Clinical trial NCT05158244
Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 Diabetes Mellitus Obesity
Sponsor: Pfizer
Start date: 2021-12-22; Completion date: 2022-06-15
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1, randomized, placebo-controlled, double-blind (investigator- and participant-blinded), sponsor-open study of PF-07081532. Study participants will receive the investigational product or placebo every day for 42 days.

The purpose of the study is to evaluate the safety, tolerability and pharmacokinetics (PK) of multiple oral doses of PF-07081532 in participants with inadequately controlled type 2 diabetes mellitus, on metformin and optionally in non-diabetic participants with obesity.

Detailed description:

Arms: arm 1: multiple dosing, once-daily for 42 days arm 2: multiple dosing, once-daily for 42 days
Interventions: intervention 1: PF-07081532 intervention 2: Placebo
Intervention descriptions: intervention 1: Study Drug, once daily for 42 days intervention 2: Placebo, once daily for 42 days

Protocol documents:
Prot_000.pdf: 
PF-07081532
Protocol C3991003
Final Protocol, 21 October 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY, TOLERABILITY,
AND PHARMACOKINETICS OF MULTIPLE ORAL DOSES OF PF-07081532 IN 
ADULT PARTICIPANTS WITH TYPE 2 DIABETES MELLITUS
Study Intervention Number:
PF-07081532
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
N/A
ClinicalTrials.gov ID:  
N/A
Protocol Number:
C3991003
Phase:
1
Brief Title: A Phase 1 Study of Multiple Oral Doses of PF-07081532 in Adult 
Participants 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.
PPD
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Final Protocol, 21 October 2021
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Document History
Document
Version Date
Original protocol
21 October 2021


PF-07081532
Protocol C3991003
Final Protocol, 21 October 2021
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................13
1.3. Schedule of Activities .............................................................................................14
2. INTRODUCTION ...............................................................................................................18
2.1. Study Rationale .......................................................................................................18
2.2. Background .............................................................................................................18
2.2.1. Nonclinical Overview.................................................................................18
2.2.1.1. Nonclinical Pharmacology........................................................18
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism........................19
2.2.1.3. Nonclinical Safety.....................................................................20
2.2.2. Clinical Overview.......................................................................................20
2.2.2.1. Clinical Safety...........................................................................22
2.3. Benefit/Risk Assessment.........................................................................................23
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................25
4. STUDY DESIGN.................................................................................................................26
4.1. Overall Design.........................................................................................................26
4.2. Scientific Rationale for Study Design.....................................................................28
4.2.1. Population(s)...............................................................................................28
4.2.2. Concomitant Medications...........................................................................28
4.2.3. Study Blinding............................................................................................29
4.2.4. Endpoints....................................................................................................29
4.2.5. Collection of Retained Research Samples..................................................30
4.3. Justification for Dose ..............................................................................................30
4.4. End of Study Definition ..........................................................................................30
5. STUDY POPULATION......................................................................................................30
5.1. Inclusion Criteria.....................................................................................................30
5.2. Exclusion Criteria....................................................................................................31
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5.3. Lifestyle Considerations..........................................................................................34
5.3.1. Meals and Dietary Restrictions...................................................................35
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................36
5.3.3. Activity .......................................................................................................37
5.3.4. Contraception..............................................................................................37
5.4. Screen Failures ........................................................................................................38
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................38
6.1. Study Intervention(s) Administered........................................................................38
6.1.1. Administration............................................................................................38
6.2. Preparation, Handling, Storage, and Accountability...............................................39
6.2.1. Preparation and Dispensing........................................................................40
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................40
6.3.1. Allocation to Study Intervention ................................................................40
6.3.2. Breaking the Blind......................................................................................40
6.4. Study Intervention Compliance...............................................................................41
6.5. Dose Modification...................................................................................................41
6.6. Continued Access to Study Intervention After the End of the Study......................41
6.7. Treatment of Overdose............................................................................................41
6.8. Concomitant Therapy..............................................................................................42
6.8.1. Permitted Medications................................................................................42
6.8.1.1. Metformin..................................................................................42
6.8.1.2. Antihypertensive and Lipid-Modifying Agents ........................42
6.8.1.3. Medications for Management of Nausea and Vomiting ...........42
6.8.2. Prohibited Medications...............................................................................42
6.8.2.1. Medications Not Permitted During the Study due to 
Potential Drug-Drug Interaction and Other Prohibited, Prior 
and Concomitant Medications...........................................................43
6.8.3. Rescue Medicine.........................................................................................43
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................43
7.1. Discontinuation of Study Intervention ....................................................................43
7.1.1. ECG Changes..............................................................................................44
7.1.2. Adverse Events...........................................................................................44


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7.1.3. Laboratory Abnormalities...........................................................................44
7.1.4. Potential Cases of Acute Kidney Injury .....................................................45
7.1.5. Prohibited Medications...............................................................................45
7.2. Participant Discontinuation/Withdrawal From the Study.......................................45
7.2.1. Withdrawal of Consent...............................................................................46
7.3. Lost to Follow-Up ...................................................................................................46
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................47
8.1. Efficacy Assessments..............................................................................................49
8.2. Safety Assessments .................................................................................................49
8.2.1. Physical Examinations................................................................................49
8.2.2. Vital Signs ..................................................................................................49
8.2.3. Electrocardiograms.....................................................................................50
8.2.4. Clinical Safety Laboratory Assessments ....................................................51
8.2.4.1. Fasting Fingerstick Blood Glucose (via Glucometer)...............51
8.2.4.2. Hypoglycemia Reporting ..........................................................52
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................53
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......53
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................54
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................54
8.3.2. Method of Detecting AEs and SAEs ..........................................................54
8.3.3. Follow-Up of AEs and SAEs......................................................................54
8.3.4. Regulatory Reporting Requirements for SAEs...........................................55
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................55
8.3.5.1. Exposure During Pregnancy......................................................55
8.3.5.2. Exposure During Breastfeeding ................................................57
8.3.5.3. Occupational Exposure .............................................................57
8.3.6. Cardiovascular and Death Events...............................................................58
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................58
8.3.8. Adverse Events of Special Interest.............................................................58
8.3.8.1. Lack of Efficacy........................................................................58
8.3.9. Medical Device Deficiencies......................................................................58


