Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
This is a Phase 1, randomized, double-blind (sponsor open), placebo controlled study in adult Chinese participants with T2DM who are receiving metformin as background antihyperglycemic medication.

Detailed description:

Arms:
arm 1: Participants will be titrated up to 6 weeks of the 8-week dosing duration to reach desired dose level 120 mg arm 2: Placebo

Interventions: intervention 1: PF-06882961 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will be administered active doses, taking 3 tablets twice daily (BID) for 8 weeks except Day 1 (QD) intervention 2: 3 matching placebo tablets taken twice daily (BID) except Day 1 (QD)

Protocol document:
Prot_000.pdf: 
PF-06882961
Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
Page 1
AN 8-WEEK, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-
CONTROLLED PHASE 1 STUDY TO EVALUATE THE PHARMACOKINETICS, 
PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF PF-06882961 IN 
CHINESE ADULTS WITH TYPE 2 DIABETES MELLITUS
Study Intervention Number:
PF-06882961
Study Intervention Name:
N/A
US IND Number:
N/A
EudraCT Number:
N/A
Protocol Number:
C3421028
Phase:
1
Short Title: A Phase 1 Study to Evaluate the Pharmacokinetics, Pharmacodynamics, 
Safety and Tolerability of PF-06882961 in Chinese 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.


PF-06882961
Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
Page 2
Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
10 Dec 2020
N/A


PF-06882961
Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
Page 3
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 ...............................................................................................................17
2.1. Study Rationale .......................................................................................................17
2.2. Background .............................................................................................................17
2.2.1. Nonclinical Overview.................................................................................18
2.2.1.1. Nonclinical Pharmacology........................................................18
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism........................18
2.2.1.3. Nonclinical Safety.....................................................................19
2.2.2. Clinical Overview.......................................................................................20
2.2.2.1. Clinical Safety...........................................................................20
2.2.2.2. Clinical Pharmacokinetics.........................................................21
2.3. Benefit/Risk Assessment.........................................................................................21
2.3.1. Risk Assessment.........................................................................................22
2.3.2. Benefit Assessment.....................................................................................25
2.3.3. Overall Benefit/Risk Conclusion................................................................25
3. OBJECTIVES , ESTIMANDS, AND ENDPOINTS ..........................................................25
4. STUDY DESIGN.................................................................................................................27
4.1. Overall Design.........................................................................................................27
4.2. Scientific Rationale for Study Design.....................................................................27
4.3. Justification for Dose ..............................................................................................29
4.4. End of Study Definition ..........................................................................................30
5. STUDY POPULATION......................................................................................................30
5.1. Inclusion Criteria.....................................................................................................30
5.2. Exclusion Criteria....................................................................................................31
5.3. Lifestyle Considerations..........................................................................................34


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Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
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5.3.1. Meals and Dietary Restrictions...................................................................34
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................35
5.3.3. Activity .......................................................................................................35
5.3.4. Contraception..............................................................................................35
5.4. Screen Failures ........................................................................................................36
6. STUDY INTERVENTION..................................................................................................36
6.1. Study Intervention(s) Administered........................................................................36
6.1.1. Administration............................................................................................37
6.1.1.1. Inpatient and outpatient visit days.............................................37
6.1.1.2. Non-visit days ...........................................................................38
6.2. Preparation/Handling/Storage/Accountability ........................................................38
6.2.1. Preparation and Dispensing........................................................................39
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................39
6.3.1. Allocation to Study Intervention ................................................................39
6.3.2. Breaking the Blind......................................................................................40
6.4. Study Intervention Compliance...............................................................................41
6.5. Concomitant Therapy..............................................................................................41
6.5.1. Medications for Glycemic Control.............................................................42
6.5.2. Antihypertensive Medications....................................................................42
6.5.3. Lipid-Modifying Medications ....................................................................42
6.5.4. Management of Nausea and Vomiting .......................................................43
6.5.5. Rescue Medicine.........................................................................................43
6.6. Dose Modification...................................................................................................43
6.7. Intervention After the End of the Study..................................................................43
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................43
7.1. Discontinuation of Study Intervention ....................................................................43
7.2. Participant Discontinuation/Withdrawal From the Study.......................................44
7.2.1. Withdrawal of Consent...............................................................................45
7.3. Lost to Follow-up....................................................................................................45
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................45
8.1. Efficacy Assessments..............................................................................................46


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Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
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8.2. Safety Assessments .................................................................................................47
8.2.1. Physical Examinations................................................................................47
8.2.3. Vital Signs ..................................................................................................47
8.2.4. Electrocardiograms.....................................................................................48
8.2.5. Management of Glycemic Control .............................................................49
8.2.5.1. Home Glucose Monitoring........................................................49
8.2.5.2. Management of Hypoglycemia .................................................49
8.2.5.3. Management of Hyperglycemia................................................51
8.2.6. Clinical Safety Laboratory Assessments ....................................................51
8.2.7. COVID-19 Specific Assessments...............................................................52
8.2.8. Pregnancy Testing ......................................................................................52
8.3. Adverse Events and Serious Adverse Events..........................................................52
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......53
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................53
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................54
8.3.2. Method of Detecting AEs and SAEs ..........................................................54
8.3.3. Follow-up of AEs and SAEs.......................................................................54
8.3.4. Regulatory Reporting Requirements for SAEs...........................................54
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................55
8.3.5.1. Exposure During Pregnancy......................................................55
8.3.5.2. Exposure During Breastfeeding ................................................56
8.3.5.3. Occupational Exposure .............................................................57
8.3.6. Cardiovascular and Death Events...............................................................57
8.3.7. Disease Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................57
8.3.8. Adverse Events of Special Interest.............................................................57
8.3.8.1. Lack of Efficacy........................................................................57
8.3.9. Medical Device Deficiencies......................................................................58
8.3.10. Medication Errors.....................................................................................58
8.4. Treatment of Overdose............................................................................................58
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8.5. Pharmacokinetics ....................................................................................................59
8.9. Immunogenicity Assessments.................................................................................60
8.10. Health Economics .................................................................................................61
9. STATISTICAL CONSIDERATIONS ................................................................................61
9.1. Estimands and Statistical Hypotheses.....................................................................61
9.2. Sample Size Determination.....................................................................................61
9.3. Analysis Sets ...........................................................................................................61
9.4. Statistical Analyses .................................................................................................62
9.4.1. General Considerations...............................................................................62
9.4.2. Primary Endpoint(s)....................................................................................62
9.4.3. Secondary Endpoint(s)................................................................................64
9.4.5. Other Safety Analyses ................................................................................64
9.4.5.1. Electrocardiogram Analyses......................................................65
9.5. Interim Analyses .....................................................................................................65
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............65
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................66
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............66
10.1.1. Regulatory and Ethical Considerations ....................................................66
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................66
10.1.2. Financial Disclosure .................................................................................67
10.1.3. Informed Consent Process ........................................................................67
10.1.4. Data Protection .........................................................................................68
10.1.5. Dissemination of Clinical Study Data ......................................................68
10.1.6. Data Quality Assurance ............................................................................70
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10.1.7. Source Documents....................................................................................71
10.1.8. Study and Site Start and Closure ..............................................................71
10.1.9. Publication Policy.....................................................................................72
10.1.10. Sponsor’s Qualified Medical Personnel .................................................73
10.2. Appendix 2: Clinical Laboratory Tests .................................................................74
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................76
10.3.1. Definition of AE .......................................................................................76
10.3.2. Definition of SAE.....................................................................................77
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................78
10.3.4. Reporting of SAEs....................................................................................81
10.4. Appendix 4: Contraceptive Guidance ...................................................................83
10.4.1. Male Participant Reproductive Inclusion Criteria....................................83
10.4.2. Female Participant Reproductive Inclusion Criteria.................................83
10.4.3. Woman of Childbearing Potential ............................................................83
10.4.4. Contraception Methods.............................................................................84
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........86
10.6. Appendix 6: ECG Findings of Potential Clinical Concern ...................................88
10.7. Appendix 7: Prohibited Prior/Concomitant Medications......................................90
10.8. Appendix 8: Abbreviations ...................................................................................92
11. REFERENCES ..................................................................................................................96


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Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
Page 8
LIST OF TABLES
Table 1.
Overall Schedule of Activities..................................................................13
Table 2.
Schedule of Activities – Study Days -1, 1, 21, 35 & 56...........................16
Table 3.
Dose Levels in Study C3421028 ..............................................................40
Table 4.
Definition of Plasma PK Parameters for PF-06882961............................63
Table 5.
Protocol-Required Safety Laboratory Assessments .................................74
Table 6.
Prohibited Prior/Concomitant Medications ..............................................90
LIST OF FIGURES
Figure 1.
Schema of Study C3421028 .....................................................................12
Figure 2.
Dose Titration Scheme .............................................................................36


PF-06882961
Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
Page 9
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 1 Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety 
and Tolerability of PF-06882961 in Chinese Adults with Type 2 Diabetes Mellitus
Rationale: The purpose of this study is to evaluate the PK, safety and tolerability of single 
and multiple oral doses of PF-06882961 in adult Chinese participants with T2DM who are 
receiving metformin as background antihyperglycemic medication. The study will be 
investigator- and participant-blind (sponsor-open), to permit a review of safety and 
tolerability in order to assess potential for drug-induced changes in participants with T2DM.  
 
Objectives , Estimands, and Endpoints:
Objectives
Estimands
Endpoints
Primary:
Primary:
Primary:
•
To characterize the plasma 
PK of PF-06882961 
following a single oral dose 
on Day 1 and following 
multiple, oral doses 
administered to adult 
Chinese participants with 
T2DM.
Not Applicable
•
Single dose (10 mg): 
AUC24, Cmax.
•
Multiple dose (40 mg, 
80 mg, 120 mg): 
AUC24, Cmax,ss.
Secondary:
Secondary:
Secondary:
•
To evaluate the safety and 
tolerability of PF-06882961 
following a single oral dose 
on Day 1 and following 
multiple, oral doses 
administered to adult 
Chinese participants with 
T2DM.
Not Applicable
•
Vital signs, 
Electrocardiograms, 
Adverse events (e.g. 
hypoglycemia and 
hyperglycemia), 
Clinical safety 
laboratory assessments.
 
