Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
This is a Phase 1, randomized, double blind (sponsor open), parallel, placebo controlled, twice daily oral dosing study of PF 06882961 in adult Japanese participants with T2DM inadequately controlled on diet and exercise alone.

Detailed description:

Arms:
arm 1: None arm 2: Participants will be titrated up to 2 weeks to reach desired dose level arm 3: Participants will be titrated up to 4 weeks to reach desired dose level arm 4: Participants will be titrated up to 6 weeks to reach desired dose level

Interventions: intervention 1: Placebo intervention 2: PF-06882961
Intervention descriptions: intervention 1: 3 matching placebo tablets taken twice a day (BID) intervention 2: Participants will be randomized to one of 3 active doses (40, 80, or 120 mg), taking 3 tablets twice daily for 8 weeks.

Protocol document:
Prot_000.pdf: 
PF-06882961 
Protocol C3421015
Final Protocol, 30 June 2020
PFIZER CONFIDENTIAL
Page 1
AN 8-WEEK PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF TWICE DAILY PF-06882961 ADMINISTRATION IN 
JAPANESE ADULTS WITH TYPE 2 DIABETES MELLITUS
Study Intervention Number:
PF-06882961
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
N/A
Protocol Number:
C3421015
Phase:
1
Short Title: A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of PF-06882961 in Japanese Adults with Type 2 Diabetes Mellitus
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
30 June 2020
N/A


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Final Protocol, 30 June 2020
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities .............................................................................................13
2. INTRODUCTION ...............................................................................................................18
2.1. Study Rationale .......................................................................................................18
2.2. Background .............................................................................................................18
2.2.1. Nonclinical Overview.................................................................................19
2.2.1.1. Nonclinical Pharmacology........................................................19
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism........................19
2.2.1.3. Nonclinical Safety.....................................................................20
2.2.2. Clinical Overview.......................................................................................21
2.2.2.1. Clinical Safety...........................................................................21
2.2.2.2. Clinical Pharmacokinetics.........................................................22
2.3. Benefit/Risk Assessment.........................................................................................22
2.3.1. Risk Assessment.........................................................................................23
2.3.2. Benefit Assessment.....................................................................................25
2.3.3. Overall Benefit/Risk Conclusion................................................................25
3. OBJECTIVES AND ENDPOINTS.....................................................................................25
4. STUDY DESIGN.................................................................................................................26
4.1. Overall Design.........................................................................................................26
4.2. Scientific Rationale for Study Design.....................................................................27
4.2.1. Study Population.........................................................................................28
4.2.2. Pharmacokinetic Parameters.......................................................................28
4.3. Justification for Dose ..............................................................................................29
4.3.1. Selection of Dose Levels ............................................................................29
4.4. End of Study Definition ..........................................................................................29
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5. STUDY POPULATION......................................................................................................29
5.1. Inclusion Criteria.....................................................................................................30
5.2. Exclusion Criteria....................................................................................................30
5.3. Lifestyle Considerations..........................................................................................33
5.3.1. Meals and Dietary Restrictions...................................................................33
5.3.1.1. Admission days (Days -2 and 55) .............................................34
5.3.1.2. During inpatient days (Days -1, 1, 56 and 57) ..........................35
5.3.1.3. Discharge days (Days 2 and 58)................................................36
5.3.1.4. Outpatient visit days (Screening, Days 8, 15, 22, 29, 36, 
43, 50 and V11 of Follow up visit)....................................................36
5.3.1.5. On Non-visit days and Unscheduled visit.................................36
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................36
5.3.3. Activity .......................................................................................................37
5.3.4. Contraception..............................................................................................37
5.4. Screen Failures ........................................................................................................37
6. STUDY INTERVENTION..................................................................................................38
6.1. Study Intervention(s) Administered........................................................................38
6.1.1. Administration............................................................................................38
6.1.1.1. Inpatient and outpatient visit days.............................................39
6.1.1.2. Non-visit days ...........................................................................39
6.2. Preparation/Handling/Storage/Accountability ........................................................40
6.2.1. Preparation and Dispensing........................................................................41
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................41
6.3.1. Allocation to Study Intervention ................................................................41
6.3.2. Breaking the Blind......................................................................................42
6.4. Study Intervention Compliance...............................................................................42
6.5. Concomitant Therapy..............................................................................................43
6.5.1. Medications for Glycemic Control.............................................................44
6.5.2. Antihypertensive Medications....................................................................44
6.5.3. Lipid Modifying Medications.....................................................................44
6.5.4. Management of Nausea and Vomiting .......................................................44
6.5.5. Rescue Medicine.........................................................................................44


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6.6. Dose Modification...................................................................................................44
6.7. Intervention After the End of the Study..................................................................44
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................45
7.1. Discontinuation of Study Intervention ....................................................................45
7.2. Participant Discontinuation/Withdrawal From the Study.......................................45
7.2.1. Withdrawal of Consent...............................................................................46
7.3. Lost to Follow up ....................................................................................................46
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................47
8.1. Efficacy Assessments..............................................................................................48
8.2. Safety Assessments .................................................................................................48
8.2.1. Physical Examinations................................................................................48
8.2.3. Vital Signs ..................................................................................................48
8.2.4. Electrocardiograms.....................................................................................49
8.2.5. Management of Glycemic Control .............................................................50
8.2.5.1. Home Glucose Monitoring........................................................50
8.2.5.2. Management of Hypoglycemia .................................................50
8.2.5.3. Management of Hyperglycemia................................................52
8.2.6. Clinical Safety Laboratory Assessments ....................................................52
8.2.7. Pregnancy Testing ......................................................................................53
8.3. Adverse Events and Serious Adverse Events..........................................................53
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......54
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................54
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................54
8.3.2. Method of Detecting AEs and SAEs ..........................................................55
8.3.3. Follow-up of AEs and SAEs.......................................................................55
8.3.4. Regulatory Reporting Requirements for SAEs...........................................55
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................55
8.3.5.1. Exposure During Pregnancy......................................................56
8.3.5.2. Exposure During Breastfeeding ................................................57
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8.3.5.3. Occupational Exposure .............................................................58
8.3.6. Cardiovascular and Death Events...............................................................58
8.3.7. Disease Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................58
8.3.8. Adverse Events of Special Interest.............................................................58
8.3.8.1. Lack of Efficacy........................................................................58
8.3.9. Medical Device Deficiencies......................................................................58
8.3.10. Medication Errors.....................................................................................58
8.4. Treatment of Overdose............................................................................................59
8.5. Pharmacokinetics ....................................................................................................60
8.9. Immunogenicity Assessments.................................................................................63
8.10. Health Economics .................................................................................................63
9. STATISTICAL CONSIDERATIONS ................................................................................63
9.1. Statistical Hypotheses .............................................................................................63
9.2. Sample Size Determination.....................................................................................63
9.3. Analysis Sets ...........................................................................................................63
9.4. Statistical Analyses .................................................................................................64
9.4.1. General Considerations...............................................................................64
9.4.2. Primary Endpoint(s)....................................................................................64
9.4.2.1. Electrocardiogram Interval Analyses ........................................65
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9.4.3. Secondary Endpoint(s)................................................................................65
9.4.3.1. Pharmacokinetic Analyses of PF-06882961 .............................65
9.4.5. Other Safety Analyses ................................................................................69
9.4.5.1. Hypoglycemia Monitoring and Reporting ................................69
9.5. Interim Analyses .....................................................................................................69
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............69
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................70
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............70
10.1.1. Regulatory and Ethical Considerations ....................................................70
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................70
10.1.2. Financial Disclosure .................................................................................71
10.1.3. Informed Consent Process ........................................................................71
10.1.4. Data Protection .........................................................................................72
10.1.5. Dissemination of Clinical Study Data ......................................................72
10.1.6. Data Quality Assurance ............................................................................74
10.1.7. Source Documents....................................................................................75
10.1.8. Study and Site Start and Closure ..............................................................75
10.1.9. Publication Policy.....................................................................................76
10.1.10. Sponsor’s Qualified Medical Personnel .................................................77
10.2. Appendix 2: Clinical Laboratory Tests .................................................................78
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................81
10.3.1. Definition of AE .......................................................................................81
10.3.2. Definition of SAE.....................................................................................82
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................83
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10.3.4. Reporting of SAEs....................................................................................86
10.4. Appendix 4: Contraceptive Guidance ...................................................................88
10.4.1. Male Participant Reproductive Inclusion Criteria....................................88
10.4.2. Female Participant Reproductive Inclusion Criteria.................................88
10.4.3. Woman of Childbearing Potential ............................................................88
10.4.4. Contraception Methods.............................................................................89
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........93
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................95
10.8. Appendix 8: Prohibited Prior/Concomitant Medications......................................97
10.9. Appendix 9: Proposed Chronology of Procedures................................................99
10.10. Appendix 10: Abbreviations .............................................................................100
11. REFERENCES ................................................................................................................104
LIST OF TABLES
Table 1.
Overall Schedule of Activities..................................................................14
Table 2.
Schedule of Activities: Visit 2 (V2) and Visit 10 (V10) ..........................16
Table 3.
Titration Scheme and Dosing Level .........................................................39
Table 4.
Dose Levels in Study C3421015 ..............................................................42
Table 5.
Definition of Plasma PK Parameters for PF-06882961 as Secondary 
Endpoint....................................................................................................66
Table 7.
Protocol-Required Safety Laboratory Assessments .................................79
LIST OF FIGURES
Figure 1.
Schema of Study C3421015 .....................................................................12
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of PF-06882961 in Japanese Adults with Type 2 Diabetes Mellitus
Rationale
The purpose of the study is to evaluate the safety, tolerability, and PK of multiple oral doses 
of PF-06882961 in adult Japanese participants with T2DM.  
 
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
•
To evaluate the safety and tolerability of multiple, 
oral doses of PF-06882961, administered to adult 
Japanese participants with T2DM.
•
Incidence of treatment emergent AEs (AEs and 
SAEs), clinical laboratory abnormalities, vital signs 
and ECG parameters during the entire study.
Secondary: 
Secondary: 
•
To characterize plasma pharmacokinetics of 
PF-06882961 following Day 1 and following 
multiple, oral doses administered to adult Japanese 
participants with T2DM.
•
PF-06882961 plasma pharmacokinetic parameters 
AUC24, Cmax, Tmax, t½ (as defined in Section 9.4.3.1, 
as appropriate for the dosing paradigm) following Day 
1, and multiple dose administration, as data permit.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Overall Design
This is a Phase 1, randomized, double-blind (sponsor-open), placebo-controlled, 4-arm, 
parallel group study of PF-06882961 in adult Japanese participants with T2DM inadequately 
controlled on diet and exercise alone.
Participants will receive oral doses of PF-06882961 or placebo in this study.  Approximately 
9 participants will be enrolled in each arm, for a total of approximately 36 (4 arms) 
participants randomized.  The randomization ratio will be 1:1:1:1 (1 of 3 active dosing 
regimens of PF-06882961 or placebo), and all 4 arms will be enrolled in parallel.  The study 
will be conducted at a single clinical site in Japan.   
Target dose levels, achieved after completion of titration, for the 4 arms of the study are 
placebo and PF-06882961 doses of 40 mg BID, 80 mg BID, and 120 mg BID.  Dose titration 
will be incorporated to enhance tolerability to PF-06882961.  
Following the screening period to confirm eligibility (up to 4 weeks), the treatment period 
will be approximately 8 weeks, followed by an approximate 4-week follow-up.  
Number of Participants
A sample size of approximately 36 participants (approximately 9 participants in each of the 
placebo and 3 PF-06882961 arms) has been selected empirically to permit adequate 
characterization of safety, tolerability, PK 
 at each dose level in Japanese participants 
with T2DM.
Intervention Groups and Duration
Following the screening period to confirm eligibility (up to 4 weeks), the treatment period 
will be approximately 8 weeks, followed by an approximate 4-week follow-up.  Dosing will 
occur with food BID, and up to 2 weeks (The target dose level: 40 mg BID), 4 weeks (The 
target dose level: 80 mg BID) or 6 weeks (The target dose level: 120 mg BID) of the 8-week 
dosing duration will be used for dose titration to maximize tolerability of PF-06882961.  
Participants will take 3 tablets of study intervention (PF-06882961 or matching placebo) in 
the morning with food and 3 tablets of study intervention in the evening with food, 
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approximately 10-12 hours apart and at approximately the same time each day.  Participants 
will take a total of 6 tablets of study intervention (PF-06882961 or matching placebo) daily.  
Participants will swallow the study intervention whole, and will not crush, chew, break, or 
dissolve the study intervention prior to swallowing.  Downward titration or dosing is not 
permitted during the study; participants who do not tolerate the titration scheme and/or 
assigned dose may be required to discontinue dosing of study intervention.
Dose Levels in Study C3421015
Dose Level Description 
(dosed BID)
Number of PF-06882961 tablets
Number of 
PF-06882961-matching placebo 
tablets
10 mg
40 mg
100 mg
10/40/100 mg
Placebo
-
-
-
3
PF-06882961 – 10 mg
1
-
-
2
PF-06882961 – 20 mg
2
-
-
1
PF-06882961 – 40 mg
-
1
-
2
PF-06882961 – 60 mg
2
1
-
-
PF-06882961 – 80 mg
-
2
-
1
PF-06882961 – 100 mg
-
-
1
2
PF-06882961 – 120 mg
2
-
1
-
Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a DMC.
Statistical Methods
All treatment arms of PF-06882961 and placebo will be reported separately.
All safety and tolerability analyses will be performed on the safety population.
AEs, ECGs, BP, PR, and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of participants.  Any clinical laboratory, 
ECG, BP, and PR abnormalities of potential clinical concern will be described.  Safety data 
will be presented in tabular and/or graphical format and summarized descriptively, where 
appropriate.
The plasma PK parameters will be summarized descriptively by treatment, dose and day, as 
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1.2. Schema
Figure 1.
Schema of Study C3421015


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PFIZER CONFIDENTIAL
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1.3. Schedule of Activities
The SOA tables (Table 1 and Table 2) provide an overview of the protocol visits and procedures.  Refer to the STUDY 
ASSESSMENTS AND PROCEDURES section of the protocol for detailed information on each procedure and assessment required 
for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SOA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.   


