflozin, ertugliflozin.  Note: These may be used as 
glycemic rescue medications (See Section 6.5.3).
Anti-hyperglycemic medications, including bromocriptine and colesevelam.
60 days
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
Immunosuppressants such as cyclosporine and tacrolimus.
60 days
Appetite or weight modifying medications, including nonprescription or 
herbals and medical grade marijuana.
60 days
Anti-psychotic medications such as olanzapine, risperidone.
60 days
Coumarin type anticoagulants or other anticoagulants (eg, dabigatran).
60 days
Anticonvulsants if prescribed for seizure disorder.
60 days

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Drug Classes and/or Drugs 
Timeframe of Restriction 
Prior to Screening Visit
Antiarrhythmic medications whose primary mechanism of action is sodium or 
potassium channel blockade (eg, procainamide, phenytoin, quinidine, 
proprafenone; as well as amiodarone, dofetilide, sotalol).
Note: -adrenergic receptor blocking agents (eg, atenolol, metoprolol) and 
calcium channel blockers (eg, diltiazem, amlodipine, nifedipine) are permitted.
60 days
Sympathomimetic agents.
Note: Inhaled -adrenergic receptor agonists (eg, albuterol) are permitted.
60 days
BCRP Substrates
Rosuvastatin.  Note: Other statins are permitted.
Sulfasalazine
Prohibited post 
randomization
Use of CYP3A4/5 substrates with narrow therapeutic index – eg, alfentanil, 
astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, and terfenadine.
Prohibited post 
randomization 
Use of chronic agents which are potent inducers of CYP3A (eg, rifampin, 
gemfibrozil, torsemide, amodiaquine).
Prohibited post 
randomization 
Use of chronic agents which are clinically significant OATP inhibitors 
(eg, cyclosporine, gemfibrozil, rifampin).
Prohibited post 
randomization 
Use of potent 3A4 inhibitors.
Prohibited post 
randomization 
Paclitaxel.
Prohibited post 
randomization 

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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:

12-lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing (except for post-dose collection) (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 (except for post-dose collection) (see
Section 8.2.2);

Fasting blood samples [for safety (see Section 8.2.5, PK (see Section 8.5),
exploratory biomarkers (see Section 8.8) and banked biospecimens (see
Section 8.8.2)]: after assessment of 12-lead ECG and vital signs but prior to dosing; 

Body weight: obtain prior to dosing and food consumption (see Section 8.6.1);

For the random, post dose PK blood collection to occur approximately 2 to 6 hours 
post dose (see Section 8.5): if collection time coincides with time of a meal/snack, 
these blood samples should be collected just prior to the meal/snack;

Other pre-dose procedures: obtain sample/perform procedure as close as possible to 
the scheduled time, but may be obtained before or after blood sample collection(s); 

Dosing: must occur with food; and where applicable, after any pre-dose blood sample 
collection(s).

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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
Absolute
AE
adverse event
ALT
alanine aminotransferase
AM
morning
aPTT
Activated partial thromboplastin time
AST
aspartate aminotransferase
AUC24
area under the curve over 24 hours
AUCinf
area under the plasma concentration-time profile from time zero
extrapolated to infinite time
AV
Atrioventricular
BBS
Biospecimen Banking System
BCRP
Breast cancer resistance protein
-hCG
beta-human chorionic gonadotropin
BID
Twice daily
BMI
Body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
C-SSRS
Columbia-Suicide Severity Rating Scale
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EC
Chronic Kidney Disease Epidemiology Collaboration
cm
Centimeter
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
CR
Controlled release
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
Ctrough
trough concentration
CV
Co-efficient of variance
%CV
percent Co-efficient of variance
CYP 
Cytochrome P450
DDI
drug-drug interaction(s)
DILI
drug-induced liver injury
DMC
data monitoring committee

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Abbreviation
Term
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl peptidase 4
DU
dispensable unit
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EFD
Embryo fetal development
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FPG
Fasting plasma glucose
FSH
follicle-stimulating hormone
FT4
free thyroxine  
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP-1
Glucagon-like peptide-1 
GLP-1R
Glucagon-like peptide-1 receptor
HAE
Hypoglycemic AE
HbA1c
Glycolated hemoglobin A1c
HDL-C
High density lipoprotein cholesterol
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
Identification
IMP
investigational medicinal product
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IP manual
investigational product manual
IR
immediate release
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IWR
interactive Web-based response
kg
kilogram

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Abbreviation
Term
K2 EDTA
ethylenediaminetetraacetic acid
lb
pound
LBBB
left bundle branch block
LDL-C
Low density lipoprotein cholesterol
LFT
liver function test
m2
Meters squared
MAR
missing at random
MATE
multidrug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
msec
Millisecond
PM MDR1
multidrug resistance mutation
MEN2
multiple endocrine neoplasia syndrome type 2
MHP
mental health professional
mL
milliliter
MMRM
mixed model repeated measures
msec
millisecond
MTC
Medullary thyroid carcinoma
N/A
not applicable
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
OATP
Organic anion transporting polypeptide
OCT
Organic cation transporter
PACL
Protocol Administrative Letter
PCD
primary completion date
PD
pharmacodynamic(s)
PHQ-9
Patient Health Questionnaire-9
PI
principal investigator
PK
pharmacokinetic(s)
PM
afternoon
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
daily
QTc
corrected QT
QTcF
Baseline corrected QT interval (Fridericia method)
qual
Qualitative
Rac
accumulation ratio
RBC
red blood cell
SAE
serious adverse event
SGLT2
sodium glucose co-transporter 2
SoA
schedule of activities

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Abbreviation
Term
SOP
standard operating procedure
SRSD
single reference safety document
SSID
Study specific identification
ST
slow titration
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
TBA
total bile acids
TBili
total bilirubin
TEAE
Treatment emergent adverse event
TI
therapeutic index
Tmax
Time to maximum concentration
TSH
Thyroid stimulating hormone
TZDs
thiazolediediones 
T1/2
Half-life
T2DM
type 2 diabetes mellitus
UGT
uridine 5'-diphospho-glucuronosyltransferase 
glucuronosyltransferase
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman of childbearing potential

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11. REFERENCES
1.
Ørskov C, Holst JJ, Knuhtsen S,et al. Glucagon-like peptides GLP-1 and GLP-2, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology 1986;119(4):1467-75.
2.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet 1987;2(8571):1300-4.
3.
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 
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