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Protocol C3421028
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PFIZER CONFIDENTIAL
Page 10
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall Design
This is a Phase 1, randomized, double-blind, sponsor-open, placebo-controlled, oral dosing 
study of PF-06882961 in adult Chinese participants with T2DM inadequately controlled on 
diet, exercise and metformin background therapy.
The study includes a total of 12 visits, of which 4 are inpatient study visits at the site (V2, 
V5, V7, V10) and 5 are outpatient visits (V3, V4, V6, V8, V9) excluding screening to the site 
(V1). Following the screening period (V1) to confirm eligibility (up to 4 weeks), participants 
will be randomized at V2 to receive PF-06882961 (or matching placebo) for a duration of 8 
weeks and complete dosing at V10. The dose of PF-06882961 will be increased following a 
prespecified titration scheme during visits V2 through V8 to reach the target dose, which will 
then be maintained through V10. The others are follow-up visits (V11 and V12). During the 
study, participants will take study intervention blindedly either at home, at an outpatient visit, 
or at the study site as an inpatient.
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Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
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Number of Participants
Participants will receive oral doses of PF-06882961 or placebo in this study. Approximately
20 participants will be randomized to PF-06882961 or placebo at a 3:1 ratio (15 participants 
to PF-06882961 and 5 participants to placebo) such that at least 8 participants in PF-
06882961 group will complete 120 mg and be evaluable for PK analysis. The study will be 
conducted at a single clinical site in China.
Intervention Groups and Duration
The target dose level is PF-06882961 120 mg BID (or matching placebo). 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 (QD at Day 1 and BID at Days 2-56), and up to 6 weeks of the 
8-week dosing duration will be used for dose titration to maximize tolerability of PF-
06882961, as depicted in Figure 1. 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. If a participant discontinues the study 
intervention, every effort should be made to contact the participant for the follow-up visits
(V11 and V12).
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
In general, PF-06882961 plasma PK concentration and parameters data will be summarized 
descriptively for single dose and multiple doses separately; safety endpoints will be 
summarized by treatment group and dose levels; 
 
PK parameters AUC24, Cmax, Cmax,ss , 
will be summarized 
descriptively with n, arithmetic mean, standard deviation, coefficient of variation (CV%), 
geometric mean, geometric CV (%), median, minimum, and maximum. Box and whisker plot 
of individual and geometric mean will be presented for AUC24, Cmax, Cmax,ss , 
 
 
Concentration data will be listed and summarized descriptively by nominal PK sampling time 
and day (dose). Mean and median of the plasma concentration-time data will be plotted by 
day (dose) against nominal PK sampling time. Spaghetti plots of individual plasma 
concentration-time data will be provided by day (dose) and actual PK sampling time. 
Safety data will be presented in tabular format according to the sponsor’s reporting standards.
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Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
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1.2. Schema
Figure 1.
Schema of Study C3421028
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Protocol C3421028
Final Protocol, 10 Dec 2020 
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Page 13
1.3. Schedule of Activities
The SoA tables ( Table 1 and Table 2) provides 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.
Table 1.
Overall Schedule of Activities
Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 8
Screen
Study Day (all activities at 0H [prior to AM dosing] unless otherwise specified)
Follow Up
ET
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12b
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 1c
-28 to
-3
-2
-1
1
2
8
15
20
21
22
29
34
35
36
43
50
55
56
57
58
63-70
84 - 91
Informed consent & demography
x
See Table 2
See Table 2
See Table 2
See Table 2
See Table 2
Review of eligibility criteria
x
x
Inpatient stay at study site
x
x
x
x
x
Discharge from inpatient stay
x
x
x
x
Outpatient visit (after 8-H fast)
x
x
x
x
x
x
x
Adverse event monitoring
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Medical history
x
x
Review prior and concomitant 
treatments
x
x
x
x
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
x
x
x
x
x
x
Review contraception use (females 
only)
x
x
x
x
x
x
x
x
x
x
x
x
x
Counseling on diet/exercise 
guidelines
x
Dispense glucometer and supplies, 
drug diary, glucose diary & provide 
training
x
Review drug diary, glucometer & 
glucose diary
xd
x
x
x
x
x
x
x
x
x
x
x
xd
x


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Protocol C3421028
Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
Page 14
Table 1.
Overall Schedule of Activities
Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 8
Screen
Study Day (all activities at 0H [prior to AM dosing] unless otherwise specified)
Follow Up
ET
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12b
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 1c
-28 to
-3
-2
-1
1
2
8
15
20
21
22
29
34
35
36
43
50
55
56
57
58
63-70
84 - 91
Glucose measurement (fasting, via 
glucometer)
x
See Table 2
See Table 2
x
x
x
x
See Table 2
x
x
x
See Table 2
x
x
x
x
See Table 2
x
x
x
x
Physical examination (height at 
Screening only)
x
x
x
x
x
Supine vital signse
x
x
x
x
x
x
x
x
x
x
x
Supine 12-lead ECGf
x
x
x
x
x
x
x
x
x
x
x
COVID-19 questionnaireh
x
x
x
x
x
x
x
x
x
x
x
x
x
COVID-19 pathogen by PCRi
x
Chest radiograph for COVID-19i
x
COVID-19 check temperaturej
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispensation of IP
x
x
x
x
x
x
x
x
Dosing on site of IP (with meal)k
x
x
x
x
x
x
x
x
x
x
x
Standardized meals/snacksl
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood Sampling for:
Plasma C-peptide
x
Hematologyi, chemistry (inc. eGFR)
x
x
x
Lipids, TSH, free T4, calcitonin, 
amylase, lipase, serum TBA, 
PT/INR/aPTT
x
x
FSH (females only) 
x
HIV, HBsAg, HBcAb, HCVAb, 
Syphilis
x
Antibodies test of COVID-19i
x
PF-06882961 PKm
x
x
x
x
x
x
Urine Sampling for:
Urine drug test
x
x
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Table 1.
Overall Schedule of Activities
Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 8
Screen
Study Day (all activities at 0H [prior to AM dosing] unless otherwise specified)
Follow Up
ET
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12b
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 1c
-28 to
-3
-2
-1
1
2
8
15
20
21
22
29
34
35
36
43
50
55
56
57
58
63-70
84 - 91
Urinalysis (and microscopy, as 
appropriate)
x
x
x
x
x
x
Blood or Urine Sampling for:
Pregnancy test (serum) (females
only) n
x 
x
x
x
x
x
x
x
x
a.
Day relative to start of study treatment (Day 1).
b.
Contact may occur via telephone contact and must occur 28 to 35 days from administration of the final dose of study intervention.
c.
Allowable time window for V3-V10 is ±1.
d.
Review glucometer and glucose diary only.
e.
Includes supine blood pressure and pulse rate; vital signs at Screening, Follow up, and early termination visit (if appropriate) are single; Triplicates vital signs should be conducted 
prior to AM dose at 0H on Days 8, 15, 22, 29, 36, 43, and 50. On Day 57, triplicate vital signs collected at 0H only. 
f.
12-lead ECG at Screening, 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 Days 8, 15, 22, 29, 36, 43, and 50. 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.
 
h.
Check exposure to positive subject, residence or travel in area of high incidence and COVID-19 related signs and symptoms. To be done at least 48 hours before and at each visit.
i.
An subsequent test will be performed if the participant has exposure to COVID-19 positive subject, or residence or travel in area of high incidence, or develop COVID-19 related 
signs and symptoms. The test may be adjusted or additional test may be required by local regulations or by the Principal Investigator.
j.
To be done at least daily during residence. To be done by participant if V12 occurs via telephone contact.
k.
During inpatient, both AM and PM dosing will occur at the study site, except discharge days (Days 2, 22, 36). On outpatient visit and discharge day, AM dosing will occur at the 
study site.
l.
Meals/snacks to occur on all days while inpatient; breakfast (lunch if needed) to be provided on outpatient visits. Detailed requirements see Section 5.3.1.
m.
PK samples to be collected prior to AM dose on Days 15, 29, and 43. 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. 
n.
For WOCBP only: 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 – Study Days -1, 1, 21, 35 & 56 
[Procedures at 0H to be completed prior to dosing or similar clock time, in the case of Day-1]
Hours Relative to Dosing at 0Ha
0
0.25
0.5
1
1.5
2
3
4
6
8
10
12
14
24
Continued inpatient stay at study site
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Adverse event monitoring
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Review prior and concomitant treatments
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Review drug, alcohol, tobacco use
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Review drug diary, glucometer & glucose diaryb
x
COVID-19 check temperature
x
Glucose measurement (fasting, via glucometer)
x
Triplicate, supine vital sign assessmentc
x
x
x
x
x
x
Triplicate, supine 12-lead ECG 
x
x
x
x
x
x
Randomization in trial (Day 1 only)
x
Dosing on site of IP with meal (Days 1, 21, 35, and 56 only)
xd
xe
Standardized meal/snackf
xg
x
x
x
Blood Sampling for:
Hematology, chemistry (inc. eGFR) (Days -1, 21, 35, 56 only)
x
Lipids, TSH, free T4, calcitonin, amylase, lipase, TBA, 
PT/INR/aPTT (Days -1 and 56 only)
x
PF-06882961 PK (Days 1, 21, 35, and 56 only)
xh
x
x
x
x
x
x
x
x
x
Urine Sampling for:
Urinalysis (and microscopy, as appropriate) (Day -1 only)
x
Blood or Urine Sampling for:
Pregnancy test (for WOCBP only) (Days 21, 35, 56 only)
x
a.
On Day -1, nominal time to match approximate clock time of collection planned on Day 1 to permit time matched comparison. 
b.
Review glucometer and glucose diary only on Day -1.
c.
Includes blood pressure and pulse rate. 
d.
Dosing expected to occur with breakfast or mixed meal. Day 1 only single dose at 0H
e.
Dosing expected to occur with dinner. No dosing at this timepoint on Day 1.
f.
Meals/snacks to occur on all days while inpatient; identical meals/snacks on Days -1, 1, 21, 35, and 56.
g.
Standard breakfast on Day 1 and all other inpatient days. 
h.
Collection following fasting duration.
CCI
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2. INTRODUCTION
GLP-1 is a neuroendocrine hormone 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 this study is to evaluate the PK, safety and tolerability of single and multiple 
oral doses of PF-06882961 in adult Chinese participants with T2DM who are receiving 
metformin as background antihyperglycemic medication. The study will be investigator- and
participant-blind (sponsor-open), to permit a review of safety and tolerability in order to 
assess potential for drug-induced changes in 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 2 epicentres (109.6 and 69.2 million of adults with diabetes in 
2015).7 The latest nationally representative epidemiological survey indicated that the overall 
prevalence of diabetes in mainland China in 2017 was 12.8% using the ADA diagnostic 
criteria and 11.2% using World Health Organization criteria. There are about 130 million 
diabetes in China and the prevalence of prediabetes was 35.2% in Chinese adults, diagnosed 
by the ADA criteria, which indicates that diabetes is really an important health problem in 
China.8 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.9 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.10 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 HbA1c levels, suggesting a need for additional 
therapeutic options.
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Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and cardiovascular safety, with at least one marketed agent demonstrating 
cardiovascular benefit.11 Based on the clinical history of injectable GLP-1R agonists, an oral 
GLP-1R agonist is expected to improve glucose control and reduce HbA1c levels in patients 
with T2DM, while decreasing food intake and body weight and avoiding the subcutaneous 
injection required by currently available peptidic GLP-1R agonists.
2.2.1. Nonclinical Overview
2.2.1.1. Nonclinical Pharmacology
In vitro primary pharmacodynamic studies demonstrated that in cells expressing recombinant
human and monkey GLP-1R, PF-06882961 concentration-dependently promotes cAMP
production. In contrast, no cAMP production was observed in cells expressing recombinant
rat, mouse, and rabbit GLP-1R at tested concentrations (<10-20 μM). In addition, PF-
06928468 (metabolite of PF-06882961) was found to be inactive against human GLP-1R.
PF-06882961 was shown to bind to the human GLP-1R using a competition binding assay. In 
vivo, PF-06882961 dose-dependently potentiated glucose-stimulated insulin secretion during 
an IVGTT in cynomolgus monkeys. Finally, PF-06882961 was also shown to reduce food 
intake in cynomolgus monkeys. In all in vivo studies, efficacious plasma levels were
consistent with the in vitro potency.
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 (TI) 
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 use 
in 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 