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Table 1.
Overall Schedule of Activities
Protocol Activity
(See Appendix 10 for abbreviations)
Screen
Study Day (all activities at 0H [prior to AM meals/dosing] unless otherwise specified)
Follow Up
ET
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
Weeks Relative to Dosing on Day 1
0
1
2
3
4
5
6
7
8
9-10
12-13
Days Relative to Dosing on Day 1b
-28 to 
-3
Day -2
to Day 1
2
8
15
22
29
36
43
50
Day 55
to Day 56
57
58 63 - 7084 - 91
Informed consent & demography
x
Inpatient stay at study site
(See Table 2 For details)
Inpatient stay at study site
(See Table 2 For details)
Review of eligibility criteria
x
Discharge from inpatient stay
x
x
Outpatient visit (after ≥8-H fast)
x
x
x
x
x
x
x
x
x
Adverse event monitoring
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Medical history
x
Review prior and concomitant 
treatments
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Review drug, alcohol, tobacco use
x
x
x
x
x
x
x
x
x
x
x
x
Review contraception use (females 
only)
x
x
x
x
x
x
x
x
x
x
x
Review dosing diary, glucometer & 
glucose log
x
x
x
x
x
x
x
xc
x
Glucose measurement (8 hours 
fasting, via glucometer, on site)
x
x
x
x
x
x
x
x
x
x
Physical examination (height at 
screening only)d
x
x
x
x
Supine vital signsf
x
x
x
x
x
x
x
x
x
x
x
Supine 12-lead ECGg
x
x
x
x
x
x
x
Dispensation of study intervention
x
x
x
x
x
x
x
x
On-site study intervention 
administration with mealh
x
x
x
x
x
x
x
x
Standardized meals/snacks
x
x
x
x
x
x
x
x
x
x
Blood sampling for:
 
Hematology, chemistry (inc. eGFR)
x
x
x
x
x
x
x
Lipids, TSH, free T4, calcitonin, 
amylase, lipase, TBA, PT/INR/aPTT 
x
x
x
x
x
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Protocol Activity
(See Appendix 10 for abbreviations)
Screen
Study Day (all activities at 0H [prior to AM meals/dosing] unless otherwise specified)
Follow Up
ET
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
Weeks Relative to Dosing on Day 1
0
1
2
3
4
5
6
7
8
9-10
12-13
Days Relative to Dosing on Day 1b
-28 to 
-3
Day -2
to Day 1
2
8
15
22
29
36
43
50
Day 55
to Day 56
57
58 63 - 7084 - 91
FSH (females only)
x
HIV, HepBsAg, HepBcAb, HCVAb, 
syphilis
x
Pregnancy test (females only)
x
x
x
x
x
x
x
x
x
x
PF-06882961 PKi
x
x
x
x
x
x
x
x
 
Urine Sampling for:
Urine drug test
x
Urinalysis (and microscopy, as 
appropriate)
x
x
x
x
x
x
x
On-site urine pregnancy test (females 
only)j
x
x
x
x
x
x
x
x
x
a.
Contact may occur via telephone and must occur 28 to 35 days from administration of the final dose of study intervention.
b.
Allowable time window for V3-V10 is ±1.
c.
Review glucometer and glucose log only.
d.
Physical examination may be performed at non-specified visits if there are findings during the previous exam or new/open AEs, if appropriate and at investigator 
discretion.
f.
Includes blood pressure and pulse rate; vital signs at Follow up, and early termination visit (if appropriate) are single; Triplicate vital signs should be conducted at 
Screening, prior to AM dose at 0H and at approximately 4H after AM dose on Days 8, 15, 22, 29, 36, 43, and 50.  On Day 57, triplicate vital signs collected at 0H 
only. When a meal or snack is scheduled at the same time as vital signs, vital signs must be obtained prior to the meal/snack (See Appendix 9).
g.
12-lead ECG at Screening, Days 15 and 43, Follow up, and early termination visit (if appropriate) are single; Triplicate ECGs should be conducted prior to AM dose 
at 0H and at approximately 4H after AM dose on Day 29.  On Day 57, triplicate ECGs 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 (See Appendix 9).
h.
During inpatient stays, both AM and PM dosing will occur on the study site, except discharge day (Day 2).  On outpatient visit and discharge day, AM dosing will 
occur at the study site, if applicable.
i.
PK samples to be collected prior to AM dose and at 4H after AM dose on Days 15, 29, and 43.  Day 2 sample to be collected at 24H after AM dose on Day 1.  Day 
50 sample to be collected at 24H after AM dose on Day 49.  Day 57 sample to be collected at 24H and 36H after AM dose on Day 56.  Day 58 sample to be collected 
at 48H after AM dose on Day 56. 
j.
At each V2 through V10, the test result must be reviewed and deemed acceptable (ie, negative), in order to continue participation in the study.
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Table 2.
Schedule of Activities: Visit 2 (V2) and Visit 10 (V10)
[Procedures at 0H to be completed prior to AM dosing or similar clock time, in the case of Day-1]
Study Daya
Day -2 (V2)
Day 55 (V10)
Day -1 and Day 1 (V2)
Day 56 (V10)
Hours Relative to Dosing at 0Hb
-
0
0.25
0.5
1
1.5
2
3
4
6
8
10
12
14
Admission (after ≥8-H fast) and continued inpatient stay at study site
x
→
→
→
→
→
→
→
→
→
→
→
→
→
Adverse event monitoring
x
→
→
→
→
→
→
→
→
→
→
→
→
→
Review prior and concomitant treatments
x
→
→
→
→
→
→
→
→
→
→
→
→
→
Review contraception use (females only)
x
Review of eligibility criteria (Day -2 only)
x
Counseling on diet/exercise guidelines (Day -2 only)
x
Dispense glucometer and supplies, dosing diary, glucose log & 
provide training (Day -2 only)
x
Review dosing diary, glucometer & glucose log (Day 55 only)
x
Glucometer measurement (8 hours fasting, via glucometer)
xc
xc
Triplicate, supine vital sign assessmentd
x
x
x
x
x
x
Triplicate, supine 12-lead ECG 
x
x
x
x
x
x
Randomization in trial (Day 1 only)
x
Study intervention administration with meal (starting on Day 1 and 
thereafter)
x
xf
x
Mixed Meal Tolerance Test (Days -1 and 56 only)
x
Standardized meal/snackg
x
xh
x
x
x
Blood sampling for:
Hematology, chemistry (inc. eGFR) (Day -1 and 56 only)
xi
Lipids, TSH, free T4, calcitonin, amylase, lipase, TBA, 
PT/INR/aPTT (Day -1 and 56 only)
xi
Pregnancy test (females only)
x
PF-06882961 PK (Days 1, 55 and 56 only)
x
xi
x
x
x
x
x
x
x
x
Urine sampling for:
Urinalysis (and microscopy, as appropriate) (Day -1 only)
x
On-site urine pregnancy test (females only)k
x
a.
Day relative to start of study treatment (Day 1).
b.
On Day -1, nominal time to match approximate clock time of collection planned on Day 1 to permit time matched comparison. 
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c.
Glucometer measures taken before breakfast on all days while inpatient.
d.
Includes blood pressure and pulse rate at all time points. 
f.
Dosing expected to occur with breakfast (on Day 1) or mixed meal (on Day 56).
g.
Meals/snacks to occur on all days while inpatient; identical meals/snacks on Days -1 and 56, and identical snacks on Days -2 and 55.
h.
Standard breakfast on Day 1 only. 
i.
Collection following fasting duration as specified in Section 5.3.1.
k.
The test result must be reviewed and deemed acceptable (ie, negative), in order to continue participation in the study.
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2. INTRODUCTION
GLP-1 is a neuroendocrine hormone that is predominantly released from the small intestine 
in response to food intake.1  GLP-1 activation of the GLP-1R stimulates insulin release, 
inhibits glucagon secretion in a glucose-dependent manner, and delays gastric emptying.2,3  
In addition, GLP-1 has been shown to increase satiety and suppress food intake.4  PF-
06882961 is an orally administered, small molecule GLP-1R agonist that has been 
demonstrated, in nonclinical models, to stimulate glucose-dependent insulin release and 
suppress food intake with equivalent efficacy to an injectable peptide GLP-1R agonist 
approved for the treatment of T2DM. 
PF-06882961 is an oral, small molecule GLP-1R agonist that is currently being investigated 
as an adjunct to diet and exercise to improve glycemic control in adult participants with 
T2DM.
2.1. Study Rationale 
The purpose of the study is to evaluate the safety, tolerability, and PK of multiple oral doses 
of PF-06882961 in adult Japanese participants with T2DM.  
 
2.2. Background 
The increase in the global prevalence of T2DM is largely attributed to rising rates of excess 
body weight and obesity.5  T2DM is estimated to affect more than 424 million people 
worldwide,6 and Asia is a major area of the rapidly emerging T2DM global epidemic, with 
China and India the top two epicentres (109.6 and 69.2 million of adults with diabetes in 
2015).7  According to National Health and Nutrition Survey in 2016 conducted by Ministry 
of Health, Labour and Welfare, there is approximately 10 million adults who are expected to 
be diabetic (HbA1c ≥6.5% or under treatment for diabetes) and 10 million patients are on the 
verge of becoming diabetic (6.0%≤HbA1c<6.5%). T2DM is characterized by insulin 
resistance, a disorder in which cells do not respond effectively to insulin, resulting in higher 
blood glucose levels.  Elevated blood glucose levels and increasing severity of insulin 
resistance result in the need for more insulin over time, eventually resulting in progressive 
pancreatic β-cell failure.8  Patients with poorly controlled T2DM have an increased risk of 
developing complications associated with both microvascular and macrovascular disease, 
including nephropathy, neuropathy, retinopathy, cardiovascular disease and stroke; and are at 
2 to 4 times increased risk of mortality than adults who do not have diabetes.9  While existing 
pharmacological options for the treatment of diabetes may provide satisfactory glycemic 
control for some patients, there remains a large number of patients who do not achieve target 
glycated hemoglobin (HbA1c) levels, suggesting a need for additional therapeutic options.
Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and cardiovascular safety, with at least one marketed agent demonstrating 
cardiovascular benefit.10  Based on the clinical history of injectable, peptidic GLP-1R 
agonists, an oral, small molecule GLP-1R agonist is expected to improve glucose control and 
reduce HbA1c levels in patients with T2DM, while decreasing food intake and body weight 
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and avoiding the subcutaneous injection required by currently available peptidic GLP-1R 
agonists.
2.2.1. Nonclinical Overview
2.2.1.1. 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’-cAMP 
production.  In vivo, PF-06882961 potentiated glucose-stimulated insulin secretion during an 
IVGTT in cynomolgus monkeys in a dose and concentration dependent manner.  
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.  
Refer to the IB for more details on the nonclinical pharmacology of PF-06882961.
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism
The oral PK of PF-06882961 in rats and monkeys indicated rapid absorption with 
bioavailability ranging from 5% to 12%.  In repeated oral dose toxicity studies in rats and 
monkeys, systemic exposure of PF-06882961 increased with increasing dose, with no 
accumulation. 
Metabolism studies showed low turnover of PF-06882961 with some oxidative and 
glucuronide metabolites.  All metabolites detected in human hepatocytes were also observed 
in hepatocytes from nonclinical species.  PF-06882961 is expected to be cleared via hepatic 
uptake by OATP, followed by metabolic clearance principally mediated by CYP (3A4/5, 
followed by CYP2C8, and CYP2C19).  Non-CYP enzymes also contributed to the 
metabolism of PF-06882961.
In vitro studies indicate that at doses planned for this study (≤120 mg BID), there is a risk of 
weak pharmacokinetic interaction via time dependent inhibition of CYP3A4 by 
PF-06882961, and therefore sensitive CYP3A4 substrates with a narrow therapeutic index 
will be excluded.  Based on in vitro data, PF-06882961 has the potential to inhibit intestinal 
BCRP, and therefore, rosuvastatin and sulfasalazine, BCRP substrates, are excluded from 
this study.  
In vitro data also suggest a risk of PF-06882961 interaction with drugs for which CYP2C8 
and UGT1A1 mediated metabolism constitutes the primary mechanism of clearance.  Studies 
indicate that PF-06882961 has a low potential to cause DDIs as a result of induction of 
CYP3A4, or inhibition of other CYP enzymes (1A2, 2B6, 2C9, 2C19 or 2D6), other UGT 
enzymes (1A4, 1A6, 1A9, 2B7, 2B15), and transporters (MDR1, OATP1B1, 1B3, OCT2, 
MATE1, MATE-2K, OAT1 and OAT3).  See Appendix 8 for a complete list of prohibited 
medications.  
Refer to the IB for more details on the nonclinical PK and metabolism of PF-06882961.


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2.2.1.3. Nonclinical Safety
General toxicology studies have been completed in cynomolgus monkeys up to 6 months in 
duration (with a 3-week lead-in and 1-month recovery) and in rats up to 6 months in duration 
(with a 1-month recovery).  The exposure limits for plasma concentrations of PF-06882961 
for clinical studies are based on the exposure at the NOAEL dose of 250 mg/kg/day in the 6-
month with 1-month recovery toxicology study in rats, due to the fact that findings in 
monkeys such as decreased food intake and body weight loss are reversible and monitorable 
in a clinical setting.  In the 6-month toxicity study in rats with 1-month recovery, the NOAEL 
was 250 mg/kg/day based on species-specific toxicity at a higher dose.  The exposure 
margins at 250 mg/kg/day were 34-fold (Cmax, free) and 15-fold (AUC24, free), to the 
observed human exposures at the highest planned clinical dose of PF-06882961, 120 mg 
BID.
A NOAEL was not established in the cynomolgus monkey 6-month toxicity study with a 3-
week lead-in and 1-month recovery, due to early euthanasia of 3 animals administered 
≥50 mg/kg/day who had clinical signs associated with adverse microscopic findings in the 
kidney and heart, which was unique to this study and had not been observed in animals 
exposed for longer duration in previous studies with similar doses.  Based on the available 
data, none of the microscopic findings observed in these moribund animals appear to be 
consistent with primary toxicological effects.  Rather, they are more consistent with 
secondary events related to prolonged inanition and the resulting negative energy state.  
Exposure margins at 50 mg/kg/day were 0.60- and 4.3-fold for Cmax in males and females, 
respectively, and were 0.27- and 1.5-fold for AUC24 in males and females, repectively.
Other toxicology studies completed in cynomolgus monkeys include a 14-week study with a 
4-week lead-in (18 weeks total exposure) and a 13-week investigative toxicology study with 
3-week lead-in (16 weeks total exposure), in which the NOAEL were 100 mg/kg/day and 
150 mg/kg/day (the highest doses administered), respectively.  At the NOAEL dose of 
100 mg/kg/day in the 14-week study with 4-week lead-in, exposure margins were 1.3-fold 
and 0.75-fold for Cmax and AUC24, respectively, based on the lack of adverse findings in 
animals that survived to the scheduled necropsy.  At the NOAEL dose of 150 mg/kg/day in 
the 13-week study with 3-week lead-in, exposure margins were 8.0- and 5.9-fold for Cmax in 
males and females, respectively, and were 5.7- and 5.2-fold for AUC24 in males and females, 
repectively, based on the absence of adverse effects in the study.  
EFD studies were completed in rats and rabbits.  Based on the lack of maternal toxicity or 
adverse effects on EFD, the NOAEL for maternal and developmental toxicity in rats was 
500 mg/kg/day (highest dose evaluated).  The exposures at 500 mg/kg/day provide margins 
of approximately 69-fold (Cmax, free) and 68-fold (AUC24, free), to the observed human 
exposures at the highest anticipated clinical dose of PF-06882961, 120 mg BID.
In embryo-fetal studies conducted in rabbits, the NOAEL for maternal and developmental 
toxicity was 250 mg/kg/day, with margins of approximately 15-fold (Cmax, total) and 3.6-fold 
(AUC24, total), to the observed human exposures at the highest anticipated clinical dose of 
PF-06882961, 120 mg BID.


