Clinical trial NCT03985293
Conditions: Diabetes Mellitus, Type 2
Sponsor: Pfizer
Start date: 2019-10-15; Completion date: 2021-07-07
Enrollment: 412 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, randomized, double-blind, placebo controlled, parallel group study is being conducted to provide data on efficacy, safety, tolerability and pharmacokinetics (PK) of multiple dose levels of PF-06882961 in adults with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and/or diet and exercise. In addition, the study is intended to enable selection of efficacious doses for future clinical development of PF-06882961.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: Participants will be titrated up to 2 weeks to reach desired dose level arm 5: Participants will be titrated up to 4 weeks to reach desired dose level arm 6: Participants will be titrated up to 6 weeks to reach desired dose level
Interventions: intervention 1: Placebo intervention 2: PF-06882961
Intervention descriptions: intervention 1: 4 matching placebo tablets taken twice a day (BID) intervention 2: Participants will be randomized to one of 5 active doses (2.5, 10, 40, 80, or 120 mg), taking 4 tablets twice daily for 16 weeks.

Protocol documents:
Prot_000.pdf: 






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Section 4.2, Scientific Rationale for Study 
Design has been revised to include updates to 
the description of titration schemes and the 
rationale for contraception requirements for 
female participants.
Rationale: Titration scheme description 
aligns with updates to Section 6 and the
rationale for contraception requirements 
for female participants has been included 
for completeness.
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 protocol finalization.
Section 4.4, Assessment of Safety and 
Tolerability While Study is Ongoing has 
been updated to indicate that an interim 
analysis will occur at least once during study 
conduct and to also include the minimum 
timeframe between blinded safety reviews.  
The triggers for pausing or stopping active 
dose(s) were moved to Section 6.6.1, 
Considerations for Pausing or Stopping 
Active Dose(s) Based on Observed Safety.
Rationale: The minimum time frame of 
monthly between safety reviews has been 
added to ensure that there is ample time to 
prepare all data reports and ensure a 
timely review of safety data.  The interim 
analysis of unblinded safety data permits 
possible updates to study conduct if 
needed.
Section 5.2, Exclusion Criteria, criterion #15 
has been revised to lower the systolic and 
diastolic blood  pressure eligibility criteria.  
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hypo-or hyper-glycemia.
Rationale: This revision is made to clarify 
that the blinding of these specific analytes 
does not occur until after the screening 
period so that eligibility can be confirmed.
Protocol Appendix 3, Sections 10.3.2, 
Definition of SAE and 10.3.3, 
Recording/Reporting and Follow-up of AEs 
and/or SAEs has been revised to align with 
Pfizer requirements.
Protocol Appendix 4, Section 10.4.2, Female 
Participant Reproductive Inclusion Criteria
and Section 10.4.4, Contraception Methods 
have been revised to clarify permitted female 
participant inclusion criteria and 
contraception requirements in cases where 
contraception is highly user dependent.  
Additionally, the requirement of females to 
not donate eggs has been removed.
Rationale: This revision is made to align 
with requirements when using 
contraception that is highly user 
dependent. PF-06882961 does not have 
risk of genotoxicity; as such the 
requirement of females to not donate eggs 
has been removed.
Protocol Appendix 9, Proposed Chronology 
of Procedures has been revised to clarify that 
body weight should be obtained prior to 
dosing and food consumption.
Rationale: Body weight is a secondary 
endpoint and must be obtained under 
standardized conditions.
Original protocol
03 April 2019
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................14
1. PROTOCOL SUMMARY...................................................................................................15
1.1. Synopsis ..................................................................................................................15
1.2. Schema ....................................................................................................................20
1.3. Schedule of Activities (SoA)...................................................................................21
2. INTRODUCTION ...............................................................................................................23
2.1. Study Rationale .......................................................................................................23
2.2. Background .............................................................................................................23
2.2.1. Nonclinical Overview.................................................................................24
2.2.1.1. Nonclinical Pharmacology........................................................24
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism........................24
2.2.1.3. Nonclinical Safety.....................................................................25
2.2.2. Clinical Overview.......................................................................................26
2.2.2.1. Clinical Safety...........................................................................26
2.2.2.2. Clinical Pharmacokinetics.........................................................27
2.3. Benefit/Risk Assessment.........................................................................................27
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................28
4. STUDY DESIGN.................................................................................................................30
4.1. Overall Design.........................................................................................................30
4.2. Scientific Rationale for Study Design.....................................................................31
4.3. Justification for Dose ..............................................................................................32
4.4. Assessment of Safety and Tolerability While Study is Ongoing............................33
4.5. End of Study Definition ..........................................................................................33
5. STUDY POPULATION......................................................................................................33
5.1. Inclusion Criteria.....................................................................................................33
5.2. Exclusion Criteria....................................................................................................34
5.3. Lifestyle Considerations..........................................................................................37
5.3.1. Dietary Restrictions ....................................................................................37
5.3.2. Alcohol, Caffeine and Tobacco ..................................................................38