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Page 19
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 7 for a complete list of prohibited 
medications.
Refer to the IB for more details on the nonclinical PK and metabolism of PF-06882961.
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 clinical dose of PF-06882961, 120 mg BID.
A NOAEL was 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 the highest doses
administered (100 mg/kg/day and 150 mg/kg/day, 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 embryo-fetal development, the NOAEL for maternal and developmental 
toxicity in rats was 500 mg/kg/day (highest dose evaluated). The exposures at 500 mg/kg/day 


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provide margins of approximately 69-fold (Cmax, free) and 68-fold (AUC24, free), to the 
observed human exposures at the 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 clinical dose of PF-06882961, 120 
mg BID.
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 been 
completed dosing with PF-06882961. C3421001, which administered single ascending oral 
doses of PF-06882961 or placebo to healthy adult participants, C3421002, which 
administered multiple ascending oral doses of PF-06882961 or placebo to adults with T2DM 
and safety results from this study are provided in Section 2.2.2.1, and C3421003, which
administered single oral doses of different formulations of PF-06882961 to healthy
participants. 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. One (1) participant in the 15 mg BID group discontinued from the study due to a 
treatment related, moderate TEAE of headache on Day 2. One (1) participant in the 50 mg 
BID group discontinued from the study due to moderate TEAEs of decreased appetite on Day 
1, nausea, vomiting, and a mild TEAE of fatigue on Day 7 (all related to study drug).
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


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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.
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,11, 12 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. In summary, PF-06882961 was generally safe and 
well tolerated in C3421002, with a safety profile in line with marketed GLP-1R agonists.
2.2.2.2. Clinical Pharmacokinetics
The clinical PK of PF-06882961 in healthy adult participants has been evaluated in two 
completed studies: C3421001 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. Dosing for 4 of the 6 cohorts was titrated for various 
amounts of time over the 28 days, with target maximum doses 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 geometric mean 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. Median 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.


PF-06882961
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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/1.73m2)
are not eligible for study entry. Renal function is 


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Page 23
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
In the clinical trial program only one mild AE
(Blood creatinine increased) has been observed.
monitored during the study by the 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.
Dose titration will be adopted to enhance 
tolerability to PF-06882961.
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.
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.
Participants will be actively monitored and those
who experience hyperglycemia, per protocol
defined criteria, may be discontinued and receive 
rescue medication.


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Page 24
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Other
During the  COVID-19 pandemic, the following is 
recommended: Risk COVID-19 contamination 
during study.
During the pandemic participant could be infected 
with the the SARS-COV-2 virus through study 
participation. This could lead to increased health 
risk for this participant and others in the study.
Confounding AE with compound.
COVID-19 specific assessments according to SoA.


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Page 25
2.3.2. Benefit Assessment
Based on the clinical experience of injectable GLP-1R agonists, an oral GLP-1R agonist is 
expected to improve glucose control, reduce HbA1c levels, diminish food intake, and 
decrease body weight in patients with T2DM, while avoiding the requirement for 
subcutaneous injections that accompanies currently available peptidic GLP-1R agonists. As 
the treatment period of this study is only 8 weeks, clinical benefit to participants with T2DM
is unlikely or limited given the short duration of this study and the early stage of 
development of PF-06882961. This study is designed to generate safety, tolerability, PK 
 
data in Chinese T2DM participants for further clinical development.
2.3.3. Overall Benefit/Risk Conclusion
In line with the clinical profile of marketed GLP-1R agonists13, 14, 15, the most frequently 
reported AEs with PF-06882961 administration have been nausea, diarrhea, dyspepsia, 
headache, and vomiting. In addition, as has been reported for marketed GLP-1R agonists, 
increases in heart rate have been observed with PF-06882961 administration, with most heart 
rate values within the normal range.
Considering all available clinical and nonclinical data, the overall benefit-risk profile of PF-
06882961 supports further clinical development in patients with T2DM.
3. OBJECTIVES , ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary:
Primary:
Primary:
•
To characterize the plasma 
PK of PF-06882961 
following a single oral 
dose on Day 1 and 
following multiple, oral 
doses administered to 
adult Chinese participants 
with T2DM.
Not Applicable
•
Single dose (10 mg): 
AUC24, Cmax.
•
Multiple dose (40 mg, 
80 mg, 120 mg): 
AUC24, Cmax,ss.
Secondary:
Secondary:
Secondary:
•
To evaluate the safety and 
tolerability of PF-
06882961 following a 
single oral dose on Day 1 
and following multiple, 
oral doses administered to 
Not Applicable
•
Vital signs, 
Electrocardiograms, 
Adverse events (e.g. 
hypoglycemia and 
hyperglycemia), 
Clinical safety 
laboratory assessments.
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Objectives
Estimands
Endpoints
adult Chinese participants 
with T2DM.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, randomized, double-blind, sponsor-open, placebo-controlled, oral dosing 
study of PF-06882961 in adult Chinese participants with T2DM inadequately controlled on 
diet, exercise and metformin background therapy.
Participants will receive oral doses of PF-06882961 or placebo in this study. Approximately 
20 participants will be randomized to PF-06882961 or placebo at a 3:1 ratio (15 participants
to PF-06882961 and 5 participants to placebo) such that at least 8 participants in PF-
06882961 group will complete 120 mg and be evaluable for PK analysis. The study will be 
conducted at a single clinical site in China.
The target dose level is PF-06882961 120 mg BID (or matching placebo). 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 (QD at Day 1 and BID at Days 2-56), and up to 6 weeks of the 
8-week dosing duration will be used for dose titration to maximize tolerability of PF-
06882961, as depicted in Figure 2. The dose of PF-06882961 will be increased following a 
prespecified titration scheme during visits V2 through V8 to reach the target dose, which will 
then be maintained through V10. 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. If a participant discontinues the study 
intervention, every effort should be made to contact the participant for the follow-up visits 
(V11 and V12).
As shown in Section 1.2, this study includes a total of 12 visits, of which 4 are inpatient 
study visits at the site (V2, V5, V7, V10) and 5 are outpatient visits (V3, V4, V6, V8, V9) 
excluding Screening to the site (V1). The others are follow-up visits (V11 and V12). 
Following the Screening visit (V1) to confirm eligibility (up to 4 weeks), participants will be 
randomized at V2 to receive PF-06882961 (or matching placebo) for a duration of 8 weeks 
and complete dosing at V10. The inpatient stays at V2 and V10 consists of 4 days and 3 
nights, while the inpatient stays of V5 and V7 consist of 3 days and 2 nights, as listed in the
SoA. For the study duration between the inpatient study visits, participants will continue 
dosing with blinded study intervention either at home, at an outpatient visit, or at the study 
site as an inpatient. Please refer to Figure 2 for the scheme of dose titration.   
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.
4.2. Scientific Rationale for Study Design
The purpose of this study is to evaluate the PK, safety and tolerability of single and multiple 
oral doses of PF-06882961 in adult Chinese participants with T2DM who are receiving 
metformin as background antihyperglycemic medication. 
 
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Results from this study will be 
compared with Global studies (C3421002 and C3421005) to facilitate the analyses of ethnic 
differences in PK, 
 and tolerability between Chinese and Westerners.
Completed studies indicated that PF-06882961 exposures in T2DM participants was 1.7-fold 
higher than that in healthy participants, despite higher body weight. In Study C3421002, the 
steady-state PK of PF-06882961 was characterized in a T2DM population. A similar Chinese
population with T2DM was selected in the current study to facilitate the PK comparison of 
PF-06882961 between Chinese and Western participants.
 
  
Based on the results from Study C3421002, the starting dose of PF-06882961 in the current 
study will be set at 10 mg BID (or matching placebo). The dose will then be up-titrated 
approximately weekly to reach the target level of 120 mg BID at Week 7. Such dose titration 
was adopted to enhance the tolerability to higher doses of PF-06882961. This titration 
scheme is identical to that in Global Study C3421005 which permits the comparison of 
tolerability between Chinese and Westerners. It is considered that gastrointestinal adverse 
events common to GLP-1R agonists are mostly expected soon after dose increases. 
Therefore, the 2-week maintenance period of 120 mg BID (Visits 8-10) is sufficient to 
characterize the safety and tolerability of PF-06882961 in the current China Phase 1 study. 
Such titration and maintenance period is identical to part of that in Study C3421005 which 
allows a comparison 
 after 8-week treatment, 
 
 The data will also be pooled with a number of other studies and assessed via 
population PK and PK
 analyses. 
 safety data obtained in Chinese participants will 
be compared with data from Study C3421005 in which similar titration and maitanance 
schedules were adopted. 
A baseline day (Day -1) with time-matched procedures will permit an improved assessment 
of safety, tolerability, 
 The participants and site
staff will be blinded to administration of active versus placebo to permit an unbiased 
assessment of tolerability and safety.
Clinical safety laboratory tests, assessments of vital signs and 12-lead ECGs, physical
examinations, and AE monitoring will provide essential data to evaluate the safety and
tolerability of PF-06882961. 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. 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.
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 mean values of them will be used for analysis at each time point. In addition to triplicate 
ECG and BP measurements taken prior to dosing of study intervention, and any morning 
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dose of permitted concomitant medications, triplicate ECG intervals and BP measurements 
will also be collected at approximate time for Cmax
on PK sampling days as specified 
in the SoA to further enhance quantification of any possible drug effect.
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.
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, the use of 
a highly effective method of contraception is required and measures will be taken to limit the 
risk of pregnancy in the female population enrolled (see Appendix 4).
The potential risk of exposure to PF-06882961 in a sexual partner of a male participant in 
this study via ejaculate is low, and therefore no contraception (condom) use in male 
participants is warranted. The calculated safety margin is ≥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.16
4.3. Justification for Dose
In this study, PF-06882961 will be administered BID in titration: starting with 10 mg and 
titrated approximately weekly up to 120 mg within 6 weeks, followed by 2-week 
maintenance at 120 mg. It is considered that steady state is achieved during each weekly 
titration step. The PF-06882961 doses selected for this study are based on observed safety, 
tolerability, PK, 
 data from the completed 4-week study comparing PF-06882961 to 
placebo in T2DM participants (Study C3421002); as well as the exposure margins relative to 
observed toxicology findings. Exposure margins for the proposed dose in this study (120 mg 
BID) are given in Section 2.2.1.3. 
Doses ranging from 10 mg BID to 120 mg BID were generally safe and well tolerated in 
Phase 1 Study C3421002. The titration scheme used in this study is slower than that used in 
C3421002. 
 