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PF-06882961 was negative in genetic toxicity testing and photosafety endpoints.  A risk 
assessment of the target organ toxicities noted in the repeat-dose toxicity studies is provided 
in the IB.  
Refer to the IB for more details on the nonclinical safety of PF-06882961.
2.2.2. Clinical Overview
As of the protocol date, 3 clinical studies, C3421001, C3421002, and C3421003 have 
completed dosing with PF-06882961.  In C3421001 and C3421003, healthy adult 
participants were randomized to receive single oral doses of PF-06882961 (or matching 
placebo).  In C3421002, adult participants with T2DM were randomized to receive oral doses 
of PF-06882961 (or matching placebo) for 28 days, and safety results from this study are 
provided in Section 2.2.2.1.  Refer to the IB for more details on these studies and the known 
drug class effects of marketed injectable GLP-1R agonists.  
2.2.2.1. Clinical Safety
Clinical data from the completed C3421001, C3421002, and C3421003 studies are provided 
in the IB for PF-06882961.
The results of C3421002, which is the only completed multiple dosing study in patients with 
T2DM to date, are summarized as below.
In study C3421002, PF-06882961 doses ranging from 10 mg BID to 120 mg BID were  
generally safe and well tolerated.   A total of 98 participants with T2DM on a background of 
metformin were randomized to receive PF-06882961 or matching placebo in a 3:1 
randomization ratio, and 92 participants completed the study.  Six (6) participants 
discontinued from the study, of which 2 discontinuations were due to treatment-related 
TEAEs, and 4 withdrew during the treatment or follow-up period for non-treatment related 
reasons. 
A total of 319 TEAEs were reported, of which the majority of the AEs (294 [92%]) were 
mild in intensity, 23 (7%) were moderate, and 2 (1%) were severe in intensity.  The most 
frequently reported TEAEs were nausea (49.0%), dyspepsia (32.7%), vomiting (26.5%), 
diarrhea (24.5%), headache (23.5%), and constipation (20.4%).  One (1) participant 
experienced a TEAE of hypoglycemia.  This AE was non-fasting, mild in severity and of 
limited duration.  
No deaths occurred in the C3421002 study.  Two (2) participants experienced 2 severe 
TEAEs during the study, 1 of which occurred in the dosing period and was considered 
treatment related, the other occurred during the follow-up period and was not considered 
treatment related.  The latter participant experienced 2 non-treatment-related SAEs, 1 of 
which occurred in the follow-up period and was a TEAE of severe intensity, and the other
occurred outside of the study reporting period.


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While there were isolated values for laboratory tests, vital signs and ECG intervals outside of 
the reference ranges, no clear adverse trends were apparent in these parameters.  As has been 
reported for marketed GLP-1R agonists,10,11 increases in heart rate have been observed, with 
mean increases ranging from 5 to 15 bpm across doses administered to date, and most heart 
rate values were within the normal range.  
2.2.2.2. Clinical Pharmacokinetics
The clinical PK of PF-06882961 in healthy adult participants has been evaluated in three
completed studies: C3421001, C3421002, and C3421003. The results of these completed 
studies are summarized in the PF-06882961 IB.  
The PK properties of PF-06882961 have been evaluated in adult participants with T2DM as 
part of the completed C3421002 study.  In this study, the first 6 cohorts received PF-
06882961 or placebo dosed BID.  Four of the 6 cohorts were titrated for various amounts of 
time over the 28 days, with a target maximum dose ranging between 10 and 120 mg BID 
across the 6 cohorts.  Approximately dose proportional increases in Cmax and AUC24 were 
observed between the doses of 10 mg BID and 120 mg BID, with Cmax ranging from 38.38 to 
685.2 ng/mL and AUC24 ranging from 455.9 to 8368 ng•h/mL.  Percent coefficients of 
variance (%CV) ranged from 32 to 94 and 41 to 87 for Cmax and AUC24 respectively on Day 
28.  Consistent with data from the completed studies, PF-06882961 was observed to have a 
t½ of approximately 4.681 to 8.090 hours.  Tmax ranged from 3 to 6 hours after the AM dose 
over the dose ranges administered. 
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06882961 may be found in the IB, which is the SRSD for this study.


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2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) PF-06882961
Thyroid C-cell tumors
The potential risks are based on product labeling for injectable 
GLP-1R agonists (ie, liraglutide, dulaglutide, and exenatide) due to 
dose-dependent and treatment duration-dependent thyroid C-cell 
tumors in nonclinical studies in rats and mice at clinically relevant 
exposures. 
Thyroid C-cell tumors have not been observed with PF-06882961 in 
clinical or nonclinical studies.
Potential participants with a personal or family 
history of medullary thyroid carcinoma or MEN2
are excluded from the clinical development 
program. Thyroid function tests are included in 
the clinical trial protocols to monitor participants’ 
thyroid function.  
Pancreatitis
The potential risks are based on product labeling for injectable 
GLP-1R agonists (ie, liraglutide, exenatide and dulaglutide). 
Pancreatitis has not been observed in the PF-06882961 clinical trial 
program.
Per exclusion criteria, potential participants with  
acute pancreatitis or a history of pancreatitis are 
not elgigible for study entry.  Serum amylase and 
lipase are monitored during the clinical studies.  
Hypoglycemia
Clinical trials with injectable GLP-1R agonists have not
demonstrated an increased risk for hypoglycemia.  However, when 
administered in combination with anti-diabetic agents that are 
known to have an increased risk of hypoglycemia (such as insulin or 
sulfonylureas), an increased risk for hypoglycemia was observed. 
Only one adverse event of mild hypoglycemia has been reported in 
the clinical development program to date.
Blood glucose is monitored frequently during 
clinical studies involving patients with T2DM, 
and hypoglycemia is a well recognized risk in 
T2DM patients.  The IB and ICD inform of the 
potential increased risk of hypoglycemia when 
PF-06882961 is administered in combination with 
anti-diabetic agents that are known to have an 
increased risk of hypoglycemia (such as insulin or 
sulfonylureas), which are prohibited in this study.
Impairment in renal function
In rats, minimal renal tubular vacuolation was observed, but this 
finding was considered to be non-adverse.
Per exclusion criteria, potential participants with 
significant renal impairment 
(<60 mL/min/1.73 m2) are not eligible for study 
entry.  Renal function is monitored at each study 


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In the clinical trial program only one mild AE (Blood creatinine 
increased) has been observed in the clinical trial program.
visit by the central lab assessments of serum 
BUN, creatinine and eGFR.
Gastrointestinal adverse 
reactions
The potential risks are based on product labeling for injectable 
GLP-1R agonists (ie, liraglutide, exenatide and dulaglutide).
In addition, gastrointestinal AEs, the majority of which were mild in 
severity, have been observed in the clinical program with 
PF-06882961.  In nonclinical studies with PF-06882961, 
gastrointestinal adverse effects have been seen in rats and monkeys.
Participants are monitored during the clinical 
study visits, via body weight, vitals signs and 
laboratory assessments, to prevent potential 
sequelae of any severe gastrointestinal reactions, 
eg, dehydration.  
Diabetic retinopathy 
complications
The potential risk is based on the product labeling for the injectable 
GLP-1R agonist semaglutide for T2DM.  This risk has not been 
listed in the prescribing information for other marketed GLP-1R 
agonists.
There are no nonclinical or clinical data involving PF-06882961 to 
suggest an increased risk of diabetic retinopathy complications.
Potential participants with a known medical 
history of active proliferative retinopathy and/or 
macular edema are excluded from the clinical 
studies.
Study Procedures 
Use of a placebo arm
Participants randomized to placebo may not experience glycemic 
lowering effect. 
A majority of the randomized study population 
will receive PF-06882961, and all participants 
will receive lifestyle counseling, which is 
standard of care for management of T2DM.  And, 
all participants will be monitored for significant 
hyperglycemia.


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2.3.2. Benefit Assessment
Based on the clinical experience of injectable GLP-1R agonists, a GLP-1R agonist is expected to 
improve glucose control, reduce HbA1c levels, diminish food intake, and decrease body weight 
in patients with T2DM.  A treatment period of 8 weeks of PF-06882961 in this study has limited 
clinical benefit to participants with T2DM.  This study is designed to generate safety, 
tolerability, PK 
 data in Japanese T2DM participants for further clinical development.
2.3.3. Overall Benefit/Risk Conclusion
Considering all available clinical and nonclinical data, the benefit-risk profile of PF-06882961 
supports continued clinical development in patients with T2DM. 
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
•
To evaluate the safety and tolerability of multiple, 
oral doses of PF-06882961, administered to adult 
Japanese participants with T2DM.
•
Incidence of treatment emergent AEs (AEs and 
SAEs), clinical laboratory abnormalities, vital signs 
and ECG parameters during the entire study.
Secondary:
Secondary: 
•
To characterize plasma pharmacokinetics of 
PF-06882961 following Day 1 and following 
multiple, oral doses administered to adult Japanese 
participants with T2DM.
•
PF-06882961 plasma pharmacokinetic parameters 
AUC24, Cmax, Tmax, t½ (as defined in Section 9.4.3.1, 
as appropriate for the dosing paradigm) following Day 
1, and multiple dose administration, as data permit.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, randomized, double-blind (sponsor-open), placebo-controlled, 4-arm, parallel 
group study of PF-06882961 in adult Japanese participants with T2DM inadequately controlled 
on diet and exercise alone.
Participants will receive oral doses of PF-06882961 or placebo in this study.  Approximately 9
participants will be enrolled in each arm, for a total of approximately 36 (4 arms) participants 
randomized.  The randomization ratio will be 1:1:1:1 (1 of 3 active dosing regimens of PF-
06882961 or placebo), and all 4 arms will be enrolled in parallel.  The study will be conducted at 
a single clinical site in Japan.   
Target dose levels, achieved after completion of titration, for the 4 arms of the study are placebo 
and PF-06882961 doses of 40 mg BID, 80 mg BID, and 120 mg BID.  Dose titration will be 
incorporated to enhance tolerability to PF-06882961.  
The maximum dose of PF-06882961 in this study will not exceed 120 mg BID.
Following the screening period to confirm eligibility (up to 4 weeks), the treatment period will 
be approximately 8 weeks, followed by an approximate 4-week follow-up.  The total duration of 
participation in this study is approximately 12 weeks, not including the screening period.  Dosing 
will occur with food BID, and up to 2 weeks (The target dose level: 40 mg BID), 4 weeks (The 
target dose level: 80 mg BID) or 6 weeks (The target dose level: 120 mg BID) of the 8-week 
dosing duration will be used for dose titration to maximize tolerability of PF-06882961, as 
depicted in Figure 1 and Table 3.  Downward titration or dosing is not permitted during the 
study; participants who do not tolerate the titration scheme and/or assigned dose may be required 
to discontinue dosing of study intervention.  
This study includes a total of 12 visits, of which 2 are inpatient study visits at the site and 7 are 
outpatient visits excluding screening to the site.  The other visits are Follow-up visit and Follow-
up telephone contact.  Participants will be randomized at V2 to receive PF-06882961 or 
matching placebo for a duration of 8 weeks, with completion of dosing at V10.  The inpatient 
stays at V2 and V10 consist of 4 days and 3 nights as listed in the SOA.  For the study duration 
between the inpatient study visits, participants will continue dosing with blinded study 
intervention provided in blister packs, either at home or at an outpatient visit to the study site.
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A Follow-up visit and a Follow-up contact (may be a phone call) will occur on V11 (Day 63-70) 
and on V12 (Day 84-91) following the first dose of study intervention on Day 1, respectively.  
Participants who discontinue prior to completion of the study for non-safety related reasons may 
be replaced, at the discretion of the PI and Sponsor.
The formulation administered in this study will be PF-06882961 tablets, or matching placebo 
(see Section 6).  A study design overview is shown in Section 1.2 and Table 3.
4.2. Scientific Rationale for Study Design
The purpose of this study is to evaluate the safety, tolerability, and PK of multiple oral doses of 
PF-06882961 in adult Japanese participants with T2DM who are receiving no background anti-
hyperglycemic medication. 
 
  Target dose levels, achieved after completion of titration, for 
the 4 arms of this study are placebo and PF-06882961 doses of 40 mg BID, 80 mg BID, and 120 
mg BID.  Dosing titration schemes are shown in Table 3.
A baseline day (Day -1) with time-matched procedures will permit an improved assessment of 
safety, tolerability, 
 within participant and placebo-adjusted 
comparison of dose-response (between participant), as appropriate.  The participants and site 
staff will be blinded to administration of each treatment to permit an unbiased assessment of 
safety.  However, a limited number of members of the Sponsor team will be unblinded to permit 
review of safety and tolerability while the study is ongoing.
Based on the tolerability data from C3421002, the titration will start at PF-06882961 10 mg BID 
(or matching placebo), then with increase every week to reach the target dose level of 40 mg BID 
at the start of Week 3, to reach the target dose level of 80 mg BID at the start of Week 5, and to 
reach the target dose level of 120 mg BID at the start of Week 7. 
All doses will be blinded and consist of 3 tablets administered BID via a blister pack, and dosing 
regimens will look the same throughout the 8-week dosing duration post randomization.  
Clinical safety laboratory tests, assessments of vital signs and 12-lead ECGs, 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, all measurements of ECG
intervals, heart rate and BP will be collected in triplicate (except as noted in the SOA) and the 
mean values will be used for analysis at each time point.  In addition to triplicate ECG and BP 
measurements taken prior to dosing of study intervention, triplicate ECG and BP measurements 
will also be collected at the approximate time to reach Cmax (Tmax) on PK sampling days as 
specified in the SOA 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 with marketed GLP-1R agonists.12  In 
addition, TSH, FT4, lipid profile, coagulation profile, and TBA will be assessed, based on 
non-adverse findings in the nonclinical studies with PF-06882961.  
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GLP-1R agonists typically are not associated with hypoglycemia unless co-administered with 
anti-diabetic agents that can cause hypoglycemia (such as insulin or sulfonylureas), which are 
prohibited in this study.  Blood glucose concentrations will be monitored throughout the study 
via glucometer, and monitoring of symptomatic hypoglycemic AEs will be performed.  In 
addition, all participants will be instructed on Day -2 regarding the symptoms associated with, 
and management of, hypoglycemia, which will permit the monitoring of symptomatic HAEs.
The potential risk of exposure to PF-06882961 in a sexual partner of a male participant in this 
study via ejaculate is low, and therefore no contraception (condom) use in male participants is 
warranted.  The calculated safety margin is ≥100-fold between the estimated partner exposure 
due to seminal transfer and the NOAEL for serious manifestations of developmental toxicity in 
nonclinical studies.  The safety margin of 100-fold is based on applying a 10-fold safety factor 
for interspecies extrapolation and a 10-fold safety factor for susceptible populations. 13
Banked Biospecimens will be collected and stored for further analyses which may, for example, 
provide greater understanding of the study intervention.
4.2.1. Study Population
Participants enrolled in this study will have inadequately controlled T2DM (as indicated by 
HbA1c at screening) on diet and exercise alone. Participants will be allowed to take certain 
concomitant medications as outlined in Section 6.5. 
Both females of childbearing potential, as well as those who are of non-childbearing potential, 
will be enrolled given the availability of EFD toxicity studies with PF-06882961.  However, as 
marketed GLP-1R agonists are listed as contraindicated in pregnancy, measures will be taken to 
limit the risk of pregnancy in the female population enrolled (see SOA and Appendix 4).
4.2.2. Pharmacokinetic Parameters
This study will include plasma sampling to examine the Day 1 and steady-state PK of 
PF-06882961.  
 
 
  
 
  
  
 
 
.  
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4.3. Justification for Dose
4.3.1. Selection of Dose Levels
In this study, PF-06882961 will be administered BID at three dose-levels for 8 weeks.  Identical 
starting dose and weekly titration steps in this study are being utilized in the non-Japanese phase 
2 study (C3421005).  The dose-titration scheme and the target dose level are shown in Table 3.  
The PF-06882961 doses selected for this study and the non-Japanese phase 2 study (C3421005) 
are based on observed safety, tolerability, PK, 
 from the non-Japanese phase 1 study
(C3421002); as well as the exposure margins relative to completed nonclinical toxicology 
studies.  Exposure margins for the highest proposed dose in this study (120 mg BID) are given in 
Section 2.2.1.3.  
For the high-dose arm, 120 mg BID, the maximum dose in the non-Japanese phase 2 study 
(C3421005), has been selected to evaluate the safety and tolerability of PF-06882961 in Japanese 
participants with T2DM so that safety and tolerability can be examined in the dose range 
including the maximum potential dose in the planned global phase 3 studies.  
With regard to the results from the non-Japanese phase 1 study (C3421002), target doses ranging 
from 10 mg BID to 120 mg BID were generally safe and well tolerated, as described in
Section 2.2.2.1.  Forty mg BID and 80 mg BID, which are the middle doses in the non-Japanese 
phase 2 study (C3421005), have been selected as the low-dose and the middle-dose arms, 
respectively. 
 
