A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF MULTIPLE ESCALATING ORAL DOSES OF PF-06882961 IN ADULT SUBJECTS WITH TYPE 2 DIABETES MELLITUS
Phase: PHASE1
Conditions: Type 2 Diabetes Mellitus
Sponsor: Pfizer

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 1
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND PHARMACODYNAMICS OF MULTIPLE 
ESCALATING ORAL DOSES OF PF-06882961 IN ADULT SUBJECTS WITH 
TYPE 2 DIABETES MELLITUS
Investigational Product Number:
PF-06882961 
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
C3421002
Phase:
1
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 2
Document History
Document
Version Date
Summary of Changes
Original protocol
22 March 2018
N/A

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................8
APPENDICES ...........................................................................................................................8
SCHEDULE OF ACTIVITIES..................................................................................................9
1. INTRODUCTION ...............................................................................................................14
1.1. Mechanism of Action/Indication.............................................................................14
1.2. Background .............................................................................................................14
1.2.1. Nonclinical Pharmacology..........................................................................15
1.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................15
1.2.3. Nonclinical Safety ......................................................................................16
1.2.4. Preliminary Summary of Clinical Experience with PF-06882961.............17
1.3. Rationale..................................................................................................................20
1.3.1. Study Rationale...........................................................................................20
1.3.1.1. Study Population .......................................................................21
1.3.1.2. Pharmacokinetic Parameters .....................................................22
1.3.2. Dose Rationale............................................................................................23
1.3.2.1. Prediction of Efficacious Dose/Concentration..........................23
1.3.2.2. Selection of Dose Levels...........................................................23
1.3.2.3. Dose Titration............................................................................24
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................25
3. STUDY DESIGN.................................................................................................................27
3.1. Study Overview.......................................................................................................27
3.2. Dose Escalation and Stopping Rules.......................................................................29
4. SUBJECT ELIGIBILITY CRITERIA...............................................................................30
4.1. Inclusion Criteria.....................................................................................................30
4.2. Exclusion Criteria....................................................................................................31
4.3. Randomization Criteria ...........................................................................................33
4.4. Lifestyle Requirements ...........................................................................................34
4.4.1. Meals and Dietary Restrictions...................................................................34
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 4
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................35
4.4.3. Activity .......................................................................................................36
4.4.4. Contraception..............................................................................................36
4.5. Sponsor’s Qualified Medical Personnel..................................................................37
5. STUDY TREATMENTS.....................................................................................................37
5.1. Allocation to Treatment ..........................................................................................38
5.2. Breaking the Blind ..................................................................................................38
5.3. Subject Compliance.................................................................................................38
5.4. Investigational Product Supplies.............................................................................39
5.4.1. Dosage Form and Packaging ......................................................................39
5.4.2. Preparation and Dispensing........................................................................39
5.5. Administration.........................................................................................................39
5.5.1. Administration of Blinded IP......................................................................39
5.5.2. Administration of Metformin and Other Concomitant Medications..........39
5.6. Investigational Product Storage ..............................................................................40
5.7. Investigational Product Accountability...................................................................40
5.7.1. Destruction of Investigational Product Supplies ........................................41
5.8. Concomitant Treatment(s).......................................................................................41
5.8.1. Medications for Glycemic Control.............................................................41
5.8.2. Antihypertensive Medications....................................................................41
5.8.3. Lipid-Modifying Medications ....................................................................42
5.8.4. Management of Nausea and Vomiting .......................................................42
5.8.5. Prohibited Medications...............................................................................42
5.8.5.1. Medications Not Permitted within 3 Months of Screening.......42
5.8.5.2. Medications Not Permitted within 4 Weeks of Screening ........42
5.8.5.3. Medications Not Permitted for Doses Above 300 mg BID.......43
5.9. Rescue Medication ..................................................................................................44
6. STUDY PROCEDURES .....................................................................................................44
6.1. Proposed Chronology of Procedures.......................................................................44
6.2. Screening.................................................................................................................45
6.3. Study Period ............................................................................................................45
6.4. Follow-up ................................................................................................................46

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 5
6.4.1. Follow-up Visit...........................................................................................46
6.4.2. Follow-up Contact ......................................................................................46
6.5. Subject Withdrawal/Early Termination ..................................................................46
7. ASSESSMENTS..................................................................................................................48
7.1. Safety.......................................................................................................................48
7.1.1. Laboratory Tests .........................................................................................48
7.1.2. Physical Examinations................................................................................50
7.1.3. Body Weight...............................................................................................50
7.1.4. Blood Pressure and Pulse Rate ...................................................................51
7.1.5. Electrocardiogram.......................................................................................51
7.1.6. Glucometer Monitoring of Glucose............................................................52
7.1.7. Hypoglycemia Reporting............................................................................53
7.2. Pharmacokinetics ....................................................................................................54
7.2.1. Plasma for Analysis of PF-06882961.........................................................54
7.2.2. Urine for Analysis of PF-06882961 and/or Metabolite Screening.............54
7.5. Blood Volume .........................................................................................................58
8. ADVERSE EVENT REPORTING......................................................................................58
8.1. Requirements...........................................................................................................58
8.1.1. Additional Details on Recording Adverse Events on the CRF...................59
8.1.2. Eliciting Adverse Event Information..........................................................60
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................60
8.1.4. Time Period for Collecting AE/SAE Information......................................60
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................60
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................60
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 6
8.1.5. Causality Assessment .................................................................................61
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................61
8.2. Definitions...............................................................................................................61
8.2.1. Adverse Events...........................................................................................61
8.2.2. Abnormal Test Findings .............................................................................62
8.2.3. Serious Adverse Events ..............................................................................62
8.2.4. Hospitalization............................................................................................63
8.3. Severity Assessment................................................................................................64
8.4. Special Situations ....................................................................................................64
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................64
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................66
8.4.2.1. Exposure During Pregnancy......................................................66
8.4.2.2. Exposure During Breastfeeding ................................................67
8.4.2.3. Occupational Exposure .............................................................68
8.4.3. Medication Errors .......................................................................................68
8.4.3.1. Medication Errors......................................................................68
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................69
9.1. Sample Size Determination.....................................................................................69
9.2. Efficacy Analysis ....................................................................................................69
9.3. Pharmacokinetic Analysis.......................................................................................69
9.3.1. Derivation of Pharmacokinetic Parameters ................................................69
9.3.2. Statistical Methods for PK Data .................................................................74
9.7. Safety Analysis........................................................................................................75
9.7.1. Electrocardiogram Analysis........................................................................75
9.7.2. Vital Sign Analysis.....................................................................................76
9.7.3. Hypoglycemia Monitoring and Reporting..................................................77
9.8. Interim Analysis ......................................................................................................77
9.9. Data Monitoring Committee ...................................................................................77
CCI
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 7
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................77
11. DATA HANDLING AND RECORD KEEPING .............................................................78
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record.....................78
11.2. Record Retention...................................................................................................78
12. ETHICS..............................................................................................................................79
12.1. Institutional Review Board/Ethics Committee......................................................79
12.2. Ethical Conduct of the Study ................................................................................79
12.3. Subject Information and Consent..........................................................................79
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................80
13. DEFINITION OF END OF TRIAL...................................................................................80
13.1. End of Trial in the United States...........................................................................80
14. SPONSOR DISCONTINUATION CRITERIA ................................................................80
15. PUBLICATION OF STUDY RESULTS..........................................................................81
15.1. Communication of Results by Pfizer ....................................................................81
15.2. Publications by Investigators ................................................................................82
16. REFERENCES ..................................................................................................................83
LIST OF TABLES
Table 1.
Overall Visit Schedule and List of Procedures.....................................................10
Table 2.
Schedule of Activities – Study Days -1, 1, 14, 21 & 28.......................................12
Table 3.
C3421001: Observed Preliminary PK Parameters, PF 06882961 Cohorts 1 
and 2......................................................................................................................19
Table 4.
C3421001: Observed Preliminary PK Parameters, PF 06882961 Cohort 3.........19
Table 5.
A Selection of Potential Doses, Predicted Human Exposure at Steady State, 
and Safety Margins with Administration of Multiple, Oral Doses of 
PF-06882961.........................................................................................................24
Table 6.
Sample Titration Scheme and Dosing Paradigm..................................................25
Table 7.
Safety Laboratory Tests........................................................................................49
Table 8.
Definition of Plasma PK Parameters for PF-06882961 in the Setting of 
BID Dosing...........................................................................................................70
Table 9.
Definition of Plasma PK Parameters for PF-06882961 in the Setting of QD 
Dosing...................................................................................................................72
Table 10.
Definition of Urine PK Parameters for PF-06882961..........................................73

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 8
LIST OF FIGURES
Figure 1.
Study Design Overview........................................................................................28
APPENDICES
Appendix 1. Abbreviations......................................................................................................84
Appendix 2. Concomitant Medications ...................................................................................88

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 9
SCHEDULE OF ACTIVITIES
The schedule of activities tables (both Table 1 and Table 2) provide an overview of the 
protocol visits and procedures.  Refer to Section 6 and Section 7 of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the 
schedule of activities tables, in order to conduct evaluations or assessments required to 
protect the well-being of the subject. Abbreviations found in Appendix 1.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 10
Table 1.
Overall Visit Schedule and List of Procedures
Protocol Activity
Screen Day 
-2
Study Day (all activities at 0H [prior to dosing] unless otherwise specified)a
Follow-upa
Early 
Termination
Study Day
-1 1
2
3
4 5-7 8 9-10 11 12-13 14 15 16-17 18 19-20 21
22 23-24 25 26-27 28 29 30b 35-42 56-63
Informed consent & demography
x
Outpatient visit (after 8-H fast)
x
x
Adverse event monitoring
x
x














x
x
x
Inpatient stay at CRU
x














x
Medical history 
x
x
See Table 2
See Table 2
See Table 2
See Table 2
See Table 2
x
Review drug, alcohol, tobacco 
use
x
x
x
Review prior and concomitant 
treatments 
x
x
x
x
Review contraception use
x
x
x
x
Physical examination (height at 
Screen only)c
x
x
x
x
Body weight
x
x
x
x
x
Supine 12-lead ECGd
x
x
x
x
x
x
x
x
x
x
x
x
x
Supine vital signse
x
x
x
x
x
x
x
x
x
x
x
x
x
Glucometer measurementf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Standardized meals/snacksg
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blinded investigational product 
administrationh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood Sampling for:
- Safety laboratory testsi
xj
x
x
x
x
x
x
- FSHk, HIV, HepBsAg, 
HepBcAb, HCVAb 
x
- HbA1c, TSH
x
- Free T4, calcitonin, amylase, 
lipase, total bile acids, lipids
x
x
- PF-06882961 PKl
x
x
x
x
x
Urine Sampling for:
- Urine drug test
x
x
- Urinalysis (and microscopy, as 
appropriate)
x
x
x
x
x

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 11
a.
Day relative to first dose of investigational product (Day 1).
b.
Discharge from CRU.
c.
Full physical exam at Screening, Day 15, Day 29, and early termination visit (if appropriate); otherwise, limited exam if findings during previous exam or new/open AEs, if 
appropriate, at investigator discretion.
d.
12-lead ECG at Screening, Day 30, Follow-up, and early termination visit (if appropriate) are single; all other study days, collect triplicate ECGs.  Triplicate ECGs should be 
conducted prior to AM dose at 0H and at approximately 4H (estimated Tmax) after AM dose on Days 2, 4, 8, 11, 15, 18, 22, and 25.  On Day 29, triplicate ECG collected at 
0H only. When a meal or snack is scheduled at the same time as an ECG, the ECG must be performed prior to the meal/snack. 
e.
Includes blood pressure and pulse rate; vital signs at Screening, Day 30, Follow-up, and early termination visit (if appropriate) are single; all other times, collect triplicates 
prior to AM dose at 0H and additional triplicates at approximately 4H (estimatedTmax) after AM dose on Days 2, 4, 8, 11, 15, 18, 22, and 25.  On Day 29, triplicate vital signs 
collected at 0H only. 
f.
On Day -2, glucometer measure should be obtained on admission to CRU. Glucometer measures on Days -1 through 30 should be obtained prior to breakfast.  Measurements
may be taken more frequently at the discretion of the investigator.
g.
Meals to be provided at approximately 0H, 4H, and 10H after AM dose; snacks may be provided, at time specified in Table 2.
h.
Dosing to occur BID with breakfast and dinner.  For QD regimen, if administered, dosing to occur with breakfast only, at time specified in Table 2.
i.
Collection following fasting duration as specified in Section 4.4.1.
j.
k.
In females to confirm postmenopausal status only. 
l.
PK samples to be collected prior to AM dose and at 4H after AM dose on Days 8 and 18.  Day 29 samples to be collected at 36H after AM dose on Day 28.  Day 30 sample to 
be collected 48H after AM dose on Day 28.
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 12
Table 2.
Schedule of Activities – Study Days -1, 1, 14, 21 & 28
[Procedures at 0H to be completed prior to dosing or similar clock time, in the case of Day-1]
Hours Relative to Dosing at 0Ha
0
0.25
0.5
1
1.5
2
3
4
6
8
10
12
14
24
Continued inpatient stay at CRU