. Given the current dose titration and 
PK sampling schedule, AUC24 and Cmax parameters from the 40 mg and 80 mg doses will be 
determined.
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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).
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.
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. Chinese male or female participants between the ages of 20 and 60 years, inclusive, at 
Visit 1 (Screen 1).

Refer to Appendix 4 for reproductive inclusion criteria for male (Section 10.4.1) 
and female (Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Patients with T2DM who are taking metformin monotherapy as their only anti-
hyperglycemic treatment. Metformin dose must be 500 mg per day and must be 
stable, defined as no change in the treatment, including dose, for at least 2 months 
prior to the Screening visit.
3. HbA1c 7.0% 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 diary for the duration 
of participation in the study.


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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 (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).

Patients who have chronic conditions other than T2DM (for example, 
hypercholesterolemia or hypertension) but are controlled by either diet or stable 
doses of medications may be included (for example, a participant with 
hypercholesterolemia on appropriate treatment is eligible).
2. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or 
pancreatic insufficiency).
3. Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes.
4. History of myocardial infarction, unstable angina, arterial revascularization, stroke, 
New York Heart Association Functional Class II-IV heart failure, or transient 
ischemic attack within 6 months of Screening (Visit 1).
5. Any malignancy not considered cured (except basal cell carcinoma and squamous cell 
carcinoma of the skin); a participant is considered cured if there has been no evidence 
of cancer recurrence in the previous 5 years.
6. Personal or family history of medullary thyroid carcinoma (MTC) or multiple 
endocrine neoplasia syndrome type 2 (MEN2), or participants with suspected MTC 
per the PI’s judgement.
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8. Acute gallbladder disease.
9. History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; positive 
testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), or hepatitis C antibody (HCVAb) or syphilis. Hepatitis B vaccination is 
allowed.
10. Known intolerance or hypersensitivity to GLP-1R agonists.
11. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
Prior/Concomitant Therapy:
12. Use of the concomitant therapies listed in Section 6.5 and Appendix 7.
Prior/Concurrent Clinical Study Experience:
13. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention
used in this study (whichever is longer). 
14. Known prior participation in a trial involving PF-06882961.
Diagnostic Assessments:
15. 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.
16. 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.
17. A positive urine drug test. Note: Participants who have been medically prescribed
opiates/opioids or benzodiazepines and report the use of these drugs to the 
investigator at Screening (Visit 1) may be allowed to participate with notification to 
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18. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary:

AST or ALT level 1.5 ×ULN.

Total bilirubin 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 > ULN.

Serum calcitonin > ULN.

Amylase or lipase > ULN.

Fasting blood glucose > 270 mg/dL (15.0 mmol/L).

eGFR<60 mL/min/1.73m2 as calculated by the CKD-EPI equation.17
19. FSBG on Day -2 of > 270 mg/dL (15.0 mmol/L).
20. A positive COVID-19 test.
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 before Screening.
22. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
23. History of sensitivity to heparin or heparin-induced thrombocytopenia only if heparin 
is used to flush IV catheters.
24. Participation in formal weight loss program is prohibited during participation in this 
study.
25. 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.


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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).
•
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 
IP until collection of the final PK blood sample.
•
Standardized meals will be provided at approximately the same time of day in each
inpatient day and outpatient visit as shown in SoA.
•
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 case report 
form, however may be submitted to the Sponsor upon request.
•
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.
•
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, 
metformin and self-administration of IP. 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.
•
Breakfast will be provided approximately 0800 ± 2 hours in each inpatient day and 
outpatient visit as shown in SoA.
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
Lunch will be provided approximately 4 hours after dosing in each inpatient day, and 
outpatient visit if needed as shown in SoA.

Dinner will be provided approximately 10 hours after dosing in each inpatient day as 
shown in SoA.

An evening snack may be permitted before 2200 hours.

Participants will be counseled on appropriate dietary and lifestyle guidelines for 
T2DM at Visit 2 and asked to maintain these guidelines throughout participation in 
the study. Counseling on dietary guidelines should be in accordance with local 
medical standards of care for patients with T2DM.

IP must be administered BID (QD in the morning on Day 1) with the morning and 
evening meals, approximately 10 hours apart on non-visit days and unscheduled visit.
5.3.2. Caffeine, Alcohol, and Tobacco

Caffeine containing products may not be consumed within 2 hours prior to measuring
vital signs and ECGs.

Participants will abstain from alcohol for 24 hours prior to each vistit to the site and
continue abstaining from alcohol until completion for all procedures of each visit. 
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, 
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 and her partner(s) 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 


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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.
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 
(QD in the morning on Day 1) with morning and evening meals. Please refer to Figure 2 for 
the scheme of dose titration.   
Figure 2.
Dose Titration Scheme
PF-06882961 and placebo tablets will be supplied to the site as packaged blisters cards and 
labeled according to local regulatory requirements.


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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
(QD on Day 1)
0 mg BID
(QD on Day 1)
Route of Administration
Oral
Oral
IMP or NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor. 
Refer to the IP Manual. 
Provided centrally by the sponsor. 
Refer to the IP Manual.
Packaging and Labeling
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) 
with the morning meal and 3 tablets of study intervention with the evening meal, 
approximately 10 hours apart and at approximately the same time each day for a total of 6 
tablets of study intervention (PF-06882961 or matching placebo) daily, except on Day 1. 
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.
6.1.1.1. Inpatient and outpatient visit days
Morning dosing at approximately 0800 ± 2 hours and evening dosing at approximately 1800
± 2 hours and the interval between them should be about 10 hours. Dosing will occur with 
food at the site on admission and during inpatient days in V2, V5, V7, and V10, except 
discharge days (Days 2, 22, 36). For discharge days and outpatient visit days, morning dosing 
at approximately 0800 ± 2 hours will occur with food at the site. Participants will be 
instructed to arrive at the site in the fasted state for each of scheduled visits. For V3-V10, 
participants will be instructed to bring their study intervention supply and dosing diary with 
them, and to withhold self-administration of study intervention on scheduled visit days until 
they are 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 


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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 if less than 8 hours, the missed 
dose should not be administered.
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.


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4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record.  All study intervention that is 
taken home by the participant, both used and unused, must be returned to the 
investigator by the participant.  Returned study intervention must not be redispensed 
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.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
A qualified staff member will dispense the study intervention using the IRT system via 
unique container numbers in the blister cards provided, in quantities appropriate according to 
the SoA.  A second staff member will verify the dispensing. The participant/caregiver 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 


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intervention will be dispensed at the study visits summarized in the SoA. Returned study 
intervention must not be redispensed to the participants.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
A randomization code using the method of random permuted blocks will be utilized to
randomize eligible participants in 3:1 ratio (PF-06882961 : placebo) prior to the first dose of 
study intervention.
Participants will receive the following number of tablets and corresponding dose level
described in Table 3.
Table 3.
Dose Levels in Study C3421028
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
-
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


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unblinded to study treatment in order to permit review of the safety, PK 
 data. The 
blinded study monitor, if assigned, will remain blinded to treatment until all monitoring for 
the study has been completed and study database has been locked. 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, blinded investigator site
personnel, or blinded study monitor 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 
administered in the site will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. 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, site 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.
The background metformin therapy should also be recorded in the diary. Investigators must 
also closely follow non-compliant participants in order to enhance their adherence to 
metformin background treatment.
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 
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changes must be captured in the CRF. Additionally, many over-the-counter medications are 
also permitted during this study.
See Appendix 7 for details regarding prohibited concomitant medications. Site 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.
6.5.1. Medications for Glycemic Control
All participants are required to be taking metformin monotherapy as their only anti-
hyperglycemic treatment prior to inclusion in this study, as listed in Section 5.1. At 
Screening, this study requires that participants have been taking a stable metformin dose of 
500 mg/day for at least 2 months prior to the Screening visit. The dose of metformin will
remain the same total daily dose that was prescribed prior to study entry until completion of
study participation (ie, Follow-up visit), except in circumstances where a change in dose is
deemed medically necessary. Any changes in doses of metformin must be captured in the 
CRF. For study visit days, participants should be instructed to refrain from morning dosing at 
home and to bring the metformin to the site for dosing at the same time as their blinded IP. 
For participants taking metformin more than once a day, the timing should be approximately 
the same on each day.
The use of other medications for glycemic control is not permitted in this study (see 
Appendix 7).
6.5.2. Antihypertensive Medications
The use of background antihypertensive agent(s) is permitted unless otherwise noted in
Appendix 7. 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 7. 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 


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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 Sections 8.2.5.2 and 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.
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 5);

Intent to become pregnant or pregnancy confirmed by serum β-hCG testing;

Safety or tolerability concern arises, in particular if not responsive to 
symptomatic management, dosing with double-blind study intervention may be 
stopped in an individual participant at the discretion of the investigator.
If the criteria for permanent discontinuation are met, the site should notify the sponsor 
Medical Monitor or sponsor Clinician.


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Note that discontinuation of study intervention does not represent withdrawal from the study.  
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated for protocol-specified follow-up procedures as depicted in the SoA.  See the 
SoA for data to be collected at the time of discontinuation of study intervention and follow-
up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
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.
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.


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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/attend a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.