 
 
    
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the follow up visit (V12), approximately 28 to 35 days post last dose of study 
intervention.
The end of the study is defined as the date of the last visit (V12) of the last participant in the 
study.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The following 
eligibility criteria are designed to select participants for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
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Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and female participants must be 20 to 70 years of age, inclusive, at the time of 
signing the ICD.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants with T2DM who are treated with diet and exercise, and are taking no 
antidiabetic medications.
3. HbA1c ≥7% and ≤10.5% at screening (Visit 1) as assessed by the study specific 
laboratory and confirmed by a single repeat test, if deemed necessary.
4. Participants who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, lifestyle considerations, and other study procedures, including the ability 
to perform self-tests of blood sugar regularly (see Section 8.2.5.1) for the duration of the 
study and maintenance of study specific glucose logs for the duration of participation in 
the study.
Body Mass Index (BMI) and Weight:
5. Total body weight >50 kg (110 lb) with BMI of 22.5 to 45.4 kg/m2.  Body weight must 
have been stable (<5% change) for 90 days prior to screening (Visit 1) as per participant 
report.
Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICD and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease 


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(including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the 
time of dosing).

Participants 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.  See Section 6.5 for further information on 
concomitant medications.
2. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or 
pancreatic insufficiency).
3. Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes, or a history of 
ketoacidosis.
4. History of myocardial infarction, unstable angina, arterial revascularization, stroke, New 
York Heart Association Functional Class II - IV heart failure, or transient ischemic attack 
within 6 months of screening (Visit 1).
5. Any malignancy not considered cured (except basal cell carcinoma and squamous cell 
carcinoma of the skin); a participant is considered cured if there has been no evidence of 
cancer recurrence in the previous 5 years.
6. Personal or family history of MTC or MEN2, or participants with suspected MTC per the 
investigator’s judgment.
7. History of acute or chronic pancreatitis.
8. Symptomatic gallbladder disease.
9. Participants with a known medical history of active proliferative retinopathy and/or 
macular edema.
10. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HepBsAg, 
HepBcAb, HCVAb or syphilis.  Hepatitis B vaccination is allowed.
11. Known intolerance or hypersensitivity to GLP-1R agonists.
12. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
Prior/Concomitant Therapy:
13. See Appendix 8 for details regarding prohibited prior/concomitant medications.


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Prior/Concurrent Clinical Study Experience:
14. Previous administration with an investigational drug within 4 months or 5 half-lives 
preceding the first dose of study intervention used in this study (whichever is longer).
15. Known prior participation in a trial involving PF-06882961.
Diagnostic Assessments:
16. Screening supine BP ≥160 mmHg (systolic) or ≥100 mmHg (diastolic), following at least 
5 minutes of supine rest.  BP should be measured in triplicate and the average of the 3 BP 
values should be used to determine the participant’s eligibility.  
17. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF interval >450 msec, 
complete LBBB, signs of an acute or indeterminate-age myocardial infarction, ST-T 
interval changes suggestive of myocardial ischemia, second- or third-degree AV block, or 
serious bradyarrhythmias or tachyarrhythmias).  

If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 
more times and the average of the 3 QTcF or QRS values should be used to determine 
the participant’s eligibility.
18. A positive urine drug test.  Note: Participants who have been medically prescribed 
opiates/opioids or benzodiazepines and report the use of these drugs to the investigator at 
screening (Visit 1) may be allowed to participate with notification to the sponsor.
19. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single repeat 
test, if deemed necessary:

AST or ALT level 2 × ULN;

TBili level 1.5 × ULN; participants with a history of Gilbert's syndrome may have 
direct bilirubin measured and would be eligible for this study provided the direct 
bilirubin level is ULN.

Fasting C-peptide <0.8 ng/mL.

TSH >1.5 × ULN.

Serum calcitonin > ULN.

Amylase or lipase > ULN.

Fasting blood glucose >270 mg/dL (15.0 mmol/L).


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•
eGFR <60 mL/min/1.73 m2 as calculated by the CKD-EPI equation. 14
20. FSBG on Day -2 of >270 mg/dL (15.0 mmol/L).
Other Exclusions:
21. History of regular alcohol consumption exceeding 7 drinks/week for female participants 
or 14 drinks/week for male participants (1 drink = 5 ounces [150 mL] of wine or 
12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months prior 
to screening.
22. Known or suspected illicit drug use.
23. Blood donation (excluding plasma donations) of approximately 400 mL for the past 3 
months or 200 mL for the past 1 month prior to dosing and participants who are planning
for blood donation for 3 month after the last dose of study intervention.
24. History of sensitivity to heparin or heparin-induced thrombocytopenia only if heparin is 
planned to flush intravenous catheters.
25. Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of 
this protocol.
26. Investigator site staff or Pfizer employees directly involved in the conduct of the study, 
site staff otherwise supervised by the investigator, and their respective family members.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions
•
Participants must abstain from all food and drink (except water) at least 8 hours prior to 
 the collection of the first blood sample (eg, 
glucometer measurement, safety laboratory, PK
 assessment) at Screening, each 
inpatient study day, each outpatient visit, and the follow-up visit.
•
Water may be consumed as desired (ad libitum).
•
Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices - see 
below) may be consumed with meals and the evening snack.
•
Participants 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 study 
intervention until collection of the final PK blood sample.  
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
Details on the meals provided to participants at Visit 2 through Visit 10, 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 site.  This information will not be collected in the CRF, however 
may be submitted to the Sponsor upon request.

On scheduled visits to the site, in the morning, from Visit 2 through Visit 10, participants 
should be instructed to arrive without having morning meal/breakfast or
self-administration of study intervention. Note: Participants may take their morning dose 
of antihypertensive and/or lipid modifying medication per their usual routine, if 
applicable.

At Visit 2 through Visit 10, inclusive, the morning meal will be consumed with the study 
intervention at the site.  

Participants will be counseled on appropriate dietary and exercise guidelines for T2DM at 
Visit 2 and asked to maintain these guidelines throughout participation in the study.  
Counseling on dietary guidelines should be in accordance with local medical standards of 
care for patients with T2DM.  Note: Participation in formal weight loss programs is 
prohibited during participation in this study.
5.3.1.1. Admission days (Days -2 and 55)

The caloric intake/menu assigned to each participant will be based on the Harris Benedict 
formula (sedentary lifestyle; to be provided to the site prior to study start) using the 
participant’s body weight measured at screening. 

Participants will not be required to consume all provided food during standard meals.

A standard breakfast will be provided with dosing at approximately 0800 hours on 
Day 55 and at approximately the same time on Day -2.

Lunch will be provided approximately 4 hours after AM dosing (approximately 
1200 hours) Day 55 and at approximately the same time on Day -2.

Dinner will be provided with dosing approximately 10 hours after AM dosing 
(approximately 1800 hours) Day 55 and at approximately the same time on Day -2. 

An evening snack may be provided at approximately 2200 hours.

Participants will receive the same snack each evening prior to the MMTT the 
following day.  Participants will be encouraged to consume the entire evening snack.


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5.3.1.2. During inpatient days (Days -1, 1, 56 and 57)

The caloric intake/menu assigned to each participant will be based on the Harris Benedict 
formula (sedentary lifestyle; to be provided to the site prior to study start) using the 
participant’s body weight measured at screening. 

On days with MMTT as listed in Table 2 of the SOA (including evening snack prior to 
MMTT) only: participants will be encouraged 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 CRF.

Participants will not be required to consume all provided food during standard meals 
on Day 1 and Day 57.

When a meal or snack is scheduled at the same time as an ECG, the meal will be 
provided after the ECG is completed. 

Breakfast will be provided with dosing at approximately 0800 hours each day while 
inpatient:

A standard breakfast will be provided on Day 1 with dosing and Day 57 except when 
the MMTT is administered; 

For the MMTT, the mixed meal will be provided as 500 mL of ENSURE® H and 
will be administered as listed in Table 2 of the SOA.  The entire ENSURE® H meal 
is to be consumed within approximately 10 minutes.  (See Section 8.6.1).

Lunch will be provided approximately 4 hours after AM dosing (approximately 
1200 hours).  On days with MMTT, lunch will be provided after the 4-hour postdose 
blood collection samples for the MMTT have been completed.

Dinner will be provided approximately 10 hours after AM dosing (approximately 1800 
hours). 

An evening snack may be provided at approximately 2200 hours.

Meals on days with MMTT, will be standardized such that the participants receive the 
same menus for all meals on these days:

Participants will be encouraged to consume their entire meals on Days -1 and 56;

If participants 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 participant 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 on the source document;


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
The start time of all meals will be captured in the CRF on days with MMTT 
including the ENSURE® H mixed-meal provided for breakfast.

Participants will be encouraged to eat all standard meals within 30 minutes on days 
with MMTT administration;
5.3.1.3. Discharge days (Days 2 and 58)

The caloric intake/menu assigned to each participant will be based on the Harris Benedict 
formula (sedentary lifestyle; to be provided to the site prior to study start) using the 
participant’s body weight measured at screening. 

Participants will not be required to consume all provided food during standard meals.

A standard breakfast will be provided with dosing at approximately 0800 hours each day.
5.3.1.4. Outpatient visit days (Screening, Days 8, 15, 22, 29, 36, 43, 50 and V11 of Follow up 
visit)

The caloric intake/menu assigned to each participant will be based on the Harris Benedict 
formula (sedentary lifestyle; to be provided to the site prior to study start) using the 
participant’s body weight measured at screening. 

Participants will not be required to consume all provided food during standard meals.

When a meal or snack is scheduled at the same time as an ECG, the meal will be 
provided after the ECGs are completed. 

A standard breakfast will be provided with dosing at approximately the same time each 
day.

Lunch will be provided approximately 4 hours after AM dosing (approximately 
1200 hours) except on V11 of follow up visit.
5.3.1.5. On Non-visit days and Unscheduled visit

The study intervention must be administered BID with the morning and evening food, 
approximately 10-12 hours apart.
5.3.2. Caffeine, Alcohol, and Tobacco

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. 

Participants will abstain from alcohol for 24 hours prior to each visit to the site and 
continue abstaining from alcohol until completion for all procedures of each visit.  Except 
above period, intake of alcohol is permitted in moderation (refer to exclusion criterion 21


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for acceptable amount of alcohol consumption).  Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.

Participants may use tobacco- or nicotine-containing products, as permitted by the site 
practices except as noted below.

Use of these products 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.  Use of these products will 
also not be permitted 2 hours before and 2 hours following any dose of 
PF-06882961/placebo.
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that the 
participant has selected an appropriate method of contraception for the individual participant
from the permitted list of contraception methods (see Appendix 4 Section 10.4.4) and will 
confirm that the participant has been instructed in its consistent and correct use.  At time points 
indicated in the SOA, the investigator or designee will inform the participant of the need to use 
highly effective contraception consistently and correctly and document the conversation and the 
participant’s affirmation in the participant’s chart (participants need to affirm their consistent and 
correct use of at least 1 of the selected methods of contraception).  In addition, the investigator or 
designee will instruct the participant to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
CONSORT publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. All screening procedures must be repeated, and the participant assigned a new 8-
digit SSID number.


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6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-06882961 and matching 
placebo tablets.
6.1. Study Intervention(s) Administered
For this study, PF-06882961 and matching placebo tablets will be administered orally BID with 
food.
PF-06882961 and placebo tablets will be supplied to the site as packaged blister cards and 
labeled according to local regulatory requirements. 
Intervention Name
PF-06882961
Placebo for PF-06882961
ARM Name
Active
Placebo
Type
Drug
Drug
Dose Formulation
Tablet
Tablet
Unit Dose Strengths
10 mg, 40 mg and 100 mg
Not applicable
Dosage Levels
10, 20, 40, 60, 80, 100, 120 mg BID
0 mg BID
Route of Administration
Oral
Oral
Sourcing
Provided centrally by the sponsor.  Refer to 
the IP Manual.
Provided centrally by the sponsor.  Refer to 
the IP Manual.  
Packaging and Labeling
Study intervention will be provided in 
blister packs.  Each blister pack will be 
labeled as required per country 
requirement.
Blinded labels will be utilized for titration 
and stable dosing blister packs.
Study intervention will be provided in blister 
packs.  Each blister pack will be labeled as 
required per country requirement.
Blinded labels will be utilized for titration 
and stable dosing blister packs.
6.1.1. Administration
Participants will take 3 tablets of study intervention (PF-06882961 or matching placebo) in the 
morning with food and 3 tablets of study intervention in the evening with food, approximately 
10-12 hours apart and at approximately the same time each day.  Participants will take a total of 
6 tablets of study intervention (PF-06882961 or matching placebo) daily.  Participants will 
swallow the study intervention whole, and will not crush, chew, break, or dissolve the study 
intervention prior to swallowing.  Downward titration or dosing is not permitted during the 
study; participants who do not tolerate the titration scheme and/or assigned dose may be required 
to discontinue dosing of study intervention.
The titration schemes to be used in this study and additional details regarding titration are 
provided in Section 1.2, Table 3 and the IP Manual.


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Table 3.
Titration Scheme and Dosing Level
Target Dose (mg) 
Study Week
1
2
3
4
5
6
7
8
Placebo
0 mg 
BID
0 mg 
BID
0 mg 
BID
0 mg 
BID
0 mg 
BID
0 mg 
BID
0 mg 
BID
0 mg 
BID
40 mg BID
10 mg 
BID
20 mg 
BID
40 mg 
BID
40 mg 
BID
40 mg 
BID
40 mg 
BID
40 mg 
BID
40 mg 
BID
80 mg BID
10 mg 
BID
20 mg 
BID
40 mg 
BID
60 mg 
BID
80 mg 
BID
80 mg 
BID
80 mg 
BID
80 mg 
BID
120 mg BID
10 mg 
BID
20 mg 
BID
40 mg 
BID
60 mg 
BID
80 mg 
BID
100 mg 
BID
120 mg 
BID
120 mg 
BID
6.1.1.1. Inpatient and outpatient visit days
Morning dosing at approximately 0800 hours and evening dosing at approximately 1800 hours 
will occur with meals at the site on admission and during inpatient days in V2 and V10, except 
discharge days.  For discharge days and outpatient visit days, morning dosing at approximately 
0800 hours will occur with meals at the site.  Participants will be instructed to arrive at the site in 
the fasted state for each of the scheduled visits. For V3-V10, participants will be instructed to 
bring their study intervention supply and dosing diary with them, and to delay self-administration 
of study intervention on scheduled visit days until directed to dose during their visit.  When 
participants dose at the site, they will self-administer the study intervention under supervision by 
site staff. The date and time of each dose administered at the site will be recorded in the site 
source documents, in the diary and in the CRF.  Additionally, the date and time of the previous 2 
doses of double-blinded study intervention prior to each of the pre-dose PK blood collections (ie, 
the 2 most recent doses prior to the visit as noted in the diary) will be entered in the CRF.  
Administration of blinded study intervention for all dosing regimens will occur under the 
conditions described in Section 5.3.1.  
6.1.1.2. Non-visit days
Dosing and administration instructions along with a dosing diary, will be provided to participants 
to support at home dosing of study intervention.  When participants self-administer the study 
intervention at home, they will record each dose in the diary.
Participants will be instructed to self-administer their study intervention according to 
administration instructions provided to the participant.
Participants should be instructed that if they forget to take their morning dose at their usual time, 
they should take the missed dose as soon as possible (with food) on the day it was missed, 
however, there must be at least an 8-hour interval between the missed dose and the next dose.  If 
a dose is missed and the interval to the next dose is less than 8 hours, the missed dose should not 
be administered.