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8.3.10. Medication Errors.....................................................................................58
8.4. Pharmacokinetics ....................................................................................................59
8.4.1. Plasma for Analysis of PF-07081532.........................................................59
8.4.2. Plasma for Analysis of 4-β-hydroxycholesterol/cholesterol ......................60
8.7. Immunogenicity Assessments.................................................................................61
8.8. Health Economics ...................................................................................................61
8.9. Pharmacodynamics..................................................................................................61
8.9.1. Liquid Meal (for MMTT)...........................................................................61
8.9.2. Plasma Glucose, Plasma Insulin, C-Peptide, Glucagon and HbA1c ..........61
8.9.3. Body Weight...............................................................................................62
9. STATISTICAL CONSIDERATIONS ................................................................................62
9.1. Statistical Hypotheses .............................................................................................62
9.2. Analysis Sets ...........................................................................................................62
9.3. Statistical Analyses .................................................................................................63
9.3.1. General Considerations...............................................................................63
9.3.2. Primary Endpoint........................................................................................63
9.3.2.1. Electrocardiogram Analyses......................................................64
9.3.3. Secondary Endpoints ..................................................................................64
9.3.4. Other Analyse(s).........................................................................................66
9.4. Interim Analyses .....................................................................................................67
9.5. Sample Size Determination.....................................................................................67
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................68
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............68
10.1.1. Regulatory and Ethical Considerations ....................................................68
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................68
10.1.2. Informed Consent Process ........................................................................69
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10.1.3. Data Protection .........................................................................................70
10.1.3.1. Data Monitoring Committee ...................................................70
10.1.4. Dissemination of Clinical Study Data ......................................................70
10.1.5. Data Quality Assurance ............................................................................71
10.1.6. Source Documents....................................................................................72
10.1.7. Study and Site Start and Closure ..............................................................73
10.1.8. Publication Policy.....................................................................................74
10.1.9. Sponsor’s Qualified Medical Personnel ...................................................74
10.2. Appendix 2: Clinical Laboratory Tests .................................................................76
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................78
10.3.1. Definition of AE .......................................................................................78
10.3.2. Definition of an SAE ................................................................................79
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................80
10.3.4. Reporting of SAEs....................................................................................84
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................85
10.4.1. Male Participant Reproductive Inclusion Criteria....................................85
10.4.2. Female Participant Reproductive Inclusion Criteria.................................85
10.4.3. Woman of Childbearing Potential ............................................................85
10.4.4. Contraception Methods.............................................................................86
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......89
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................91
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI.......93
10.9. Appendix 9: Prohibited Medications Not Permitted From Screening ..................95
10.10. Appendix 10: Abbreviations ...............................................................................96
11. REFERENCES ................................................................................................................101
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LIST OF TABLES
Table 1.
Overall Visit Schedule and List of Procedures (use with Table 2 for 
full details)................................................................................................15
Table 2.
Detailed Schedule (selected study days)...................................................17
Table 3.
Completed and Ongoing Clinical Studies.................................................21
Table 4.
Populations to be Analyzed ......................................................................63
Table 5
Definition of Plasma PK Parameters for PF-07081532............................65
Table 6.
Protocol-Required Safety Laboratory Assessments .................................76
LIST OF FIGURES
Figure 1.
Sample Dosing Scheme ............................................................................27


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Final Protocol, 21 October 2021
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: A Phase 1 Study of Multiple Oral Doses of PF-07081532 in Adult Participants 
With Type 2 Diabetes Mellitus
Rationale
The purpose of this study is to evaluate the safety, tolerability, and PK of multiple doses of 
PF-07081532 in participants with T2DM, inadequately controlled on metformin. The study 
may also enroll non-diabetic participants with obesity. 
The study will also assess the effect on PD biomarkers, including MDG.
Objectives, Endpoints, and Estimands
Objectives
Endpoints
Primary: 
Primary: 

To evaluate the safety and tolerability of
multiple doses of PF-07081532, 
administered orally, in adult participants 
with inadequately controlled T2DM on 
metformin and if enrolled, in non-diabetic 
participants with obesity.

Assessment of AEs, safety laboratory 
tests, vital signs and 12-lead ECGs.
Secondary: 
Secondary: 

To characterize plasma PK of 
PF-07081532 following multiple doses 
administered orally, in adult participants 
with inadequately controlled T2DM on 
metformin and if enrolled, in non-diabetic 
participants with obesity.

PF-07081532 plasma PK parameters 
AUC24, Cmax, Tmax on Day 1 and Day 
42 and t½ on Day 42, as data permit.
Exploratory: 
Tertiary: 

To characterize the PD effect on glucose, 
insulin, glucagon, and C-peptide 
excursions after a MMTT following 
multiple doses of PF-07081532, 
administered orally, in adult participants 
with inadequately controlled T2DM on 
metformin.

CFB in response to MMTT at all 
postdose timepoints as specified in the 
SoA for AUC(0-4) for glucose, insulin, 
glucagon, and C-peptide.


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Final Protocol, 21 October 2021
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Objectives
Endpoints

To explore the PD effect on MDG*, 
HbA1c*, plasma glucose, plasma insulin, 
and HOMA-IR following multiple doses 
of PF-07081532, administered orally, in 
adult participants with T2DM 
inadequately controlled on metformin and, 
if enrolled, in non-diabetic participants 
with obesity.

CFB at all post-dose timepoints as 
specified in the SoA for: 

Fasting plasma glucose;

Fasting plasma insulin;

HOMA-IR;

HbA1c*;

MDG*.

To assess the PD effect on body weight 
changes following multiple doses of 
PF-07081532, administered orally, in 
adult participants with T2DM 
inadequately controlled on metformin and 
if enrolled, in non-diabetic participants
with obesity.

CFB in body weight at all post-dose 
timepoints as specified in the SoA.

To further characterize plasma PK of 
PF-07081532 following multiple doses 
administered orally, in adult participants 
with inadequately controlled T2DM on 
metformin and if enrolled, in non-diabetic 
participants with obesity.

Additional PF-07081532 plasma PK 
parameters following multiple dose 
administration including, as data 
permit: AUC24(dn), AUCinf, AUClast, 
Cav, CL/F, Cmax(dn), Cmin, Rac, 
Rac,Cmax, PTR, Vz/F
Estimands are not applicable.
*not analyzed in non-diabetic population with obesity, if enrolled.
Overall Design
Brief Summary
This is a Phase 1, randomized, double-blind, sponsor-open, placebo-controlled study to 
assess the safety, tolerability, and PK of multiple oral doses of PF-07081532 in adult 
participants with type 2 diabetes mellitus and in non-diabetic participants with obesity, if 
enrolled.


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Number of Participants
Within each cohort, approximately 12 participants will be randomized to receive either 
PF-07081532 or placebo (9 PF-07081532: 3 placebo) for a treatment duration of 42 days 
(approximately 6 weeks). 
Intervention Groups and Duration
The duration of the study from the Screening visit to the last follow-up visit will be 
approximately 16 weeks, of which 52 days will be inpatient at the CRU, followed by a follow 
up period of 4-5 weeks, post last dose. Screening may take up to 28 days prior to 
randomization. The treatment period with double-blind study intervention will be once daily, 
for 42 days.
The study will begin with 3 planned cohorts and may be conducted concurrently, partially 
overlapping or sequentially. Based on emerging data,up to 3 additional cohorts may be added 
to evaluate additional doses, dosing schemes, or additional patient population ie, non-diabetic 
participants with obesity. 
A sample dosing scheme with dose designations (in mg/day) for planned cohorts is below. 
The actual doses, treatment sequence and dose increments will be provided to the 
investigator, prior to the start of each cohort.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
Primary endpoint: clinical safety laboratory tests, thorough assessments of vital signs and 
12-lead ECGs, physical examinations, and AE monitoring will be performed to provide 
essential data to evaluate the safety and tolerability of PF-07081532.
Secondary endpoints: PK parameters for PF-07081532 including AUC24, Cmax, Tmax on Day 1 
and Day 42 and t½, following multiple dose administration on Day 42 will be derived from 


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the concentration-time profiles using non-compartmental methods as data permit, and will be 
summarized descriptively.


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1.2. Schema
Dose levels represent PF-07081532 or matching placebo.
Proposed doses; Dosing in Cohort 1 will be conducted as shown; actual doses, dose increments and dosage duration for 
subsequent cohorts may be adjusted based on emerging data.
Additional cohorts may be added to explore additional doses and dosing schemes 
The cohorts in this study may be run concurrently, partially overlapping or sequentially.


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1.3. Schedule of Activities
The SoA table 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.