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5.3.3. Physical Activity.........................................................................................38
5.3.4. Contraception..............................................................................................38
5.4. Screen Failures ........................................................................................................38
6. STUDY INTERVENTION..................................................................................................39
6.1. Study Intervention(s) Administered........................................................................39
6.2. Preparation/Handling/Storage/Accountability ........................................................40
6.2.1. Preparation and Dispensing........................................................................42
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................42
6.3.1. Allocation to Investigational Product .........................................................42
6.3.2. Breaking the Blind......................................................................................43
6.4. Study Intervention Compliance...............................................................................43
6.5. Concomitant Therapy..............................................................................................43
6.5.1. Metformin...................................................................................................44
6.5.2. Medications for Glycemic Control.............................................................44
6.5.3. Antihypertensive Medications....................................................................44
6.5.4. Lipid Modifying Medications.....................................................................44
6.5.5. Glycemic Rescue Medicine........................................................................45
6.6. Dose Modification...................................................................................................45
6.6.1. Considerations for Pausing or Stopping Active Dose(s) Based on 
Observed Safety...............................................................................................45
6.7. Intervention After the End of the Study..................................................................45
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................46
7.1. Discontinuation of Study Intervention ....................................................................46
7.1.1. Criteria for Discontinuation........................................................................46
7.2. Participant Discontinuation/Withdrawal From the Study.......................................46
7.3. Lost to Follow-up....................................................................................................47
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................48
8.1. Efficacy Assessments..............................................................................................49
8.1.1. Primary Efficacy Parameter: HbA1c..........................................................49
8.1.2. Secondary 
 Efficacy Parameters .............................................49
8.2. Safety Assessments .................................................................................................49
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8.2.1. Physical Examinations................................................................................49
8.2.2. Body Weight...............................................................................................50
8.2.3. Vital Signs ..................................................................................................50
8.2.3.1. Blood Pressure and Pulse Rate..................................................50
8.2.4. Electrocardiograms.....................................................................................51
8.2.5. Management of Glycemic Control .............................................................51
8.2.5.1. Home Glucose Monitoring........................................................52
8.2.5.2. Management of Hypoglycemia .................................................52
8.2.5.3. Management of Hyperglycemia................................................54
8.2.6. Clinical Laboratory Assessments ...............................................................54
8.2.7. Pregnancy Testing ......................................................................................55
8.3. Adverse Events and Serious Adverse Events..........................................................55
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......56
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................56
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................56
8.3.2. Method of Detecting AEs and SAEs ..........................................................56
8.3.3. Follow-up of AEs and SAEs.......................................................................57
8.3.4. Regulatory Reporting Requirements for SAEs...........................................57
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................57
8.3.5.1. Exposure During Pregnancy......................................................57
8.3.5.2. Exposure During Breastfeeding ................................................58
8.3.5.3. Occupational Exposure .............................................................58
8.3.6. Medication Errors .......................................................................................58
8.4. Treatment of Overdose............................................................................................59
8.6. Pharmacodynamics..................................................................................................60
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8.9. Health Economics ...................................................................................................62
9. STATISTICAL CONSIDERATIONS ................................................................................62
9.1. Estimands and Statistical Hypotheses.....................................................................62
9.1.1. Estimands....................................................................................................62
9.2. Sample Size Determination.....................................................................................64
9.3. Populations for Analysis .........................................................................................65
9.4. Statistical Analyses .................................................................................................65
9.4.1. Efficacy Analyses .......................................................................................66
9.4.2. Safety Analyses ..........................................................................................67
9.4.2.1. Electrocardiogram Analyses......................................................67
9.5. Interim Analyses .....................................................................................................68
9.5.1. Data Monitoring Committee.......................................................................68
9.6. 
/PD Unblinding Plan ..........................................................................................68
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................69
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............69
10.1.1. Regulatory and Ethical Considerations ....................................................69
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................69
10.1.2. Financial Disclosure .................................................................................70
10.1.3. Informed Consent Process ........................................................................70
10.1.4. Data Protection .........................................................................................71
10.1.5. Dissemination of Clinical Study Data ......................................................71
10.1.6. Data Quality Assurance ............................................................................73
10.1.7. Source Documents....................................................................................74
10.1.8. Study and Site Closure..............................................................................74
10.1.9. Publication Policy.....................................................................................75
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10.1.10. Sponsor’s Qualified Medical Personnel .................................................76
10.2. Appendix 2: Clinical Laboratory Tests .................................................................77
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................80
10.3.1. Definition of AE .......................................................................................80
10.3.2. Definition of SAE.....................................................................................81
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................82
10.3.4. Reporting of SAEs....................................................................................85
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................87
10.4.1. Male Participant Reproductive Inclusion Criteria....................................87
10.4.2. Female Participant Reproductive Inclusion Criteria.................................87
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................87
10.4.4. Contraception Methods.............................................................................88
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........93
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................95
10.8. Appendix 8: Prohibited Prior/Concomitant Medications......................................97
10.9. Appendix 9: Proposed Chronology of Procedures................................................99
10.10. Appendix 10: Abbreviations .............................................................................100
11. REFERENCES ................................................................................................................104
LIST OF TABLES
Table 1.
Randomized Regimens in Study C3421005.............................................19
Table 2.
Titration and Dosing Scheme ...................................................................40
Table 3.
Randomized Regimens in Study C3421005.............................................42
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1. PROTOCOL SUMMARY 
1.1. Synopsis
Short Title: A 16-Week Study to Evaluate the Efficacy and Safety of PF-06882961 in 
Adults with Type 2 Diabetes Mellitus 
Rationale
This multicenter, randomized, double-blind, placebo controlled, parallel group study is being 
conducted to provide data on efficacy, safety, tolerability 
 of 
multiple dose levels of PF-06882961 in adults with type 2 diabetes mellitus (T2DM)
inadequately controlled on metformin and/or diet and exercise.  In addition, the study is 
intended to enable selection of efficacious doses for future clinical development of 
PF-06882961.
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Objectives, Estimands, and Endpoints
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary:
To compare the effect of multiple dose 
levels of PF-06882961 versus placebo on
glycated hemoglobin (HbA1c) in 
participants with T2DM on stable doses
of metformin and/or diet and exercise.
Change from baseline in HbA1c
at Week 16.
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 on stable doses of 
metformin and/or diet and exercise 
without the benefit of glycemic rescue 
medication while on treatment.
Secondary: 
Secondary:
Secondary: 
To compare the effect of multiple dose 
levels of PF-06882961 versus placebo on 
glycemic control in participants with 
T2DM on stable doses of metformin 
and/or diet and exercise.
Response as defined by an
HbA1c <7% at Week 16.
Estimand 2: This estimand is intended to 
provide a population level estimate of the 
odds ratio treatment effect (PF-06882961
versus placebo) on a binary responder 
endpoint in participants on stable doses of
metformin and/or diet and exercise 
without the benefit of glycemic rescue 
medication.
Change from baseline in HbA1c 
at Weeks 2, 4, 6, 8 and 12.
Estimand 1A as above.
Change from baseline in fasting 
plasma glucose at Weeks, 2, 4, 
6, 8, 12 and 16.
Estimand 3: This estimand will be the 
same as 1A.
To compare the effect of multiple dose 
levels of PF-06882961 versus placebo on
body weight in participants with T2DM 
on stable doses of metformin and/or diet 
and exercise.
Change from baseline in body 
weight at Weeks 2, 4, 6, 8, 12 
and 16.
Estimand 4: This estimand will be the 
same as 1A.
To characterize the safety and 
tolerability of multiple dose levels of 
PF-06882961 administered to 
participants with T2DM on stable doses 
of metformin and/or diet and exercise.
Incidence of treatment 
emergent adverse events 
[adverse events (AEs) and
serious adverse events (SAEs)], 
clinical laboratory 
abnormalities, vital signs 
(blood pressure and pulse rate)
and electrocardiogram (ECG)
parameters (heart rate, QT, 
QTcF, PR and QRS intervals).
There are no defined estimands for these 
endpoints and they will be analyzed using 
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Overall Design
This Phase 2b, multi-center, randomized, double-blind, placebo-controlled, 6 - arm, parallel 
group, study will assess efficacy and safety of twice daily administration of PF-06882961 in 
adult participants with T2DM inadequately controlled on metformin monotherapy or diet and 
exercise alone.  At least 80% of the enrolled participants are required to be on metformin 
prior to screening.  While a smaller proportion of participants managing their T2DM with
diet and exercise only is permitted, this proportion should be no more than approximately 
20% of the enrolled participants.
Following the screening period to confirm eligibility (up to 4-weeks), the study will consist 
of a 2-week placebo run-in period, prior to randomization on Day 1.  The treatment period 
will be 16 weeks, followed by an approximate 4-week follow-up.  The total duration of 
participation in the study is approximately 22 weeks, not including the screening period.  
Dosing will occur with food twice daily (BID), and up to 6 weeks of the 16-week dosing 
duration will be used for dose titration to maximize tolerability of PF-06882961. 
Number of Participants
Approximately 400 participants (approximately 67 participants per treatment arm) will be
randomized to ensure completion of approximately 300 participants (approximately 
50 participants per treatment arm).  Randomization will be stratified according to background 
diabetes treatment (presence or absence of metformin therapy).
Intervention Groups and Duration
Following the screening period, the study will consist of a 2-week placebo run-in period, 
prior to randomization on Day 1.  The treatment period will be 16 weeks.
Participants will take 4 tablets of investigational product (IP) (PF-06882961 or matching 
placebo) in the morning with food and in the evening with food, for a total of 8 tablets of IP 
daily.  The same dosing paradigm will be used during the placebo run-in period.  Morning 
dosing will occur with food at the site at Visits 2 through 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 on scheduled visit days until they arrive for their clinic visit.