Adverse event monitoring














Body weight (Days -1, 14, and 28 only)
x
Triplicate, supine 12-lead ECG 
x
x
x
x
x
x
Triplicate, supine vital sign assessmentb
x
x
x
x
x
x
Glucometer measurementc
x
Mixed meal tolerance test (Days -1, 14, and 28, only)
x
Standardized meal/snackd
xe
x
x
x
Blinded investigational product administration QD or BID (Days 1, 14, 21, and 
28 only)
xf
xg
Blood sampling for:
- Safety laboratory tests (Days -1, 14, 21, and 28 only)h
x
- Banked biospecimen Prep D1.5 (Day 1 only)i
x
- HbA1c, TSH (Day -1 and 28 only)
x
- Free T4, calcitonin, amylase, lipase, total bile acids, lipids 
(Days -1, 14, and 28 only)
x
- PF-06882961 PK (Days 1, 14 or 21[depending on Cohort]k, and 28 only)
xh,l
x
x
xl
x
x
x
x
x
x
- Metabolite scouting (0H on Day 1 and all time points on Day 28)
x
x
x
x
xm
xm
Urine sampling for:
- Urinalysis and microscopy, as appropriate (Days 1, 14, 21, and 28 only)
x
- PK predose spot urine (urine blank ) (Day 1 only)
x
- PF-06882961 PK (Day 28 only)
x












xn
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 13
a.
On Day -1, nominal time to match approximate clock time of collection planned on Day 1 to permit time-matched comparison. 
b.
Includes blood pressure and pulse rate at all time points. 
c.
Glucometer measures taken before breakfast on all days while inpatient.
d.
Meals/snacks to occur on all days while inpatient; identical meals/snacks on Days -1, 14, and 28.
e.
Standard breakfast on Day 1 and 21 only. 
f.
Dosing expected to occur with breakfast or mixed meal.
g.
Dosing expected to occur with dinner (BID regimen only).
k.
PK samples obtained at all listed timepoints on Day 1 and Day 28 for all cohorts.  For Cohorts 1 & 2, PK samples obtained at all listed timepoints on Day 14 (not Day 21).  
For Cohorts 3 & 4, PK samples obtained at all listed timepoints on Day 21 (not Day 14).  For Cohort 5 and optional Cohorts (if used), decision to obtain PK samples on 
Day 14 or Day 21 will be provided in writing prior to initiation of dosing for those cohorts. 
l.
For Cohorts 1 & 2, on Day 21 only, PK samples will be obtained at 0H and 4H.  For Cohorts 3 &4, on Day 14 only, PK samples will be obtained at 0H and 4H.  For Cohort 5 
and optional Cohorts (if used), decision to obtain PK samples at only 0H and 4H on Day 14 or Day 21 will be provided in writing prior to initiation of dosing for those 
cohorts.
m.
For optional QD regimen only (if utilized), metabolic scouting samples to be collected at 12H and 24 H post-dose on Day 28.
n.
Urine collection for PK to occur over 0-24H.
C
C
I

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 14
1. 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 the injectable peptidic GLP-1R agonists that are approved for the treatment of type 2 
diabetes mellitus (T2DM).
The purpose of this study is to characterize the safety, tolerability, pharmacokinetics (PK) 
and pharmacodynamics (PD) of multiple oral doses of PF-06882961 in adult subjects with 
T2DM.
1.1. Mechanism of Action/Indication
PF-06882961 is an oral GLP-1R agonist that is currently being developed as an adjunct to 
diet and exercise to improve glycemic control in adults with T2DM. 
1.2. 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 380 million people 
worldwide,6 and the prevalence of T2DM within the United States (US) is estimated to range 
from 12 to 14%.7  T2DM is characterized by insulin resistance, a disorder in which cells do
not respond effectively to insulin, resulting in higher blood glucose levels.  Elevated blood 
glucose levels and increasing severity of insulin resistance result in the need for more insulin 
over time, eventually resulting in progressive pancreatic -cell failure.8  Patients with poorly 
controlled T2DM have an increased risk of developing complications associated with both 
microvascular and macrovascular disease, including nephropathy, neuropathy, retinopathy, 
cardiovascular disease and stroke; and are at 2 to 4 times increased risk of mortality than 
adults who do not have diabetes.9 While existing pharmacological options for the treatment 
of diabetes may provide satisfactory glycemic control for some patients, there remains a large 
number of patients who do not achieve target glycated hemoglobin (HbA1c) levels, 
suggesting a need for additional therapeutic options. 
Based on the successful 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.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 15
1.2.1. Nonclinical Pharmacology
In vitro primary PD studies demonstrated that, in cells expressing recombinant human and 
cynomolgus monkey GLP-1R, PF-06882961 dose-dependently promotes 3’-5’-cyclic 
adenosine monophosphate (cAMP) production with concentrations corresponding to 50% of 
the maximum effect (EC50) of 11.7 and 12.3 nM, respectively.  In contrast, no cAMP 
production was observed in cells expressing recombinant rat, mouse, and rabbit GLP-1R at 
tested concentrations (EC50 >10-20 M). PF-06882961 was shown to bind to the human 
GLP-1R with a mean binding inhibition constant (Ki) of 80.1 nM using a competition 
binding assay.  In vivo, PF-06882961 potentiated glucose-stimulated insulin secretion during 
an intravenous glucose tolerance test (IVGTT) in cynomolgus monkeys in a dose- and 
concentration-dependent manner.  Finally, PF-06882961 was also shown to reduce food 
intake in cynomolgus monkeys.  In all in vivo studies, efficacious plasma levels were 
consistent with the in vitro potency.
1.2.2. Nonclinical Pharmacokinetics and Metabolism
Single-dose PK studies with PF-06882961 were conducted after intravenous (IV) and oral 
administration to rats and nonhuman primates.  The toxicokinetics (TK) of PF-06882961 
were determined in 1-month repeated oral dose toxicity studies in male and female rats, and 
in a 6-week toxicity study in male and female nonhuman primates.  The fraction unbound (fu) 
of PF-06882961 in rat, nonhuman primates, and human plasma was 0.0178, 0.0182, and 
0.0293, respectively.  PF-06882961 is a substrate for organic anion transporting polypeptides 
(OATP)1B1, OATP1B3, and OATP2B1, multi-drug resistance protein (MDR)1 (also known 
as P-glycoprotein; P-gp), and breast cancer resistant protein (BCRP) in vitro. PF-06882961 
is expected to be cleared via hepatic uptake by OATP, followed by metabolic elimination by 
cytochrome P450 (CYP) enzymes. The metabolic clearance pathway for PF-06882961 in 
humans is principally mediated by cytochrome P450 (CYP) (72%), with a major contribution 
from CYP3A4/5 (50%) and minor contributions from CYP2C8 (13%) and CYP2C19 (9%) as 
determined in cryopreserved human hepatocytes.  The in vitro and in vivo metabolic profile 
of PF-06882961 in the preclinical toxicity species (rat and nonhuman primates) and human 
hepatocytes was similar across species, with no evidence of human specific metabolites.  
The in vitro inhibitory potential of PF-06882961 against major human CYP and uridine 
glucuronosyl transferase (UGT) enzymes has been characterized in human liver microsomes 
(HLM). Potential for drug-drug interaction (DDI) was evaluated using the projected 
unbound intestinal lumen or liver concentrations at the anticipated range of doses to be 
examined in this study. PF-06882961 is a weak time- and nicotinamide adenine dinucleotide 
phosphate-oxidase (NADPH)-dependent inhibitor of CYP 3A4/5 activity, and there is a 
potential for interaction with relevant sensitive substrates at PF-06882961 doses where 
projected area under the curve from time 0 to 24 hours (AUC24) exposure is expected to 
exceed approximately 7392 ng•h/mL.  Based on preliminary modeling of PK data emerging 
from the ongoing first-in-human (FIH) study, this AUC24 is currently predicted to be 
achieved at doses exceeding 300 mg twice daily (BID, Table 5), although this dose level may 
be refined based on emerging data from this study.  In addition, PF-06882961 is a reversible 
inhibitor of CYP2C8 and UGT1A1, suggesting that there may be a potential for interaction 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 16
over the anticipated range of doses to be examined in this study with drugs that are primarily 
metabolized by these enzymes.
The potential for PF-06882961 to inhibit various uptake and efflux drug transporters was
evaluated in stably expressed mammalian cellular systems or vesicle-based transporter 
systems. Evaluation of the DDI potential, using the projected unbound intestinal lumen or 
portal inlet concentrations at the anticipated range of doses to be examined in this study,
suggests that there may be a potential for interaction with drugs (eg, rosuvastatin) that are 
subject to active intestinal/hepatic uptake by OATP2B1/1B1 and/or intestinal efflux mediated 
by BCRP.
1.2.3. Nonclinical Safety
In the 6-week general toxicology study in nonhuman primates at doses of 50, 75, and 
100 mg/kg/day, no adverse findings were observed at any of the administered dose levels.  
Test article-related, but nonadverse findings were observed at all doses including slightly 
decreased food consumption, transiently decreased body weight in females, sporadic emesis, 
decreased systolic, diastolic and/or mean blood pressure (BP), and alterations in select 
hematology and clinical chemistry parameters.  In a single-dose cross-over safety 
pharmacology cardiovascular study in nonhuman primates, nonadverse increases in BP, heart 
rate, and left ventricular contractility were noted at 75 mg/kg (unbound maximum observed 
concentration [Cmax] 23.0 ng/mL and area under the curve from time zero to 24 hours
[AUC24] 206 ng•h/mL) and increased corrected QT interval (QTc) was noted at 250 mg/kg.  
The only nonclinical species for which PF-06882961 activates the GLP-1 receptor is the 
nonhuman primate; therefore, toxicology studies in rats were used to evaluate off-target 
pharmacology.  In oral toxicity studies in rats up to 1-month in duration, adverse findings 
were observed only at the highest dose of 1000 mg/kg/day, which was not tolerated due to 
mortality and unscheduled euthanasia secondary to decreased food consumption, decreased 
body weight, and moribund condition.  Adverse microscopic findings in this study at 
1000 mg/kg/day were noted in the heart (mild to moderate degeneration/necrosis of 
cardiomyocytes), thymus (decreased lymphocyte cellularity, secondary to stress), stomach 
(erosion or ulcer), and Harderian gland (acinar necrosis and neutrophilic inflammation).  
At 1000 mg/kg/day, test article-related, but nonadverse findings included heart (vacuolation 
of cardiomyocytes), cecum (single cell necrosis of epithelial cells), Harderian gland
(degeneration/regeneration), kidney (vacuolation of tubular epithelium associated with higher 
creatinine and blood urea nitrogen), liver (hepatocellular hypertrophy), salivary gland 
(atrophy or single cell necrosis of acinar cells), and adipose tissue (decreased lipid content).  
There were no adverse test article-related findings at doses up to 500 mg/kg/day for 1 month.  
Minimal cardiomyocyte degeneration/necrosis noted in 2/20 animals at 250 mg/kg/day and 
1/6 males surviving to scheduled necropsy at 1000 mg/kg/day was not considered adverse 
due to the minimal severity and limited distribution.  However, this finding was not observed 
in a subsequent 1-month study in rats up to 500 mg/kg/day.  Other nonadverse findings were 
noted at 150 mg/kg/day in the cecum and at 250 mg/kg/day in the liver (hepatocellular 
vacuolation associated with higher total bilirubin [Tbili] and hepatobiliary enzymes), thyroid