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Table 1.
Overall Visit Schedule and List of Procedures (use with Table 2 for full details)
Protocol Activity 
Screen
Study Day (all activities at 0H [prior to dosing] unless otherwise specified) 
Follow-Up
Early 
Termination
Abbreviations used in this table may be found in 
Appendix 10.
-7 -1
1
2 3-7 8 9-13 14 15-21 22 23-27 28 29 30-35 36 37-41 42
43
44
45
49-56 70-77a
Outpatient visit (after ≥8-H fast)
x
x
Informed consent
x
Adverse event monitoring
x
→→→→→→
→
→
→
→
→
→→
→
→
→
→
→
→
x
x
x
x
Demography and height
x
Inpatient stay at CRU
x →→→→→
→
→
→
→
→
→→
→
→
→
→
→
→
x
Medical history 
x
x
Review drug, alcohol, tobacco use
x
x
x
Review prior/concomitant treatments
x
x
x
x
x
Review contraception use/requirement
x
x
x
x
x
Physical examinationb
x
x
x
x
x
Body weight
x
x
x
x
x
x
x
x
x
x
x
COVID-19 questionnairec
x
x
COVID-19 testingd
x
x
COVID-19 check temperaturee
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Supine 12-lead ECGf
x
See Table 2
See Table 2
xg
x
x
x
See Table 2
x
x
See Table 2
xg
x
x
x
x
Supine vital signs (blood pressure and pulse)h
x
xg
x
x
x
x
x
xg
x
x
x
x
Fasting fingerstick blood glucose measurementi
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Standardized meals/snacksj
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Liquid meal (for MMTT)k
IP Administration
Blinded IP administrationl
x
x
x
x
x
x
x
x
x
x
x
x
Blood Sampling for:
- Safety laboratory testsm
x
x
x
x
x
x
x
- FSH,n HIV, HBsAg, HBcAb, HCVAb, HBsAb
x
- Free T4, calcitonin, amylase, lipase, HbA1c, 
TSH, lipids
x
x
- Glucose, insulin, C-peptide,m glucagon
- PF-07081532 PK
xg
x
x
x
x
x
xo
xo
xo
x
- 4-β-hydroxycholesterol/cholesterol
Urine Sampling for:
- Urine drug test
x
x
- Urinalysis (and microscopy, as appropriate)
x
x
x
x
x
x
x
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a.
This follow-up contact may be conducted as a phone call.
b.
Full physical exam at times indicated; limited exam for previous findings, new/open AEs, or investigator discretion.
c.
Enquire about exposure to positive participant, residence or travel in area of high incidence and check for COVID-19 related signs and symptoms.
d.
The testing for COVID-19 pathogen by PCR will be performed at Screening and Admission. At Admission, testing will be done prior to confinement. Additional testing may 
be conducted at the discretion of the investigator.
e.
To be done at least daily during residence.
f.
Single 12-lead ECG at Screening, follow-up and Early Termination (if applicable). Measure in triplicate at all other times indicated.
g.
Measurement/sample at 0H corresponds to the 24H timepoint as detailed in Table 2 (ie, listed in both tables, but only one sample/measurement should be collected).
h.
Single vital signs at Screening, follow-up and Early Termination (if applicable). Measure in triplicate at all other times indicated.
i.
Fingerstick glucose via glucometer on admission to CRU and prior to breakfast on all inpatient days; may be more frequent at the discretion of the investigator.
j.
Meals to be provided on all days while inpatient at approximately 0H, 4H, and 10H relative to dosing; snacks may be provided. Refer to Section 5.3.
k.
This procedure is to be conducted in participants enrolling with T2DM only.
l.
Dose administration to occur with breakfast or liquid meal daily on Days 1 to 42, inclusive, see Section 5.3 and Section 6.
m.
See Appendix 2 for safety lab tests to be collected at each timepoint, see Section 5.3 for fasting requirements. Note: C-peptide is collected as part of safety labs at Screening.
n.
FSH in females to confirm postmenopausal status only.
o.
PK samples on Day 43, 44, and 45 are to be collected 24H, 36H, 48H, and 72H after the final PF-07081532 dose on Day 42.
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Table 2.
Detailed Schedule (selected study days)
Study Day
Hours Relative to Dosing at 0Ha
0
0.25 0.5
1
1.5
2
3
4
6
8
10
12
16
24b
Triplicate, supine 12-lead ECG
Days -1, 1, and 42
x
x
x
x
x
x
x
Triplicate, supine vital sign (blood pressure and pulse)
Days -1, 1, and 42
x
x
x
x
x
x
x
Fasting fingerstick blood glucose measurementb,c
All inpatient days
x
Liquid meal (for MMTT)d
Days -1, 28e and 42
x
Standardized meal/snackf
all inpatient days
xg
x
x
x
Blinded investigational product administration
Daily: Day 1 to Day 42
xh
Blood sampling for:
- Safety laboratory testsi
Days -1, 28, and 42
xj
- HbA1ck, TSH
Days -1, 28, and 42
xj
- Plasma glucosel
Days -1, 28e and 42
xj
x
x
x
x
x
x
x
x
x
x
x
x
x
- Plasma insulinl
Days -1 and 42
xj, m
x
x
x
x
x
x
x
- Plasma C-peptidek, glucagonk )
Days -1 and 42
xj
x
x
x
x
x
x
x
- Free T4, calcitonin, amylase, lipase, lipids
Days -1, 28, and 42
xj
- PF-07081532 PK
Days 1 and 42
x
x
x
x
x
x
x
x
x
x
x
- 4-β-hydroxycholesterol/cholesterol
Days 1 and 42
x
- Retained research samples for Prep D1.5
Day -1 onlyn
x
- Retained research samples for Prep B1.5 and Prep B2.5
Day -1 and Day 42
x
Urine sampling for:
- Urinalysis and microscopy, as appropriate
Days -1, 28, and 42
x
a.
On Day -1, time of 0H procedures to match approximate planned clock time of collection on Day 1. All other days, 0H procedures to be completed pre-dose.
b.
The 24H sample is to be collected prior to dosing on the following morning, as indicated in Table 1.
c.
Fingerstick glucose via glucometer on admission to CRU and prior to breakfast on all inpatient days; may be more frequent at the discretion of the investigator.
d.
Liquid meal given at 0H (or on Day -1 at the anticipated clock time of Day 1 dose) to be consumed over 10 mins. The 0.25 H sample is 5 minutes after completion of the 
liquid meal. This procedure is to be conducted in participants enrolling with T2DM only.
e.
Indicated procedures will be conducted on Days -1, 28, and 42 for Cohort 1; decision for Day 28 procedures in subsequent cohorts will be provided in writing prior to 
initiation of dosing for each cohort.
f.
Standardized meals/snacks to be provided on all days while inpatient; identical meals/snacks on days when MMTT is being conducted. Refer to Section 5.3.
g.
Standard breakfast NOT provided on days when MMTT is being conducted; refer to Section 5.3.
h.
Dosing to occur with breakfast or liquid meal daily from Day 1 to day 42, inclusive.
i.
See Appendix 2: Clinical Laboratory Tests for safety lab tests to be collected at each timepoint.
j.
See Section 5.3 for fasting requirements. 
k.
Participants enrolling with T2DM only.
l.
Fasting (0H) sample is to be collected in all participants. Post-dose timepoints in participants enrolling with T2DM only.
m.
Fasting (time 0H only) insulin to be measured in triplicate on Day -1 and Day 42, all other measurements single, see Section 8.9.2.
n.
If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a participant visit.
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2. INTRODUCTION
GLP-1 is a neuroendocrine hormone that is predominantly released from the small intestine 
in response to food intake.1 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-07081532 is a potent and selective, orally administered, small molecule GLP-1R agonist 
that is being developed as an adjunct to diet and exercise to improve glycemic control in 
adults with T2DM. 
2.1. Study Rationale 
The purpose of the study is to evaluate the safety, tolerability and PK of multiple doses and 
different dosing schemes of PF-07081532 in participants with T2DM, inadequately 
controlled on metformin and, if enrolled, in non-diabetic participants with obesity. 
The study will also assess the effect of PF-07081532 on PD biomarkers, including MDG in 
participants with T2DM.
2.2. Background 
Diabetes is estimated to affect approximately 425 million adults (8.8% of people aged 
20-79 years) world-wide. 5,6 . The increase in the global prevalence of T2DM is largely 
attributed to rising rates of excess body weight and obesity.7
T2DM is characterized by insulin resistance, a disorder in which cells do not respond 
effectively to insulin, resulting in higher blood glucose levels. Elevated blood glucose levels 
and increasing severity of insulin resistance result in the need for more insulin over time, 
eventually resulting in progressive pancreatic β-cell failure.8 Patients with poorly controlled 
T2DM have an increased risk of developing complications associated with both 
microvascular and macrovascular disease, including nephropathy, neuropathy, retinopathy, 
cardiovascular disease and stroke, and are at 2 to 4 times increased risk of mortality than 
adults who do not have diabetes.9 While existing pharmacological options for the treatment 
of diabetes may provide satisfactory glycemic control for some patients, there remain many 
patients who do not achieve target HbA1c levels, suggesting a need for additional therapeutic 
options. 
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 
a majority of 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-07081532 promotes cAMP production. 
 