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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.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
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 
350 mL and will follow the requirements of laboratory. 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.
8.1. Efficacy Assessments
Efficacy assessments are not evaluated in this study.


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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, assessments of the head, ears, eyes, 
nose, mouth, skin, heart and lung examinations, lymph nodes, and gastrointestinal, 
musculoskeletal, and neurological systems. Height and weight will also be measured and 
recorded.
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 mmHg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
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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 utilizing limb leads 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 QTc intervals and QRS complex. Alternative lead placement 
methodology using torso leads (eg, Mason-Likar) is not recommended given the potential 
risk of discrepancies with ECGs acquired using standard limb lead placement. 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 5 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 QTc 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 
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ECG values of potential clinical concern are listed in Appendix 6.
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 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 diary 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 diary 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 diary.
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.
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 


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(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 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 dairy at each time 
point specified in the SoA, as well as results reported by the laboratory, the investigator must 
assess the glucose values as well as any symptoms documented.
HAE is defined as one of the following:18, 19
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 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 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 him/herself. Neurologic impairment, and not the 
age of the participant, is the explanation for why the participant could not treat 
him/herself and required the assistance of another person.
2. The participant exhibited at least one of the following neurological symptoms:

Memory loss;

Confusion;

Uncontrolled behavior;

Irrational behavior;


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
Unusual difficulty in awakening;

Suspected seizure;

Seizure;

Loss of consciousness.
3. Either:

If blood glucose was measured and was 54 mg/dL (2.7 mmol/L) using 
glucometer (or 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 laboratory).
After randomization, participants noted to have a fasting glucose value (during home glucose
monitoring) meeting the above definition of hyperglycemia must be instructed to repeat the
measurement the next day (following at least an 8 [preferably 10] hour fast, except water). If 
the second measurement also meets the above definition, participants must be asked to return 
to the site a day later (following at least an 8 [preferably 10] hour fast, except water) and 
have blood collected for FPG (and sent to the 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 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. 


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Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 to 35 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.7. COVID-19 Specific Assessments
Participants will be tested for SARS-COVID-19 infection on Screening visit and a 
subsequent COVID-19 test will be performed if the participant has exposure to COVID-19 
positive subject, or residence or travel in area of high incidence, or develop COVID-19 
related signs and symptoms. The test may be adjusted or additional test may be required by 
local regulations or by the Principal Investigator.
Exposure to positive subject, residence or travel in area of high incidence and COVID-19 
related signs and symptoms will be checked, at least 48 hours before and at each visit.
COVID-19 temperature checking will be done at least daily during residence.
8.2.8. Pregnancy Testing
Pregnancy tests may be urine or serum tests, and must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP 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.


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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.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, after the last administration of the study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator 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 AEs or SAEs after the participant has 
concluded study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 


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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.
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.


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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.
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 exposed 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 all possible routes of exposure, 
eg, ingestion, inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by all possible routes of exposure, eg, ingestion, inhalation or skin 
contact 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.


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
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).
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 


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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 together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
This part is not applicable in this study.
8.3.7. Disease Related Events and/or Disease Related Outcomes Not Qualifying as AEs 
or SAEs
This part is not applicable in this study.
8.3.8. Adverse Events of Special Interest
This part is not applicable in this study.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.


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8.3.9. Medical Device Deficiencies
This part is not applicable in this study.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 12 tablets within a 24-hour time 
period 2 hours will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.


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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.
8.5. Pharmacokinetics 
Blood samples of approximately 3 mL, to provide a minimum of 1 mL plasma, will be 
collected 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.
Samples will be used to evaluate the PK of PF-06882961. Samples collected for analyses of 
PF-06882961 plasma concentrations 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, 
Genetic analyses will not be performed on these plasma samples. Participant confidentiality 
will be maintained.
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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. 
 
 
 
 
 
 
 
  
 
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
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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. Estimands and Statistical Hypotheses
There is no statistical hypothesis tests planned for this study and estimand is not applicable.
9.2. Sample Size Determination
The sample size of this study is not based on statistical considerations. A sufficient number 
of participants will be screened to achieve approximately 20 participants randomly assigned 
to study intervention and at least 8 evaluable participants completing multiple titration dosing 
up to 120 mg in order to evaluate the primary endpoints of AUC24 and Cmax,ss at Day 56. 
The participants will be randomized at a 3:1 ratio with 15 participants being randomized to 
PF-06882961 and 5 participants being randomized to placebo for the purpose of descriptively 
evaluating the safety 
 endpoints.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention
"Enrolled" means a participant's, or their legally authorized
representative’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.
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Defined Analysis Set
Description
PK Concentration 
Analysis Set
It is defined as all participants randomized and treated with 
PF-06882961 who have at least 1 plasma concentration value 
collected. The PK concentration analysis set will be used for 
plasma concentration summaries and plots.
PK Parameter Analysis 
Set
It is defined as all participants randomized and treated with 
PF-06882961 who have at least 1 of the PK parameters of 
interest. The PK parameter analysis set will be used for 
analyses on the PK parameters.
 
 
Safety Analysis Set (SAS)
It is defined as all participants who are randomized and 
receive at least one dose of study medications.  The safety 
population will be used for the safety analyses.
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
In general, PF-06882961 plasma PK concentration and parameters data will be summarized 
descriptively for single dose and multiple doses separately; safety endpoints will be 
summarized by treatment group and dose levels; 
 
 
9.4.2. Primary Endpoint(s)
AUC24, Cmax, Cmax,ss will be summarized descriptively with n, arithmetic mean, standard 
deviation, coefficient of variatiation (CV%), geometric mean, geometric CV (%), median, 
minimum, and maximum. Box and whisker plot of individual and geometric mean will be 
presented.
Concentration data will be listed and summarized descriptively by PK sampling time and day 
(dose). Summary profiles (mean and median) of the plasma concentration-time data will be 
plotted by day (dose) against nominal PK sampling time. Mean and median profiles will be 
presented on both linear-linear and loglinear scales. Spaghetti plots of individual plasma 
concentration-time data will be plotted by day (dose) and actual PK sampling time.
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The PK parameters to be assessed in this study, their definition and method of determination 
are outlined in the following Table 4. For summary statistics and summary (mean and 
median) plots by sampling time, the nominal PK sampling time will be used. For individual 
participant plots by time, the actual PK sampling time will be used.
Table 4.
Definition of Plasma PK Parameters for PF-06882961
Parameter
Day 1 (D1) or
Steady State (SS)
Definition
Method of Determination
Cmax
D1 & SS
Maximum observed concentration 
observed from time zero to 24 hours 
Observed directly from data
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 
Cmax1 (dn), 
Cmax2 (dn) 
and Cmax
(dn)
D1 & SS 
Cmax1, Cmax2 and Cmax normalized 
to a 1 mg dose.
Cmax1/Dose
Cmax2/Dose
Cmax/Dose
 
 
 
AUCtau1 and 
AUCtau2
SS
Area under the plasma concentration-time 
profile from time zero to time tau, where 
tau1 = 0 to 10 hours and tau2 = 10 to 24 
hours
Linear/Log trapezoidal 
method
AUCtau1
(dn) and
AUCtau2
(dn)
SS
AUCtau1 and AUCtau2 normalized to a 1 
mg dose
AUCtau1/Dose
AUCtau2/Dose
AUC24
D1 
Area under the plasma concentration-time 
profile from time zero to time 24 hours
Linear/Log trapezoidal 
method 
AUC24
SS 
Area under the plasma concentration-time 
profile from time zero to time 24 hours
AUCtau1 + AUCtau2
AUC24 (dn)
D1 & SS
AUC24 normalized to a 1 mg dose.
AUC24/Total Daily Dose
 
 
 
 
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Table 4.
Definition of Plasma PK Parameters for PF-06882961
Parameter
Day 1 (D1) or
Steady State (SS)
Definition
Method of Determination
 
 
 
 
 
 
9.4.3. Secondary Endpoint(s)
Please refer to Section 9.4.5.
 
 
 
 
 
9.4.5. Other Safety Analyses
Adverse events, ECGs, vital signs and safety laboratory, urinalysis data will be reviewed on 
an ongoing basis during the study and summarized in a clinical study report 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.
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Medical history, as applicable, collected during the course of the study will be considered as 
source data and will not be captured for inclusion into the study database, unless otherwise 
noted. However, any untoward findings identified on physical exams conducted after the 
administration of the first dose of study medication will be captured as an adverse event, if 
those findings meet the definition of an adverse event. Data collected at Screening that is 
used for inclusion/exclusion criteria, such as laboratory data, ECGs and vital signs will be 
considered source data, and will not be captured for inclusion into the study database, unless 
otherwise noted. Demographic data collected at Screening will be included in the study 
database.
Safety data will be presented in tabular format according to the sponsor’s reporting standards.
9.4.5.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTc 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
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
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.
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 investigator and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.


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10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  The participant should be given 
sufficient time and opportunity to ask questions and to decide whether or not to participate in 
the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICD.


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Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples.  The investigator 
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a participant's agreement to allow specimens to be 
used for additional research. Participants who decline to participate in this optional 
additional research will not provide this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.  In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
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www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods.  Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data.  Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.


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10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the clinical monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan
Study and Site Start and Closure.
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 supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent. The contact card contains, at a minimum, protocol and study intervention identifiers, 
participant numbers, contact information for the investigator site, and contact details for a 
contact center in the event that the investigator site staff cannot be reached to provide advice 
on a medical question or problem originating from another healthcare professional not 
involved in the participant’s participation in the study.  The contact number can also be used 
by investigator staff if they are seeking advice on medical questions or problems; however, it 
should be used only in the event that the established communication pathways between the 
investigator site and the study team are not available.  It is therefore intended to augment, but 
not replace, the established communication pathways between the investigator site and the 
study team for advice on medical questions or problems that may arise during the study.  The 
contact number is not intended for use by the participant directly, and if a participant calls 
that number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests (Table 5) 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.
Table 5.
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
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 (β-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
•
Plasma C-peptide
•
COVID-19 pathogen by PCR
•
Antibodies test of COVID-19
Additional Tests
(Needed for Hy’s Law)
CCI
CCI


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Table 5.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
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 (THC),
opiates/opioids, benzodiazepines, and amphetamines (others are site and study specific).
Investigators must document their review of each laboratory safety report.
 
 
CCI


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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 adverse 


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events (AEs); 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 
for every event before the initial transmission of the SAE data to the sponsor.


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
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.

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.


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
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.