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 17
(alterations in thyroid hormones and hypertrophy of follicular cells), and pancreas (decreased 
zymogen content).  Alterations in clinical laboratory parameters, including increased total 
plasma bile acids, were also observed.  
PF-06882961 did not induce micronuclei in the reticulocytes from peripheral blood of male 
and female rats at doses of 50, 250, or 1000 mg/kg/day.  PF-06882961 was negative for the 
potential of phototoxicity in the neutral red uptake phototoxicity study in BALB/c 3T3 
fibroblasts.  PF-06882961 was negative in all genetic toxicity assays and was monitored in 
the pivotal in vivo toxicity and safety pharmacology studies.  
The no observed adverse effect level (NOAEL) in the pivotal 6-week toxicity study in 
nonhuman primates was 100 mg/kg/day (mean combined-sex unbound Cmax 24.2 ng/mL and 
AUC24 175 ng•h/mL), and the NOAEL in a pivotal 1-month toxicity study in rats was 
500 mg/kg/day (mean combined-sex unbound Cmax 767 ng/mL and AUC24 5856 ng•h/mL). 
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure (IB).  
1.2.4. Preliminary Summary of Clinical Experience with PF-06882961 
As of the issuance of this protocol, there is 1 ongoing clinical study, C3421001, which is the 
first to administer PF-06882961 to humans.  C3421001 is an investigator- and 
subject-blinded (sponsor-open), randomized, placebo-controlled, single ascending oral dose, 
study conducted at 1 clinical research unit (CRU).  To date, 25 healthy adult subjects (men 
and women of non-childbearing potential) have been randomized to receive PF-06882961 or 
placebo in 3 cohorts, and each subject has participated in up to 4 crossover periods.  
Cohorts 1 (n=8) and 2 (n=9) were conducted with an interleaving, dose-escalation design.  
Subjects were administered single doses of PF-06882961 or placebo in the fasted state, 
except 1 period administered in the fed state with a high fat breakfast.  Cohort 3 (n=8) was 
administered split doses of PF-06882961 or placebo, administered 8 hours apart, in the fed 
state with standard breakfast and snack. PF-06882961 or placebo was administered as an 
immediate release (IR) tablet for all periods except 1 period for Cohort 1, which was 
administered as an IR oral solution.  Draft preliminary safety and PK data from the 4 periods 
of Cohorts 1, 2 and 3 are currently available.
As this study is ongoing, all data presented here are preliminary and subject to change.  To 
date, PF-06882961 has demonstrated an acceptable safety profile, and there have been 
neither serious adverse events (SAEs) nor adverse events (AEs) of severe intensity reported.  
Overall, no adverse, clinically significant changes in safety laboratory parameters, 
electrocardiograms (ECGs), and vital signs have been observed.  Over the dose range of 
3 mg to 300 mg administered in Periods 1-4 for Cohorts 1-3, a total of 100 AEs were 
reported.  The majority (95) was mild in severity and 5 were moderate in severity.  The most 
frequently encountered AEs were related to the gastrointestinal (GI) system and included 
nausea, anorexia, and vomiting. 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 18
An overview of PF-06882961 plasma PK parameters based on preliminary data observed 
following single-dose, oral administration of IR tablets and an IR oral solution is given in 
Table 3 and Table 4.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 19
Table 3.
C3421001: Observed Preliminary PK Parameters, PF 06882961 Cohorts 1 and 2
Dose/Cohort/ 
Conditions
Cmax
Geometric Mean 
ng/mL (%CV)
Tmax
Median 
hr (range)
AUClast
Geometric Mean 
ng.h/mL (%CV)
t1/2
Arithmetic Mean 
hr (%CV)
3 mg/ Cohort 1/ 
IR tablet fasted
6.4 (59.1)
2 (1.25-4)
39.2 (53.5)
3.17 (34.9)
10 mg/ Cohort 2/ 
IR tablet fasted
13.2 (53.6)
6 (3-6)
86.4 (53.8)
4.01 (20.4)
25 mg/ Cohort 1/ 
IR solution fasted
52.3 (50.2)
2 (1.25-2)
271 (28.5)
4.64 (26.9)
30 mg/ Cohort 1/ 
IR tablet fasted
41.2 (62.4)
4 (1.25-6)
297 (44.8)
4.52 (36.4)
100 mg/ Cohort 2/ 
IR tablet fasted
176 (91.4)
6 (0.75-6)
1120 (46.9)
5.78 (35.2)
100 mg/ Cohort 2/ 
IR tablet high-fat meal
76.8 (23.3)
6 (6-12)
918 (52.2)
4.86 (17.9)
300 mg/ Cohorts 1+2/ 
IR tablet fasted
732 (91.2)
4 (0.3-12)
4810 (44.5)
5.55 (27.6)
NOTE that these parameters have been calculated based on preliminary data from the ongoing C3421001 study using planned sample collection times and 
are subject to update on final reporting. %CV = percent coefficient of variance
Table 4.
C3421001: Observed Preliminary PK Parameters, PF 06882961 Cohort 3
Dose
Cmax0-8H
Geometric Mean 
ng/mL (%CV)
Tmax0-8H
Median 
hours (range)
Cmax
Geometric Mean 
ng/mL (%CV)
Tmax
Median 
hours (range)
AUClast
Geometric Mean 
ng.h/mL (%CV)
t1/2
Arithmetic Mean 
hours (%CV)
20+20 mg (40 mg split)
29.4 (26)
6 (4-6)
35.8 (34.7)
12 (6-12)
491 (26.7)
5.33 (23.6)
50+50 mg (100 mg split)
62.4 (44.5)
6 (2-8)
84.9 (33.9)
12 (6-14)
1260 (42)
5.12 (15.6)
150+150 mg (300 mg split)
126 (33.8)
6 (6-6)
199 (36.3)
12 (6-24)
3810 (28.7)
5.62 (28.8)
200+100 mg (300 mg split)
144 (46.8)
6 (6-8)
268 (86.7)
10 (6-24)
3900 (39.5)
5.22 (17.8)
NOTE that these parameters have been calculated based on preliminary data from the ongoing C3421001 study using planned sample collection times and are 
subject to update on final reporting. 
Cohort 3 conditions: IR tablet administered at 0H with standard breakfast and at 8H with snack. 
%CV = percent coefficient of variance

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 20
1.3. Rationale 
1.3.1. Study Rationale 
The purpose of this study is to evaluate the safety, tolerability, and PK of multiple oral doses 
of PF-06882961 in adult subjects with T2DM.  The study will also assess the effect of 
repeated, oral doses of PF-06882961 on PD biomarkers, 
 
  
The study includes 5 planned cohorts, with 3 optional cohorts to permit thorough exploration 
of the dose range along with potential assessment of dosing (including once daily [QD] 
and/or BID administration) and/or titration regimens, as informed by emerging safety, 
tolerability, PK, or PD data from this study.  PF-06882961 will be administered via the IR 
tablet formulation for a majority of the cohorts. 
 
 
 
 
 
  
Given that the current study is the first to administer repeated doses of PF-06882961 to 
humans, an escalating design with careful on-going review of safety and PK of PF-06882961
is proposed.  A baseline day (Day -1) with time-matched procedures will permit an improved 
assessment of safety, tolerability, as well as PD effects, ie, change from baseline (CFB, 
within subject) and placebo-adjusted comparison of dose-response (between subject), as 
appropriate. The subjects and site staff (except those involved in the preparation of doses) 
will be blinded to administration of active versus placebo in each cohort to permit an 
unbiased assessment of safety. However, a limited number of members of the Sponsor team 
will be unblinded to permit a real-time review of safety and tolerability in order to assess 
potential for drug-induced changes.
Total duration of dosing PF-06882961/placebo in this study is proposed for up to 4 weeks, as 
supported by completed nonclinical toxicity studies in rats and nonhuman primates.  Dose 
titration is anticipated to be included in most cohorts to enhance tolerability to higher doses 
of PF-06882961.  In the 5 planned cohorts, at least 2 weeks of dosing at each target dose 
level is anticipated. This duration is expected to permit sufficient assessment of safety, 
tolerability, PK and PD of PF-06882961.
Clinical safety laboratory tests, thorough assessments of vital signs and 12-lead ECGs, 
physical examinations, and AE monitoring will provide essential data to evaluate the safety 
and tolerability of PF-06882961.  
 
In an effort to reduce variability and better quantify potential changes in heart rate and BP 
during the study, all measurements of ECG, heart rate and BP will be collected in triplicate 
(except as noted in the Schedule of Activities) and the mean heart rate and mean systolic and 
diastolic BP will be used for analysis at each time point.  In addition to triplicate BP 
CCI
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 21
measurements taken prior to dosing of investigational product (IP), metformin, and any 
morning dose of permitted concomitant medications, triplicate BP measurements will also be 
collected at approximate time for Cmax (Tmax) on PK sampling days as specified in the 
Schedule of Activities to further enhance quantification of any possible drug effect.  
As part of the clinical safety laboratory tests, calcitonin, amylase, and lipase will be assessed, 
as these laboratory parameters have been shown to increase in patients treated with marketed 
GLP-1R agonists.10  In addition, thyroid stimulating hormone (TSH), free thyroxine (FT4), 
lipids, coagulation profile, and total bile acids will be assessed, based on non-adverse 
findings in the nonclinical studies with PF-06882961 (see Section 1.2.4).  
 
 
 
 
While GLP-1R agonists typically are not associated with hypoglycemia unless 
co-administered with anti-diabetic agents that can cause hypoglycemia (such as insulin or 
sulfonylureas), blood glucose concentrations will be monitored throughout the study via
glucometer at least once daily (pre-breakfast), and careful monitoring of symptomatic 
hypoglycemic AEs will be performed.
Dosing of PF-06882961 is planned to occur in the fed state, ie, with breakfast in all dosing 
regimens and with dinner for BID dosing regimens.  If thought necessary to achieve study 
objectives (eg, to assess tolerability or exposure), the timing of meals or snacks relative to 
study treatment administration may be altered during any of the study cohorts; should this be 
necessary, details will be provided to investigators in writing.
1.3.1.1. Study Population
The population for this study will be male and female adult subjects with T2DM. Female 
subjects will be confirmed as women of non-childbearing potential since, at the present time,
embryo-fetal developmental toxicology studies with PF-06882961 have not been conducted.  
In male subjects, appropriate measures to minimize potential transfer of PF-06882961 via 
semen to a partner are required (refer to Section 4.4). 
Subjects enrolled in this study will have inadequately controlled T2DM (as indicated by 
HbA1c at screening) on metformin monotherapy, which is considered first-line therapy for 
glycemic control according to current treatment guidelines.12 At screening, this study 
requires that subjects have been taking a minimum stable metformin dose of 500 mg/day for 
at least 2 months prior to the screening visit.  The dose of metformin, where possible, is 
expected to remain the same until completion of study participation (ie, Follow-up visit).  A 
clinical drug-drug interaction (DDI) study with metformin has not been conducted at this 
time, as in vitro data suggest that PF-06882961 is not expected to impact the PK of 
metformin via inhibition of organic cation transporter (OCT)2, and the risk of a clinical 
interaction is deemed negligible.
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 22
In addition, subjects will be allowed to take certain concomitant medications as outlined in 
Section 5.8.
1.3.1.2. Pharmacokinetic Parameters
As is typical for multiple ascending dose (MAD) studies with investigational agents, this 
study will include plasma sampling to examine the Day 1 and steady-state PK of 
PF-06882961.  Urine samples will also be collected to evaluate the proportion of 
drug excreted via renal elimination.  Plasma PK and urine samples will be collected for 
exploratory metabolite identification.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 23
1.3.2. Dose Rationale
1.3.2.1. Prediction of Efficacious Dose/Concentration
A clinically efficacious dose of PF-06882961 should provide HbA1c lowering over 12 weeks 
of at least 1% from a baseline of 8.0%, assuming a background of anti-hyperglycemic 
medications. Using preliminary modeling of PK data emerging from the ongoing FIH study, 
this dose is predicted to be approximately 131 mg BID, which is projected to yield an 
average unbound efficacious concentration (Ceff) of approximately 6.9 nM (130 ng/mL total), 
at steady state.
1.3.2.2. Selection of Dose Levels 
The nonclinical safety profile of PF-06882961 was adequately characterized to support 
progression into human clinical studies encompassing dosing periods up to 4 weeks in
duration (see Section 1.2.3).  
The doses proposed for this study were determined considering all relevant information 
obtained from nonclinical safety studies along with preliminary safety, tolerability, and PK 
data observed in the ongoing study C3421001.  
A starting dose of 15 mg PF-06882961 BID is planned.  At this dose, the projected average 
concentration of PF-06882961 at steady-state is approximately 9-fold below the projected
Ceff (see Section 1.3.2.1). Based on preliminary data from study C3421001 (Section 1.2.4) , 
this dose is expected to have an acceptable safety and tolerability profile. 
The dose range for this study was chosen in order to appropriately bracket the projected 
efficacious dose to cover the potential impact of uncertainty in projection of efficacious 
concentration or of unanticipated factors on drug exposure, while accommodating feasibility 
considerations including tablet burden.  The highest planned dose will be identified as the 
dose deemed to be the maximum tolerated dose (MTD) upon repeated administration or a
total daily dose of 1600 mg (800 mg BID), whichever is the most conservative.  At steady 
state, a dose of 800 mg BID is projected to yield an average concentration approximately 
6-fold above the projected Ceff (see Section 1.3.2.2) and is projected to yield Cmax and AUC24
exposures approximately 16- and 11-fold below the defined human exposure limits ie, the 
NOAEL in a 4-week toxicology study in rats (see Section 1.2.3 and Section 3.2).  
Dose escalation to the NOAEL in the 4-week toxicology study in rats is proposed due to the 
fact that no adverse findings were noted at the highest dose administered in nonhuman 
primates and that nonadverse findings such as decreased food intake were reversible in the 
nonhuman primates and are monitorable in a clinical setting (Section 1.2.3).  Predicted 
exposure levels and safety margins for a range of anticipated doses for this study are 
provided in Table 5 below.  All exposure-based safety margins were calculated using 
unbound concentrations.  This table gives an overview of the potential dose levels however
the increment of Cmax and AUC24 between dose levels will be targeted to be approximately 
semi-logarithmic.  