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. PF-07081532 was shown to bind to the 
human GLP-1R using a competition binding assay. In vivo, PF-07081532 potentiated 
glucose-stimulated insulin secretion during an IVGTT in cynomolgus monkeys at plasma 
exposures that were consistent with its in vitro potency.
Details of the nonclinical pharmacology program are included in the IB.
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Further details of the nonclinical pharmacokinetics and metabolism program are included in 
the IB.
2.2.1.3. Nonclinical Safety
PF-07081532 was evaluated in genetic toxicity studies and oral, repeat-dose rat and 
cynomolgus monkey toxicity studies as well as cardiovascular and neuropulmonary safety 
pharmacology studies. 
 
 
 
In the 8-week oral gavage toxicity study conducted in cynomolgus monkey at 20, 60, and 
100 mg/kg/day, no adverse effects were detected and the NOAEL was defined as the high 
dose of 100 mg/kg/day. 
 
A 6-week oral gavage toxicity study was conducted in Wistar Han rats with PF-07081532 
and the intermediate dose of 100 mg/kg/day was considered to be the NOAEL
. Details of both studies can be found in the IB.
Safety pharmacology studies conducted to assess potential pharmacodynamic effects on 
central nervous and respiratory systems did not identify any effects at doses up to 300 mg/kg 
in rats. 
 
 
 
 
 
 
PF-07081532 was not mutagenic or clastogenic both in vitro and in vivo (rat micronucleus 
study) and was negative for phototoxic potential.
2.2.2. Clinical Overview
The safety of PF-07081532 has been assessed in 1 completed clinical Study C3991001, and 
is being assessed in 1 ongoing clinical Study C3991002.
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Table 3.
Completed and Ongoing Clinical Studies
Study 
Identifier
Study Design and Type of 
Control
Dosing Regimen, 
Formulation Dose
Number of 
Participants 
Randomized
Population
Treatment Duration
Study Status
C3991001
Phase 1, double-blind, 
randomized, placebo controlled, 
single ascending dose study. Two 
interleaving cohorts of healthy 
adult participants with crossover, 
placebo substitution design. 
One cohort of healthy adult 
Japanese participants with 
crossover placebo substitution 
design.
PF-07081532 or 
placebo. 
Orally administered 
solution 
Dose Range: 10 mg 
to 200 mg
PF-07081532: 22 
Placebo: 12
Healthy 
Adult 
Participants
Single dose 
Completed
C3991002
Phase 1, randomized, 
double-blind (investigator- and 
participant-blind), sponsor-open, 
placebo-controlled, multiple oral 
dose-escalating study.
Orally administered 
tablet 
Part A: 10 
(8 PF-07081532: 2 
placebo) planned 
participants/cohort
Multiple doses
Ongoing: 
dosing completed, 
data analysis and 
reporting ongoing
Target dose range: 
PF-07081532 10 mg 
to 180 mg or 
placebo
Adult 
Participants 
with T2DM
28 days’ dosing
Target dose 
PF-07081532 
180 mg or placebo
Part B: 15
(12 PF-07081532: 
3 placebo) 
planned 
participants/cohort
Adult 
Participants
with 
Obesity
42 days’ dosing
Target dose 
PF-07081532 
180 mg or placebo
Part C: 10
(8 PF-07081532: 2 
placebo) planned 
participants/cohort
Adult 
Participants 
with T2DM
42 days’ dosing
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2.2.2.1. Clinical Safety 
Clinical data for the completed study, C3991001, are provided in the current version of the 
IB. 
A blinded summary of currently available data from study C3991002 is provided below. 
These data should be considered preliminary and subject to update on final reporting of the 
study’s results. PF-07081532 or matching placebo have been administered to a total of 
51 participants with T2DM and 15 participants with obesity. A dose titration approach was 
used, where doses within a cohort were titrated up to a target dose over the dosing period.
The duration of titration varied across cohorts. The target doses ranged from 10 mg (no 
titration phase) to 180 mg PF-07081532 or matching placebo. Each cohort was expected to 
receive study drug at the target dose level for a minimum stable dosing period of 7 days.
Four cohorts of participants with T2DM have been randomized to receive doses of 
PF-07081532 (target doses of 10 mg to 120 mg) or matching placebo once daily for 28 days.
One cohort of 10 participants with T2DM has been randomized to receive PF-07081532 
titrated to a target dose of 180 mg, or matching placebo, once daily for 42 days. One cohort 
of 15 participants with obesity has been randomized to receive PF-07081532 titrated to a 
target dose of 180 mg or matching placebo once daily for 42 days. One participant who 
completed dosing (blinded target dose 30 mg/placebo) experienced an SAE of acute gallstone 
pancreatitis during the follow-up period. The investigator reported that there was a 
reasonable possibility that the event was related to blinded study drug. The totality of 
available data, including medical history, has been reviewed by the Sponsor. The overall 
evidence, in the opinion of Sponsor, points to gallstone, rather than drug-induced 
pancreatitis, as the likely cause of this event. There was no change to the benefit/risk profile 
of PF-07081532, nor was any change to the conduct of the ongoing clinical study judged to 
be required. 
A majority of TEAEs reported have been mild in severity. The most frequently reported 
TEAEs have been in the GI system as consistent with reports for marketed GLP-1R agonists.
While there have been isolated values for laboratory tests, vital signs and ECG intervals 
outside of the reference ranges, no clear adverse trends were apparent in these parameters. As 
has been reported for marketed GLP-1R agonists,10,11 a trend toward modest increases in 
heart rate has been observed, with most heart rate values within the normal range.
 
 
 
 
 
 
 
 
 