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Table 1.
Randomized Regimens in Study C3421005
Regimen
Regimen Description 
(dosed twice-daily)
Number of PF-06882961 tablets
Number of 
PF-06882961-matching 
placebo tablets
2.5 mg
10 mg
40 mg
100 mg
2.5 mg
10/40/100 mg
A
Placebo
-
-
-
-
1
3
B
PF-06882961 – 2.5 mg
1
-
-
-
-
3
C
PF-06882961 – 10 mg
-
1
-
-
1
2
D
PF-06882961 – 40 mg
-
-
1
-
1
2
E
PF-06882961 – 80 mg
-
-
2
-
1
1
F
PF-06882961 – 120 mg
-
2
-
1
1
-
Per the study estimands, if IP is permanently discontinued, the participant will remain in the 
study and continue to follow all protocol specified visits and procedures according to the 
SoA with the exception of dosing activities 
Data Monitoring Committee
This study will use an internal review committee (IRC); an external data monitoring 
committee will not be utilized. An IRC charter will be developed to govern the details of any 
interim analysis and IRC operations.  
Statistical Methods
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined in Section 9 and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.
The primary estimand will be the population average treatment effect on the change from 
baseline in HbA1c at Week 16 of PF-06882961 compared to placebo in the absence of 
glycemic rescue medication while on treatment and stable doses of background metformin 
and/or diet and exercise. 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. The population-based treatment effect 
will be the difference in the mean change from baseline in each PF-06882961 arm compared 
to placebo.  
A secondary estimand will be the population odds ratio of the treatment effect of achieving 
HbA1c <7% at Week 16 of PF-06882961 compared to placebo in the absence of glycemic 
rescue medication in participants while on treatment and on stable doses of background 
metformin and/or diet and exercise.  All other key secondary continuous clinical endpoints 
will be analyzed using the primary estimand described above.
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The primary analysis of the primary endpoint will be conducted using a mixed model 
repeated measures (MMRM) analysis of the change from baseline in HbA1c through 
Week 16. The primary analysis will include all participants randomly assigned to IP and 
who take at least 1 dose of IP. The MMRM will include treatment, time, strata (metformin 
vs. diet and exercise alone) 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 and 
no adjustments will be made for multiplicity.
1.2. Schema