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 24
Table 5.
A Selection of Potential Doses, Predicted Human Exposure at Steady State, 
and Safety Margins with Administration of Multiple, Oral Doses of 
PF-06882961
Proposed Dose (mg)
Total Cmax (ng/mL)a
Total AUC24 (ng/h/mL)a
Predicted Cmax 
Safety Marginb
Predicted AUC24
Safety Marginb
15 mg BID
32.2
360
813
555
50 mg BID
109
1202
240
166
150 mg BID
321
3600
81.5
55.5
300 mg BID
650
7392
40.3
27.0
a.
Predicted steady state exposure following 14 days of dosing at target daily dose.
b.
Relative to free (human fu = 0.0293) PF-06882961, Cmax of 767 ng/mL and AUC24 of 5856 ng·h/mL at 
the NOAEL dose in a 1-month toxicity study in rats.
c.
Predicted exposures presented for doses proposed for Cohorts 1-4. Doses for Cohort 5 and optional 
cohorts (if studied) are to be determined (TBD).
d.
While a selection of potential doses is presented in this table, the increment of Cmax and AUC24 in dose 
escalation will be targeted to be no more than approximately semi-logarithmic.  Dose escalation rules are 
summarized in Section 3.2.
See Section 1.2.2, Section 1.2.3, and Section 1.3.2.1.
1.3.2.3. Dose Titration 
All cohorts in this study will complete a total of 28 days of dosing. Cohort 1 will be dosed 
with 15 mg BID or placebo BID for all 28 days with no titration. For the planned Cohorts 
2-5, it is expected that these cohorts will require up to approximately 2 weeks of titration, in 
addition to at least 14 days of dosing at the target dose level, and a sample dosing titration 
scheme is shown in Table 6. This sample titration scheme is provided for illustrative 
purposes only, and dose titration paradigms specified in Table 6 may be modified based on 
the emerging safety, tolerability, or PK data.  For optional cohorts, additional titration 
schemes, including up to 4 weeks of dose titration without a dosing period at a target dose 
level, may be explored. The total duration of dose administration in any given subject will 
not exceed 28 days. The dose titration schedule will be provided in writing prior to the start 
of each cohort, whether planned or optional.  
During the titration period, if a subject does not tolerate titration to the next dose level, as 
determined by the principal investigator (PI) and with notification to the Sponsor, the subject 
may be reverted to the previously tolerated dose level, and dose titration to the next higher 
dose may be delayed by 1 to 2 days or longer, as needed.  
Following down-titration, 2 separate attempts at up-titration to the next dose level are 
permitted, per investigator discretion. If, per investigator assessment, unacceptable 
intolerance (eg, severe vomiting) occurs shortly following dose administration, the dose will 
not be readministered and the subject will resume dosing at the next scheduled dosing time. 
Subjects whose dose level is tolerability-limited may continue in the study for the intended 
duration of their assigned cohort (with 28 days dosing in total) at their own individual MTD, 
as judged to be appropriate by the PI and Sponsor. For Cohorts 2-5, titration will not be 
permitted after Day 14 and subjects should remain on the same dose (even if lower than the 
target dose) from Days 15-28.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 25
Actual doses, titration dosing schedules and target exposures may be adjusted during the
study based on emerging human safety and PK data but will not be predicted to exceed the 
PK stopping limits of a total Cmax of 26177 ng/mL and a total AUC24 of 199860 ng∙h/mL, as 
listed in Section 3.2.
Table 6.
Sample Titration Scheme and Dosing Paradigm
Cohorta
Study Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 through 28b
1
15 mg 
BID
15 mg 
BID
15 mg 
BID
15 mg 
BID
15 mg 
BID
15 mg 
BID
15 mg 
BID
15 mg BID
2
15 mg 
BID
50 mg 
BID
50 mg 
BID
50 mg 
BID
50 mg 
BID
50 mg 
BID
50 mg 
BID
50 mg BID
3
15 mg 
BID
50 mg 
BID
100 mg 
BID
150 mg 
BID
150 mg 
BID
150 mg 
BID
150 mg 
BID
150 mg BID or 
MTDc
4
15 mg 
BID
50 mg 
BID
100 mg 
BID
150 mg 
BID
200 mg 
BID
250 mg 
BID
300 mg 
BID
300 mg BID or 
MTD
a. Doses and dose titration approaches for Cohort 5 and optional cohorts (if studied) are to be determined 
(TBD).
b. Dosing administered from Days 15 through 28.
c. For subjects not able to reach to target dose of that cohort, the individual MTD for that subject may be 
permitted.
For all dosing and titration regimens, matching placebo will also be administered.
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective: 
Primary Endpoints: 

To evaluate the safety and 
tolerability of ascending, 
multiple, oral doses of 
PF-06882961, administered to 
adult subjects with T2DM.

Assessment of AEs, safety laboratory tests, vital 
signs and 12-lead ECGs.
Secondary Objectives: 
Secondary Endpoints: 

To characterize plasma 
pharmacokinetics of 
PF-06882961 following Day 1 
and following multiple, oral 
doses administered to adult 
subjects with T2DM.

PF-06882961 plasma pharmacokinetic 
parameters AUC24, Cmax, Tmax, t½ (as defined in 
Section 9.3.1, as appropriate for the dosing 
paradigm) following Day 1, and multiple dose 
administration, as data permit.

To characterize the PK of 
PF-06882961 in urine following 
multiple, oral doses administered 
to adult subjects with T2DM.

Urine PK parameters for PF-06882961, as data 
permit: Ae24, Ae24%, and CLr.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 26
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 27
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. STUDY DESIGN
3.1. Study Overview
This is a randomized, double-blind (sponsor-open), parallel, placebo-controlled, multiple oral 
dose-escalating study of PF-06882961 in subjects with T2DM on a background of metformin
monotherapy.
Subjects will receive oral doses of PF-06882961 or placebo in this study.  A total of 
approximately 12 subjects (9 active and 3 placebo) will be enrolled in each cohort, for a total 
of approximately 60 (Cohorts 1-5) or up to approximately 96 (if including optional 
Cohorts 6-8) subjects randomized. As a result, the maximum number of cohorts in the study 
will not exceed 8, corresponding to a maximum of 96 completed subjects. The 
randomization ratio within a cohort will be 3:1 between PF-06882961 and placebo. The 
study will be conducted at approximately 2-5 clinical sites in the US. Attempts will be made 
to equally balance the enrollment of subjects to active and placebo across sites within each 
cohort. It is not necessary for every site to participate in every cohort.  For each cohort, an 
attempt will be made to have at least 1 subject randomized to placebo per site, which will be 
facilitated through block randomization.
Dose titration will be incorporated to enhance tolerability to PF-06882961 (see 
Section 1.3.2.3). Doses and dose titration schemes in the escalation sequence may be 
modified or repeated as guided by emerging safety, and PK data.  The size of the dose 
increment and titration rate may be reduced or increased as the study progresses dependent 
C
C
I

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 28
upon emerging PK, safety and tolerability data, but dose increments from one cohort to the 
succeeding cohort will not be greater than approximately semi-logarithmic. Doses and
dosing durations for Cohort 5 and optional Cohorts 6-8 will be provided to investigators in 
writing prior to initiation of dosing in these cohorts. Predicted steady state exposures for all 
cohorts will also not exceed the proposed PK stopping limits (see Section 1.3.2.3 and
Section 3.2).
Subjects will be admitted to the clinical research unit (CRU) on or before Day -2 and may be 
discharged at PI discretion following completion of all assessments on Day 30, as described 
in Table 1and Section 7.  For individual subjects, the total duration of participation from the 
Screening visit to the on-site Follow-up visit will be approximately 15 weeks.  A Follow-up 
visit and a Follow-up contact (may be a phone call) will occur 35-42 days and 56-63 days 
following the first dose of IP on Day 1, respectively. Subjects who discontinue prior to 
completion of the study may be replaced, at the discretion of the PI and Sponsor.
Dosing is anticipated to occur with food, as listed in the Schedule of Activities and
Section 4.4.1.  
The formulations administered in this study will be PF-06882961 
 
tablets, or matching placebo (see Section 5).  A Sample study design overview is shown in
Figure 1, however, treatment sequences, actual doses, target exposures, formulation, fasting
state, titration, and dose increments may be adjusted during the study based on emerging 
safety, tolerability, and PK data. 
Figure 1.
Study Design Overview
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 29
3.2. Dose Escalation and Stopping Rules 
Dose escalation and stopping rules will be used to determine whether the MTD has been 
attained.  Dose escalation may be stopped if it is determined that the limits of safety and/or 
tolerability have been reached.  This decision will be made after a discussion takes place 
between the sponsor study team and the PI.  The sponsor study team may not overrule the 
PI’s decision to stop dose escalation.  If dose escalation is stopped because of any of these 
criteria, additional cohorts may receive the same or lower doses of the IP.
The dose escalation will be halted based on the following criteria:

If 50% or more of the subjects receiving active drug at a given dose level (but not 
subjects receiving placebo) develop similar clinically significant laboratory, ECG, or 
vital sign abnormalities, or severe AEs in the same organ class, indicating 
dose-limiting intolerance.

Dosing will be paused for any serious adverse event (SAE) that occurs in a subject 
receiving active treatment until causality is fully assessed by the PI and sponsor.  
Dosing may resume if the SAE is determined to be not drug-related by the PI and 
sponsor.  If the SAE is determined to be either drug-related or unknown, either dosing 
will cease or the SAE will be evaluated by the sponsor’s protocol review committee 
(or similar review group), which is independent of the study team and investigators.
If the protocol review committee determines that dosing may resume, a plan that 
mitigates risks to subjects with the resumption of dosing will be implemented. Such a 
plan could include measures such as a revision of inclusion/exclusion criteria, 
repeating or reducing the dose, or adding appropriate safety monitoring.

It is determined that the limit of safety and/or tolerability has been reached.  This 
decision will be made following discussions between the study team and the 
investigators.

Other findings that, at the discretion of the study team and the investigators, indicate 
that dose escalation should be halted.

If, at any dose level, the average exposure reaches or exceeds the PK stopping limits:

Cmax: 26177 ng/mL total (ie, 767 ng/mL unbound) or

AUC24: 199860 ng∙h/mL total (ie, 5856 ng∙h/mL unbound).

If, based on the observed data, the group mean Cmax or AUC (based on total plasma 
concentration) of the next planned dose is projected to exceed the escalation limits, 
that dose will not be explored.  Modified doses may be explored if they are not 
expected to exceed PK stopping criteria.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 30
Progression to the next cohort dose level will occur if the prior dose was determined to be 
sufficiently tolerated and after satisfactory review of the available safety and PK data. Data 
required for dose escalation evaluation will be determined by cohort:

For Cohorts 1 and 2: dose escalation will be based on review of safety and PK data 
through Day 14 (as listed in Table 1 and Table 2 in the Schedule of Activities). 

For Cohorts 3 and 4: Dose escalation will be based on review of safety data and PK 
through Day 21 (as listed in Table 1 and Table 2 in the Schedule of Activities).

For Cohort 5 and optional Cohorts 6, 7 and 8 (if evaluated): timing of safety and PK 
data will be determined based on dosing paradigm for that cohort, and will be either 
Day 14 safety and PK or Day 21 safety and PK (as listed in Table 1 and Table 2 in the 
Schedule of Activities). The timing of safety and PK required for dose escalation for 
these cohorts will be provided in writing prior to initiation of dosing for these cohorts.

For all study cohorts, each dose escalation will be based on review of available safety 
and PK data for at least 8 subjects (including at least 1 placebo) from that cohort. 
Details on safety assessments included in dose escalation review are provided in Section 7.1
and Table 1.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects 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 subject is suitable for this protocol.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
1. Patients with T2DM who are taking metformin monotherapy as their only 
anti-hyperglycemic treatment.  Metformin dose must be 500 mg per day and must be 
stable, defined as no change in the treatment, including dose, for at least 2 months
prior to the screening visit.  For further information, see Section 5.8.
2. HbA1c 7.0% and 10.5% at screening.  
3. Body mass index (BMI) of 24.5 to 45.4 kg/m2; and a total body weight >50 kg 
(110 lb).
4. Males and female subjects of non-childbearing potential between the ages of 18 and
70 years, inclusive of age at the time of the screening visit.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 31
Female subjects of nonchildbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause and have a serum follicle-stimulating hormone (FSH) level 
confirming the postmenopausal state;  
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are
considered to be of childbearing potential.
5. Evidence of a personally signed and dated informed consent document (ICD) 
indicating that the subject has been informed of all pertinent aspects of the study. 
6. Subjects who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).

Patients who have chronic conditions other than T2DM (for example, 
hypercholesterolemia or hypertension) but are controlled by either diet or stable
doses of medications may be included (for example, a subject with 
hypercholesterolemia on appropriate treatment is eligible). See Section 5.8 for 
further information on concomitant medications.
2. Subjects with any of the following medical conditions: 

Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, or any area of intestinal resection, active inflammatory bowel 
disease or pancreatic insufficiency);

Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes; 

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;

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 32

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;

History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; 
positive testing for HIV, hepatitis B surface antigen (HepBsAg), hepatitis B core 
antibody (HepBcAb), or hepatitis C antibody (HCVAb);

Personal or family history of medullary thyroid carcinoma (MTC) or multiple 
endocrine neoplasia syndrome type 2 (MEN2), or subjects with suspected MTC 
per the PI’s judgement;

Acute pancreatitis or history of chronic pancreatitis;

Acute gallbladder disease. 
3. At Screening, subjects with an estimated glomerular filtration rate (eGFR)
<60 mL/min/1.73m2 as calculated by the modification of diet in renal disease 
equation (MDRD), and confirmed via a single repeat, if deemed necessary.
4. A positive urine drug test.  Subjects that have been medically prescribed 
benzodiazepines and report the use of these drugs to the investigator at the screening 
visit may be allowed to participate if approved by the sponsor.
5. 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 
before screening.
6. Administration of an investigational drug within 30 days (or as determined by the 
local requirement) or 5 half-lives preceding the first dose of IP (whichever is longer).  
7. Screening supine BP 160 mmHg (systolic) or 100 mmHg (diastolic), following at 
least 5 minutes of supine rest.  If BP is 160 mmHg (systolic) or 100 mmHg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the subject’s eligibility.
8. Screening supine 12-lead ECG demonstrating a corrected QT (QTcF) interval 
>450 msec or a QRS interval >120 msec.  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 subject’s eligibility.
9. Subjects 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:  

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 33

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level
1.5 × upper limit of normal (ULN);

Total bilirubin level 1.5 × ULN; 

Fasting C-peptide <0.8 ng/mL;

TSH > ULN;

Serum calcitonin > ULN;

Amylase > ULN or lipase > ULN;

Blood glucose >270 mg/dL.
10. Fasting fingerstick blood glucose (FSBG) on Day -2 of >270 mg/dL.
11. Fertile male subjects who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for the 
duration of the study and for at least 28 days after the last dose of IP.  
12. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.  
13. History of sensitivity to heparin or heparin-induced thrombocytopenia only if heparin 
is used to flush IV catheters.
14. Unwilling or unable to comply with the criteria in the Lifestyle Requirements section 
of this protocol.
15. Subjects who are 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 subjects who are Pfizer employees, including their family members,
directly involved in the conduct of the study.
16. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or IP administration or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the subject inappropriate for entry into this study.
4.3. Randomization Criteria
Subjects will be randomized into the study provided they have satisfied all subject eligibility 
criteria outlined in Section 4.1 and Section 4.2.  The randomization ratio within a cohort will 
be 3:1 between PF-06882961 and placebo.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 34
4.4. Lifestyle Requirements
The following guidelines are provided:
4.4.1. Meals and Dietary Restrictions

4-hour fast (except water) prior to admission to CRU on Day -2.