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2.3. Benefit/Risk Assessment
This study is designed primarily to generate safety, tolerability, and PK data from adult 
participants with T2DM and, potentially, participants with obesity and without T2DM. The 
purpose of the study is to provide the basis for further clinical development of PF-07081532 
as a potential new, pharmacological agent for the treatment of T2DM. 
Based on the clinical history of injectable GLP-1R agonists, an oral GLP-1R agonist is 
expected to improve glucose control, reduce HbA1c levels, diminish food intake, and 
decrease body weight in patients with T2DM, while avoiding the requirement for 
subcutaneous injections that accompany a majority of currently available peptidic GLP-1R 
agonists.
As of the issuance of this protocol, no specific human risks associated with PF-07081532 
administration have been identified. The doses being evaluated in this study are anticipated to 
be in the range of doses previously tested. Data gathered during nonclinical and clinical 
studies with PF-07081532 to date are summarized in the current IB and in Section 2.2. 
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention – PF-07081532
Potential risks 
associated with 
marketed GLP-1R
agonists including 
thyroid C-Cell tumors, 
pancreatitis, changes in 
heart rate and blood 
pressure
The potential risks are based on 
product labeling for marketed GLP-1R 
agonists (liraglutide, dulaglutide, and 
exenatide); additional information is 
provided in the current IB.
•
Study includes inpatient 
monitoring of the participants 
following administration of 
multiple, oral doses of the 
investigational product. 
•
Potential participants with a 
personal or family history of 
medullary thyroid carcinoma or 
MEN2 are not eligible for study 
entry. Potential participants with 
acute pancreatitis or a history of 
chronic pancreatitis are not 
eligible for study entry.
•
Clinical safety laboratory tests, 
including thyroid function, serum 
amylase and lipase, thorough 
assessments of vital signs and 
ECGs, physical examinations and 
adverse event monitoring will be 
undertaken throughout the dosing 
period.
Gastrointestinal adverse 
events
The potential risks are based on 
product labeling for marketed GLP-1R 
agonists (liraglutide, exenatide and 
Participants are monitored during the 
study to prevent potential sequelae of 
any severe gastrointestinal reactions, 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
dulaglutide). In addition, 
gastrointestinal AEs, the majority of 
which were mild in severity, have been 
observed in the clinical program with 
PF-07081532 to date.
eg, dehydration. Concomitant 
medication for nausea is permitted in 
the study
Other Factors Potentially Impacting Study Results
Risk of COVID-19 
exposure
N/A
All participants will be tested for 
COVID-19 and confirmed negative, 
prior to admission to the site; once 
admitted, all participants will be 
monitored daily for COVID-related 
symptoms, including fever
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07081532 may be found in the current version of the IB, which is the 
SRSD for this study.
Considering all available clinical and nonclinical data, the benefit-risk profile of 
PF-07081532 supports continued clinical development.


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3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Endpoints
Primary: 
Primary: 

To evaluate the safety and tolerability of
multiple doses of PF-07081532, 
administered orally, in adult participants 
with inadequately controlled T2DM on 
metformin and, if enrolled, in non-diabetic 
participants with obesity.

Assessment of AEs, safety laboratory 
tests, vital signs and 12-lead ECGs.
Secondary: 
Secondary: 

To characterize plasma PK of 
PF-07081532 following multiple doses 
administered orally, in adult participants 
with inadequately controlled T2DM on 
metformin and, if enrolled, in non-diabetic 
participants with obesity.

PF-07081532 plasma PK parameters 
AUC24, Cmax, Tmax on Day 1 and Day 
42 and t½ on Day 42, as data permit.
Exploratory: 
Exploratory: 

To characterize the PD effect on glucose, 
insulin, glucagon, and C-peptide 
excursions after a MMTT following 
multiple doses of PF-07081532, 
administered orally, in adult participants 
with inadequately controlled T2DM on 
metformin.

CFB in response to MMTT at all 
postdose timepoints as specified in the 
SoA for AUC(0-4) for glucose, insulin, 
glucagon, and C-peptide.

To explore the PD effect on MDG*, 
HbA1c*, plasma glucose, plasma insulin, 
and HOMA-IR following multiple doses 
of PF-07081532, administered orally, in 
adult participants with T2DM 
inadequately controlled on metformin and,
if enrolled, in non-diabetic participants
with obesity.

CFB at all post-dose timepoints as 
specified in the SoA for: 

Fasting plasma glucose;

Fasting plasma insulin;

HOMA-IR;

HbA1c*;

MDG*.


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Objectives
Endpoints

To assess the PD effect on body weight 
changes following multiple doses of 
PF-07081532, administered orally, in 
adult participants with T2DM 
inadequately controlled on metformin and,
if enrolled, in non-diabetic participants
with obesity.
CFB in body weight at all post-dose 
timepoints as specified in the SoA.

To further characterize plasma PK of 
PF-07081532 following multiple doses 
administered orally, in adult participants 
with inadequately controlled T2DM on 
metformin and, if enrolled, in non-diabetic 
participants with obesity.

Additional PF-07081532 plasma PK 
parameters following multiple dose 
administration including, as data 
permit: AUC24(dn), AUCinf, AUClast,
Cav, CL/F, Cmax(dn), Cmin, Rac, 
Rac,Cmax, PTR, Vz/F.
Estimands are not applicable.
*not analyzed in non-diabetic population with obesity, if enrolled.
4. STUDY DESIGN
4.1. Overall Design
This is a randomized, double-blind (investigator- and participant- blind), sponsor-open, 
placebo-controlled, multiple oral dose-escalating study of PF-07081532. 
In this study, adult participants with T2DM inadequately controlled on metformin will be 
enrolled and will receive PF-07081532 or placebo daily, for 42 days. 

Enrollment in 3 cohorts is planned with approximately 12 participants 
(9 PF-07081532: 3 placebo) per cohort. 
A sample dosing scheme is provided below. Dosing in Cohort 1 will be conducted as shown. 
Increments in doses and duration of dosing at each step for subsequent cohorts, as well as the 
number of cohorts conducted, may be adjusted based on emerging data. The dosing scheme 
for each cohort will be provided in writing prior to its initiation. 


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Figure 1.
Sample Dosing Scheme
If a participant does not tolerate dose increment to the next dose level, as determined by the 
investigator and with notification to the sponsor, the participant may be reverted to the 
previously tolerated dose level. Following this dose modification, 2 separate attempts at 
increasing the dose to the next dose level are permitted, per investigator discretion. If, per 
investigator assessment, unacceptable intolerance (eg, severe vomiting) occurs shortly 
following dose administration, the dose will not be re-administered on the same day, and the 
participant may resume dosing at the current dose level at the next scheduled dosing time. 
Participants whose dose level is tolerability-limited may continue in the study for the 
intended duration of their assigned cohort at their own individual MTD, as judged to be 
appropriate by the PI and sponsor.
The planned cohorts in the study (Cohorts 1-3) may be conducted concurrently, partially 
overlapping or sequentially. The sponsor may decide not to conduct all planned cohorts, if it 
is judged that study objectives have been met. Up to 3 additional cohorts may be enrolled if 
judged necessary to meet the study objectives. One or more of the study cohorts may be 
conducted in non-diabetic participants with obesity, see Section 4.2.1 and Section 5.
Determination of eligibility will occur within 28 days of randomization based on criteria 
including medical history, vital sign, ECG and laboratory parameters, as detailed in 
Section 5. Participants deemed eligible will be admitted to the CRU 7 days prior to start of 
dosing (Day -7) and will remain on-site until at least Day 45, post first dose. 
The treatment period with double-blind study intervention will be 42 days, with study drug 
administered once daily. The participants within a given cohort will be blinded to the study 
treatment (PF-07081532 versus placebo). Participants who discontinue prior to completion of 
the study may be replaced, at the discretion of the PI and sponsor.
Upon discharge from the CRU, participants will return to the CRU 7 to 14 days after the last 
administration of IP for an on-site follow-up visit. A further follow-up contact with 
participants will be conducted at least 28 days and up to 35 days after the last administration 
of IP; this contact may be done via a phone call.