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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 T2DM.
PF-06882961 is an oral GLP-1R agonist that is currently being investigated as an adjunct to 
diet and exercise to improve glycemic control in adult participants with T2DM.
2.1. Study Rationale 
This multicenter, Phase 2b, randomized, double-blind, placebo controlled, parallel group 
study is being conducted to provide data on efficacy, safety, tolerability 
 of multiple 
dose levels of PF-06882961 in adults with T2DM inadequately controlled on metformin
and/or diet and exercise. In addition, the study is intended to enable selection of efficacious
doses for future clinical development of PF-06882961.
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 β-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.
Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and cardiovascular safety, with at least one marketed agent 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.
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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To compare the effect of multiple 
dose levels of PF-06882961 versus
placebo on HbA1c in participants 
with T2DM on stable doses of 
metformin and/or diet and exercise.
Change from baseline in 
HbA1c at Week 16.
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 on 
stable doses of metformin and/or diet 
and exercise without the benefit of 
glycemic rescue medication while on 
treatment.
Secondary: 
Secondary:
Secondary: 
To compare the effect of multiple
dose levels of PF-06882961 versus 
placebo on glycemic control in 
participants with T2DM on stable 
doses of metformin and/or diet and 
exercise.
Response as defined by an
HbA1c <7% at Week 16.
Estimand 2: This estimand is intended 
to provide a population level estimate 
of the odds ratio treatment effect 
(PF-06882961 versus placebo) on a 
binary responder endpoint in 
participants on stable doses of 
metformin and/or diet and exercise 
without the benefit of glycemic rescue 
medication.
Change from baseline in
HbA1c at Weeks 2, 4, 6, 8 
and 12.
Estimand 1A as above.
Change from baseline in 
fasting plasma glucose at 
Weeks 2, 4, 6, 8, 12 and 16.
Estimand 3: This estimand will be the 
same as 1A.
To compare the effect of multiple 
dose levels of PF-06882961 versus
placebo on body weight in 
participants with T2DM on stable 
doses of metformin and/or diet and 
exercise.
Change from baseline in
body weight at Weeks 2, 4, 
6, 8, 12 and 16.
Estimand 4: This estimand will be the 
same as 1A.
To characterize the safety and 
tolerability of multiple dose levels of 
PF-06882961 administered to 
participants with T2DM on stable 
doses of metformin and/or diet and 
exercise.
Incidence of treatment 
emergent adverse events 
(AEs and SAEs), clinical 
laboratory abnormalities, 
vital signs (blood pressure 
and pulse rate) and ECG 
parameters (heart rate, QT, 
QTcF, PR and QRS 
intervals).
There are no defined estimands for 
these endpoints and they will be 
analyzed using Pfizer data standards 
as applicable.










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4.4. Assessment of Safety and Tolerability While Study is Ongoing
During study conduct, after approximately every 25% of the total planned randomizations
[for example: 100 subjects (25%), 200 subjects (50%), and 300 subjects (75%), of planned 
approximately 400 subjects], blinded safety review will be conducted by selected members 
of the Sponsor’s study team. Blinded safety reviews will be separated by at least one month 
from the previous review. An Interim Analysis (IA) of the unblinded safety data by the IRC 
will occur at least once while the study is ongoing, as described in Section 9.5.
4.5. 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 IP.
The end of the study is defined as the date of the last visit (Visit 11), by the last participant 
across all sites globally.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 (or the minimum country-specific 
age of consent if >18) and 75 years, inclusive, at Visit 1.

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. Patients with T2DM who are treated with metformin and/or diet and exercise. 