Subjects must abstain from all food and drink (except water) at least 8 hours prior to 
the collection of the first blood sample at Screening, each inpatient study day , and 
the follow-up visit (eg, safety laboratory, PK, or PD assessment).

Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices - see 
below) may be consumed with meals and the evening snack.

The initial caloric intake/menu assigned to each subject will be based on the Harris 
Benedict formula (sedentary lifestyle; to be provided to the site prior to study start) 
using the subject’s body weight measured at screening.

On days with MMTT as listed in Table 2 of the Schedule of Activities (including 
evening prior to MMTT) only: subjects will be required to consume all provided 
food, including the liquid meal and all standard meals provided on these days. In 
addition, the approximate percentage of food consumed should be recorded in the 
case report form (CRF).

Subjects will not be required to consume all provided food during standard meals
on other study days.

When a meal or snack is scheduled at the same time as an ECG, the meal will be 
provided after the ECGs are completed. 

Breakfast will be provided at approximately 0800 hours each day:

A standard breakfast will be provided after dosing on all days except those when 
the MMTT is administered; 

For the MMTT, the mixed meal will be provided as 16 ounces of Ensure Plus®
and will be administered as listed in Table 2 of the Schedule of Activities. The 
entire Ensure Plus® meal is to be consumed within 10 minutes. (See 
Section 7.3.1).

Lunch will be provided approximately 4 hours after AM dosing (approximately
1200 hours) and at approximately the same time on each non-dosing day. On days 
with MMTT, lunch will be provided after the 4-hour postdose blood collection
samples for the MMTT have been completed.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 35

Dinner will be provided approximately 10 hours after AM dosing (approximately
1800 hours), and after dosing, and at approximately the same time on each 
non-dosing day.

An evening snack may be provided at approximately 2200 hours.

Subjects will receive the same snack each evening prior to the MMTT the 
following day. Subjects will be encouraged to consume the entire evening snack.

Meals on days with MMTT, will be standardized such that the subjects receive the
same menus for all meals on these days:

Subjects will be encouraged to consume their entire meals on Day -1 and evening 
snack on Day -2; 

If subjects do not consume their entire meal on Day -1, they will be instructed to 
consume the same amount of food (±10%) on the other days with MMTT that 
they ate on Day-1. If a subject consumes approximately <90% or >110% of what 
s/he consumed on Day -1 based on visual inspection by the site staff, the 
approximate percentage consumed should be noted in the CRF; 

The start time of all meals will be captured in the CRF on days with MMTT
including the Ensure Plus® mixed-meal provided for breakfast.

Subjects will be encouraged to eat all standard meals within 30 minutes on days 
with MMTT administration; 

Details on the meals provided to subjects, including the menu items, portion sizes and
approximate calories with nutritional macronutrient (% carbohydrate, fat and protein)
breakdown of the meal will be maintained in source documentation at the CRUs.
This information will not be collected in the case report form, however may be
submitted to the Sponsor upon request.

Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos) from 7 days prior to the first dose of IP until 
collection of the final PK blood sample.
4.4.2. Alcohol, Caffeine, and Tobacco

Subjects will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample.  Subjects 
may undergo an alcohol breath test or blood alcohol test at the discretion of the 
investigator.

Caffeine containing products, up to two 8-ounce cups of coffee or its equivalent per
day, will be permitted except at times outlined below. 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 36

Caffeine containing products may not be consumed within 2 hours prior to 
measuring vital signs and ECGs, and may not be consumed on days with MMTT;

Subjects may use tobacco- or nicotine-containing products during the study during
scheduled smoking breaks, as permitted by the CRU practices except as noted below.

Smoking will not be permitted during frequent sampling procedures (eg, will not 
be permitted until after the MMTT procedures), and will not be permitted within 
2 hours prior to any vital sign and ECG assessments. Smoking will also not be 
permitted 2 hours before and 2 hours following any dose of 
PF-06882961/placebo.
4.4.3. Activity

Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.
4.4.4. Contraception
All fertile male subjects who are, in the opinion of the investigator, sexually active and at risk 
for pregnancy with their partner(s) must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days after the last dose of IP.  The investigator or his or her designee, in 
consultation with the subject, will confirm that the subject has selected an appropriate 
method of contraception for the individual subject and his partner(s) from the permitted list 
of contraception methods (see below) and will confirm that the subject has been instructed in 
its consistent and correct use.  At time points indicated in the Schedule of Activities, the 
investigator or designee will inform the subject of the need to use highly effective 
contraception consistently and correctly and document the conversation and the subject’s 
affirmation in the subject’s chart (subjects 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 subject to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the subject or partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD). 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 37
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of IP and continuing for at least 28 days after the last dose of IP.
4.5. 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 portal. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study 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 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. For sites other than 
a Pfizer CRU, the contact number is not intended for use by the subject directly, and if a 
subject calls that number, he or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, IP is defined as a pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference/comparator in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 38
For this study, the IP is PF-06882961 and its matching placebo, both administered as oral 
tablets.
5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system.  The site personnel (study coordinator or specified 
designee) will be required to enter or select information including but not limited to the 
user’s identification (ID) and password, the protocol number, and the subject number.  The 
site personnel will then be provided with a treatment assignment and randomization number.  
The IRT system will provide a confirmation report containing the subject number and
randomization number assigned.  The confirmation report must be stored in the site’s files.
Subjects will receive the blinded IP (PF-06882961 or matching placebo) corresponding to 
their assigned randomization number.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
5.2. Breaking the Blind
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be a manual process.  Blinding codes should be broken 
only in exceptional circumstances when knowledge of the actual treatment code is absolutely 
essential for further management of the subject.  Investigators are encouraged to discuss with 
a member of the study team if they believe that unblinding is necessary.  When the blinding 
code is broken, the reason must be fully documented and entered on the CRF.
Blood specimens will be obtained from all subjects for PK analysis to maintain the study 
blind at the investigator site. Specimens from subjects randomized to placebo will not be 
routinely analyzed.  Investigator site staff [with the exception of the site pharmacist(s) and 
pharmacy assistant(s)] and blinded study monitor, if assigned, will be blinded to study 
treatment (PF-06882961 or placebo).  Other specified Pfizer personnel, including the 
separate unblinded monitor(s) (if assigned), will be unblinded to subject treatments in order 
to permit real-time interpretation of the safety and PK data; and provide information 
necessary to potentially alter the dose-escalation sequence.  The blinded study monitor will 
remain blinded to treatment until all monitoring for the study has been completed. To 
minimize the potential for bias, treatment randomization information will be kept 
confidential by Pfizer unblinded personnel and will not be released to the blinded 
investigator or blinded investigator site personnel until the study database has been locked or 
the investigator requests unblinding for safety reasons. 
5.3. Subject Compliance
IP will be administered under the supervision of investigator site personnel.  The oral cavity 
of each subject will be examined following dosing to ensure the IP was taken.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 39
5.4. Investigational Product Supplies
5.4.1. Dosage Form and Packaging
PF-06882961 will be supplied as 1 mg, 10 mg, and 100 mg IR or 50 mg 
 tablets for oral 
administration.  Matching placebo tablets will also be provided.  PF-06882961 or placebo 
tablets will be subsequently provided to the subjects in individual dosing containers 
according to their assigned treatment.  Multiple tablets may be required to deliver the total 
dose.
Subjects will continue taking their own metformin medication brought from home (or 
provided by the site, if necessary) at the same dose and frequency that was prescribed prior to 
entry into the study.
5.4.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject/caregiver by 
qualified staff.  Dispensing is defined as the provision of IP, concomitant treatments, and 
accompanying information by qualified staff member(s) to a healthcare provider, subject, or 
caregiver in accordance with this protocol.  Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities.
PF-06882961 and placebo tablets will be dispensed at the CRU by 2 operators, 1 of whom is 
an appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist).  The 
tablets will be provided in dose containers and labeled in accordance with Pfizer regulations 
and the clinical site’s labeling requirements.  The IP will be administered in a blinded fashion 
to the subject.
5.5. Administration
5.5.1. Administration of Blinded IP
Administration of blinded IP for all dosing regimens will occur under the conditions 
described in Section 4.4.1.  
Subjects will swallow the IP whole, without manipulating or chewing the IP prior to 
swallowing.  
5.5.2. Administration of Metformin and Other Concomitant Medications
On all study days while in the CRU, subjects will also be given their morning dose of 
metformin, brought from home, at the same time as their blinded IP. For subjects taking 
metformin more frequently than once a day, the investigator will determine the appropriate 
times during the day to administer those doses, however the timing should be the same 
between inpatient days, and care should be exerted to minimize changes to the subject’s 
stable medication routine. Some flexibility around dosing times of concomitant medications 
is allowed (see Section 5.8), but as much as possible, subjects should maintain a similar 
CC
I

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 40
dosing schedule for all concomitant medications, including metformin, as they did prior to 
the study.
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all IPs are 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.
IPs should be stored in their original containers and in accordance with the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product-label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the IP must be quarantined and not used until Pfizer provides 
permission to use the IP.  It will not be considered a protocol deviation if Pfizer approves the 
use of the IP after the temperature excursion. Use of the IP prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions. 
5.7. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the IP supplies.  All IPs will be accounted for using a drug accountability 
form/record. 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 41
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused IP (eg, at the 
site).  If destruction is authorized to take place at the investigator site, the PI 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.
5.8. Concomitant Treatment(s)
Subjects in this trial will be allowed to be on certain concomitant medications that have been 
prescribed to treat concurrent diseases such as hyperlipidemia and hypertension. Attempts 
must be made not to alter the doses and regimens of the background medications after 
randomization and for the duration of participation in this study. Any changes must be 
captured in the CRF. 
Treatments taken within 28 days before the first dose of IP will be documented as a prior 
treatment.  Treatments taken after the first dose of IP will be documented as concomitant 
treatments.
Medications, prescription or non-prescription or herbal supplements not specifically listed in 
Section 5.8.5 may be permitted, but only after review and approval by the Sponsor. 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatment at each clinic visit.
5.8.1. Medications for Glycemic Control
All subjects are required to be taking metformin monotherapy prior to inclusion in this study, 
as listed in Section 4.1. At screening, this study requires that subjects have been taking a 
minimum metformin dose of 500 mg/day for at least 2 months prior to the screening visit.  
The dose of metformin, where possible, is expected to remain the same until completion of 
study participation (ie, Follow-up visit).  
Use of other medications for glycemic control is not permitted in this study (see 
Section 5.8.5).
5.8.2. Antihypertensive Medications
The use of background antihypertensive agent(s) is permitted (unless noted in Section 5.8.5). 
Doses of antihypertensive agents must be stable for at least 4 weeks prior to screening and 
throughout the study. Changes in dosing regimen of such agents, if necessary, may be
permitted after discussion with the Sponsor. These changes must be captured in the CRF.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 42
5.8.3. Lipid-Modifying Medications
The use of background lipid-modifying agents is permitted (except as noted in Section 5.8.5). 
Doses of such lipid-modifying agents must be stable for at least 4 weeks prior to screening 
and throughout the study. Changes in dosing regimen of such agents are not permitted 
during the study.
5.8.4. Management of Nausea and Vomiting
Nausea and vomiting have been reported with administration of GLP-1R agonists.  Subjects 
complaining of nausea may be managed conservatively with bed rest and/or fluid 
management at the discretion of the investigator.  If the nausea and vomiting are not 
amenable to conservative management, anti-emetics (eg, prochlorperazine, promethazine, 
ondansetron) may be administered at the investigator’s discretion with notification to the 
sponsor and entry in the CRF.
5.8.5. Prohibited Medications
5.8.5.1. Medications Not Permitted within 3 Months of Screening
The use of the following classes of agents is not permitted within 3 months prior to
screening and for the duration of participation in the study:

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone;

Subcutaneously administered agents for glycemic control (eg, insulin, exenatide,
liraglutide, pramlintide).
5.8.5.2. Medications Not Permitted within 4 Weeks of Screening
In addition to the above, subjects on the following background medications must have these 
agents discontinued at least 4 weeks prior to Screening:

Other oral anti-diabetic medications, including: 

Sulfonylureas such as acetohexamide, chlorpropamide, tolazamide, tolbutamine,
glimepiride, glipizide, glyburide;

Meglitinide analogues such as repaglinide, nateglinide;

Dipeptidyl peptidase-4 inhibitors (DPP-4i) such as sitagliptin, saxagliptin,
vildagliptin;

α-glucosidase inhibitors such as acarabose, miglitol;

Sodium-glucose cotransporter-2 (SGLT2) inhibitors such as canagliflozin;