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The total duration of the study from the Screening visit to the last follow-up visit will be 
approximately 16 weeks of which 52 days will be inpatient at the CRU, followed by a 
follow-up period of 4-5 weeks, post last dose.
The study will be conducted in the USA. 
4.2. Scientific Rationale for Study Design
The primary objective of the study is to evaluate the safety and tolerability of multiple doses 
of PF-07081532 administered with different doses and dosing schemes over 42 days in 
participants with T2DM, inadequately controlled on metformin. Due to the 
gastrointestinal-related tolerability issues associated with GLP-1 receptor agonism12 that 
have been shown to tolerate with repeated dosing, this study will evaluate safety and 
tolerability of different starting doses and titration increments in order to optimize the 
titration schemes for studies of longer duration.
4.2.1. Population(s)
Participants enrolled in this study will be adults with inadequately controlled T2DM (as 
indicated by HbA1c at screening) on metformin monotherapy, which is considered first-line 
therapy for glycemic control according to current treatment guidelines.13 At screening, this 
study requires that participants with T2DM have been taking a minimum stable metformin 
dose of at least 500 mg/day for at least 2 months prior to the screening visit. The dose of 
metformin, where possible, is expected to remain the same until completion of study 
participation (ie, follow-up visit). Available in vitro data suggest that PF-07081532 is not 
expected to impact the PK of metformin via inhibition of OCT2, and the risk of a clinical 
interaction is deemed negligible. One or more cohorts of non-diabetic participants with 
obesity may be enrolled in this study. The safety, tolerability, PK and PD data collected in 
this study may be used to select doses and dosing scheme algorithms for future studies of 
PF-07081532.
The population planned for this study will be male and female adult participants. Female 
participants will be WONCBP, since at the present time embryofetal development toxicity 
studies with PF-07081532 have not been conducted. In male participants appropriate 
measures are expected to be followed to limit potential transfer of PF-07081532 in semen to 
partners (see Appendix 4).
4.2.2. Concomitant Medications
 
 
 
 
 
For more 
information regarding concomitant medications in this study, see Section 6.8.
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4.2.3. Study Blinding
To permit an unbiased assessment of safety, the participants’ treatment assignments 
(PF-07081532 versus placebo, but not cohort designation) will be blind to both site staff 
(except those involved in preparation of doses) as well as the study participants. However, to 
permit real-time review of the safety and PK data, a limited number of sponsor study team 
members will be unblinded (see Section 9.4).
4.2.4. Endpoints
Clinical safety laboratory tests, thorough assessments of vital signs and 12-lead ECGs, 
physical examinations, and AE monitoring will provide essential data to evaluate the safety 
and tolerability of PF-07081532. To supplement standard clinical safety laboratory tests, 
calcitonin, amylase, lipase, TSH, T4 and lipid panel will be assessed based on the study 
population and guided by data available on marketed GLP-1R agonists.12 In addition, TBA 
will be assessed, based on non-adverse findings in the nonclinical studies with PF-07081532 
(see Section 2.2.2 and the IB).
While GLP-1R agonists typically are not associated with hypoglycemia unless co-
administered with anti-diabetic agents that can cause hypoglycemia (such as insulin or
sulfonylureas), blood glucose concentrations will be monitored throughout the study via a
glucometer at least once daily (pre-breakfast), and careful monitoring of symptomatic
hypoglycemic AEs will be performed.
In an effort to reduce variability and better quantify any potential changes in heart rate and
BP during the study, all measurements of ECG and vital signs (pulse and BP) will be 
collected in triplicate (except as noted in the SoA) and the mean values will be used for 
analysis at each time point.
The effect of PF-07081532 on glucose response in participants with T2DM will be evaluated 
by determining the change from baseline in MDG. Since MDG is the time-averaged response 
over a day, it is expected that this glycemic parameter will be predictive of longer term 
glycemic control. The effect of PF-07081532 on body weight, FPG and other glycemic 
markers including insulin, C-peptide, HbA1c, and glucagon will also be assessed. FPG and 
FPI levels will be assessed and used to calculate HOMA-IR. In order to reduce variability in 
FPI for HOMA-IR calculation,14triplicate measurements will be collected as indicated in the 
SoA and Section 8.9.2. In an effort to reduce variability, minimize any potential effect of 
placebo or CRU confinement and better quantify any potential changes to these parameters, 
the participants will be admitted to the CRU on Day -7 in order to monitor compliance with 
background metformin and recommended diet.
Baseline (Day -1) assessments with time-matched procedures will permit within participant 
comparisons, as appropriate. In addition, placebo-adjusted (between participant) comparisons 
of dose-response will also be conducted. 


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4.2.5. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide understanding of the study intervention.
4.3. Justification for Dose
Doses for the study will be determined considering all relevant information obtained from 
nonclinical safety studies along with safety, tolerability, and PK data observed in completed 
study C3991001, ongoing Study C3991002 and emerging data from prior cohorts of this 
study, as applicable. The dose levels to be assessed in this study are anticipated to be within 
the dose range evaluated in C3991002 (10 mg to 180 mg QD), where no safety concerns with 
PF-07081532 have been identified. The total duration of dosing for PF-07081532 or placebo 
in this study will be 42 days, as supported by completed nonclinical toxicity studies (see 
Section 2.2.1.3).
Cohort 1 will receive PF-07081532 20 mg, or placebo, QD for 28 days followed by 60 mg or 
placebo, QD for the remaining 14 days. This was selected to assess whether a starting dose of 
20 mg QD offers a profile that will allow its use as the initial titration step in future longer 
duration studies. The dosing schemes in subsequent cohorts may be adjusted based on 
emerging data in order to generate valuable information (eg, on different starting doses or 
dose increment steps) that will enable optimization of the dosing schemes for use in future 
studies. The doses and dose increments will be selected for this study in order to obtain data 
on these initial steps and not to necessarily reach the target doses where efficacy of 
PF-07081532 could be evaluated in future studies of longer duration.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the trial globally.
A participant is considered to have completed the study if he/she has completed all periods of 
the study, including the last visit or the last scheduled procedure shown in the SoA.
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:


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Age and Sex:
1. Male and female participants must be between the ages of 18 and 70 years, inclusive, 
at the time of signing the ICD. 
2. Females must be of non childbearing potential.

Refer to Appendix 4 for reproductive criteria for males (Section 10.4.1) and 
females (Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
3. Patients with T2DM who are treated with metformin.
Note: Participants must be taking metformin monotherapy as their only anti-
hyperglycemic treatment. Metformin dose must be at least 500 mg per day and must 
be stable, defined as no change in the treatment and participant-reported compliance 
with treatment, for at least 2 months prior to the screening visit.
4. HbA1c ≥7.0% and ≤10.5% at screening (confirmed by a single repeat, if necessary). 
Note: For non-diabetic participants with obesity (if enrolled), HbA1c <6.5% at 
screening. 
5. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight and BMI:
6. Total body weight >50 kg (110 lbs) and BMI ≥24.5 to ≤45.5 kg/m2.
Note: For non-diabetic participants with obesity (if enrolled) BMI >30.5 to 
≤45.5 kg/m2.
Informed Consent:
7. 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, hepatic, psychiatric, neurological, dermatological, or 


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allergic disease (including drug allergies but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).

Participants who have chronic conditions other than T2DM and obesity (for 
example, hypercholesterolemia or hypertension) but are controlled by either diet 
or stable doses of 2 or fewer medications may be included (for example, a 
participant with hypercholesterolemia on appropriate treatment is eligible). See
Section 6.8 for further information on concomitant medications.

For non-diabetic participants with obesity (if enrolled), a medical history of 
T2DM.
2. Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes.
3. Evidence or history of clinically significant cardiovascular disease. In particular, 
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.
4. 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.
5. Acute pancreatitis or history of chronic pancreatitis.
6. Acute gallbladder disease. 
7. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or 
pancreatic insufficiency).
8. Personal or family history of MTC or MEN2, or participants with suspected MTC per 
the investigator’s judgement.
9. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concomitant Therapy:
10. Participants who have received any vaccine within the 1 week prior to admission to 
the CRU.
11. Use of any prohibited concomitant medication(s) or those unwilling/unable to use a 
permitted concomitant medication(s). Refer to Section 6.8 and Appendix 8.