For participants taking metformin, the metformin dose must have been stable for 
at least 60 days prior to the screening visit (Visit 1).


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
Enrollment of participants on diet and exercise only (ie, no anti-diabetic 
medications) will be limited to ≤20% of total participant population.
3. HbA1c ≥7% and ≤10.5% at screening (Visit 1) as assessed by the study specific
laboratory and confirmed by a single repeat test, if deemed necessary.  
4. 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-tests of blood sugar regularly (see Section 8.2.5.1) for the
duration of the study and maintenance of study specific glucose logs for the duration 
of participation in the study.
Body Mass Index (BMI) and Weight:
5. Total body weight >50 kg (110 lb) with BMI of 24.5 to 45.4 kg/m2 (for sites in North 
America and Europe) or BMI 22.5 to 45.4 kg/m2 (for sites in Asia).  Body weight 
must have been stable (<5% change) for 90 days prior to screening (Visit 1) as per 
participant report.
Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Any 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.
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).


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5. Any malignancy not considered cured (except basal cell carcinoma and squamous cell 
carcinoma of the skin); a subject 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 subjects with suspected MTC per 
the investigator’s judgment.
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).
Prior/Concomitant Therapy:
12. See Appendix 8 for details regarding prohibited prior/concomitant medications.
Prior/Concurrent Clinical Study Experience:
13. 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). 
14. Known prior participation in a trial involving PF-06882961 or known intolerance to a 
GLP-1R agonist.
Diagnostic Assessments:
15. Screening supine blood pressure (BP) ≥160 mmHg (systolic) or ≥100 mmHg 
(diastolic), following at least 5 minutes of supine rest.  BP should be measured in 
triplicate and the average of the 3 BP values should be used to determine the 
participant’s eligibility. Note: Participants with an arm circumference greater than 
the largest cuff size or those with a mid-arm circumference >52 cm are not eligible.


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16. Screening 12-lead electrocardiogram (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.  
17. A positive urine drug test. Note: Participants who have been medically prescribed 
opiates/opioids or benzodiazepines and report the use of these drugs to the 
investigator at screening (Visit 1) may be allowed to participate with notification to 
the sponsor.  
18. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study specific laboratory and confirmed by a single 
repeat test, if deemed necessary:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
≥2 times the upper limit of normal (ULN).

Total bilirubin level ≥1.5 times the ULN.

Fasting C peptide <0.8 ng/mL.

TSH >1.5 times the ULN.

Serum calcitonin > the ULN.

Amylase or lipase > the ULN.

Fasting plasma blood glucose >270 mg/dL (15 mmol/L) at screening (Visit 1) or 
placebo run-in (Visit 2).

Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 as calculated by 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.14
Other Exclusions:
19. Compliance of <89% based on pill count (See Section 6.4) during the 2-week placebo 
run-in period, as assessed prior to randomization on Day 1.


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20. History of regular alcohol consumption exceeding 7 drinks/week for female subjects 
or 14 drinks/week for male subjects (1 drink = 5 ounces [150 mL] of wine or 
12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months 
prior to screening (Visit 1).
21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to randomization (Day 1).
22. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
23. 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
•
Participants must abstain from all food and drink (except water) for at least 
8 (preferably 10) hours prior to any body weight measurements and blood sample 
collections
•
Water may be consumed as desired (ad libitum).
•
IP must be administered BID in the morning and evening with food, approximately 
10-12 hours apart.
•
On scheduled visits to the site, in the morning, from Visit 2 through Visit 9, 
participants should be instructed to arrive without having food/breakfast, 
self-administration of IP, and morning dose of concomitant medication for the control 
of glycemia, if applicable, for the given day. Note: Participants may take their 
morning dose of antihypertensive and/or lipid modifying medication per their usual 
routine, if applicable.
•
At Visit 2 through Visit 9, inclusive, the above-mentioned medications will be 
administered at the site with food.  
•
Participants will be counseled on appropriate dietary and lifestyle guidelines for 
T2DM at Visit 2 and asked to maintain these guidelines throughout participation in 
the study.  Counseling on dietary guidelines should be in accordance with local 
medical standards of care for patients with T2DM. Note; Participation in formal 
weight loss programs should be avoided during participation in this study.
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5.3.2. Alcohol, Caffeine and Tobacco

Intake of alcohol is permitted in moderation (refer to exclusion criterion 20 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 a normal pace is permitted.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
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 
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. 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. 


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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 the placebo run-in, 
placebo tablets will be packaged in blister cards according to local regulatory requirements.  
For participants taking metformin, they 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.
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 Strengths
2.5 mg, 10 mg, 40 mg and 100 mg
Not applicable
Target Dosage Levels
(achieved upon titration)
2.5, 10, 40, 80, 120 mg BID
0 mg BID
Route of Administration
Oral
Oral
Sourcing
Provided centrally by the sponsor.  
Refer to the Investigational Product 
Manual.
Provided centrally by the sponsor.  
Refer to the Investigational Product
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 
placebo run-in, titration and stable 
dosing 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 
placebo run-in, titration and stable 
dosing blister packs.
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, for a total of 8 tablets of IP daily.  
Participants will swallow the IP whole, and will not crush, chew, break, or dissolve the IP 
prior to swallowing.  The same dosing paradigm will be used during the placebo run-in 
period.  