Systemic glucocorticoids such as prednisone, dexamethasone, triamcinolone,
budesonide, betamethasone;

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 43

Note: As an exception, steroid-containing inhalers, nasal sprays and topical
formulations are permitted in this study;

Immunosuppressants such as cyclosporine and tacrolimus;

Appetite- or weight-modifying medications, including non-prescription or herbals;

Pharmacological agents with approved indication for weight loss such as orlistat and 
sibutramine;

(Medical-grade) marijuana, regardless of medical indication;

Anti-psychotic medications such as olanzapine, risperidone;

Antidepressant medications such as tricyclic agents, selective serotonin reuptake
inhibitors, and serotonin/norepinephrine reuptake inhibitors;

Coumarin-type anticoagulants or other anticoagulants (eg, dabigatran);

Anticonvulsants;

Opioids;

Antiarrhythmic;

Non-selective β-blockers;

Thiazide diuretics >25 mg per day;

Sympathomimetic agents; 

Rosuvastatin.
5.8.5.3. Medications Not Permitted for Doses Above 300 mg BID
As described in Section 1.2.2, PF-06882961 is a reversible inhibitor of CYP2C8 and 
UGT1A1 and is a weak time- and NADPH-dependent inhibitor of CYP3A4/5. As such, 
PF-06882961 at doses where projected AUC24 exposure is expected to exceed approximately 
7392 ng.h/mL should not be administered with drugs that are primarily metabolized by these 
enzymes.  
Based on preliminary modeling of PK data emerging from the ongoing FIH study, this 
AUC24 is currently predicted to be achieved at PF-06882961 doses exceeding 300 mg BID
(Table 4).  Therefore, for cohorts administered doses of PF-06882961 above
300 mg BID only (this dose level may be refined based on emerging data from this study), 
subjects on a background therapy (for example, for treatment of hypertension or 
dyslipidemia) which is known to have a high risk of DDI through CYP3A, CYP2C8 or 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 44
UGT1A1, must switch to another acceptable treatment, as determined by the subject’s 
physician or the PI, at least 4 weeks prior to Day 1 (a non-exhaustive list of such medications 
is provided in Appendix 2).  In addition, subjects must be in a stable condition, conforming 
to all Inclusion/Exclusion criteria (see Section 4.1 and Section 4.2).
5.9. Rescue Medication
There is no rescue therapy to reverse any AEs observed with administration of IP; standard 
medical supportive care must be provided to manage the AEs (see Section 5.8.4 for 
management of nausea and vomiting).
For medical management of hypoglycemia, the investigator may administer oral 
carbohydrate, glucagon, or IV glucose according to his or her medical judgment. At a 
minimum however, treatment or administration of a scheduled meal should be given if 
glucose falls <60 mg/dL for at least 15 minutes, irrespective of whether the subject exhibits 
symptoms. Investigators may choose to administer treatment sooner if subjects have 
bothersome symptoms of hypoglycemia along with glucose values of 70 mg/dL.
No rescue therapy will be provided for hyperglycemia. If a subject has sustained elevated
fasting plasma glucose concentrations that are >270 mg/dL on 3 consecutive measurements
over 3 days, that subject will be discontinued, and the investigator will recommend further 
appropriate glycemic treatment according to the local healthcare standards and national
guidelines.
6. STUDY PROCEDURES
6.1. Proposed Chronology of Procedures
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible.

ECGs: obtain prior to vital sign measurements and as close as possible to the 
scheduled time, but prior to blood specimen collection (refer to Section 7.1.5);

Vital Signs (BP and pulse rate): obtain as close as possible to the scheduled time, but 
prior to blood specimen collection (refer to Section 7.1.4);

Fasting blood samples: after assessment of 12-lead ECG and vital signs but prior to 
dosing;

PK blood specimens: obtain at the scheduled time (refer to Section 7.2.1);

Other pre-dose procedures: obtain all other procedures as close as possible to the 
scheduled time, but may be obtained before or after blood specimen collection;

Dosing: must occur at the scheduled nominal time (refer to Section 5.5) and following 
predose blood sample collection.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 45

If an IV catheter is placed for serial blood sample collections, ECGs and vital signs 
(pulse rate, BP) assessments should be either collected prior to the insertion of the 
catheter or sufficient rest period after catheter insertion introduced to minimize 
impact of catheter placement on these assessments.
6.2. Screening
Refer to the Schedule of Activities for the study procedures to be completed at the screening 
visit.  A signed and dated ICD will be obtained from each subject at the screening visit before 
performing any protocol-specific procedures.  
Subjects will be screened within 28 days prior to administration of the blinded IP to confirm 
that they meet the subject selection criteria for the study.  The investigator (or an appropriate 
delegate at the investigator site) will obtain informed consent from each subject in 
accordance with the procedures described in Section 1.2.3.
A subject who qualified for this protocol but did not enroll from an earlier cohort/group may 
be used in a subsequent cohort/group for this study.  Subjects may be re-screened and all 
screening procedures must be repeated and the subject assigned a new 8-digit study-specific 
subject identification number (SSID) number.  This criterion would also apply to subjects 
who screened for this study more than 28 days prior to dosing. 
To prepare for study participation, subjects will be instructed on the information in 
Section 4.4 and Section 5.8 of the protocol.
6.3. Study Period
Refer to the Schedule of Activities for the study procedures to be completed during the Study 
Period.
 
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain in the CRU until 
such abnormalities are deemed not clinically significant, or it is safe for outpatient follow-up.  
If the subject is unable or unwilling to remain in the CRU and/or when outpatient follow-up 
is deemed appropriate, the Pfizer medical monitor (or designated representative) should be so 
notified, and the investigator should make every effort to arrange follow-up evaluations at 
appropriate intervals to document the course of the abnormalities.
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 46
6.4. Follow-up 
6.4.1. Follow-up Visit
Subjects will return to the CRU 7 to 14 days following the last dose of IP for a Follow-up 
visit.  Refer to the Schedule of Activities Table 1 and Table 2 for the study procedures to be 
completed at this visit.
6.4.2. Follow-up Contact
Follow-up contact will be completed at least 28 calendar days and up to 35 calendar days 
after the last administration of the investigational product to capture any potential AEs (see 
Section 8.1.4) and to confirm appropriate contraception usage (see Section 4.4.4).  Contact 
with the subject may be done via a phone call.
6.5. Subject Withdrawal/Early Termination
Withdrawal of consent: 
Subjects 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 subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.  
Subjects 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 investigational product 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 subject 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.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  All 
attempts should be documented in the subject’s medical records.  If it is determined that the 
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death.  If the investigator’s use of a third-party representative to assist in the follow-up 
portion of the study has been included in the subject’s informed consent, then the investigator 
may use a sponsor-retained third-party representative to assist site staff with obtaining the 
subject’s contact information or other public vital status data necessary to complete the 
follow-up portion of the study.  The site staff and representative will consult publicly 
available sources, such as public health registries and databases, in order to obtain updated 
contact information.  If, after all attempts, the subject remains lost to follow-up, then the 
last-known-alive date as determined by the investigator should be reported and documented 
in the subject’s medical records.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 47
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also 
Section 8.1.3) or behavioral reasons, or the inability of the subject to comply with the 
protocol-required schedule of study visits or procedures at a given investigator site.  The 
early termination visit applies only to subjects who are randomized and then are prematurely 
withdrawn from the study.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, CRU staff may send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow-up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request that the subject return for a final visit, if applicable, and follow up with the subject 
regarding any unresolved AEs.
It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  At the 
early-withdrawal visit, every effort must be made to complete the following assessments:

Full physical examination, if there is a new or open AE or clinically significant 
abnormal physical finding from the last visit;

Supine BP and pulse rate measurements;

12-Lead ECG measurement;

Blood and urine specimens for safety laboratory tests;

Blood sample for PK analysis.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the subject’s safety was preserved.
If the subject withdraws from the study and also withdraws consent 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.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor provided that the nature of the safety event does not 
preclude dose escalation and that exposure stopping limits are observed.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 48
7. ASSESSMENTS
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 subject.  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.
7.1. Safety
7.1.1. Laboratory Tests
The following clinical laboratory tests will be performed at times defined in the 
Schedule of Activities 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.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 49
Table 7.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
PT/INR/aPTT
BUN/urea
Creatinine
Plasma glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST
ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Serum total bile acidsd
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
FSHb
Urine drug screening
HIVc
HepBsAgc
HepBcAbc
HCVAbc
HbA1c
C-peptided
Additional Tests
(Needed for Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
For female subjects to confirm post-menopausal status only; at screening.
c.
At Screening only.
d.
Assessed at Screening for exclusion, but also as part of MMTT.

The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol
(THC), opiates/opioids, benzodiazepines, and amphetamines.

In addition to the clinical laboratory tests listed in Table 7, blood samples will be 
drawn and analyzed for calcitonin, amylase, lipase, lipid panel, TSH and FT4 at the 
time points listed in Table 1 and Table 2 in the Schedule of Activities. Review of 
these data is not required prior to dose escalation in each cohort, cumulative results 
will be reviewed as they become available.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 50
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.  Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings.  These data will not be included in the clinical study report (CSR).  Samples 
to be used for this purpose will be shipped to either a Pfizer-approved BBS facility or other 
designated laboratory and retained for up to 1 year following the completion of the study.
7.1.2. Physical Examinations
Physical examinations should be performed at nominal time points specified in the 
Schedule of Activities of this protocol.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination 
will include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
and gastrointestinal, musculoskeletal, and neurological systems.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, and subject-reported symptoms.
7.1.3. Body Weight
Body weight measurements will be obtained at the time points outlined in the 
Schedule of Activities.  If possible, the same scale should be used for a particular subject for 
all body weight measurements obtained at the CRU. For measuring weight, a scale with 
appropriate range and resolution is used and must be placed on a stable, flat surface. 
Body weight will be measured at outpatient visits to the study site as listed in Table 1 of the 
Schedule of Activities under the following conditions:

After void of urine;

After removal of shoes, bulky layers of clothing, and jackets so that only light 
clothing remains; 

While remaining still during measurement.
During admission to the CRU, body weight will be measured at the time points listed in 
Table 2 of the Schedule of Activities.  Measurement will be taken under the following 
conditions:

In the morning, prior to eating and drinking;

After the subject has been asked to void;

While wearing only a hospital gown and no shoes;

While remaining still during measurement. 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 51
7.1.4. Blood Pressure and Pulse Rate
BP and pulse rate will be measured at times specified in the Schedule of Activities section of 
this protocol.  Additional collection times, or changes to collection times, of BP and pulse 
rate will be permitted, as necessary, to ensure appropriate collection of safety data.
Supine BP will be measured with the subject’s arm supported at the level of the heart, and 
recorded to the nearest mmHg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. Subjects should be 
instructed not to speak during measurements.  When triplicate BP and pulse rate are required, 
they will be obtained approximately 2 to 4 minutes apart; the average of the triplicate BP and 
pulse rate measurements collected at each nominal time point on Day -1 will serve as each 
subject’s time-controlled baseline values.
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP
and pulse rate should be obtained prior to the nominal time of the blood collection (refer to 
Section 6.1).
7.1.5. Electrocardiogram 
12-Lead ECGs should be collected at times specified in the Schedule of Activities section of 
this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. When a meal or snack is scheduled at the same time as an 
ECG, the ECG must be performed prior to the meal/snack.
Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average of 
the triplicate ECG measurements collected at each nominal time point on Day -1 will serve 
as each subject’s time-controlled baseline QTcF value.
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  
If the QTcF interval is increased by 45 msec from the baseline, or an absolute QTcF value 
is 500 msec for any scheduled ECG, then 2 additional ECGs will be collected, 
approximately 2 to 4 minutes apart, to confirm the original measurement.  If either of the 
QTcF values from these repeated ECGs remains above the threshold value (ie, is 45 msec 
from the baseline, or is 500 msec), then a single ECG must be repeated at least hourly until 
QTcF values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 52
Further ECG monitoring will occur if a) the mean value from the triplicate measurements for 
any post-dose QTcF interval is increased by 30 msec from the baseline and is >450 msec;
or b) an absolute QTcF value is 500 msec for any scheduled ECG. If either of these 
conditions occurs, then single ECG measurements must be repeated at least hourly until 
QTcF values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.
If QTcF values remain 500 msec (or 30 msec from the baseline and >450 msec) for 
greater than 4 hours (or sooner, at the discretion of the investigator), or QTcF intervals get 
progressively longer, the subject should undergo continuous ECG monitoring.  A cardiologist 
should be consulted if QTcF intervals do not return to less than 500 msec (or to <45 msec 
above the baseline) after 8 hours of monitoring (or sooner, at the discretion of the 
investigator).
ECG data will be submitted to a central laboratory for overread measurement of ECG 
intervals and overall interpretation.  The central ECG laboratory will be blinded to treatment 
allocation.  The final ECG report from the central laboratory should be maintained in the 
subject’s source documentation and be the final interpretation of the ECG recording.  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement or technical aberration as contributing to the ECG abnormality.  It is important 
that leads are 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.
7.1.6. Glucometer Monitoring of Glucose
Investigators will monitor FSBG using glucometer measurements at the times specified in the 
Schedule of Activities. FSBG measurements should be taken before breakfast while the 
subject is confined to the CRU. 
FSBG readings will be maintained at the sites in source documents, and only the glucose 
results from the laboratory will be reported in the study database. The sites may share the 
FSBG readings with the Sponsor for the purpose of dose-escalation decisions, but these data 
will be stored in the sites’ source documents unless related to an AE as described below. 
Specifically, if an FSBG result is 70 mg/dL, a second FSBG should be obtained to confirm 
the glucose value, in addition to a venous sample that will be sent to the clinical laboratory 
for confirmation. If the value from this second FSBG is also 70 mg/dL, the second value 
will be recorded as a hypoglycemic AE. FSBG will continue to be monitored until the 
glucose value returns to >70 mg/dL. Samples may be taken more frequently if deemed 
necessary by the investigator. FSBG readings from a glucometer are permitted at any time if 
the investigator or subject notes symptoms of hypoglycemia.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 53
7.1.7. Hypoglycemia Reporting
Hypoglycemia will be assessed and reported in several categories: severe hypoglycemia,
documented symptomatic hypoglycemia, asymptomatic hypoglycemia, and probable
hypoglycemia.
Severe hypoglycemia: In order to be considered severe hypoglycemia all of the following
criteria must be met:

The subject required the assistance of another person to actively administer
carbohydrate, glucagon, or other resuscitative actions.