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


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


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10.5. Appendix 5: 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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Final Protocol, 10 Dec 2020 
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10.6. Appendix 6: 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 patients in sinus rhythm, with documented periods of 
asystole 3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free patients with atrial fibrillation and bradycardia with 1 
or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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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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10.7. Appendix 7: Prohibited Prior/Concomitant Medications
The use of the following classes of agents is not permitted within the timeframe indicated in 
Table 6 and for the duration of participation in the study. 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.
Table 6.
Prohibited Prior/Concomitant Medications
Drug Classes and/or Drugs
Timeframe of 
Restriction Prior 
to Screening Visit
Thiazolidinediones (TZDs) such as pioglitazone.
3 Months
Subcutaneously administered agents for glycemic control (eg, 
insulin, exenatide, liraglutide, dulaglutide, semaglutide). Note: Short-
term (ie, ≤7 days) insulin administration is permitted if participant is 
hospitalized.
3 Months
Oral GLP-1 receptor agonists such as oral semaglutide.
3 Months
Other oral anti-diabetic medications, including: 

Biguanides except metformin.

Sulfonylureas such as acetohexamide, chlorpropamide,
glyclopyramide, glibenclamide, gliclazide, glimepiride.

Meglitinide analogues such as repaglinide, nateglinide, 
mitiglinide.

Dipeptidyl peptidase 4 inhibitors (DPP 4i) such as sitagliptin, 
alogliptin, saxagliptin, linagliptin, vildagliptin, teneligliptin, 
anagliptin, trelagliptin, omrigliptin.

α glucosidase inhibitors such as acarbose, voglibose, miglitol.

Sodium glucose cotransporter 2 (SGLT2) inhibitors such as 
ipragliflozin, luseogliflozin, tofogliflozin, canagliflozin, 
empagliflozin, dapagliflozin, ertugliflozin.

Anti-hyperglycemic medications, including bromocriptine and 
colesevelam.
4 Weeks
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.
4 Weeks
Immunosuppressants such as cyclosporine and tacrolimus.
4 Weeks
Appetite or weight modifying medications, including nonprescription 
or herbals.
4 Weeks
Pharmacological agents with approved indication for weight loss 
such as mazindol.
4 Weeks
Anti-psychotic medications such as olanzapine, risperidone.
4 Weeks


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Table 6.
Prohibited Prior/Concomitant Medications
Drug Classes and/or Drugs
Timeframe of 
Restriction Prior 
to Screening Visit
Coumarin type anticoagulants or other anticoagulants (eg, 
dabigatran).
4 Weeks
Anticonvulsants if prescribed for seizure disorder.
4 Weeks
Antiarrhythmic medications whose primary mechanism of action is 
sodium or potassium channel blockade (eg, procainamide, quinidine, 
proprafenone; as well as amiodarone, sotalol). 
Note: β-adrenergic receptor blocking agents (eg, atenolol, 
metoprolol) and calcium channel blockers (eg, diltiazem, amlodipine, 
nifedipine) are permitted.
4 Weeks
Sympathomimetic agents.
Note: Inhaled β-adrenergic receptor agonists (eg, albuterol) are 
permitted.
4 Weeks
Rosuvastatin. Note: Other statins are permitted.
4 Weeks
Sulfasalazine
4 Weeks
Use of CYP3A4/5 substrates with narrow therapeutic index – eg, 
cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
and tacrolimus.
4 Weeks
Use of chronic agents which are potent inducers of CYP3A (eg, 
rifampin).
4 Weeks
Use of chronic agents which are clinically significant OATP 
inhibitors (eg, cyclosporine, rifampin).
4 Weeks
Use of potent 3A4 inhibitors.
Note: Short term use of potent CYP3A inhibitors (eg, ketoconazole, 
itraconazole) for management of fungal infections ≥4 weeks prior to 
Visit 1 (Screening) is acceptable but use must be avoided post 
randomization.
4 Weeks
Paclitaxel, torsemide.
4 Weeks
Herbal supplements and other natural products (including Traditional 
Chinese Medicine).
4 Weeks


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Final Protocol, 10 Dec 2020 
PFIZER CONFIDENTIAL
Page 92
10.8. Appendix 8: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
%CV
coefficient of variation, percent
Abs
absolute
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCtau
area under the concentration-time curve at steady state over the 
dosing interval τ
AV
atrioventricular
BCRP
breast cancer resistance protein
β-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
cAMP
cyclic adenosine monophosphate
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
maximum observed concentration
Cmax,ss
maximum observed concentration, steady state
CONSORT
Consolidated Standards of Reporting Trials
COVID
coronavirus disease
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
CCI
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Abbreviation
Term
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
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
FU
follow up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
HAE
hypoglycemic adverse event
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDL-C
high-density lipoprotein cholesterol
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
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IP manual
investigational product manual
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Abbreviation
Term
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
LBBB
left bundle branch block
LDL-C
low-density lipoprotein cholesterol
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
msec
millisecond
MTC
medullary thyroid carcinoma
N/A
not applicable
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
OAT
organic anion transporter
OATP
organic anion transporting polypeptides
OCT
organic cation transporter
PCR
polymerase chain reaction
pH
potential of hydrogen
PI
Principal Investigator
PK
pharmacokinetic(s)
POC
proof of concept 
PR
pulse rate
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
once daily
QRS
time from ECG Q wave to the end of the S wave corresponding to 
ventricle depolarization
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
CCI
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Abbreviation
Term
SAE
serious adverse event
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SGLT2
Sodium glucose cotransporter 2
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SS
steady-state
SSID
study-specific subject identification
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
T4
thyroxine
TBA
total bile acids
TBili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
TI
therapeutic index
TSH
thyroid stimulating hormone
TZDs
Thiazolidinediones
UGT
uridine 5'-diphospho-glucuronosyltransferase 
glucuronosyltransferase
ULN
upper limit of normal
US
United States
V#
Visit, where # is a numerical value
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; 9th Edition Available from: http://www.idf.org/diabetesatlas. 
Accessed: 04 Feb 2019. 
7
Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes
mellitus and its complications. Nat Rev Endocrinol. 2018;14:88-98.
8
Yongze Li, Di Teng, Xiaoguang Shi, et al. Prevalence of diabetes recorded in 
mainland China using 2018 diagnostic criteria from the American Diabetes Association: 
national cross sectional study. BMJ. 2020 Apr 28;369:m997. 
9
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.
10
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.
11
Drucker, DL. The ascending GLP-1 road from clinical safety to reduction of
cardiovascular complications. Diabetes. (2018);67:1710-9.
12
Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon-like peptide-1 
receptor agonists on heart rate. Cardiovasc Diabetol. (2017);16:6.
13
VICTOZA [Package insert]. Bagsvaerd, Denmark; Novo Nordisk A/S; 2015.
                                                


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14
Ozempic [Package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; 2017
15
Trulicity [Package Insert]. Indianapolis, IN: Eil Lilly and Company; 2017.
16
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.
17
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009;150:604-12.
18
American Diabetes Association. Standards of medical care in diabetes -2020. 
Diabetes Care. 2020 Jan;43(Suppl 1):S66-S76.
19
Chinese Diabetes Society. China guidelines for the prevention and treatment of type 2 
diabetes (version 2017). Chin J Diabetes Mellitus. 2018;10(1):4-67.

SAP_001.pdf: 
Protocol C3421028 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3421028
AN 8-WEEK, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-
CONTROLLED PHASE 1 STUDY TO EVALUATE THE PHARMACOKINETICS, 
PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF PF-06882961 IN 
CHINESE ADULTS WITH TYPE 2 DIABETES MELLITUS
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
19 Jan 2022


Protocol C3421028 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives, Endpoints, and Estimands............................................................6
2.1.1. Primary Estimand(s).....................................................................................7
2.1.2. Secondary Estimand(s).................................................................................7
2.1.3. Additional Estimand(s).................................................................................7
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint(s) ..................................................................................................9
3.2. Secondary Endpoint(s) ..............................................................................................9
3.4. Baseline Variables...................................................................................................11
3.5. Safety Endpoints .....................................................................................................11
3.5.1. Adverse Events (AEs).................................................................................11
3.5.1.1. Hypoglycemic Adverse Event (HAE).......................................11
3.5.2. Laboratory Data..........................................................................................12
3.5.2.1. Change form Baseline Summaries ............................................12
3.5.3. Vital Signs ..................................................................................................13
3.5.4. Electrocardiograms.....................................................................................13
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................15
5.1. Hypotheses and Decision Rules ..............................................................................15
5.2. General Methods .....................................................................................................15
5.2.1. Analyses for PK Concentration and Parameters.........................................15
5.2.2. Analyses for Continuous Endpoints ...........................................................15
5.2.3. Analyses for Categorical Endpoints ...........................................................16
5.3. Methods to Manage Missing Data ..........................................................................16
5.3.1. Concentrations Below the Limit of Quantification ....................................16
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5.3.2. Deviations, Missing Concentrations and Anomalous Values.....................16
5.3.3. Pharmacokinetic Parameters.......................................................................16
6. ANALYSES AND SUMMARIES ......................................................................................17
6.1. Primary Endpoint(s) ................................................................................................17
6.2. Secondary Endpoint(s) ............................................................................................18
6.4. Subset Analyses.......................................................................................................19
6.5. Baseline and Other Summaries and Analyses.........................................................20
6.5.1. Baseline Summaries....................................................................................20
6.5.2. Study Conduct and Participant Disposition................................................20
6.5.3. Concomitant Medications and Nondrug Treatments..................................20
6.5.4. Treatment Compliance................................................................................20
6.5.5. COVID-19 Related Analyses .....................................................................20
6.6. Safety Summaries and Analyses .............................................................................20
6.6.1. Adverse Events...........................................................................................21
6.6.2. Laboratory Data..........................................................................................21
6.6.3. Vital Signs Data..........................................................................................21
6.6.4. ECG Data....................................................................................................22
6.6.5. Physical Examination .................................................................................22
7. INTERIM ANALYSES.......................................................................................................22
7.1. Introduction .............................................................................................................22
7.2. Interim Analyses and Summaries............................................................................22
8. REFERENCES ....................................................................................................................23
9. APPENDICES .....................................................................................................................24
9.1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .........24
9.3. List of Abbreviations...............................................................................................25
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
Definition of Plasma PK Parameters for PF-06882961............................10
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Table 3.
Descriptive Summris for Primary PK Parameters Following the 
Single Dose/Multiple Doses .....................................................................17
 
LIST OF FIGURES
Figure 1.
Schema of Study.........................................................................................8
Figure 2.
Dose Titration Scheme ...............................................................................9
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1
03 Feb 2021
Original 
10 Dec 2020
N/A
N/A
2
19 Jan 2022
Original 10 
Dec 2020
Made some 
clarifications on 
variables to be 
analyzed and 
added some 
analyses per 
team discussion 
for comparison 
with other 
studies within 
the asset.
•
Added descriptions on baseline 
variables in Section 3.4, especially 
added variable of “duration of 
diabetes”.
•
Added description on vital signs and 
ECG variables in Section 3.5.3 and 
Section 3.5.4, clarified the baseline 
definition, description of time-matched 
changes and added time-matched 
double difference.
 