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6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study interventions 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated recording) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.  At a minimum, daily minimum and 
maximum temperatures for all site storage locations must be documented and available 
upon request.  Data for nonworking days must indicate the minimum and maximum 
temperatures since previously documented for all site storage locations upon return to 
business.
3. Any excursions from the study intervention label storage conditions should be reported to 
Pfizer upon discovery along with any actions taken.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention must 
be quarantined and not used until Pfizer provides permission to use the study 
intervention.  Specific details regarding the definition of an excursion and information the 
site should report for each excursion will be provided to the site in the IP Manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the label.
5. Study interventions should be stored in their original containers.
6. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
7. The head of the medical institution (where applicable) or study intervention administrator
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the IPAL 
or sponsor-approved equivalent. All study interventions will be accounted for using a 
study intervention accountability form/record.  All study intervention that is taken home 
by the participant, both used and unused, must be returned to the investigator by the 
participant.  Returned study intervention must not be redispensed to the participants.
8. Further guidance and information for the final disposition of unused study interventions 
are provided in the IP Manual.  All destruction must be adequately documented.  If 
destruction is authorized to take place at the investigator site, the investigator must ensure 
that the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Pfizer.


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Upon identification of a product complaint, notify the sponsor within 1 business day of discovery 
as described in the IP Manual.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make the 
study intervention ready for administration or dispensing to the participant by qualified staff.  
Dispensing is defined as the provision of study intervention, concomitant treatments, and 
accompanying information by qualified staff member(s) to a healthcare provider, participant in 
accordance with this protocol.  Local health authority regulations or investigator site guidelines 
may use alternative terms for these activities.
A qualified staff member will dispense the study intervention using the IRT system via unique 
container numbers in the blister cards provided, in quantities appropriate according to the SOA.  
The participant should be instructed to maintain the product in the blister cards provided 
throughout the course of dosing and return the blister cards to the site at the next study visit.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system 
(IWR).  The site personnel (study coordinator or specified designee) will be required to enter or 
select information including but not limited to the user’s ID and password, the protocol number, 
and the participant number.  The site personnel will then be provided with a treatment 
assignment, randomization number, and DU or container number when study intervention is 
being supplied via the IRT system.  The IRT system will provide a confirmation report 
containing the participant number, randomization number, and DU or container number 
assigned.  The confirmation report must be stored in the site’s files.  Study intervention will be 
dispensed at the study visits as summarized in the SOA.  Returned study intervention must not be 
redispensed to the participants.
A randomization code using the method of random permuted blocks will be utilized to 
randomize eligible participants in 1:1:1:1 ratio (1 of 3 active dosing regimens of PF-06882961 or 
placebo) prior to the first dose of study intervention.
Participants will receive the following number of tablets and corresponding dose level described 
in Table 4.


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Table 4.
Dose Levels in Study C3421015
Dose Level Description 
(dosed BID)
Number of PF-06882961 tablets
Number of 
PF-06882961-matching placebo 
tablets
10 mg
40 mg
100 mg
10/40/100 mg
Placebo
-
-
-
3
PF-06882961 – 10 mg
1
-
-
2
PF-06882961 – 20 mg
2
-
-
1
PF-06882961 – 40 mg
-
1
-
2
PF-06882961 – 60 mg
2
1
-
-
PF-06882961 – 80 mg
-
2
-
1
PF-06882961 – 100 mg
-
-
1
2
PF-06882961 – 120 mg
2
-
1
-
The study-specific IRT reference manual and IP Manual will provide the contact information and 
further details on the use of the IRT system.
6.3.2. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s treatment 
assignment is warranted. Participant safety must always be the first consideration in making 
such a determination. If the investigator decides that unblinding is warranted, the investigator 
should make every effort to contact the sponsor prior to unblinding a participant’s treatment 
assignment unless this could delay further management of the participant. If a participant’s 
treatment assignment is unblinded, the sponsor must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and CRF.
The study-specific IRT reference manual and IP Manual will provide the contact information and 
further details on the use of the IRT system.
Blood specimens will be obtained from all participants for PK analysis to maintain the study 
blind at the investigator site.  The investigator site staff and blinded study monitor, if assigned, 
will be blinded to study treatment.  Other specified Pfizer personnel will be unblinded to study 
treatment in order to permit interpretation of the safety, tolerability, PK 
 data while the 
study is ongoing.  The blinded study monitor, if assigned, will remain blinded to treatment until 
all monitoring for the study has been completed.  Specimens from participants randomized to 
placebo will not be routinely analyzed.  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.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
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administered in the site will be recorded in the source documents and recorded in the CRF.  
Study site personnel will examine each participant’s mouth to ensure that the study intervention 
was ingested.
When participants self-administer study intervention at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by counting returned 
tablets during the site visits and documented in the source documents and CRF. Deviation(s) 
from the prescribed dosage regimen should be recorded in the CRF.  At each visit from V3 to 
V10, sites should assess the blister cards for compliance.  Compliance (as assessed by tablet 
count) will be defined as self-administration, by the participants of ≥80% of the study supplied 
study intervention from Day 1 through Week 8, inclusive.  Investigators must closely follow 
non-compliant, randomized, participants in order to enhance their adherence to treatment.  
Any participant who fails to meet the criterion of ≥80% compliance will be re-educated by the 
site staff on the importance of compliance with study intervention.
A record of the number of study intervention tablets dispensed to and taken by each participant 
must be maintained and reconciled with study intervention and compliance records.  Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions, will also be 
recorded in the CRF.
6.5. Concomitant Therapy
Participants in this study will be allowed to be on certain concomitant medications that have 
been prescribed.  Attempts should be made not to alter the doses and regimens of the background 
medications after randomization and for the duration of participation in this study, except in 
circumstances where a change in dose is deemed medically necessary.  Any changes must be 
captured in the CRF.  Additionally, many over-the-counter medications are also permitted during 
this study.  
See Appendix 8 for details regarding prohibited concomitant medications.  Sites are encouraged 
to contact the sponsor should there be questions as to whether a medication is permitted or 
prohibited.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
All concomitant treatments taken during the study must be recorded with indication, daily dose, 
and start and stop dates of administration.  All participants will be questioned about concomitant 
treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be documented 
as a prior treatment.  Treatments taken after the first dose of study intervention will be 
documented as concomitant treatments.


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6.5.1. Medications for Glycemic Control
The use of other medications for glycemic control is not permitted in this study (see 
Appendix 8).
6.5.2. Antihypertensive Medications
The use of background antihypertensive agent(s) is permitted unless otherwise noted in 
Appendix 8.  Doses of antihypertensive agent(s) must be stable for at least 4 weeks prior to 
screening and throughout the study, except in circumstances where a change in dose is deemed 
medically necessary.  Any changes in doses of these medications must be captured in the CRF. 
6.5.3. Lipid Modifying Medications
The use of background lipid modifying agents is permitted unless otherwise noted in 
Appendix 8.  Doses of such lipid modifying agents must be stable for at least 4 weeks prior to 
screening and throughout the study, except in circumstances where a change in dose is deemed 
medically necessary.  Any changes in doses of these medications must be captured in the CRF. 
6.5.4. Management of Nausea and Vomiting
Nausea and vomiting have been reported with administration of GLP-1R agonists.  Participants 
complaining of nausea may be managed conservatively with bed rest and/or fluid management at 
the discretion of the investigator.  If the nausea and vomiting are not amenable to conservative 
management, anti-emetics may be administered at the investigator’s discretion with notification 
to the sponsor and entry in the CRF.
6.5.5. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with study intervention; standard medical 
supportive care must be provided to manage the AEs. Standard medical supportive care must be 
provided to manage the AEs, including administration of carbohydrates to treat HAE (see 
Section 8.2.5.2.1).  Please also see Section 8.2.5.2 and Section 8.2.5.3 for management of 
hypoglycemia and hyperglycemia, respectively.
6.6. Dose Modification
Dose titration schemes are utilized for each study intervention dosing arm in this study as 
described in Section 6.1.1.  However, each dosing regimen will be provided in blister packs, and 
dose adjustment, either during dose titration or steady state dosing, will not be permitted per 
protocol.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following:

Criteria for a potential DILI (Hy’s law) case are met (see Appendix 6);

Intent to become pregnant or pregnancy confirmed by serum -hCG testing;

Safety or tolerability concern arises, in particular if not responsive to symptomatic 
management, dosing with double-blind study intervention may be stopped in an 
individual participant at the discretion of the investigator.  
If the criteria for permanent discontinuation are met, the site should notify the sponsor Medical 
Monitor or sponsor Clinician.
If study intervention is definitively discontinued, the participant will not remain in the study for 
further evaluation. See the SOA for data to be collected at the time of discontinuation of study 
intervention.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted. See the SOA for assessments to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and then 
are prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  
The participant will be permanently discontinued both from the study intervention and from the 
study at that time.


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If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the site 
study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) for 
disclosure of future information, no further evaluations should be performed and no additional 
data should be collected.  The sponsor may retain and continue to use any data collected before 
such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study and 
must continue to be followed for protocol-specified follow-up procedures.  The only exception to 
this is when a participant specifically withdraws consent for any further contact with him or her 
or persons previously authorized by the participant to provide this information.  Participants 
should notify the investigator in writing of the decision to withdraw consent from future 
follow-up, whenever possible.  The withdrawal of consent should be explained in detail in the 
medical records by the investigator, as to whether the withdrawal is only from further receipt of
study intervention or also from study procedures and/or posttreatment study follow-up, and 
entered on the appropriate CRF page.  In the event that vital status (whether the participant is 
alive or dead) is being measured, publicly available information should be used to determine 
vital status only as appropriately directed in accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study;

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SOA. Protocol waivers or exemptions 
are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or awareness to 
determine whether the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SOA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Participants will be screened within 28 days prior to administration of the study intervention to 
confirm that they meet the study population criteria for the study.  If the time between screening 
and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug shipment), then 
participants do not require rescreening if the laboratory results obtained prior to first dose 
administration meet eligibility criteria.
Every effort should be made to ensure that protocol-required tests and procedures are completed 
as described.  However, it is anticipated that from time to time there may be circumstances 
outside the control of the investigator that may make it unfeasible to perform the test.  In these 
cases, the investigator must take all steps necessary to ensure the safety and well-being of the 
participant.  When a protocol-required test cannot be performed, the investigator will document 
the reason for the missed test and any corrective and preventive actions that he or she has taken 
to ensure that required processes are adhered to as soon as possible.  The study team must be 
informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and shipment 
instructions and contact information will be provided to the investigator site prior to initiation of 
the study.
The total blood sampling volume for individual participants in this study is approximately 450
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.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.


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8.1. Efficacy Assessments
Efficacy assessments are not evaluated in this study.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SOA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any perceived 
safety issues.
8.2.1. Physical Examinations
A physical examination will include, at a minimum, head, ears, eyes, nose, mouth, skin, heart 
and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and neurological 
systems. 
Physical examinations must be conducted by a physician. 
Height will be measured at screening only. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
 
 
 
  
 
 
 
 
 
8.2.3. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm (preferably 
CCI


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the dominant arm) will be used throughout the study.  Participants should be instructed not to 
speak during measurements.  When a meal or snack is scheduled at the same time as measuring 
BP and PR, the measuring BP and PR must be performed prior to the meal/snack.  When 
triplicate BP and PR are required, they will be obtained approximately 2 to 4 minutes apart; the 
average of the triplicate BP and PR measurements collected at each nominal time point on 
Day -1 will serve as each participant’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.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
8.2.4. Electrocardiograms
Standard 12-lead ECGs should be collected at times specified in the SOA section of this protocol
using an ECG machine that automatically calculates the heart rate and measures PR, QT, and 
QTcF intervals and QRS complex.  All scheduled ECGs should be performed after the 
participant 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 
participant’s time-controlled baseline QTcF value. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  
If a) a postdose QTcF interval remains ≥30 msec from the baseline and is >450 msec; or b) an 
absolute QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF intervals get progressively longer, the participant 
should undergo continuous ECG monitoring.  A cardiologist should be consulted if QTcF 
intervals do not return to less than the criterion listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTcF
value is prolonged, as defined above, repeat measurements may not be necessary if a qualified 
medical provider’s interpretation determines that the QTcF values are in the acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.


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8.2.5. Management of Glycemic Control
HAEs and FPG will be routinely monitored during participation in the study.
Based on this information, as well as review of the results reported by the central laboratory, an 
assessment of any symptomatic and asymptomatic occurrence of hypo- or hyper-glycemia must 
be undertaken.
8.2.5.1. Home Glucose Monitoring

To aide in management of their T2DM, all participants will be provided home glucose 
monitoring supplies including a glucometer, instructions on the use of the glucometer and 
accompanying supplies.

Home glucose monitoring logs will be provided to participants for completion at home 
and brought to each visit to the site along with the glucometers.  Investigators must 
review the home glucose monitoring logs completed by the participants and the readings 
stored in the glucometer device at all time points listed in the SOA.

Participants must perform home glucose monitoring at least 3 times weekly following at 
least an 8-(preferably 10-) hour fast (except water).  However, the investigator may 
recommend daily home glucose monitoring if needed.

Less frequent glucose monitoring will NOT be considered a protocol deviation unless the 
participant fails to monitor his/her glucose for 3 or more consecutive days.

If the participant experiences symptoms of hypoglycemia, home glucose monitoring 
should be performed, and these symptoms, along with the glucometer measurement, 
should be captured on the home glucose monitoring log.

If the participant uses his/her own glucometer, and not one provided by the Sponsor, a 
protocol deviation will NOT be recorded provided the investigator is still able to monitor 
the participant’s daily glucose values according to the criteria stated above.
8.2.5.2. Management of Hypoglycemia
GLP-1R agonists typically are not associated with hypoglycemia unless co-administered with 
anti-diabetic agents that can cause hypoglycemia (such as insulin or sulfonylureas), which are 
prohibited in this study.  Blood glucose concentrations will be monitored throughout the study 
via glucometer, and monitoring of symptomatic hypoglycemic AEs will be performed.  In 
addition, all participants will be instructed on Day -2 regarding the symptoms associated with, 
and management of, hypoglycemia, which will permit the monitoring of symptomatic HAEs.
Any episode of hypoglycemia must be captured on the Adverse Event Form CRF with specific 
details captured on the Hypoglycemic Event Details CRF.  For the definition of a hypoglycemic 
episode and severity categorization see Section 8.2.5.2.1 below.