The subject exhibited at least one of the following neurological symptoms:

Memory loss;

Uncontrollable behavior;

Irrational behavior;

Unusual difficulty in awakening;

Suspected seizure;

Seizure;

Loss of consciousness. 

The subject had one of the following:

Blood glucose <50 mg/dL, or

If blood glucose was not measured, the clinical manifestations were reversed by 
carbohydrate administration.
Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by a measured glucose concentration 70 mg/dL. 
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of
hypoglycemia but with a measured glucose concentration 70 mg/dL.
Probable symptomatic hypoglycemia: An event, during which typical symptoms of
hypoglycemia are not accompanied by a “real time” glucose determination, but were
presumably caused by a plasma glucose concentration 70 mg/dL. The clinical picture must
include prompt resolution with oral carbohydrates, subcutaneous glucagon, or intravenous
glucose.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 54
7.2. Pharmacokinetics
7.2.1. Plasma for Analysis of PF-06882961 
During all study periods, sufficient volume of blood (approximately 3 mL) to provide a 
minimum of approximately 1 mL plasma for PK analysis will be collected into appropriately 
labeled tubes containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) at times 
specified in the Schedule of Activities section of the protocol.  
The actual times may change, but the number of samples will remain the same.  All efforts
will be made to obtain the PK samples at the exact nominal time relative to dosing.  For 
samples up to and including 10 hours post-dose, samples obtained within 10% of the nominal 
time (eg, within 6 minutes of a 60 minute sample) from dosing will not be captured as a 
protocol deviation, as long as the exact time of the collection is noted on the source 
document and data collection tool (eg, CRF).  For samples more than 10 hours post-dose, 
samples obtained 1 hour away from the nominal time post dosing will not be captured as a 
protocol deviation, as long as the exact time of the collection is noted on the source 
document and data collection tool (eg, CRF). 
Samples will be analyzed using a validated analytical method in compliance with Pfizer
standard operating procedures (SOPs).
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PK of the IP, samples may be used for metabolite identification 
and/or evaluation of the bioanalytical method, as well as for other internal exploratory 
purposes.  These data will not be included in the CSR.
7.2.2. Urine for Analysis of PF-06882961 and/or Metabolite Screening
Urine will be collected at times specified in the Schedule of Activities.  

Prior to dosing on Day 1, each subject must complete a forced void with an aliquot
(approximately 10 mL) from this urine (urine blank) labeled and stored frozen for 
measurement of drug concentrations, per detailed instructions offered in a laboratory 
manual prior to the start of the study. 

Following dosing on Day 28, each void post dose will be collected and saved in a 
container and stored in refrigerated conditions (ie, 2-8C) for the duration of the 
collection interval, as specified in Table 2 of the Schedule of Activities. 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 55

At the end of the collection interval, subjects must complete a forced void 
with this complete void included as part of the interval collection;

The urine container will be mixed thoroughly and total volume plus weight of 
the urine collected during the interval recorded;

An aliquot (approximately 20 mL) will be labeled and stored frozen for the 
potential measurement of drug concentrations and for potential metabolite
screening per detailed instructions offered in a laboratory manual prior to the 
start of the study; and the remaining urine discarded. 
Details regarding the processing, storage and shipping of the samples will be provided in the
lab manual.  The shipment address and assay lab contact information will be provided to the 
investigator site prior to initiation of the study.  The urine samples must be processed as 
indicated to maintain sample integrity. Any deviations from the urine sample processing 
steps given in the protocol or lab manual, including any actions taken, must be documented 
and reported to the sponsor. On a case-by-case basis, the sponsor may make a determination 
as to whether sample integrity has been compromised. Any sample deemed outside of 
established stability, or of questionable integrity, will be considered a protocol deviation.  
Samples for analysis of PF-06882961 PK will be analyzed using validated analytical methods
in compliance with Pfizer standard operating procedures.
Metabolite screening may be conducted at selected dose(s) first; based on these results a 
decision on whether or not to analyze samples from remaining doses may be made.  As part 
of understanding the properties of the study drug, urine samples may be used for evaluation 
of the bioanalytical method as well as for other internal exploratory purposes. These data 
would be used for internal exploratory purposes and would not be included in the CSR. 
 
 
 
 
 
 
 
 
 
 
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 56
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 57
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 58
 
 
  
 
 
 
 
 
 
 
 
7.5. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
550 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. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 59
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this 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 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  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.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 60
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject 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 investigational 
product must be reported to Pfizer Safety.
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.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 61
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease (omit for oncology and anti-retroviral 
studies);

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 62

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 63

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 64

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. 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 subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects 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 lab sample).  

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 65
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 subject’s 
individual baseline values and underlying conditions. Subjects 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:

Subjects 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 subjects 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).
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 subject 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, 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, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
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), 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 66
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) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.2. Exposure to the Investigational Product 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.
8.4.2.1. Exposure During Pregnancy
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 subject or subject’s partner becomes or is found to be pregnant during the subject’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 subject 
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 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 67
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 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the 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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.2.2. 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.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 68
8.4.2.3. 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 subject 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.
8.4.3. Medication Errors
Other exposures to the investigational product 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 
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 69
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
A sample size of up to approximately 12 subjects per cohort (9 active, 3 placebo) has been 
selected to minimize exposure to humans to a new chemical entity while allowing adequate 
characterization of safety and tolerability, PK, and PD at each dose level.  
9.2. Efficacy Analysis
Efficacy analysis is not applicable to this study. 
9.3. Pharmacokinetic Analysis
The PK concentration population will be defined as all randomized subjects who received at 
least 1 dose of PF-06882961 and in whom at least 1 plasma PK concentration value is 
reported.  The PK parameter analysis population will be defined as all randomized subjects 
who received at least 1 dose of PF-06882961 and who have at least 1 of the PK parameters of 
interest calculated.  PK samples from placebo samples will not be routinely analyzed.
Analysis and reporting of preliminary, qualitative characterization of metabolite profile of
PF-06882961 using pooled plasma and urine samples, if performed, will be reported
separately (and not included in the CSR).
9.3.1. Derivation of Pharmacokinetic Parameters
The PK parameters for PF-06882961 following Day 1 and multiple dose administration will 
be derived from the concentration-time profiles, as data permit.  The PK parameters to be 
assessed in this study, their definition and method of determination are outlined in Table 8, 
Table 9 and Table 10.  Actual PK sampling times will be used in the derivation of PK 
parameters.  Rac parameters will be calculated for titration cohorts after appropriate dose 
normalization. Additional detail on PK parameter definition for titrated and non-titrated 
cohorts will be provided in the SAP.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 70
Table 8.
Definition of Plasma PK Parameters for PF-06882961 in the Setting of BID Dosing
Parameter
Day 1 (D1) or 
Steady State (SS)
Definition
Method of Determination
Cmax1 and Cmax2
D1 & SS
Cmax1: maximum plasma concentration during the 
dosing interval τ1 =0 to 10 hours 
Cmax2: maximum plasma concentration during the 
dosing interval τ2=10 to 24 hours
Observed directly from data
Cmax
D1 & SS
Maximum plasma concentration observed from time 
zero to 24 hours
Observed directly from data
Tmax, 
Tmax1 and Tmax2
D1 & SS
Time for Cmax, Cmax1 and Cmax2
Observed directly from data as time of first 
occurrence
Cmax1 (dn), 
Cmax2(dn) and 
Cmax(dn)
D1 & SS
Cmax1, Cmax2 and Cmax normalized to a 1 mg dose.
Cmax1/Dose
Cmax2/Dose
Cmax/Dose
AUC1 and 
AUC2
D1 & SS
Area under the plasma concentration-time profile 
from time zero to time τ, where τ1 = 0 to 10 hours and 
τ2=10 to 24 hours k
Linear/Log trapezoidal method
AUC τ1(dn) and 
AUCτ2(dn)
D1 & SS
AUC τ1 and AUCτ2 normalized to a 1 mg dose.
AUCτ1/Dose
AUCτ2/Dose
AUC24
D1 & SS
Area under the plasma concentration-time profile 
from time zero to time 24 hours
AUCτ1 +AUCτ2
AUC24 (dn)
D1 & SS
AUC24 normalized to a 1 mg dose.
AUC24/Dose
AUClast
SS
Area under the plasma concentration-time profile 
from time zero to time of last quantifiable 
concentration
Linear/Log trapezoidal method
AUCinf
SS
Area under the plasma concentration-time profile 
from time zero extrapolated to infinite time
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable time point 
estimated from the log-linear regression analysis
and 
kel is the terminal phase rate constant calculated 
by a linear regression of the log-linear 
concentration-time curve.  Only those data points 
judged to describe the terminal log-linear decline 
will be used in the regression.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 71
AUCinf(dn)
SS
AUCinf normalized to a 1 mg dose
AUCinf/Dose
CL/F
SS
Apparent clearance over 24 hours
Dose/AUC24
Cmin
SS
Minimum plasma concentration during the interval 0 
to 24 hours.
Observed directly from data
Cav
SS
Average plasma concentration over 24 hours.
AUC24/24
Rac
SS
Observed accumulation ratio for AUC24
Non-titrated cohort(s): Steady State AUC24 / Day 
1 AUC24
Titrated cohorts: Rac parameters will be 
calculated after appropriate dose normalization
Rac,Cmax1
Rac,Cmax2 and 
Rac,Cmax
SS
Observed accumulation ratio for Cmax
Non-titrated cohort(s): Steady State Cmax1 / Day 
1 Cmax1
Steady State Cmax2 / Day 1 Cmax2 
and Steady State Cmax / Day 1 Cmax
Titrated cohorts: Rac parameters will be 
calculated after appropriate dose normalization
PTR
SS
Peak-to-trough ratio
Cmax/Cmin
t½
SS
Terminal half-life
Loge(2)/kel, where kel is the terminal phase rate 
constant calculated by a linear regression of the 
log-linear concentration-time curve.  Only those 
data points judged to describe the terminal 
log-linear decline will be used in the regression.
Vz/F
SS
Apparent volume of distribution
Dose/(AUC24 * kel)

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 72
Table 9.
Definition of Plasma PK Parameters for PF-06882961 in the Setting of QD Dosing
Parameter
Day 1 or Steady 
State (SS)
Definition
Method of Determination
Cmax
D1 & SS
Maximum plasma concentration observed from time 
zero to 24 hours
Observed directly from data
Tmax
D1 & SS
Time for Cmax
Observed directly from data as time of first 
occurrence
Cmax (dn)
D1 & SS
Cmax normalized to a 1 mg dose.
Cmax/Dose
AUC24
D1 & SS
Area under the plasma concentration-time profile 
from time zero to time 24 hours
Linear/Log trapezoidal method
AUC24 (dn)
D1 & SS
AUC24 normalized to a 1 mg dose.
AUC24/Dose
AUClast
SS
Area under the plasma concentration-time profile 
from time zero to time of last quantifiable 
concentration
Linear/Log trapezoidal method
AUCinf
SS
Area under the plasma concentration-time profile 
from time zero extrapolated to infinite time
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable time point 
estimated from the log-linear regression analysis
and 
kel is the terminal phase rate constant calculated 
by a linear regression of the log-linear 
concentration-time curve.  Only those data points 
judged to describe the terminal log-linear decline 
will be used in the regression..
AUCinf(dn)
SS
AUCinf normalized to a 1 mg dose
AUCinf/Dose
CL/F
SS
Apparent clearance
Dose/AUC24
Cmin
SS
Minimum plasma concentration during the interval 0 
to 24 hours.
Observed directly from data
Cav
SS
Average plasma concentration over 24 hours.
AUC24/24
Rac
SS
Observed accumulation ratio for AUC24
Non-titrated cohort(s): Steady State AUC24 / Day 
1 AUC24
Titrated cohorts: Rac parameters will be 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 73
calculated after appropriate dose normalization
Rac,Cmax
SS
Observed accumulation ratio for Cmax
Non-titrated cohort(s): Steady State Cmax / Day 
1 Cmax
Titrated cohorts: Rac parameters will be 
calculated after appropriate dose normalization
PTR
SS
Peak-to-trough ratio
Cmax/Cmin
t½
SS
Terminal half-life
Loge(2)/kel, where kel is the terminal phase rate 
constant calculated by a linear regression of the 
log-linear concentration-time curve.  Only those 
data points judged to describe the terminal 
log-linear decline will be used in the regression.
Vz/F
SS
Apparent volume of distribution
Dose/(AUC24 * kel)
Table 10.
Definition of Urine PK Parameters for PF-06882961
Parameter
Steady State (SS)
Definition
Method of Determination
Ae24
SS
Amount of unchanged drug recovered in urine over 
24 hours
Sum of [urine concentration * sample volumea] 
for each collection over the dosing interval 
Ae24 %
SS
Percent of dose recovered in urine as unchanged drug
100* Ae24/Dose
CLr
SS
Renal clearance
Ae24/AUC24
asample volume = (Urine weight in g / 1.020), where 1.020 g/mL is the approximate specific gravity of urine.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 74
9.3.2. Statistical Methods for PK Data
No formal inferential statistics will be applied to the PK data.
Plasma concentration of PF-06882961 will be descriptively summarized and plotted by
treatment, day and nominal PK sampling time.  Individual subject mean and median profiles 
of the plasma concentration-time data will be plotted by dose and day using actual and 
nominal times, respectively. Mean and median profiles will be presented on both 
linear-linear and log-linear scales.  
The plasma and urine PK parameters will be summarized descriptively by treatment and day, 
as appropriate.  Dose normalized (to 1 mg) parameters (as listed in Table 8) may be plotted 
against dose (using a logarithmic scale) for each day, and will include individual subject 
values and the geometric means for each dose.  Attainment of steady state will be assessed by 
a plot of predose concentrations over time.  
The observed accumulation ratio for AUC24 and Cmax (as listed in Table 8) will be 
summarized descriptively by treatment.  It will be analyzed after natural log transformation 
using a one-way analysis of variance with a single term for treatment. The means and 
90% confidence intervals (CIs) obtained from the model will be back-transformed to provide 
means and 90% CIs for the accumulation for each treatment. 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 75
 