 
 
 
•
Added summary of treatment 
compliance in Section 6.5.4.
•
Added COVID-19 related analyses in 
Section 6.5.5.
•
Added some AE analyses in Section 
6.6.1. Added the summary of number of 
TEAEs by severity, SOC and PT. 
Added the summaries for AEs of 
interest.
•
Added analyses for laboratory, vital 
signs and ECG data in Section 6.6.2, 
6.6.3 and 6.6.4. Clarified the summary 
for time-matched changes and added 
summary for time-matched double 
difference.
•
Added the categories for QTcF in 
Section 9.1.
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2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3421028.  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
The purpose of this study is to evaluate the PK, safety and tolerability of single and multiple 
oral doses of PF-06882961 in adult Chinese participants with T2DM who are receiving 
metformin as background antihyperglycemic medication. The study will be investigator- and
participant-blind (sponsor-open), to permit a review of safety and tolerability in order to 
assess potential for drug-induced changes in participants with T2DM.  
 
Objectives , Estimands, and Endpoints:
Objectives
Estimands
Endpoints
Primary:
Primary:
Primary:
•
To characterize the plasma 
PK of PF-06882961 
following a single oral dose 
on Day 1 and following 
multiple, oral doses 
administered to adult 
Chinese participants with 
T2DM.
Not Applicable
•
Single dose (10 mg): 
AUC24, Cmax.
•
Multiple dose (40 mg, 
80 mg, 120 mg): 
AUC24, Cmax,ss.
Secondary:
Secondary:
Secondary:
•
To evaluate the safety and 
tolerability of PF-06882961 
following a single oral dose 
on Day 1 and following 
multiple, oral doses 
administered to adult 
Chinese participants with 
T2DM.
Not Applicable
•
Vital signs, 
Electrocardiograms, 
Adverse events (e.g. 
hypoglycemia and 
hyperglycemia), 
Clinical safety 
laboratory assessments.
 
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2.1.1. Primary Estimand(s)
None.
2.1.2. Secondary Estimand(s)
None. 
2.1.3. Additional Estimand(s)
None.
2.2. Study Design
This is a Phase 1, randomized, double-blind, sponsor-open, placebo-controlled, oral dosing 
study of PF-06882961 in adult Chinese participants with T2DM inadequately controlled on 
diet, exercise and metformin background therapy.
Participants will receive oral doses of PF-06882961 or placebo in this study. Approximately 
20 participants will be randomized to PF-06882961 or placebo at a 3:1 ratio (15 participants
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to PF-06882961 and 5 participants to placebo) such that at least 8 participants in PF-
06882961 group will complete 120 mg and be evaluable for PK analysis. The study will be 
conducted at a single clinical site in China.
The target dose level is PF-06882961 120 mg BID (or matching placebo). 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 dose of PF-
06882961 will be increased following a prespecified titration scheme during visits V2 
through V8 to reach the target dose, which will then be maintained through V10. 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. See Figure 1 and Figure 2 for schema of the design and dose titration.
Figure 1.
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Figure 2.
Dose Titration Scheme
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The primary endpoints of the study are 
•
Single dose (10 mg): Area under the plasma concentration-time profile from time zero to 
24 hours (AUC24), maximum observed concentration observed from time zero to 24 
hours (Cmax) collected at Day 1.
•
Multiple dose (40 mg, 80 mg, 120 mg): AUC24, Cmax,ss collected at steady state.
3.2. Secondary Endpoint(s)
The secondary endpoints of the study are safety endpoints including vital signs, 
electrocardiograms, adverse events (e.g. hypoglycemia and hyperglycemia), clinical safety 
laboratory assessments.
More details of the safety endpoint are described in Section 3.5.
 
 
 
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The PK parameters (primary endpoints 
) for PF-06882961 will be 
calculated from the concentration-time data using non-compartmental methods. Definition 
and method of determination are described in Table 2 below. 
Table 2.
Definition of Plasma PK Parameters for PF-06882961
Parameter
Day 1 (D1) or
Steady State (SS)
Definition
Method of Determination
Cmax
D1 & SS
Maximum observed concentration 
observed from time zero to 24 hours 
Observed directly from data
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 
Cmax1 (dn), 
Cmax2 (dn) 
and Cmax
(dn)
D1 & SS 
Cmax1, Cmax2 and Cmax normalized to a 1 
mg dose.
Cmax1/Dose
Cmax2/Dose
Cmax/Dose
 
 
 
AUCtau1 and 
AUCtau2
SS
Area under the plasma concentration-time 
profile from time zero to time tau, where 
tau1 = 0 to 10 hours and tau2 = 10 to 24 
hours
Linear/Log trapezoidal 
method
AUCtau1
(dn) and
AUCtau2
(dn)
SS
AUCtau1 and AUCtau2 normalized to a 1 
mg dose
AUCtau1/Dose
AUCtau2/Dose
AUC24
D1 
Area under the plasma concentration-time 
profile from time zero to time 24 hours
Linear/Log trapezoidal 
method 
AUC24
SS 
Area under the plasma concentration-time 
profile from time zero to time 24 hours
AUCtau1 + AUCtau2
AUC24 (dn)
D1 & SS
AUC24 normalized to a 1 mg dose.
AUC24/Total Daily Dose
 
 
 
 
 
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Table 2.
Definition of Plasma PK Parameters for PF-06882961
Parameter
Day 1 (D1) or
Steady State (SS)
Definition
Method of Determination
 
 
 
 
 
.
D1=Day 1. SS=Steady Status. dn= Dose Normalized value.
 
 
 
3.4. Baseline Variables
Baseline variables include age, gender, race, ethnicity, height, weight, body mass index, 
duration of diabetes, 
. Baseline variables for vital sign and 
ECG data are described in Section 6.6.3 and Section 6.6.4. Baseline variables are those 
collected on Day -1 or last measurement during screening visits before Day 1.
The duration of diabetes will the time from primary diagnosis date to the randomization date 
into this study.
3.5. Safety Endpoints
3.5.1. Adverse Events (AEs)
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
started during the effective duration of treatment. 
All events that start on or after the first dosing day and time/start time, if collected, but before 
the last dose plus the lag time will be flagged as TEAEs.  If an AE starts on the same day as 
the first dose date, it will be considered treatment emergent unless the case report form data 
indicates otherwise via explicitly recording time for AE onset and treatment dosing.
3.5.1.1. Hypoglycemic Adverse Event (HAE)
Details of hypoglycemia AEs will be recorded in the Case Report Form (CRF) as a separate 
page. The definition and severity of categorization of HAE are described in the protocol 
Section 8.2.5.2.1.
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For programming purposes, the hypoglycemic AE categories are based on the following:
•
Severe Hypoglycemia: Severe is checked in the severity criteria of the CRF. This
assessment will be made by the PI based on the protocol definition.
•
Documented Symptomatic Hypoglycemia: If (1 ̢ Did the subject have symptoms 
of hypoglycemia?) Yes and (2 ̢ Was blood glucose measured?) Yes and result <70 
mg/dL on the CRF, but hypoglycemia is not classified as severe.
•
Asymptomatic Hypoglycemia: If (1) No and (2) Yes and result <70 mg/dL on the
CRF, but hypoglycemia is not classified as severe.
•
Probable Symptomatic Hypoglycemia: If (1) Yes and (2) No and (2b ̢ If blood 
glucose was not measured, did symptoms resolve when treated with carbohydrate or 
glucagon?) Yes on the CRF, but hypoglycemia is not classified as severe.
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the 
hematological, clinical chemistry, urinalysis, and other safety tests will be assessed against 
the criteria specified in the sponsor reporting standards.
Baseline will be the last predose measurement collected on Day -1.
3.5.2.1. Change form Baseline Summaries
Focused change from baseline summaries of the following safety laboratory endpoints will be 
assessed: 
•
Change from baseline in calcitonin to all post-dose time points as per the Schedule of 
activities (SoA) in the protocol .
•
Change from baseline in amylase to all post-dose time points as per the SoA.
•
Change from baseline in lipase to all post-dose time points as per the SoA.
•
Change from baseline in thyroid stimulating hormone (TSH) to all post-dose time points 
as per the SoA.
•
Change from baseline in free thyroxine (free T4) to all post-dose time points as per the 
SoA.
•
Change from baseline in lipid profile (total cholesterol, direct LDL cholesterol, HDL 
cholesterol and triglycerides) to all post-dose time points as per the SoA.


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
Change from baseline in liver function tests (ALT, AST, alkaline phosphatase, and total 
bilirubin) to all post-dose time points as per the SoA.
3.5.3. 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. 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).
3.5.4. 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, PR, QT, QTcF 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).
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention
"Enrolled" means a participant's, or their legally authorized
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process. 
Potential participants who are screened for the purpose of 
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the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Defined Analysis Set
Description
PK Concentration 
Analysis Set
It is defined as all participants randomized and treated with 
PF-06882961 who have at least 1 plasma concentration value 
collected. The PK concentration analysis set will be used for 
plasma concentration summaries and plots.
PK Parameter Analysis 
Set
It is defined as all participants randomized and treated with 
PF-06882961 who have at least 1 of the PK parameters of 
interest. The PK parameter analysis set will be used for 
analyses on the PK parameters.
 
 
Safety Analysis Set (SAS)
It is defined as all participants who are randomized and 
receive at least one dose of study medications.  The safety 
population will be used for the safety analyses.
Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are randomized but not treated.
If a participant 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 and PK analyses, 
where applicable.
Protocol Deviations
Participants who experience events that may affect their PK profile (eg lack of compliance 
with dosing) 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 potential 
important deviations and COVID-19 related deviations (if any) prior to database closure.
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5. GENERAL METHODOLOGY AND CONVENTIONS
The study data will be analyzed following the database release once all paricipants have 
completed the study (or discontinued from study).
5.1. Hypotheses and Decision Rules
None.
5.2. General Methods
In general, PF-06882961 plasma PK concentration and parameters data will be summarized 
descriptively for single dose and multiple doses separately; safety endpoints will be 
summarized by treatment group and dose levels; 
 
 
5.2.1. Analyses for PK Concentration and Parameters
Concentration data will be listed and summarized descriptively by PK sampling time and day 
(dose level). Summary profiles (mean and median) of the plasma concentration-time data 
will be plotted by day (dose level) against nominal PK sampling time. Mean and median 
profiles will be presented on both linear-linear and loglinear scales. Spaghetti plots of 
individual plasma concentration-time data will be plotted by day (dose level) and actual PK 
sampling time.
The primary endpoints AUC24, Cmax, Cmax,ss,  
 will be
summarized descriptively with n, arithmetic mean, standard deviation, coefficient of 
variatiation (CV%), geometric mean, geometric CV (%), median, minimum, and maximum. 
Box and whisker plot of individual and geometric mean will be presented for dose 
normalized AUC24, Cmax, Cmax,ss.
5.2.2. Analyses for Continuous Endpoints
Continous endpoints will be summarized descriptively by treatment, dose level and day (if 
collected multiple days for same dose level) with summary statistics of n, mean, standard 
deviation, median, minimum, and maximum.
 