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Participants noted to have a fasting glucose value (during home glucose monitoring) meeting the 
definition of hypoglycemia must be instructed to repeat the measurement the next day (following 
at least an 8 [preferably 10] hour fast, except water).  If the second measurement also meets the 
below definition, participants must be asked to return to the site within 1 to 3 days (following at 
least an 8 [preferably 10] hour fast, except water) and have blood collected and sent to the central 
laboratory for analysis of FPG.
8.2.5.2.1. Definition and Severity of Categorization of Hypoglycemic Adverse Event (HAE)
Based on review of the participant completed home glucose monitoring log at each time point 
specified in the SOA, as well as results reported by the central laboratory, the investigator must 
assess the glucose values as well as any symptoms documented.
HAE is defined as one of the following: 15
1. Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of HAE 
but a glucose value of <70 mg/dL (3.9 mmol/L) using either glucometer (FSBG) or 
sponsor-identified central laboratory (plasma glucose);
2. Documented symptomatic hypoglycemia: An event during which typical symptoms of 
HAE are accompanied with a glucose value of <70 mg/dL (3.9 mmol/L) using 
glucometer (or sponsor-identified central laboratory) and the clinical picture includes 
prompt resolution with food intake, subcutaneous glucagon, or glucose admnistration; 
3. Probable symptomatic hypoglycemia: An event during which symptoms of HAE are 
not accompanied by a glucose determination but was presumably caused by a glucose 
concentration of <70 mg/dL (3.9 mmol/L), and the clinical picture includes prompt 
resolution with food intake, subcutaneous glucagon, or glucose admnistration.
Each episode of HAE must be categorized with respect to severity.  In order to characterize the 
event as severe, all three (3) criteria below must be met:
1. The participant was unable to treat himself/herself.  Neurologic impairment, and not the 
age of the participant, is the explanation for why the participant could not treat 
himself/herself and required the assistance of another person.
2. The participant exhibited at least one of the following neurological symptoms:

Memory loss;

Confusion;

Uncontrolled behavior;

Irrational behavior;

Unusual difficulty in awakening;


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
Suspected seizure;

Seizure;

Loss of consciousness.
3. Either:

If blood glucose was measured and was ≤54 mg/dL (2.7 mmol/L) using glucometer 
(or central laboratory); or

If blood glucose was not measured, the clinical manifestations were reversed by oral 
carbohydrates, subcutaneous glucagon, or glucose admnistration.
Events that do not meet all the criteria above for severe HAE are characterized as mild or 
moderate in severity.
Any episode of HAE must be captured on the HAE CRF.
8.2.5.3. Management of Hyperglycemia
Hyperglycemia is defined as the following:

Fasting glucose ≥270 mg/dL (15.0 mmol/L) using glucometer (or central laboratory). 
After randomization, participants noted to have a fasting glucose value (during home glucose 
monitoring) meeting the above definition of hyperglycemia must be instructed to repeat the 
measurement the next day (following at least an 8 [preferably 10] hour fast, except water).  If the 
second measurement also meets the above definition, participants must be asked to contact the 
site and return to the site a day later (following at least an 8 [preferably 10] hour fast, except 
water) and have blood collected for FPG (and shipped to the central laboratory for analysis).
The investigator should determine if the participant collected the samples after an adequate 
fasting period; and if the participant is following recommended dietary guidelines.  Proper 
dietary and collected procedures should be reinforced with the participant.
If the results from the central laboratory confirm the readings using glucometer, the participant 
should be discontinued, and the investigator will recommend further appropriate glycemic 
treatment according to the local healthcare standards and national guidelines.
8.2.6. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SOA for the 
timing and frequency.  All protocol-required laboratory assessments, as defined in Appendix 2, 
must be conducted in accordance with the laboratory manual and the SOA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any perceived 
safety issues.  


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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. Clinically 
significant abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the participant's 
condition.
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 28 to 35 days after the last dose of study intervention should be repeated 
until the values return to normal or baseline or are no longer considered clinically significant by 
the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential drug-
induced liver injury.
8.2.7. Pregnancy Testing
Pregnancy tests will be both urine and serum tests, and must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in all females at the times listed in the SOA.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention.  Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests may also be 
repeated if requested by IRBs/ ECs or if required by local regulations.  
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue and 
obtain adequate information both to determine the outcome and to assess whether the event
meets the criteria for classification as an SAE or caused the participant to discontinue the study 
intervention (see Section 7.1). 
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.


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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) 
for each participant begins from the time the participant provides informed consent, which is 
obtained before the participant’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving study intervention), through and including a minimum 
of 28 calendar days, except as indicated below, after the last administration of the study 
intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator 
and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention because 
of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the 
CT SAE Report Form.
Investigators are not obligated to actively seek AE or SAE after the participant has concluded 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study, and he/she considers the event to be reasonably 
related to the study intervention, the investigator must promptly report the SAE to Pfizer using 
the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in Appendix 3. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded on 
the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.


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8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. For each event, the investigator must pursue and obtain adequate 
information until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of possible 
causality.  Any information relevant to the event, such as concomitant medications and illnesses, 
must be provided.  In the case of a participant death, a summary of available autopsy findings 
must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator awareness.


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8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing study 
intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to study 
intervention due to environmental exposure. Below are examples of environmental 
exposure during pregnancy:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then exposes his female partner prior to or around the time 
of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to termination 
of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental 
Form, regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until 28 days after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in the 
study, the information is not recorded on a CRF; however, a copy of the completed CT 
SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all 
EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural integrity of 
the terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).


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Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets the 
criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, 
neonatal death, or congenital anomaly), the investigator should follow the procedures for 
reporting SAEs. Additional information about pregnancy outcomes that are reported to Pfizer 
Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the infant death as related or possibly related to exposure 
to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further follow-up 
of birth outcomes will be handled on a case-by-case basis (eg, follow-up on preterm infants to 
identify developmental delays). In the case of paternal exposure, the investigator will provide 
the participant with the Pregnant Partner Release of Information Form to deliver to his partner.  
The investigator must document in the source documents that the participant was given the 
Pregnant Partner Release of Information Form to provide to his partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:

A female participant is found to be breastfeeding while receiving or after discontinuing 
study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental exposure 
during breastfeeding is a female family member or healthcare provider who reports that 
she is breastfeeding after having been exposed to the study intervention by inhalation or 
skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours of 
the investigator’s awareness, irrespective of whether an SAE has occurred.  The information 
must be reported using the CT SAE Report Form.  When exposure during breastfeeding occurs 
in the setting of environmental exposure, the exposure information does not pertain to the 
participant enrolled in the study, so the information is not recorded on a CRF. However, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically approved 
for use in breastfeeding women (eg, vitamins) is administered in accord with authorized use.  
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
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8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the study 
intervention, which may or may not lead to the occurrence of an AE. Such persons may include 
healthcare providers, family members, and other roles that are involved in the trial participant’s 
care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness regardless of whether there is an associated SAE.  The information must 
be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy of 
the completed CT SAE Report Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease Related Events and/or Disease Related Outcomes Not Qualifying as AEs or 
SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study intervention
by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report Form 
to Pfizer Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether
associated with an AE)
Only if associated with an SAE


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Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the investigator, 
the medication error is recorded on the medication error page of the CRF and, if applicable, any 
associated AE(s), serious and nonserious, are recorded on the AE page of the CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report Form 
only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 12 tablets within a 24-hour time period 
2 hours will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-06882961 (whichever is 
longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 2 days from the date of the last dose of
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.


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8.5. Pharmacokinetics 
Blood samples of approximately 3 mL, to provide a minimum of 1 mL of plasma, will be 
collected into appropriately labeled tubes containing K2EDTA for measurement of plasma 
concentrations of PF-06882961 as specified in the SOA.  Instructions for the collection and 
handling of biological samples will be provided in the laboratory manual or by the sponsor. The 
actual date and time (24-hour clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts will 
be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 10% of 
the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will not be 
captured as a protocol deviation, as long as the exact time of the collection is noted on the source 
document and the CRF.  Collection of samples more than 10 hours after dose administration that 
are obtained ≤1 hour away from the nominal time relative to dosing will not be captured as a 
protocol deviation, as long as the exact time of the collection is noted on the source document 
and the CRF. This protocol deviation window does not apply to samples to be collected more 
than 10 hours after dose administration at outpatient/follow-up visits with visit windows.
The date/time of the blood collection and the date/time of the previous at least two doses of 
blinded study intervention prior to each of the blood collections related to PK (both pre- and
post- dose samples) should be noted in a dosing diary (or similar) by the participants and 
captured in the CRF.  
Samples will be used to evaluate the PK of PF-06882961. Samples collected for analyses of 
PF-06882961 plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, 
  These data 
may not be included in the CSR.
Genetic analyses will not be performed on these plasma samples.  Participant confidentiality will 
be maintained.
Samples collected for measurement of plasma concentrations of PF-06882961 will be analyzed 
using a validated analytical method in compliance with applicable 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.  
Drug concentration information that would unblind the study will not be reported to investigator
sites or blinded personnel until the study has been unblinded.
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8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study is 
outlined here and further detailed in a SAP, which will be maintained by the sponsor.  The SAP 
may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
No formal inferential statistics will be applied to the safety, tolerability, PK 
 data.
9.2. Sample Size Determination
A sample size of approximately 36 participants (approximately 9 participants in each of the 
placebo and 3 PF-06882961 arms) has been selected empirically to permit adequate 
characterization of safety, tolerability, PK 
 at each dose level in Japanese participants 
with T2DM.  Participants who discontinue prior to completion of the study for non-safety related 
reasons may be replaced, at the discretion of the PI and Sponsor.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
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Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention
"Enrolled" means a participant's agreement to participate in a 
clinical study following completion of the informed consent 
process.  Potential participants who are screened for the purpose 
of determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  Participants will 
be analyzed according to the product they actually received.
PK concentration
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and in whom at least 1 
plasma PK concentration value is reported.
PK parameter
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and who have at least 1 
of the PK parameters of interest calculated.
 
 
9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will describe 
the analyses and procedures for accounting for missing, unused, and spurious data. This section 
is a summary of the planned statistical analyses of the primary and secondary endpoints.
9.4.1. General Considerations
All treatment arms of PF-06882961 and placebo will be reported separately.
9.4.2. Primary Endpoint(s)
All safety and tolerability analyses will be performed on the safety population.
AEs, ECGs, BP, PR, and safety laboratory data will be reviewed and summarized on an ongoing 
basis during the study to evaluate the safety of participants.  Any clinical laboratory, ECG, BP, 
and PR abnormalities of potential clinical concern will be described.  Safety data will be 
presented in tabular and/or graphical format and summarized descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will not be 
required to be reported, unless otherwise noted.  However, any untoward findings identified on 
physical and/or neurological examinations conducted during the active collection period will be 
captured as AEs, if those findings meet the definition of an AE.  Data collected at screening that 
are used for inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs, will be 
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considered source data, and will not be required to be reported, unless otherwise noted.  
Demographic data collected at screening will be reported.
9.4.2.1. Electrocardiogram Interval Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTcF values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate 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 participant’s 
individual tracing will be described in a safety section of the CSR 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.
Changes from baseline will be defined as the change between the postdose QTcF value and the 
average of the time-matched baseline triplicate values on Day -1.
9.4.3. Secondary Endpoint(s)
9.4.3.1. Pharmacokinetic Analyses of PF-06882961
The PK parameters (AUC24, Cmax, Tmax, t½) 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 5.  Actual PK sampling times will be used in the derivation of PK parameters.  
Additional detail on PK parameter definition will be provided in the SAP.
No formal inferential statistics will be applied to the PK data.
The plasma PK parameters will be summarized descriptively by treatment, dose and day, as 
appropriate.  


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Table 5.
Definition of Plasma PK Parameters for PF-06882961 as Secondary Endpoint
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
AUC24
D1 & ss
Area under the plasma concentration-time profile 
from time zero to time 24 hours
AUCτ1 +AUCτ2
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.


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9.4.5. Other Safety Analyses
9.4.5.1. Hypoglycemia Monitoring and Reporting
The HAEs will be listed in a separate table and summarized categorically.
 
9.5. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an sponsor-open
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment,
 and/or supporting clinical 
development. 
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a DMC. 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the head of the medical institution and reviewed and approved by the IRB/EC 
before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
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10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  The participant should be given 
sufficient time and opportunity to ask questions and to decide whether or not to participate in 
the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.
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Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research.  The optional 
additional research does not require the collection of any further samples. The investigator 
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a participant's agreement to allow specimens to be 
used for additional research. Participants who decline to participate in this optional
additional research will not provide this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.  In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
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www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
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10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator or authorized site personnel for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. The investigator or authorized site personnel must ensure that the 
records continue to be stored securely for as long as they are maintained.
When participant data are to be deleted, the investigator or authorized site personnel will 
ensure that all copies of such data are promptly and irrevocably deleted from all systems.


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


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
Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.


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10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study team on demand system.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site staff cannot be reached to 
provide advice on a medical question or problem originating from another healthcare 
professional not involved in the participant’s participation in the study.  The contact number 
can also be used by investigator staff if they are seeking advice on medical questions or 
problems; however, it should be used only in the event that the established communication 
pathways between the investigator site and the study team are not available.  It is therefore 
intended to augment, but not replace, the established communication pathways between the 
investigator site and the study team for advice on medical questions or problems that may 
arise during the study.  For sites other than a Pfizer CRU, the contact number is not intended 
for use by the participant directly, and if a participant calls that number, he or she will be 
directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following laboratory tests will be performed at times defined in the SOA section of this 
protocol.  Additional laboratory results may be reported on these samples as a result of the 
method of analysis or the type of analyzer used by the clinical laboratory, or as derived from 
calculated values.  These additional tests would not require additional collection of blood.  
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.


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Table 7.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
eGFR
Plasma glucose
Calcium
Sodium
Potassium
Chloride
AST
ALT
Total bilirubin
GGT
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
Urine pregnancy test
Lipid panel:

Total cholesterol

Direct LDL-C

HDL-C

Triglycerides
TSH
Free T4
Calcitonin
Amylase
Lipase
Serum total bile acids
PT/INR/aPTT
Serum pregnancy test (-
hCG)
At screening and/or Day-2 
only:

FSHb

Urine drug screeningc

Hepatitis B surface 
antigen

Hepatitis B core antibody

Hepatitis C antibody

Human 
immunodeficiency virus

Syphilis
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 (repeat)
PT/INR (repeat)
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 confirmation of postmenopausal status only.
c.
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol, opiates/opioids, 
benzodiazepines, and amphetamines (others are site and study specific).
Investigators must document their review of each laboratory safety report.


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After randomization, the investigator site and other blinded personnel will be blinded to
plasma glucose obtained after the first dose of study intervention measured by the central 
laboratory, unless the FPG meets the criterion for hypo-or hyper-glycemia as listed in 
Section 8.2.5.2 and Section 8.2.5.3. 


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


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


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


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and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must 
be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP
supplemental form for 
EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.


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


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


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
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.


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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below 
during the intervention period and for at least 28 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any reproductive 
safety risk of the study intervention(s).  The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention.

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with high user dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention,
which corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s).  In addition, a second effective method of contraception, as 
described below, must be used.  The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:


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1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition, a

High FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation*.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.


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


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*) Not approved in Japan.