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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 is 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 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 
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 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.


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6.2.1. Preparation and Dispensing
The IP will be dispensed using an Interactive Response Technology (IRT) drug management 
system at each visit according to the SoA.  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
Allocation to treatment will occur via an IRT system.  A randomization code using the 
method of random permuted blocks will be utilized to randomize eligible participants in 
1:1:1:1:1:1 ratio (1 to 5 of active dosing regimens of PF-06882961 or placebo) prior to the 
first dose of IP.
Participants will be stratified at randomization (Day 1) by the presence or absence of 
metformin as background medication.
The system will be programmed with blind-breaking instructions.  Refer to Section 6.3.2 for
further details.
6.3.1. Allocation to Investigational Product
Participants will be randomized to receive one of the IP regimens described in Table 3.
Table 3.
Randomized Regimens in Study C3421005
Regimen
Regimen Description 
(dosed twice-daily)
Number of PF-06882961 tablets
Number of 
PF-06882961-matching 
placebo tablets
2.5 mg
10 mg
40 mg
100 mg
2.5 mg
10/40/100 mg
A
Placebo
-
-
-
-
1
3
B
PF-06882961 – 2.5 mg
1
-
-
-
-
3
C
PF-06882961 – 10 mg
-
1
-
-
1
2
D
PF-06882961 – 40 mg
-
-
1
-
1
2
E
PF-06882961 – 80 mg
-
-
2
-
1
1
F
PF-06882961 – 120 mg
-
2
-
1
1
-
Allocation of participants to treatment groups will proceed through the use of an IRT system 
(interactive Web-based response [IWR]). The IRT system will provide a confirmation report 
containing the participant number, randomization number, and dispensable unit (DU) or 
container number assigned.  The confirmation report must be stored in the site’s files. 
IP will be dispensed at the study visits summarized in the SoA. 
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.


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In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded
IP records at the site(s) to verify that randomization/dispensing has been done accurately.
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. Compliance will be assessed by 
counting returned tablets. At V4, which occurs during the first 4 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 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 through Week 16, inclusive.  Investigators 
must closely follow non-compliant, randomized, participants in order to enhance their 
adherence to treatment. Any participant who fails to meet the criterion of 
≥80% compliance will be re-educated by the site staff on the importance of 
compliance with IP.
6.5. Concomitant Therapy
Participants in this study will be allowed to be on certain concomitant medications that have 
been prescribed. Attempts should be made not to alter the doses and regimens of the 
background medications after randomization and for the duration of participation in this 
study, except in circumstances where a change in dose is deemed medically necessary.  Any 
changes must be captured in the CRF. Additionally, many over-the-counter medications are 
also permitted during this study.  


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Treatments taken within 28 days before the first dose of IP will be documented as prior 
treatment.  Treatments taken after the first dose of 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.
6.5.1. Metformin
At least 80% of all participants are required to be taking metformin monotherapy prior to
inclusion in this study as listed in Section 5.1.  For participants taking metformin, this study 
requires that participants have been taking stable doses of metformin for at least 60 days 
prior to the screening visit.  Participants will continue taking their own metformin medication 
at the same total daily dose that was prescribed prior to study entry through the first follow 
up visit (ie, Visit 10, Week 17-18), except in circumstances where a change in dose is 
deemed medically necessary.  For study visit days, participants should be instructed to refrain 
from morning dosing 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 8.2.5.3).
6.5.3. 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. 
6.5.4. Lipid Modifying Medications
The use of background lipid modifying agents is permitted unless otherwise noted in 
Appendix 8. Doses of such lipid modifying agents must be stable for at least 4 weeks prior 
to screening and throughout the study, except in circumstances where a change in dose is 
deemed medically necessary.  Any changes in doses of these medications must be captured in 
the CRF. 


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6.5.5. Glycemic Rescue Medicine
Participants with hyperglycemia as defined in Section 8.2.5.3 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: metformin (for those 
participants who were not taking metformin at randomization), sulfonylureas, or sodium 
glucose co-transporter 2 (SGLT2) inhibitors.  For participants who were taking a submaximal 
dose of metformin, 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. Standard medical supportive care must 
be provided to manage the AEs, including administration of carbohydrates to treat 
hypoglycemic adverse events (HAE) (see Section 8.2.5.2.1).
6.6. Dose Modification
6.6.1. Considerations for Pausing or Stopping Active Dose(s) Based on Observed Safety
The decision to stop dosing for 1 or more active dose(s) of PF-06882961 may be considered 
based on recommendations from the IRC according to their review of unblinded, study-level
emerging, observed safety data (see Section 9.5), for reasons such as the following:

More than 50% of participants develop a moderate or severe AE in the 
gastrointestinal system organ class (SOC) not responsive to symptomatic 
management.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue 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.  
Per the study estimands, if IP is permanently discontinued, the participant will remain in the 
study and continue to follow all protocol specified visits and procedures according to the 
SoA with the exception of dosing activities 
 
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 (β-hCG) testing.  
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 study discontinuation 
and follow-up and for any further evaluations that need to be completed. 
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.
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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:
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;


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
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.
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.