 
 
 
 
 
 
 
 
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5.2.3. Analyses for Categorical Endpoints
Categorical endpoints will be summarized descriptively by treatment, dose level and day (if 
collected multiple days for same dose level) with n, number of observed values, and 
percentages.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the CDISC and Pfizer Standard (CaPS) rules for 
imputation will be applied.
5.3.1. Concentrations Below the Limit of Quantification
In all 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.)
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 participant discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular treatment with ≥3 evaluable measurements.  For statistical 
analyses (ie ANOVA), PK parameters coded as NC will also be set to missing; and analyses 
will not be performed for a particular parameter if more than 50% of the data are NC.
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If an individual participant 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.
 
 
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
The primary endpoints, AUC24 (Day 1 and Steady State), Cmax (D1), Cmax,ss,  will be 
summarized descriptively as described in Section 5.2.1. 
In addition, to support the assessment of primary endpoints, AUCtau1 (Steady State), AUCtau2
(Steady State), Cmax1 (Steady State), Cmax2 (Steady State), AUCtau1(dn) (Steady State), 
AUCtau2(dn) (Steady State), AUC24(dn) (Day 1 and Steady State), Cmax1(dn),  Cmax2(dn), Cmax 
(dn),  Cmax,ss (dn) will also be summarized descriptively. Box and whisker plots will be 
generated for AUC24 (dn) (Day 1 and Steady State), Cmax(dn)(D1), Cmax,ss(dn). See Table 3. 
The PK parameter analysis set will be used for the aforementioned summaries and plots.
Table 3.
Descriptive Summris for Primary PK Parameters Following the Single
Dose/Multiple Doses
Summarized by Dose Level
Parameter
Summary Statistics
AUC24 (D1 and SS), Cmax (D1),  Cmax,ss
N, arithmetic mean, median, cv%, 
standard deviation, minimum, 
maximum, geometric mean and 
geometric cv%.
AUCtau1 (SS), AUCtau2 (SS), Cmax1 (SS),  Cmax2 (SS)
AUCtau1 (dn) (SS), AUCtau2 (dn) (SS), AUC24 (dn) (D1 and 
SS), Cmax1 (dn) (SS),  Cmax2 (dn) (SS), Cmax (dn) (D1),  Cmax,ss
(dn)
D1=Day 1. SS=Steady Status. dn= Dose Normalized value. cv=Coefficient of Variation.
Presentations for PF-06882961 concentrations will be generated for the single dose and 
multiple doses separately, including:
•
A listing of all concentrations sorted by participant ID and nominal time postdose,
and page by dose level for multiple dosing days.  The concentration listing will also 
include the actual times.  Deviations from the nominal time will be given in a separate 
listing.
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•
A summary of concentrations by dose level and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, cv, minimum, 
maximum and the number of concentrations above the lower limit of quantification.
•
Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by dose levels (all dose levels on the same plot per scale for 
multiple dosing days) based on the summary of concentrations by dose level and 
nominal time postdose.
•
Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by dose levels (all dose levels on the same plot per scale for 
multiple dosing days) based on the summary of concentrations by dose level and 
nominal time postdose.
•
Individual concentration time plots by by dose (on both linear and semi-log scales)
against actual time postdose (there will be separate spaghetti plots for the single dose 
and each multiple dose level per scale).
•
Individual concentration time plots by participant (on both linear and semi-log scales)
and dose level against actual time postdose (there will be separate plots for each 
participant on single dose, and separate plots for each participant with all dose levels 
on the same plot per scale).
For summary statistics and median/mean plots by sampling time, the nominal PK sampling 
time will be used. For individual participant plots by time, the actual PK sampling time will 
be used. The PK concentration analysis set will be used for all the concentration data 
summaries and plots. 
6.2. Secondary Endpoint(s)
The secondary safety endpoints will be summarized using the safety analysis set as described 
in Sections 5.2.2 and 5.2.3, and analyses for each safety endpoint are described in Section 
6.6.
 
 
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6.4. Subset Analyses
None.
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6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographic and baseline characteristics (age, gender, race, ethnicity, weight, height, body 
mass index and duration of diabetes) collected prior to the first dose of the study intervention
will be summarized by treatment group following the CaPS.
6.5.2. Study Conduct and Participant Disposition
Participant disposition will be reported by showing the number (and percent) of participants 
completed study, discontinued from studies, as well as the number (and percent) of 
participants analyzed for each analysis set by treatment group.
6.5.3. Concomitant Medications and Nondrug Treatments
All concomitant medications as well as nondrug treatments will be provided in the listings.
A separate listing restricted to metformin will also be produced.
6.5.4. Treatment Compliance
A summary table of treatment compliance will be produced by study week according to 
current sponsor reporting standards.
ĀStudy Week” will be calculated using actual visit dates per dose titration dates, rather than 
the calendar days. For example, if dose missing occurs on Day 8 and dose titration occurs on 
Day 9 for a given patient, then the dose missing is considered to have occurred on Week 1 
for this patient (Week 1 is Day1 to Day 8 for this patient).
6.5.5. COVID-19 Related Analyses
Considering the small sample size in this study, no separate summary tables are planned for 
COVID-19 related analyses. Only some key listings will be previded. e.g.,
Protocol Deviations related to COVID-19,
Subject Discontinuations Related to COVID-19,
COVID-19 related Adverse Events.
6.6. Safety Summaries and Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to the CaPS.


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6.6.1. Adverse Events
Adverse events will be reported in accordance with the CaPS by treatment group and dose
level.
Besides the standard incidence and severity of TEAE summaries, the number of TEAEs (all 
causality and treatment related) by severity, System Organ Class, and Preferred Term will 
also be produced.
The hypoglycemic AEs will be listed in a separate table and summarized categorically (See 
Section 3.5.1.1) by treatment and dose level.
 
 
 
 
 
 
 
 
 
6.6.2. Laboratory Data
Incidence of laboratory test (including hematological, clinical chemistry, urinalysis tests) 
abnormalities (without regard to baseline abnormality, with normal baseline and abnormal 
baseline respectively) will be reported.
Baseline value and CFB for the laboratory tests of interest listed in Section 3.5.2.1 will be 
summarized descriptively via the method stated in Section 5.2.2.
6.6.3. Vital Signs Data
Baseline values, absolute values and changes from time-matched baseline values in supine 
systolic, supine diastolic blood pressure and pulse rate will be summarized by treatment, time 
post-dose and day with descriptive statistics stated in Section 5.2.2 (according to CaPS).
Tables will be paged by parameter. Baseline is as defined in Section 3.5.3.
Maximum absolute values and maximum changes from time-matched baseline for vital signs 
will also be summarized descriptively as stated in Section 5.2.3 using categories as defined in 
Appendix 1 (Section 9.1).  
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All planned and unplanned post dose time points will be counted in these categorical 
summaries.The time-matched double differences in vital signs obtained following the Day 1 
treatment, as defined in Section 3.5.3, 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.
6.6.4. ECG Data
Baseline values, absolute values and changes from time-matched baseline in QT, heart rate, 
QTcF interval, PR interval and QRS complex will be summarized by treatment and time 
post-dose and day with descriptive statistics stated in Section 5.2.2 following CaPS. Tables 
will be paged by parameter. Baseline is as defined in Section 3.5.4.
Maximum increase from time-matched baseline for QTcF and heart rate will be summarized 
by treatment, according to sponsor reporting standards.
The number (%) of participants with maximum absolute value and maximum increase from 
baseline for QTcF, PR and QRS (see Appendix 1 in Section 9.1) will be summarized using 
method stated in Section 5.2.3.
All planned and unplanned post-dose time-points will be counted in these categorical 
summaries. 
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 
3.5.4, will be summarized (N, mean, 90% confidence interval) for each treatment and time 
point.
6.6.5. 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. Physical Examination
Physical examinations will be summarized by treatment and dose level in accordance to 
CaPS.
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study.
7.1. Introduction
None.
7.2. Interim Analyses and Summaries
None.


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8. REFERENCES
None.


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9. APPENDICES
9.1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Degree of
Prolongation
Mild (msec)
Moderate (msec)
Severe 
(msec)
Absolute value
450 < QTcF <= 480
480 < QTcF <= 500
>500
Increase from 
baseline
30 < Increase <= 60
>60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from baseline
Baseline >200 and max. 
≥25% increase
Baseline ≤200 and max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) increase 
from baseline
≥50% increase
Categories for Vital Signs
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
         BP: blood pressure.
Measurements that fulfill these criteria are to be listed in report.
 
 
 
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9.3. List of Abbreviations
Abbreviation
Term
%CV
coefficient of variation, percent
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCtau
area under the concentration-time curve at steady state over the 
dosing interval τ
BID
twice daily
BLQ
below the limit of quantification
BP
Blood pressure
CaPS
CDISC and Pfizer Standard
CDISC
clinical data interchange standards consortium
CFB
change from baseline
Cmax
maximum observed concentration
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Abbreviation
Term
Cmax,ss
maximum observed concentration, steady state
COVID
coronavirus disease
CRF
case report form
dn
dose normalized
ECG
electrocardiogram
HAE
hypoglycemic adverse event
HDL
high-density lipopritein
LDL
lower-density lipoprotein
LLQ
lower limit of quantification
N/A
not applicable
NC
not calculated
ND
not done
NS
no sample
PK
pharmacokinetic(s)
QRS
time from ECG Q wave to the end of the S wave corresponding to 
ventricle depolarization
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
SAP
statistical analysis plan
SAS
safety analysis set
SoA
Schedule of Activies
SS
steady-state
T2DM
type 2 diabetes mellitus
TEAE
Treatment emergent adverse event
TSH
thyroid stimulating hormone
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