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CCI


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


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


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


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


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10.8. Appendix 8: Prohibited Prior/Concomitant Medications
The following medications are prohibited until the first follow-up visit (ie, Visit 11, 
Week 9-10), unless stated otherwise.  If a participant receives a prohibited medication, the 
investigator should contact the Sponsor Clinician or Sponsor Medical Monitor to determine if 
the participant may remain in the study.  
Drug Classes and/or Drugs 
Timeframe of Restriction 
Prior to Screening Visit
Thiazolidinediones such as pioglitazone.
90 days
Subcutaneously administered agents for glycemic control (eg, insulin, 
exenatide, liraglutide, dulaglutide).  Note: Short-term (ie, ≤7 days) of insulin 
administration is permitted if participant is hospitalized.
90 days
Pharmacological agents with approved indication for weight loss such as 
mazindol.
90 days
Oral anti-diabetic medications, including:
Biguanides such as metformin, buformin.
Sulfonylureas such as acetohexamide, chlorpropamide, glyclopyramide, 
glibenclamide, gliclazide, glimepiride. 
Meglitinide analogues such as repaglinide, nateglinide, mitiglinide.
DPP-4i such as sitagliptin, alogliptin, saxagliptin, linagliptin, vildagliptin, 
teneligliptin, anagliptin, trelagliptin, omrigliptin.
glucosidase inhibitors such as acarbose, voglibose, miglitol.
SGLT2 inhibitors such as ipragliflozin, luseogliflozin, tofogliflozin, 
canagliflozin, empagliflozin, dapagliflozin.
Anti-hyperglycemic medications, including bromocriptine.
60 days
Systemic glucocorticoids such as prednisone, dexamethasone, triamcinolone, 
budesonide.  Note: As an exception, steroid-containing inhalers, nasal sprays 
and topical formulations are permitted.  Note: Intercurrent treatment with 
systemic corticosteroids during participation in the study may be permitted if 
treatment does/will not exceed 7 days.
60 days
Immunosuppressants such as cyclosporine and tacrolimus.
60 days
Appetite or weight modifying medications, including nonprescription or 
herbals.
60 days
Anti-psychotic medications such as olanzapine, risperidone.
60 days
Coumarin type anticoagulants or other anticoagulants (eg, dabigatran).
60 days
Anticonvulsants if prescribed for seizure disorder.
60 days
Antiarrhythmic medications whose primary mechanism of action is sodium or 
potassium channel blockade (eg, procainamide, quinidine, proprafenone; as 
well as amiodarone, sotalol).
60 days


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Drug Classes and/or Drugs 
Timeframe of Restriction 
Prior to Screening Visit
Note: -adrenergic receptor blocking agents (eg, atenolol, metoprolol) and 
calcium channel blockers (eg, diltiazem, amlodipine, nifedipine) are 
permitted.
Sympathomimetic agents.
Note: Inhaled -adrenergic receptor agonists (eg, albuterol) are permitted.
60 days
BCRP Substrates 
Rosuvastatin.  Note: Other statins are permitted.
Sulfasalazine
Prohibited post 
randomization
Use of CYP3A4/5 substrates with narrow therapeutic index – eg, 
cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and 
tacrolimus.
Prohibited post 
randomization 
Use of agents which are potent inducers of CYP3A (eg, rifampin).
Prohibited for 2 weeks 
before randomization and 
post randomization 
Use of agents which are clinically significant OATP inhibitors 
(eg, cyclosporine, rifampin).
Prohibited post 
randomization
Use of potent 3A4 inhibitors
Prohibited post 
randomization 
Paclitaxel, torsemide.
Prohibited post 
randomization 


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10.9. Appendix 9: Proposed Chronology of Procedures
For the procedures described below, where multiple procedures are scheduled at the same 
timepoint(s) relative to dosing, the following chronology of events should be adhered to:
•
12-lead ECG: obtain prior to blood samples, and prior to dosing (except for post-dose 
collection) (see Section 8.2.4);
•
Vital Signs (BP, PR): obtain prior to obtaining blood samples and prior to dosing 
(except for post-dose collection) (see Section 8.2.3); 
•
Fasting blood samples (for safety [see Section 8.2.6], PK [see Section 8.5], 
 
after assessment of 
12-lead ECG and vital signs but prior to dosing (If an IV catheter is utilized for blood 
sample collections, ECGs and vital sign assessments [PR and BP] should be collected 
prior to the insertion of the catheter.); 
•
Post-dose PK blood collection to occur approximately 4 hours post-dose (see 
Section 8.5): if collection time coincides with time of a meal/snack, these blood 
samples should be collected just prior to the meal/snack;
•
Other pre-dose procedures: obtain sample/perform procedure as close as possible to 
the scheduled time, but may be obtained before or after blood sample collection(s); 
•
Dosing: must occur in the morning with food and in the evening with food; and where 
applicable, after any pre-dose blood sample collection(s). 
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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
%CV
percent coefficients of variance
Abs
absolute
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AV
atrioventricular
BCRP
breast cancer resistance protein
β-hCG
β-human chorionic gonadotropin
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
cAMP
cyclic adenosine monophosphate
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
total clearance of drug from eg, plasma
Cmax
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DPP-4i
dipeptidyl peptidase-4 inhibitors
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
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Abbreviation
Term
EDP
exposure during pregnancy
EFD
embryo-fetal developmental
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FSBG
fingerstick blood glucose
FSH
follicle-stimulating hormone
FT4
free thyroxine
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
HAE
hypoglycemic adverse event
HbA1c
hemoglobin A1c
HCVAb
hepatitis C antibody
HepBcAb
hepatitis B core antibody
HepBsAg
hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IND
Investigational New Drug 
INR
international normalized ratio
IP Manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
IVGTT
intravenous glucose tolerance test
IWR
interactive Web-based response
K2EDTA
dipotassium edetic acid (ethylenediaminetetraacetic acid)
LBBB
left bundle branch block
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Abbreviation
Term
LFT
liver function test
MATE
multidrug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR1
multidrug resistance mutation
MEN2
multiple endocrine neoplasia syndrome type 2
MMTT
mixed-meal tolerance test
msec
millisecond
MTC
medullary thyroid carcinoma
N/A
not applicable
NOAEL
no observed adverse effect level
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PD
pharmacodynamic(s)
pH
potential of hydrogen
PI
principal investigator
PK
pharmacokinetic(s)
PR
pulse rate
PT
prothrombin time
PVC
premature ventricular contraction/complex
QTc
corrected QT interval
QTcF
corrected QT using Fridericia’s formula
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SGLT2
sodium glucose cotransporter 2
SOA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
ss
steady-state
SSID
single subject identifier
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
Terminal phase half-life
T2DM
type 2 diabetes mellitus
TBA
total bile acids
TBili
total bilirubin
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Abbreviation
Term
TEAE
treatment-emergent adverse event
Tmax
time to reach Cmax
TSH
thyroid stimulating hormone
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman of childbearing potential


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11. REFERENCES
1.
Ørskov C, Holst JJ, Knuhtsen S,et al. Glucagon like peptides GLP-1 and GLP-2, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology 1986;119(4):1467-75.
2.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet 1987;2(8571):1300-4.
3.
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide-1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 
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: https://www.idf.org/e-library/epidemiology-
research/diabetes-atlas/134-idf-diabetes-atlas-8th-edition.html <Accessed Feb 4, 2019>.
7.
Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes 
mellitus and its complications. Nat Rev Endocrinol 2018;14(2):88-98.
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.
Drucker, DL. The ascending GLP-1 road from clinical safety to reduction of 
cardiovascular complications. Diabetes (2018);67:1710-9.
11.
Lorenz et al. Differential effects of glucagon-like peptide-1 receptor agonists on heart 
rate. Cardiovasc Diabetol (2017);16:6.
12.
VICTOZA [Package insert], Drugs@FDA. 2019 Jun., Available:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022341s031lbl.pdf
<Accessed May 20, 2020>.
13.
Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update. 
Clin Transl Med 2016;5(1):23-37.


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14.
Levey AS, Stevens LA, Schmid CH, et al. A New Equation to Estimate Glomerular 
Filtration Rate. Ann Intern Med 2009;150:604-12.
15.
American Diabetes Association. Standards of medical care in diabetes -2019. Diabetes 
Care. 2019 Jan;42(Suppl 1):S1-S193.

SAP_001.pdf: 
Protocol C3421015 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3421015
AN 8-WEEK PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, AND
PHARMACODYNAMICS OF TWICE DAILY PF-06882961 ADMINISTRATION IN 
JAPANESE ADULTS WITH TYPE 2 DIABETES MELLITUS
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
06-Apr-2021


Protocol C3421015 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives, Endpoints, and Estimands............................................................6
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint(s) ..................................................................................................8
3.1.1. Adverse Events.............................................................................................8
3.1.1.1. Hypoglycemia Monitoring..........................................................9
3.1.2. Electrocardiograms.......................................................................................9
3.1.3. Vital Signs ....................................................................................................9
3.1.4. Laboratory Data..........................................................................................10
3.2. Secondary Endpoint(s) ............................................................................................12
3.2.1. Pharmacokinetic Endpoints as Secondary Endpoint ..................................12
 
3.4. Baseline Variables...................................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
4.1. Treatment Misallocations........................................................................................16
4.2. Protocol Deviations.................................................................................................16
4.2.1. Deviations Assessed Prior to Randomization.............................................17
4.2.2. Deviations Assessed Post-Randomization..................................................17
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5. GENERAL METHODOLOGY AND CONVENTIONS....................................................17
5.1. Hypotheses and Decision Rules ..............................................................................17
5.2. General Methods .....................................................................................................17
5.2.1. Analyses for Continuous Endpoints ...........................................................17
5.2.2. Analyses for Categorical Endpoints ...........................................................17
5.2.3. Anlayises of Time to event Endpoints........................................................17
5.3. Methods to Manage Missing Data ..........................................................................18
5.3.1. Concentrations Below the Limit of Quantification ....................................19
5.3.2. Deviations, Missing Concentrations and Anomalous Values.....................19
5.3.3. Pharmacokinetic Parameters.......................................................................19
5.3.4. Pharmacodynamic Parameters....................................................................19
6. ANALYSES AND SUMMARIES ......................................................................................20
6.1. Primary Endpoint(s) ................................................................................................20
6.1.1. Adverse events............................................................................................20
6.1.1.1. Hypoglycemia Monitoring........................................................20
6.1.1.2. Time to First Occurrence of AEs of Interest.............................20
6.1.1.3. Percentage of Participants with Ongoing AEs of Interest.........20
6.1.2. Electrocardiograms.....................................................................................21
6.1.3. Vital Signs ..................................................................................................22
6.1.4. Laboratory Data..........................................................................................23
6.2. Secondary Endpoint(s) ............................................................................................23
6.2.1. Pharmacokinetic Endpoints as Secondary Endpoint ..................................23
6.4. Subset Analyses.......................................................................................................26
6.5. Baseline and Other Summaries and Analyses.........................................................26
6.5.1. Baseline Summaries....................................................................................26
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6.5.2. Study Conduct and Participant Disposition................................................26
6.5.3. Concomitant Medications and Nondrug Treatments..................................27
6.5.4. Medical History ..........................................................................................27
6.5.5. Treatment Compliance................................................................................27
6.6. Other Analyse(s) .....................................................................................................27
7. INTERIM ANALYSES.......................................................................................................27
8. REFERENCES ....................................................................................................................27
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
Protocol-Required Safety Laboratory Assessments .................................11
Table 3.
Pharmacokinetic Endpoints as Secondary Endpoint ................................12
Table 5.
Categories for QTcF Assessment .............................................................21
Table 6.
Categories for PR and QRS Assessment ..................................................21
Table 7.
Categories for Vital Signs.........................................................................22
Table 8.
PK Parameters to be Summarized Descriptively......................................23
LIST OF FIGURES
Figure 1.
Schema of Study C3421015 .......................................................................8
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
21 Aug 2020
Original 
30 Jun 2020
N/A
N/A
2
06 Apr 2021
Original 
30 Jun 2020
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Updated the 
analysis based 
on the blinded
data review
Delete the recurrence analysis from Section 
6.1.1.2.
Clarified the 
details
Add the following sentences in Section 
6.1.1.3.
To calculate the percentage each week, the 
total number of participants who had not 
discontinued from the treatment prior to that 
respective week will be the denominator 
(note: if a participant did discontinue from 
the treatment during that respective week,
they would be included in the denominator).
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“Study Week” will be calculated using 
actual visit dates, rather than calendar days.
For example, if vomiting occurs on Day 8 
and Visit 2 occurs on Day 9 for a given 
patient, then the vomiting is considered to 
have occurred on Week 1 for this patient 
(Week 1 is Day1 to Day 8 for this patient).
 
 
 
 
 
 
Clarified the 
details
Add the following sentence in Section 6.5.5.
“Study Week” will be calculated using 
actual visit dates, rather than calendar days.
For example, if vomiting occurs on Day 8 
and Visit 2 occurs on Day 9 for a given 
patient, then the vomiting is considered to 
have occurred on Week 1 for this patient 
(Week 1 is Day1 to Day 8 for this patient).
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3421015.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
There are no estimands in this study. Analysis population and methods to manage missing 
data are shown in Section 4 and Section 5.3, respectively.
Objectives
Endpoints
Primary: 
Primary: 
•
To evaluate the safety and tolerability of multiple, 
oral doses of PF-06882961, administered to adult 
Japanese participants with T2DM.
•
Incidence of treatment emergent AEs (AEs and 
SAEs), clinical laboratory abnormalities, vital signs 
and ECG parameters during the entire study.
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Secondary: 
Secondary: 
•
To characterize plasma pharmacokinetics of 
PF-06882961 following Day 1 and following 
multiple, oral doses administered to adult Japanese 
participants with T2DM.
•
PF-06882961 plasma pharmacokinetic parameters 
AUC24, Cmax, Tmax, t½ (as defined in Section 9.4.3.1 in 
the protocol, as appropriate for the dosing paradigm) 
following Day 1, and multiple dose administration, as 
data permit.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2. Study Design
This is a Phase 1, randomized, double-blind (sponsor-open), placebo-controlled, 4-arm,
parallel group study of PF-06882961 in adult Japanese participants with T2DM inadequately 
controlled on diet and exercise alone.
Participants will receive oral doses of PF-06882961 or placebo in this study.  Approximately 
9 participants will be enrolled in each arm, for a total of approximately 36 (4 arms) 
participants randomized.  The randomization ratio will be 1:1:1:1 (1 of 3 active dosing 
regimens of PF-06882961 or placebo), and all 4 arms will be enrolled in parallel.  The study 
will be conducted at a single clinical site in Japan.
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Target dose levels, achieved after completion of titration, for the 4 arms of the study are 
placebo and PF-06882961 doses of 40 mg BID, 80 mg BID, and 120 mg BID.  Dose titration 
will be incorporated to enhance tolerability to PF-06882961.
Following the screening period to confirm eligibility (up to 4 weeks), the treatment period 
will be approximately 8 weeks, followed by an approximate 4-week follow-up.
Figure 1.
Schema of Study C3421015
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Incidence of treatment emergent AEs (AEs and SAEs), clinical laboratory abnormalities, 
vital signs and ECG parameters during the entire study.
3.1.1. Adverse Events
An adverse event is considered treatment emergent (TEAE) relative to a given treatment if:
The event starts during the effective duration of treatment (i.e. starting after the first 
dose but before the last dose plus lag time)
The effective duration of treatment is determined by the lag time. Any event occurring within 
the lag time, whether this occurs during a break in treatment or at the end of treatment, is 
attributed to the corresponding treatment period. The lag time is defined by the Pfizer 
Standard of 365 days post last dose of study intervention.
A 3-tier approach will not be used to summarize TEAEs due to small sample size.


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3.1.1.1. Hypoglycemia Monitoring
Hypoglycemia AEs will be recorded in the Case Report Form (CRF) as a separate page. 
Details of when these will be recorded are given in the protocol Section 8.2.5.2.
For programming purposes, the hypoglycemic AE categories are based on the following: 

Severe Hypoglycemia: Severe is checked in the severity criteria of the CRF. This 
assessment will be made by the principal investigator based on the protocol 
definition. 

Documented Symptomatic Hypoglycemia: If (2 – Did the subject have symptoms of 
hypoglycemia?) Yes and (3 – Was blood glucose measured?) Yes and result <70 
mg/dL (3.9 mmol/L) on the CRF, but hypoglycemia is not classified as severe. 

Asymptomatic Hypoglycemia: If (2) No and (3) Yes and result <70 mg/dL (3.9 
mmol/L) on the CRF, but hypoglycemia is not classified as severe. 