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Prior/Concurrent Clinical Study Experience:
12. 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).
13. Known prior participation (ie, randomized and received at least 1 dose of 
investigational product) in a trial involving PF-07081532. Note that a given 
individual may only participate in one cohort of this study.
Diagnostic Assessments:
14. A positive urine drug screen at screening or admission.
Note: Participants who have been medically prescribed benzodiazepines and report 
the use of these drugs to the investigator at the screening visit may be allowed to 
participate if approved by the sponsor.
15. Positive testing at screening for HIV, HBsAg, HBcAb, HBsAb or HCVAb. Positive 
COVID-19 test at screening or admission.
Note: A positive HBsAb due to hepatitis B vaccination is permissible.
16. Screening supine BP ≥160 mm Hg (systolic) or ≥100 mm Hg (diastolic) following at 
least 5 minutes of supine rest. 
If BP is ≥160 mm Hg (systolic) or ≥100 mm Hg (diastolic), the BP should be 
repeated 2 more times and the average of the 3 BP values should be used to determine 
the participant’s eligibility.
17. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, baseline 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. Computer-interpreted ECGs should be 
overread by a physician experienced in reading ECGs before excluding participants.
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 times ULN; 


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
Total bilirubin level ≥1.5 times the 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;

TSH > ULN;

Fasting C-peptide <0.8 ng/mL;

Serum calcitonin > ULN;

Amylase > ULN;

Lipase > ULN;

eGFR <60 mL/min/1.73m2 as calculated by MDRD equation;

FPG >270 mg/dL at screening or admission.
Other Exclusions:
19. History of alcohol abuse or binge drinking and/or any illicit drug use or dependence 
within 6 months of Screening.
Note: Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more 
alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 
14 units per week (1 unit = 8 ounces ([240 mL] beer, 1 ounce [30 mL] of 40% spirit 
or 3 ounces [90 mL] of wine).
20. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
21. History of sensitivity to heparin or heparin induced thrombocytopenia, if heparin is 
used to flush IV catheters. 
22. Known intolerance to any GLP-1R agonist.
23. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol, including restrictions on caffeine, alcohol and tobacco use.
24. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study. 
5.3. Lifestyle Considerations
The following guidelines are provided:


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5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 8 hours prior 
to the blood sample collection at the outpatient Screening and on-site follow-up 
visits. 

Participants are required to fast for 4 hours (except water) prior to admission to CRU.

Participants must abstain from all food and drink (except water) at least 8 hours prior 
to the first blood sample on inpatient study days [eg, for FSBG, safety laboratory, PK, 
or PD assessment].

Noncaffeinated drinks (except as indicated below) may be consumed with meals and 
the evening snack. 

Participants will refrain from consuming red wine, grapefruit, or 
grapefruit-related citrus fruits (eg, Seville oranges, pomelos, grapefruit juices) 
from 7 days prior to the first dose of investigational product until collection of the 
final PK blood sample.

The initial caloric intake/menu assigned to each participant will be based on the 
Harris Benedict formula (sedentary lifestyle; to be provided to the site prior to study 
start) using the participant’s body weight measured at screening. 

Breakfast will be provided at approximately 0800 hours on each inpatient day: 

A standard breakfast will be provided for consumption after dosing on all days 
except those when liquid meal (for MMTT) is administered;

On days where liquid meal is administered, in lieu of breakfast, the meal will be 
provided as 16 ounces of Ensure Plus® and will be administered as listed in the 
SoA. The entire Ensure Plus® meal is to be consumed within 10 minutes (See 
Section 8.9.1).

Lunch will be provided approximately 4 hours after dosing (approximately 
1200 hours) and at approximately the same time on each inpatient day. On days 
withliquid meal for breakfast, lunch will be provided after the 4-hour post-dose blood 
collection samples for the MMTT have been completed.

Dinner will be provided approximately 10 hours after dosing (approximately 
1800 hours) and at approximately the same time on each inpatient day.

An evening snack may be permitted at approximately 2200 hours on non-MMTT 
days. On days when the MMTT is performed, an evening snack will be provided. 

On days with MMTT as listed in the SoA (including the evening prior to MMTT) 
participants will be encouraged to consume all provided food, including the liquid 


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meal and all standard meals and snacks provided on these days. Meals on these 
days will be standardized such that participants receive the same menus for all 
meals on these days (including the evening prior).

If participants do not consume their entire meal on Day -1, they will be instructed 
to consume the same amount of food (±10%) on the other days with MMTT that 
they ate on Day -1. 

The start time of all meals (including liquid Ensure Plus™meal) on these days 
will be noted in the CRU source documents and should be available to the sponsor 
on request. Participants will be encouraged to eat all standard meals within 
30 minutes on days with liquid meal administration.

Participants will receive the same snack each evening prior to the MMTT the 
following day. On these days, participants will be encouraged to consume the 
entire evening snack. 

Participants will not be required to consume all provided food during standard 
meals on other study days. 

When a meal or snack is scheduled at the same time as an ECG, the meal will be 
provided after the ECGs are completed. 

Details on the meals provided to participants including the menu items, portion sizes, 
and approximate calories with nutritional macronutrient (% carbohydrate, fat and 
protein) breakdown of the meal will be maintained in source documentation at the 
CRUs. This information will not be collected in the case report form; however, it may 
be submitted to the sponsor on request. The approximate percentage of food 
consumed (based on visual inspection by the site staff) should likewise be recorded in 
CRU source documents. 
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from alcohol for 24 hours (or as specified above for red 
wine) prior to admission to the CRU and continue abstaining from alcohol until 
collection of the final blood sample at the follow-up visit. Participants may undergo 
an alcohol breath test or blood alcohol test at the discretion of the investigator.

Caffeine-containing products, up to the equivalent of two 8-ounce cups of coffee per 
day, will be permitted. 

However, participants must abstain from caffeine-containing products for a 
minimum of 2 hours prior to all vital signs and ECG measurements conducted 
throughout study participation (from screening to the final follow-up visit).

On days when MMTT is conducted, participants may ingest caffeine-containing 
products (up to the equivalent of two 8-ounce cups of unsweetened black coffee 


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per day). This may be permitted provided that there are no additional calories 
consumed and there is no anticipated impact to the MMTT data, that is no sugar, 
sweetener, flavorings, milk, cream etc.

Participants may use tobacco- or nicotine-containing products as permitted by the 
CRU (eg, during smoking breaks, or in specified locations).
However, smoking may not be permitted when it would interfere with the timing of 
scheduled study procedures or during frequent sampling procedures (eg, MMTT). In 
addition, participants must abstain from use of tobacco- or nicotine-containing 
products:

For a minimum of 2 hours prior to all vital sign and ECG measurements;

For a minimum of 2 hours prior to and following administration of investigational 
product.
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.

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing.
5.3.4. Contraception 
The investigator or his or her designee, in consultation with the male participant, will confirm 
that the participant has selected an appropriate method of contraception for the individual 
male participant and his partner(s) from the permitted list of contraception methods 
(seeAppendix 4) and will confirm that the participant has been instructed in its consistent and 
correct use. At time points indicated in the SoA, the investigator or designee will inform the 
male participant of the need to use effective contraception consistently and correctly and 
document the conversation and the male 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’s female partner.
Female participants will not require use of contraception as they cannot be women of 
childbearing potential.