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The total blood sampling volume for individual participants in this study is approximately 
295 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
Efficacy assessments for this study include measurements of HbA1c, fasting plasma glucose, 
and body weight which are covered in detail in Section 8.2.
8.1.1. Primary Efficacy Parameter: HbA1c
HbA1c is the primary efficacy parameter for this study.  See Section 8.2.6 covering clinical 
laboratory tests.
8.1.2. Secondary 
 Efficacy Parameters
See Section 8.2.6 (clinical laboratory assessments) for details regarding fasting plasma 
glucose. Participants achieving HbA1c <7% will be calculated based on HbA1c assessments 
as described in Section 8.2.6.
See Section 8.2.2 for details regarding assessment of body weight.
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.
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Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2. 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 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:

While 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.
8.2.3. Vital Signs
8.2.3.1. Blood Pressure and Pulse Rate
In this study, assessment of vital signs [systolic BP, diastolic BP, and pulse rate (PR)] 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.  See Section 5.2.

BP and PR will be measured via an automated device using an oscillometric method 
(not auscultation).

Assessment of BP and PR can be manual (rather than using an automated device), 
only if an automated device is not available; however when done manually PR 
must be measured in the brachial/radial artery for at least 30 seconds.


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
Supine BP and PR 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 V3, V5, V7 and V9 with a brief interval 
(eg, 1-2 minutes) between successive triplicate assessments.

Same arm (preferably the dominant arm) will be used for BP and PR assessments
throughout the study, whenever possible.

Participants should be instructed not to speak during BP and PR 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 PR will be permitted, as 
necessary, to ensure appropriate collection of safety data.
8.2.4. 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 PR, 
QT, and QTcF intervals and QRS complex. Triplicate assessments will be measured at V3, 
V5, V7 and V9 with a brief interval (eg, 2-5 minutes) between successive triplicate 
assessments.  All scheduled ECGs should be performed after the participant has rested 
quietly for at least 10 minutes in a supine position. 
If a post dose QTcF interval remains ≥30 msec from the baseline and is a) >450 msec; or 
b) an absolute QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTcF intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.5. Management of Glycemic Control
Hypoglycemic adverse events (HAEs) and fasting plasma glucose will be routinely 
monitored during participation in the study.


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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.
8.2.5.1. Home Glucose Monitoring

To aide in management of their T2DM, 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.  
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 placebo run-in visit (V2).

Participants 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 will NOT be considered a protocol deviation unless 
the participant fails to monitor his/her glucose for 3 or more consecutive days.

If the 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 the 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.
8.2.5.2. Management of Hypoglycemia
Any episode of hypoglycemia must be captured on the Adverse Event CRF with specific 
details captured on the Hypoglycemia Adverse Event Form CRF.  For the definition of a 
hypoglycemic episode and severity categorization see Section 8.2.5.2.1 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.


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8.2.5.2.1. 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 one of the following:15
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);
2. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose value of <70 mg/dL (3.9 mmol/L) using 
glucometer (or sponsor-identified central laboratory) 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.  In order to characterize 
the event as severe, all three (3) criteria below must be met:
1. The participant was unable to treat him/herself.  Neurologic impairment, and not the 
age of the participant, is the explanation for why the participant could not treat 
him/herself and required the assistance of another person.
2. The participant exhibited at least one of the following neurological symptoms:

Memory loss;

Confusion;

Uncontrolled behavior;

Irrational behavior;

Unusual difficulty in awakening;

Suspected seizure;

Seizure;


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
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 the criteria above for severe HAE are characterized as mild or 
moderate in severity.
Any episode of HAE must be captured on the HAE CRF.
8.2.5.3. Management of Hyperglycemia
Hyperglycemia is defined as the following:

Fasting glucose ≥270 mg/dL (15.0 mmol/L) using glucometer (or central laboratory). 
After randomization, participants noted to have a fasting 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 6.5.5).
8.2.6. Clinical 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.


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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.
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.
8.2.7. Pregnancy Testing 
Pregnancy tests will be both urine and serum tests, and must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in all females at the times listed in the SoA.  
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 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected) and at the end of the study.  Pregnancy tests may also be repeated if 
requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether 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
During the active collection period, both nonserious AEs and SAEs are recorded on the AE 
section of the CRF.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.


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8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for 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 investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 28 calendars 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.


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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
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.
