Probable Symptomatic Hypoglycemia: If (2) Yes and (3) No and (3a – If blood 
glucose was not measured, did symptoms resolve when treated with carbohydrate or 
glucagon?) Yes on the CRF, but hypoglycemia is not classified as severe. 
3.1.2. Electrocardiograms
Standard 12-lead ECG (including heart rate, PR, QT, QTcF intervals and QRS complex) will 
be obtained at times detailed in the schedule of activities given in the protocol. The average 
of the triplicate readings collected at each appropriate assessment time will be calculated for 
each ECG parameter, if applicable.
Change from time-matched baseline for heart rate, PR, QT, QTcF intervals and QRS 
complex will be calculated for each post baseline measurement.
Baseline is defined as the time-matched value from the average of the triplicate recordings on 
Day -1.
In addition, the time-matched double difference in heart rate, QT, QTcF, PR and QRS 
measures is calculated in the following steps: (1) subtract predose value on Day 1 from all 
postdose values; (2) subtract the value at 0 hours on Day -1 from all other values on Day -1; 
(3) take the difference between the adjusted postdose value in (1) and its time-matched value 
in (2).
3.1.3. Vital Signs
Vital sign measurements (blood pressure and pulse rate) will be taken as detailed in the 
schedule of activities given in the protocol. The average of the triplicate measurements at 
each appropriate assessment time will be calculated for each blood pressure and pulse rate, if 
applicable.
Changes from time-matched baseline for supine systolic and diastolic blood pressure and 
pulse rate will be calculated for each post baseline measurement.


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Baseline is defined as the time-matched value from the average of the triplicate recordings on 
Day -1.
In addition, the time-matched double difference in supine blood pressures and pulse rate 
measurements is calculated in the following steps: (1) subtract predose value on Day 1 from 
all postdose values; (2) subtract the value at 0 hours on Day -1 from all other values on Day -
1; (3) take the difference between the adjusted postdose value in (1) and its time-matched 
value in (2).
3.1.4. Laboratory Data
Safety laboratory tests (hematology, chemistry, urine testing and other clinical laboratory 
tests) will be performed as described in the protocol˄Table 2˅.
To determine if there are any clinically significant laboratory abnormalities, the safety tests 
will be assessed against the criteria specified in the sponsor reporting standards. The 
assessment will take into account whether each participant’s baseline test result is within or 
outside the laboratory reference range for the particular laboratory parameter.
Baseline for all laboratory measurements will be defined as the Day -1, 0H time point for 
each measure.


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Table 2.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
eGFR
Plasma glucose
Calcium
Sodium
Potassium
Chloride
AST
ALT
Total bilirubin
GGT
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
Urine pregnancy test
Lipid panel:
Total cholesterol
Direct LDL-C
HDL-C
Triglycerides
TSH
Free T4
Calcitonin
Amylase
Lipase
Serum total bile acids
PT/INR/aPTT
Serum pregnancy test (-
hCG)
At screening and/or Day-2 
only:

FSHb

Urine drug screeningc

Hepatitis B surface 
antigen

Hepatitis B core antibody

Hepatitis C antibody

Human 
immunodeficiency virus

Syphilis
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 (repeat)
PT/INR (repeat)
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 confirmation of postmenopausal status only.
c.
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol, opiates/opioids, 
benzodiazepines, and amphetamines (others are site and study specific).


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3.2. Secondary Endpoint(s)
3.2.1. Pharmacokinetic Endpoints as Secondary Endpoint
Blood samples for PK analysis of PF-06882961 will be taken according to the schedule of 
activities given in the protocol. 
PK parameters for plasma PF-06882961 following single and multiple dose administration of 
PF-06882961 will be derived using standard noncompartmental methods, as data permit for 
each treatment and Day [Day 1 and Day 56], from the concentration time profiles in the table 
as follows:
Table 3.
Pharmacokinetic Endpoints as Secondary Endpoint
Parameter
Definition
Method of Determination
Analysis
Plasma Parameters
Cmax
Maximum plasma concentration 
observed from time zero to 24 hours
Observed directly from data
ln, D
Cmax1
Cmax1: maximum plasma 
concentration during the dosing 
interval τ1 =0 to 10 hours 
Observed directly from data
ln, D
Cmax2
Cmax2: maximum plasma 
concentration during the dosing 
interval τ2=10 to 24 hours
Observed directly from data
ln, D
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence
R, D
Tmax1
Time for Cmax1
Observed directly from data as time 
of first occurrence
R, D
Tmax2
Time for Cmax2
Observed directly from data as time 
of first occurrence
R, D
AUC24
Area under the plasma 
concentration-time profile from time 
zero to time 24 hours
AUCτ1 +AUCτ2
ln, D
t1/2*
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.
R, D
Key: D=displayed with descriptive statistics, ln=natural-log transformed, R=raw (untransformed), *=not 
calculated at Day 1.
 
 
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3.4. Baseline Variables
Full details on the covariates to be included in analyses are given in Section 5.2.4 and Section 
5.2.5.
Baseline variables are age, gender, race, ethnicity, height, weight, body mass index, duration 
of diabetes, 
 eGFR, systolic blood pressure, and diastolic blood pressure.  
Baseline variables are those collected on Day 1 prior to dosing or last measurement during 
screening visits before Day 1.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
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Participant Analysis 
Set
Description
Enrolled/Randomly 
assigned to study 
intervention 
"Enrolled" means a participant's agreement to participate in a 
clinical study following completion of the informed consent 
process.  Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  Participants 
will be analyzed according to the product they actually 
received.
PK concentration
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and in whom at least 
1 plasma PK concentration value is reported.
PK parameter
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and who have at 
least 1 of the PK parameters of interest calculated.
 
 
4.1. Treatment Misallocations
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are randomized but not treated.  
If a subject takes a treatment that is not consistent with the treatment they are randomized to, 
for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, PK 
 
analyses, where applicable.
4.2. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg, vomiting) may be 
excluded from the PK analysis.  At the discretion of the pharmacokineticist a concentration 
value may also be excluded if the deviation in sampling time is of sufficient concern or if the 
concentration is anomalous for any other reason.  
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
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4.2.1. Deviations Assessed Prior to Randomization
At screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 5.1 and 5.2 of the protocol.
4.2.2. Deviations Assessed Post-Randomization
Any significant deviation from the protocol will be reviewed prior to database closure and a 
decision taken regarding evaluation for each analysis population.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
No formal inferential statistics will be applied to the safety, PK 
 data.
5.2. General Methods
All treatment arms of PF-06882961 and placebo will be reported separately.
5.2.1. Analyses for Continuous Endpoints
Continuous endpoints and relevant safety endpoints will be presented using summary 
statistics: number of observations, arithmetic mean, standard deviation, median, minimum 
and maximum values.
5.2.2. Analyses for Categorical Endpoints
Categorical endpoints and relevant safety endpoints will be presented using summary 
statistics: number of observations, counts and percentages.
5.2.3. Anlayises of Time to event Endpoints
A Kaplan-Meier curve will be produced based on the time to the event of interest (starting 
from the time of start of dosing on Day 1) for each treatment separately and will be plotted 
on the same graph. No statistical testing for differences between treatment will be 
considered.
Details of censoring are included in Section 6.1.1.2.
 
 
 
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5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
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5.3.1. Concentrations Below the Limit of Quantification
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. In listings BLQ values will be reported as “<LLQ”, where LLQ will be 
replaced with the value for the lower limit of quantification (LLQ).
5.3.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
5.3.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (ie, not calculated). (Note that NC values will not be generated beyond 
the day that a subject discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with ≥3 evaluable measurements.
If a subject receives a dose that was not assigned based on the randomized titration scheme, 
the data from that Day will not be included in any summary statistics but will be included in 
listings.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
 
 
 
 
 
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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Adverse events
Adverse events will be reported in accordance with the sponsor reporting standards.
Incidence and severity of treatment emergent adverse event (TEAE) tables will additionally 
be produced (‘All causality’ and ‘Treatment related’, separately) to summarise the total 
number of adverse events by preferred term, which will be reported by treatment group
(Placebo, 40 mg BID, 80 mg BID and 120 mg BID) and overall.
6.1.1.1. Hypoglycemia Monitoring
The hypoglycemic AEs will be listed in a separate table and summarized categorically by 
treatment as per Section 5.2.2.
6.1.1.2. Time to First Occurrence of AEs of Interest
Exploratory summaries on the time to the first occurrence of AEs of interest will be produced 
using Kaplan-Meier (KM) Curves as described in Section 5.2.3. Participants who discontinue 
from the study, discontinue from IP or initiate glycemic rescue medication prior to the start 
of the AE event of interest will be censored at the discontinuation/initiation date.
The three AEs of interest are: diarrhea, nausea and vomiting (based on preferred term). A 
separate KM plot for each AE will be produced separately.
Listings of AEs of interest will be produced.
6.1.1.3. Percentage of Participants with Ongoing AEs of Interest
Exploratory summaries on the percentage of participants reporting AEs of interest will be 
produced by week and treatment as per Section 5.2.2.
A line plot of the percentages over each week will be produced based on the summary 
statistics with a separate line for each treatment.
The AEs of interest are diarrhea, nausea and vomiting (based on preferred term); where a 
separate table and plot will be produced for each AE.
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To calculate the percentage each week, the total number of participants who had not 
discontinued from the treatment prior to that respective week will be the denominator (note:
if a participant did discontinue from the treatment during that respective week, they would be 
included in the denominator).
“Study Week” will be calculated using actual visit dates, rather than calendar days. For 
example, if vomiting occurs on Day 8 and Visit 2 occurs on Day 9 for a given patient, then 
the vomiting is considered to have occurred on Week 1 for this patient (Week 1 is Day1 to 
Day 8 for this patient).
6.1.2. Electrocardiograms
Absolute values and changes from time-matched baseline for the ECG parameters QT 
interval, heart rate, QTcF interval, PR interval, and QRS complex will be summarized by 
treatment and time using sponsor reporting standards.  Tables will be paged by parameter.  
Baseline is as defined in Section 3.1.2.
Mean change from time-matched baseline in ECG parameters will be plotted against day (for 
Day 1 and Day 56).  On each plot there will be 1 line for each treatment.  Corresponding 
individual plots of change from time-matched baseline will also be produced for each 
treatment.
Maximum increase from time-matched baseline for QTcF and heart rate will be summarized 
by treatment, according to sponsor reporting standards.
ECG endpoints and change from time matched baseline (QTcF, PR and QRS) will also be 
summarized descriptively by treatment using the following categories. Numbers and 
percentages of participants meeting the categorical criteria will be provided. All planned and 
unplanned post-dose time-points will be counted in these categorical summaries. All values 
meeting the criteria of potential clinical concern will be listed.
Table 5.
Categories for QTcF Assessment
Degree of 
Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
Table 6.
Categories for PR and QRS Assessment
Parameter
Criteria
PR (ms)
max. ≥300
PR (ms) increase from baseline
Baseline >200 and
max. ≥25% increase
Baseline ≤200 and
max. ≥50% increase
QRS (ms)
max. ≥140
QRS (ms) increase from baseline
≥50% increase


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Listings of subjects with any single post-dose value 500 msec will also be produced for 
QTcF.
The time-matched double differences in QT interval, heart rate, QTcF interval, PR interval, 
and QRS complex measures obtained following the Day 1 treatment, as defined in Section 
3.1.2, will be summarized (N, mean, 90% confidence interval) for each treatment and time 
point.
Mean time-matched double differences in ECG parameters will be plotted against time 
postdose for Day 1 and Day 56 separately.  On each plot there will be 1 line for each 
treatment and a single line for the placebo group(s).  Corresponding individual plots of 
time-matched double differences will also be produced for each treatment.
The time matched double differences in QTcF will be plotted against PF-06882961 
concentration.  This will be a scatter plot for all observations where QTcF and drug 
concentration are recorded.  Placebo data will also be included (with drug concentration set 
to zero).  Different symbols will be used for each treatment.  
6.1.3. Vital Signs
Absolute values and change from time-matched baseline in supine systolic and diastolic 
blood pressure and pulse rate will be summarized by treatment, time post-dose and day, 
according to sponsor reporting standards.  Tables will be paged by parameter.  Baseline is as 
defined in Section 3.1.3.
Mean change from time-matched baseline for supine systolic and diastolic blood pressure 
and pulse rate will be plotted against time post-dose and day.  On each plot there will be 
1 line for each treatment.  Corresponding individual plots of change from time-matched 
baseline will also be produced for each treatment.
Maximum absolute values and change from time-matched baseline for vital signs will also be 
summarized descriptively by treatment using the following categories.  Numbers and 
percentages of subjects meeting the categorical criteria will be provided.  All planned and 
unplanned post-dose timepoints will be counted in these categorical summaries.  All values 
meeting the criteria of potential clinical concern will be listed.
Table 7.
Categories for Vital Signs
Parameter
Criteria
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120


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The time-matched double differences in vital signs obtained following the Day 1 treatment, 
as defined in Section 3.1.3, will be summarized (N, mean, 90% confidence interval) for each 
treatment and time point.
Mean time-matched double differences in vital signs will be plotted against time post-dose
for Day 1 and Day 56 separately. On each plot there will be 1 line for each treatment.  
Corresponding individual plots of time-matched double differences will also be produced for 
each treatment.
6.1.4. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 3.1.4.
6.2. Secondary Endpoint(s)
6.2.1. Pharmacokinetic Endpoints as Secondary Endpoint
The PK parameters detailed in Section 3.2.1 will be listed and summarized for subjects in the 
PK parameter analysis set (as defined in Section 4).  Missing values will be handled as 
detailed in Section 5.3.3.  Each PK parameter will be summarized descriptively by treatment, 
dose and day (Day 1 and Day 56) as detailed in Section 3.2.1. 
The parameters will include the set of summary statistics as specified in the table below:
Table 8.
PK Parameters to be Summarized Descriptively
Parameter
Matrix
Summary Statistics
Cmax, Cmax1, Cmax2, AUC24
Plasma
N, arithmetic mean, median, CV%, 
standard deviation, minimum, 
maximum, geometric mean and 
geometric CV%.
Tmax, Tmax1, Tmax2
Plasma
N, median, minimum, maximum.
t1/2*
Plasma
N, arithmetic mean, median, CV%, 
standard deviation, minimum, 
maximum.
*=not calculated at Day 1.
There will be one summary table for all PK parameters. The treatment subheading will 
include the matrix, dose information and day.  As per Section 5.3.3, data collected on days 
that subjects received anything other than the assigned dose based on the titration scheme 
will only be listed and not summarized as part of the summary table.
Supporting data from the estimation of t½ will be listed where applicable:  terminal phase 
rate constant (kel); goodness of fit statistic from the log-linear regression (r2); and the first, 
last, and number of time points used in the estimation of kel. This data may be included in 
the clinical study report.


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No formal inferential statistics will be applied to the PK data.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.4. Subset Analyses
No subset analysis will be conducted for this study.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Baseline data (age, gender, race, ethnicity, height, weight, body mass index, duration of 
diabetes,
systolic blood pressure, and diastolic blood pressure) 
will be summarized by treatment and overall.
6.5.2. Study Conduct and Participant Disposition
The following participant dispositions will be summarized.
•
A summary of participant discontinuations up to end of study;
•
Summary of participant dispositions analyzed for PK
 as well as for safety;
•
Summary of numbers of participant treated by treatment group.
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Data will be reported in accordance with the sponsor reporting standards.
6.5.3. Concomitant Medications and Nondrug Treatments
All concomitant medications as well as nondrug treatments will be summarized in 
accordance with the sponsor reporting standards.
6.5.4. Medical History
All medical histories will be summarized in accordance with the sponsor reporting standards.
6.5.5. Treatment Compliance 
A summary table of treatment compliance by week will be produced by week according to 
current sponsor reporting standards. 
“Study Week” will be calculated using actual visit dates, rather than calendar days. For 
example, if vomiting occurs on Day 8 and Visit 2 occurs on Day 9 for a given patient, then 
the vomiting is considered to have occurred on Week 1 for this patient (Week 1 is Day1 to 
Day 8 for this patient).
 
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. As this is an sponsor-open
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating PK
 modeling, and/or supporting clinical 
development.
8. REFERENCES
1
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. 
Homeostasis model assessment: insulin resistance and β-cell function from fasting 
plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419.
                                                
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