 
 
 
 
9.7. Safety Analysis
All subjects who received at least 1 dose of study medication will be included in the safety 
analyses and listings. AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed 
and summarized on an ongoing basis during the study to evaluate the safety of subjects.  Any 
clinical laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will 
be described.  Safety data will be presented in tabular and/or graphical format and 
summarized descriptively, where appropriate.
Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will not be required to be reported, 
unless otherwise noted.  However, any untoward findings identified on physical and/or 
neurological examinations conducted during the active collection period will be captured as 
AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported.
In addition, C-peptide and HbA1c screening data will be collected and reported as 
demographic data.
9.7.1. Electrocardiogram Analysis
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS interval will be summarized by treatment and time.
The number (%) of subjects with maximum postdose QTcF values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment
Prolongation
Mild
Moderate
Severe
Absolute value (msec)
450 - <480
480 - <500
500
Increase from baseline 
in QTcF (msec) 
30 - <60
60
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 76
In addition, the number of subjects with corrected and uncorrected QT values >500 msec will 
be summarized.
At the nominal time points, the mean of the triplicate measurements will be used to represent 
a single observation at that time point. If any of the 3 individual ECG tracings has a QTcF
value >500 msec, but the mean of the triplicates is not >500 msec, the data from the subject’s 
individual tracing will be described in a safety section of the study report in order to place the 
>500 msec value in appropriate clinical context. However, values from individual tracings 
within triplicate measurements that are >500 msec will not be included in the categorical 
analysis unless the average from the triplicate measurements is also >500 msec.
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach.  If a PK/PD 
relationship is found, the impact of subject factors (covariates) on the relationship will be 
examined.  The results of such analyses will not be included in the CSR. 
9.7.2. Vital Sign Analysis
Supine blood pressures and pulse will be recorded at each assessment time indicated in the
Schedule of Activities. The average of any triplicate measurements will be calculated prior 
to analyzing the data.
The maximum decrease/increase in blood pressures and pulse rate from time-matched
baseline (Day -1) over all measurements taken post-dose, will be determined for each
subject.
No formal inferential statistics will be applied to the vital signs data. 
Actual values and changes from time-matched baseline in supine systolic and diastolic and 
pulse rate will be summarized by treatment, time postdose and day.
The supine systolic and diastolic BP and pulse rate measurements obtained following the 
Day 1 dose will have their corresponding Day 1 predose value subtracted from them. These 
values will then be compared with their corresponding values on Day-1, ie, the change in the 
time-matched Day -1 value from the baseline measure on that day. The differences will be 
summarized (N, mean, 90% CI) for each dose and time point. In addition, for supine systolic 
and diastolic BP and pulse rate, the time matched baseline subtracted differences between 
each dose and placebo will be summarized (N, mean, 90% CI) for each dose, time postdose 
and day.
Maximum values and maximum changes from time-matched baseline for vital signs will also
be summarized descriptively by treatment using categories as defined in the statistical
analysis plan. Numbers and percentages of subjects meeting the categorical criteria will be
provided and individual values listed in the CSR.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 77
9.7.3. Hypoglycemia Monitoring and Reporting
The hypoglycemic AEs (obtained from site glucometer readings) will be listed in a separate
table and summarized categorically.
9.8. Interim Analysis
No formal interim analysis will be conducted for this study. However, as this is a 
sponsor-open study, the sponsor will conduct unblinded reviews of the data during the course 
of the study for the purpose of safety assessment and facilitating dose-escalation decisions. 
In addition, these reviews may facilitate PK/PD modeling and/or supporting clinical 
development.
9.9. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, to ensure that the protocol and Good Clinical 
Practices (GCPs) are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs are accurate.  The investigator and institution will 
allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer 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 subject’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
For studies conducted at non-Pfizer investigator sites, 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. 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 78
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 79
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 80
The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the subject’s personal 
data.  The investigator further must ensure that each study subject 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 investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. 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. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in the United States
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-06882961 at any time.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 81
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In 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 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are 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 subject 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 patients 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.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 82
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the
PI of the results of the study based on information collected or generated by the PI, whether 
or not the results are favorable to the Pfizer product.  However, to ensure against inadvertent 
disclosure of confidential information or unprotected inventions, the investigator will provide 
Pfizer an opportunity to review any proposed publication or other type of disclosure of the 
results of the study (collectively, “publication”) before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 83
16. REFERENCES
1.
Ørskov C, Holst JJ, Knuhtsen S,et al. Glucagon-like peptides GLP-1 and GLP-2, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology 1986;119(4):1467-75.
2.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet 1987;2(8571):1300-4.
3.
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 
1997;273(5):E981-8.
4.
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest 1998;101(3):515-20.
5.
Hu FB. Globalization of diabetes: the role of diet, lifestyle and genes. Diabetes Care 
2011;34:1249-57.
6.
IDF Diabetes Atlas; 8th Edition: http://www.idf.org/diabetesatlas <Accessed Feb 13, 
2018>.
7.
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.
8.
DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the 
treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95.
9.
Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular 
and microvascular complications of type 2 diabetes (UKPDS 35): prospective 
observational study. BMJ 2000;321:405-12.
10.
VICTOZA[Package insert], Drugs@FDA. 2016 Apr., Available: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022341s025lbl.pdf 
<Accessed Oct 26, 2016>.
11.
Nagar S, Remmel RP. Uridine diphosphoglucuronosyltransferase pharmacogenetics and 
cancer. Oncogene 2006;25:1659-72.
12.
American Diabetes Association. Standards of medical care in diabetes-2018. Diabetes 
Care; 2018; 41 (Suppl 1):S73-S85.

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 84
Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
Abs
Absolute
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC24
area under the curve from time zero to 24 hours
AUClast
area under the concentration-time profile from time zero to the time
of the last quantifiable concentration
BBS
Biospecimen Banking System
BCRP
breast cancer resistant protein
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
cAMP
cyclic adenosine monophosphate
Ceff
efficacious concentration
CFB
change from baseline
CI
confidence interval
CK
creatine kinase
cLogP
partition coefficient
CL
clearance
CL/F
apparent clearance
CLp
plasma clearance
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variance
CYP
cytochrome P
DCT
data collection tool
CC
I

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 85
Abbreviation
Term
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DPP-4i
dipeptidyl peptidase-4 inhibitors
EC50
50% of the maximum effect concentration
EC
ethics committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
EDTA
edetic acid (ethylenediaminetetraacetic acid)
eGFR
estimated glomerular filtration rate
EU
European Union
EudraCT
European Clinical Trials Database
F
oral bioavailability
FIH
first-in-human
FPI
fasting plasma insulin
FPG
fasting plasma glucose
FSBG
fingerstick blood glucose
FSH
follicle-stimulating hormone
FT4
free thyroxine
fu
fraction unbound
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
HbA1c
glycated hemoglobin
HepBcAb
hepatitis B core antibody
HepBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HLM
human liver microsomes
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 86
Abbreviation
Term
IP manual
investigational product manual
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
IVGTT
intravenous glucose tolerance test
IWR
interactive Web-based response
K2EDTA
dipotassium ethylenediaminetetraacetic acid
Ki
binding inhibition constant
LFT
liver function test
LSLV
last subject last visit 
MAD
multiple ascending dose
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
multi-drug resistance protein
MDRD
modification of diet in renal disease equation
MEN2
multiple endocrine neoplasia syndrome type 2
MTC
medullary thyroid carcinoma
MTD
maximum tolerated dose
N/A
not applicable
NADPH
nicotinamide adenine dinucleotide phosphate
NAFLD
nonalcoholic fatty liver disease
NOAEL
no observed adverse effect level
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PBPK
physiologically based pharmacokinetic
PCD
primary completion date
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
PGx 
pharmacogenomic(s)
pH
potential of hydrogen
PI
principal investigator
PK
pharmacokinetic(s)
PT
prothrombin time
QD
daily
QTc
corrected QT interval
QTcF
QT interval corrected for heartrate using Fridericia’s formula 
C
CI
CCI
CCI

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 87
Abbreviation
Term
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SD
standard deviation
SGLT2
sodium-glucose cotransporter-2 
SoC
standard of care
SOP(s)
standard operating procedure(s)
SRSD
single reference safety document
SS
steady state
SSID
study-specific subject identification number
t1/2
half-life
T2DM
type 2 diabetes mellitus
TBD
to be determined
TBili
total bilirubin
THC
tetrahydrocannabinol
TK
toxicokinetic
Tmax
time for Cmax
TSH
thyroid stimulating hormone
TZDs
thiazolidinediones
UGT
uridine glucuronosyl transferase
ULN
upper limit of normal
US
United States
Vss
distribution volume
WBC
white blood cell

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 88
Appendix 2. Concomitant Medications
Subjects on a background therapy which is known have a high risk of Drug-Drug Interaction 
must discontinue those treatments and be placed on alternative medication, as judged 
appropriate by the subject’s physician or the Principal Investigator, as described in 
Section 5.8.  These medications include, but are not limited to, those indicated in the table 
below.
Note that only drugs used for the treatment of hypertension or dyslipidemia (common 
concomitant chronic diseases in T2DM patients) are listed here.  Background therapies not 
specifically mentioned here should be assessed for potential interactions by the Principal 
Investigator on a case-by-case basis.
Indication
1. Excluded Medication
2. Allowable Medication
Hypertension
Renin Inhibitors:
Aliskiren (Texturna®)
Diuretics:
Eplerenone (Inspra®)
Calcium Channel Blockers
including:
Felodipine (Plendil®)
Nifedipine (Adalat®, Procardia®)
Amlodipine (Norvasc®)
Diltiazem (Cardizem® LA)
Nimodipine (Nimotop®)
Verapamil (Verelan® PM)
Alpha/Beta Adrenergic 
Antagonists:
Carvedilol (Coreg ®)
Diuretics:
Bumetanide (Bumex®)
Chlorothiazide (Diuril®)
Furosemide (Lasix®)
Hydrochlorothiazide 
(Esidrix®)
Spironolactone (Aldactone®)
Alpha/Beta Adrenergic 
Antagonists:
Acebutolol (Sectral ®)
Atenolol (Tenormin ®)
Betaxolol (Kerlone ®)
Bisoprolol (Zebeta ®) 
Esmolol (Brevibloc ®)
Labetalol (Trandate ®)
Metoprolol (Toprol-XL ®, 
Lopresor ®) 
Nadolol (Corgard ®)
Nebivolol (Bystolic ™) 
Pindolol (Visken ®)
Propranolol Inderal ® 
Timolol Timoptic ® 
Angiotensin Converting 
Enzyme (ACE) Inhibitors:
Benazepril (Lotensin®)
Enalapril (Vaseretic®)
Fosinopril (Monopril®)
Lisinopril (Prinivil®)

PF-06882961 
C3421002
Final Protocol, 22 March 2018
Page 89
erindopril (Aceon®)
Ramipril (Altace®)
Angiotensin II Inhibitors –
Angiotensin Receptor 
Blockers (ARBs):
Candesartan (Atacand®)
Eprosartan (Teveten®)
Irbesartan  (Avapro®)
Losartan (Cozaar®)
Olmesartan (Benicar®)
Telmisartan (Micardis®)
Valsartan (Diovan®)
Dyslipidemia
HMG CoA Reductase Inhibitors 
(Statins):
Atorvastatin (Lipitor ®)  
Lovastatin (Mevacor®)
Simvastatin (Zocor®)
Fluvastatin (Lescol®)
Rosuvastatin (Crestor®)
Fibric Acid Derivatives:
Gemfibrozil (Lopid®)
Cholesterol Absorption Inhibitors:
Ezetimibe (Zetia®)
HMG CoA Reductase 
Inhibitors (Statins):
Pitavastatin (Livalo®)
Pravastatin (Pravachol®)
Fibric Acid Derivatives:
Fenofibrate (Tricor®)