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9.4.1. Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary: Change 
from baseline in 
HbA1c at Week 16.
A MMRM analysis of the change from baseline in HbA1c through
Week 16 will be used to estimate the treatment effect related to the 
primary Estimand 1A.
The MMRM will include treatment, time, strata (metformin vs. diet 
and exercise alone) 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.
The MMRM model will be fitted to change from baseline to 
Weeks 2, 4, 6, 8, 12 and 16 from the Estimand Set 1A. 
Missing values will be imputed as part of the MMRM model 
assumptions.
No adjustments will be made for multiplicity.
Secondary: 
Response as 
defined by an
HbA1c <7% at 
Week 16.
A logistic regression analysis of participants who reached a HbA1c 
goal of <7% at Week 16 and those that didn’t will be used to 
estimate the treatment effect related to the secondary estimand 2.
The logistic regression model will include a term for treatment, 
strata (metformin vs. diet and exercise alone), and baseline HbA1c
will be included as a covariate.  
This model will be fitted to the Week 16 timepoint only from the 
Estimand Set 1A.  No adjustments will be made for multiplicity.
Secondary: Change 
from baseline in 
fasting plasma 
glucose through 
and at Weeks 2, 4, 
6, 8, 12 and 16.
Changes from baseline in fasting plasma glucose at Weeks 2, 4, 6, 8,
12 and 16 will be analyzed using a similar MMRM model to that
used for the primary endpoint.  Baseline fasting plasma glucose will 
be included as a covariate in the model, rather than baseline HbA1c.  
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 3.
Secondary: Change 
from baseline in 
body weight at 
Weeks 2, 4, 6, 8, 12 
and 16.
Changes from baseline in body weight will be analyzed using a 
similar MMRM model to that used for the primary endpoint.  
Baseline body weight will be included as a covariate in the model, 
rather than baseline HbA1c. 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 4.
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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 investigational 
product, 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 sub investigators 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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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 investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following laboratory tests will be performed at times defined in the SoA section of this 
protocol.  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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After randomization, the sponsor study team and site will be blinded to HbA1c, fasting 
plasma glucose, 
measured by the central laboratory, 
unless the fasting plasma glucose meets the criterion for hypo-or hyper-glycemia as listed in 
Section 8.2.5.2 and 8.2.5.3.
CCI








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events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the 
investigational product under study during pregnancy or breastfeeding, and occupational 
exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the 
investigational product 
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 








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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 woman of child bearing potential (WOCBP) (see definitions below in 
Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below
during the intervention period and for at least 28 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any reproductive 
safety risk of the study intervention(s). The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
interevention. 

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with high usere dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention, 
which corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s).  In addition, a second effective method of contraception, as 
described below, must be used.  The investigator should evaluate the effectiveness of
the contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential (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.


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Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as 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.


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


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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 investigational
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

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 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, 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.


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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 investigational product. 
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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10.6. 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 times the 
upper limit of normal (× 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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10.8. Appendix 8: Prohibited Prior/Concomitant Medications
The following medications are prohibited until the first follow-up visit (ie, Visit 10, 
Week 17-18), 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, 
tolbutamide, glimepiride, glipizide, glyburide. Note: These may be used as 
glycemic rescue medications (See Section 6.5.5).
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 6.5.5).
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
Antiarrhythmic medications whose primary mechanism of action is sodium or 
potassium channel blockade (eg, procainamide, phenytoin, quinidine, 
propafenone; as well as amiodarone, dofetilide, sotalol).
Note: -adrenergic receptor blocking agents (eg, atenolol, metoprolol) and 
60 days


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Drug Classes and/or Drugs 
Timeframe of Restriction 
Prior to Screening Visit
calcium channel blockers (eg, diltiazem, amlodipine, nifedipine) are permitted.
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).
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, torsemide, amodiaquine.
Prohibited post 
randomization 




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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
AST
aspartate aminotransferase
AUC24
area under the curve at 24 hours
AV
atrioventricular
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
β-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
cAMP
cyclic adenosine monophosphate
CFB
change from baseline
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
%CV
percent coefficients of variance
CYP
cytochrome P450
DDI
drug drug interaction
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
CCI


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Abbreviation
Term
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 adverse event
HbA1c
glycated hemoglobin 
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
investigator’s brochure
IR
immediate release
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
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVGTT
intravenous glucose tolerance test
IWR
interactive Web-based response
LBBB
left bundle branch block
LFT
liver function test
MAR
missing at random
MATE
multidrug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
CCI
CCI
CCI


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Abbreviation
Term
MDG
mean daily glucose
MDR1
multidrug resistance mutation
MEN2
multiple endocrine neoplasia syndrome type 2
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 polypeptides
OCT
organic cation transporter
PCD
primary completion date
PD
pharmacodynamic(s)
PI
principal investigator
PR
pulse rate
PT
prothrombin time
PVC
premature ventricular complex
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
standard deviation
SGLT2
sodium glucose co-transporter 2
SMP
study monitoring plan
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SSID
study specific subject identification
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
t½
half life
T2DM
type 2 diabetes mellitus
TBA
total bile acids
TBili
total bilirubin
TEAE
treatment emergent adverse event
TI
therapeutic index
Tmax
time to maximal concentration
CC
I


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Abbreviation
Term
TSH
thyroid stimulating hormone
TZD
thiazolediediones
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.
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2.
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Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
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4.
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
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Hu FB. Globalization of diabetes: the role of diet, lifestyle and genes. Diabetes Care 
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Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and Trends in Diabetes 
Among Adults in the United States, 1988-2012. JAMA 2015;314:1021.
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DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the 
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Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular 
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10.
Drucker, DL. The ascending GLP-1 road from clinical safety to reduction of 
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14.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek 
JW, Eggers P, Van Lente F, Greene T, Coresh J. A New Equation to Estimate 
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ICH Harmonised Guideline E9 (R1); Estimands and Sensitivity Analysis in Clinical 
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