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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/enrolled in the study. 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 eligibility criteria for participation in this study (screen 
failure) may not be rescreened. As an exception, a participant who otherwise qualified for 
this study but did not enroll due to positive COVID-19 test, due to recent vaccination (see 
Section 5.2), or due to exhibiting COVID-19-related symptoms or potential exposure, may be 
rescreened after an appropriate interval, if judged appropriate by the investigator. In such 
cases, all screening procedures must be repeated and the participant assigned a new 8-digit 
SSID.
A participant who qualified for this study but did not enroll for administrative reasons (eg,
delays in IP shipping, cohort filled) may be re-screened. In such cases, all screening 
procedures must be repeated (if the time between screening and dosing exceeds 28 days) and 
the participant assigned a new 8-digit SSID.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
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, the term investigational product may be used 
synonymously with study intervention.
For the purposes of this protocol, study intervention refers to PF-07081532 or matching 
placebo.
6.1. Study Intervention(s) Administered
PF-07081532 and matching placebo will be supplied by Pfizer as tablets. The tablets will be 
supplied to the CRU in bulk along with individual dosing containers for unit dosing.
6.1.1. Administration
On Day 1, participants will receive IP at approximately 0800 hours (plus or minus 2 hours). 
Dosing of IP is planned to occur in the fed state, ie, with breakfast. Details on meals and 
dietary requirements and activity restrictions are given in Lifestyle Considerations section of 
the protocol. Investigator site personnel will administer investigational product with 
approximately 240 mL ambient temperature water. Participants will swallow the 
investigational product whole, and will not manipulate or chew the investigational product 
prior to swallowing. 


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
Blinding will be maintained by keeping the number of tablets the same for 
PF-07081532 and placebo within a given cohort. 
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the 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.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.


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Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
Study intervention and placebo will be prepared by qualified unblinded site personnel 
according to the IP manual. The study intervention will be administered in a blinded fashion 
to the participants.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
All participants will be assigned to randomized study intervention using a randomization 
scheme, maintained by Pfizer (or designated CRO vendor). Investigators will remain blinded 
to each participant’s assigned study intervention throughout the course of the study.
Unblinded personnel will access randomization scheme to prepare or dispense the 
appropriate study treatment. 
The randomization scheme/list will be provided directly and securely to the site 
pharmacist(s). The unblinded pharmacist(s) will be responsible for the preparation and 
dispensing of all study intervention and will endeavor to ensure that there are no differences 
in time taken to dispense or visual presentation following randomization and no blinded site 
staff are able to view the administration.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.
6.3.2. Breaking the Blind 
The method for breaking the blind in this study will be manual. A sealed envelope that 
contains the study intervention assignment(s) for each participant will be provided to the 
investigator. The sealed envelope will be retained by the investigator (or representative) in a 
secured area. 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. When the 
blinding code is broken, the reason must be fully documented and entered on the CRF/DCT.
Once the study is complete, all envelopes (sealed and opened) must be inventoried and 
retained until authorization for destruction has been provided.


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6.4. Study Intervention Compliance
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic 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.
6.5. Dose Modification
Refer to Section 4.3 for details of dosing scheme, and circumstances under which 
modifications may be acceptable.
6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. Treatment of Overdose
For this study, any dose of PF-07081532 greater than 2.5 g is projected to result in exposures 
greater than 404255 ng/mL for Cmax (ie, 152 ng/mL unbound) or 5664894 ng∙h/mL for 
AUC24 (ie, 2130 ng∙h/mL unbound) within a 24-hour time period and will be considered an 
overdose. The exposures above are based on the unbound exposures at the NOAEL in the 
NHP toxicity study (see Section 2.2.1.3) after accounting for protein binding in humans.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician 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-07081532 (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 Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 3 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.


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6.8. Concomitant Therapy
6.8.1. Permitted Medications
Participants may be on certain concomitant medications that have been prescribed to treat 
concurrent diseases such as hyperlipidemia and hypertension. Attempts must be made not to 
alter the doses and regimens of the background/concomitant medications after randomization 
and for the duration of participation in this study. Any changes must be captured in the CRF. 
Where applicable, participants are expected to bring their supply of permitted prescription 
medications prior to confinement to the unit.
Medications, prescription or non-prescription, or herbal supplements not specifically listed in 
the protocol may be permitted, but only after review and approval by the sponsor
6.8.1.1. Metformin
All participants enrolling with T2DM are required to be taking metformin monotherapy at a 
minimum dose of 500 mg/day. On all study days while in the CRU, participants will be given 
their morning dose of metformin at the same time as PF-07081532/placebo. 
Sponsor will not provide metformin during the study and participants are expected to bring 
their current supply of metformin prior to confinement to the unit. 
For participants taking metformin more frequently than once a day, the investigator will 
determine the appropriate times during the day to administer those doses. For metformin 
(required) and other permitted concomitant medications, the timing of administration should 
be the same between inpatient days, and care should be taken to minimize changes to the 
participants stable medication routine. The dose of metformin, where possible, is expected to 
remain the same until completion of study participation ie, last follow-up visit. 
6.8.1.2. Antihypertensive and Lipid-Modifying Agents
The use of background antihypertensive and/or lipid-modifying agent(s) is permitted, unless 
prohibited as per Prohibited Medications section of the protocol. Doses of such agents must 
be stable for at least 4 weeks prior to screening and are expected to remain the same until 
completion of study participation (ie, follow-up visit). 
6.8.1.3. Medications for Management of Nausea and Vomiting
Nausea and vomiting have been reported with administration of GLP-1R agonists. 
Participants experiencing such symptoms may be managed conservatively with bed rest 
and/or fluid management at the discretion of the investigator. If the nausea and vomiting are 
not amenable to conservative management, anti-emetics (eg, prochlorperazine, promethazine, 
ondansetron) may be administered at the investigator’s discretion with notification to the 
sponsor and entry in the CRF.
6.8.2. Prohibited Medications
Use of medications, other than metformin, for glycemic control is not permitted in this study.


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6.8.2.1. Medications Not Permitted During the Study due to Potential Drug-Drug 
Interaction and Other Prohibited, Prior and Concomitant Medications
See Appendix 8 for list of prohibited concomitant medications due to potential drug-drug 
interaction and Appendix 9 for a list of other, prohibited prior and concomitant medications. 
Sites are encouraged to contact the sponsor should there be questions as to whether a 
medication is permitted or prohibited.
6.8.3. Rescue Medicine
There is no rescue therapy to reverse AEs observed with PF-07081532; standard medical 
supportive care must be provided to manage any AEs (see Section 6.8.1.3).
For medical management of hypoglycemia, the investigator may administer oral 
carbohydrate, glucagon, or IV glucose according to his or her medical judgment. At a 
minimum however, treatment or administration of a scheduled meal should be given if 
glucose falls <60 mg/dL for at least 15 minutes, irrespective of whether the participant 
exhibits symptoms. Investigators may choose to administer treatment sooner if participants 
have bothersome symptoms of hypoglycemia along with glucose values of ≤70 mg/dL.
No rescue therapy will be provided for hyperglycemia. If a participant has sustained elevated 
fasting plasma glucose concentrations that are >270 mg/dL on 3 consecutive measurements 
over 3 days, that participant will be discontinued, and the investigator will recommend 
further appropriate glycemic treatment according to the local healthcare standards and 
national guidelines.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: ECG changes, 
adverse events, laboratory abnormalities, potential cases of acute kidney injury or taking of 
prohibited medications, as described below. 
Note that discontinuation of study intervention does not represent withdrawal from the study.
If study intervention is permanently discontinued, the participant will remain in the study to 
be evaluated for safety and PK, if possible. 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.


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7.1.1. ECG Changes
A participant who meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 

QTcF >500 msec.

Change from baseline: QTcF >60 msec and QTcF > 450 msec.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.2. Adverse Events
Treatment will be discontinued and the participant withdrawn from the study for:

Treatment-related SAEs;

Other serious or severe AEs, at the discretion of the investigator or sponsor.
7.1.3. Laboratory Abnormalities
All of the following laboratory abnormalities require discontinuation if they are confirmed:

Hyperglycemia: see Section 6.8.3 and Section 8.2.4.2;

Creatine kinase >10 × ULN;
Note: Urine myoglobin and SCr will be performed as reflex testing for any participant 
with creatine kinase >10 × ULN.

AST or ALT that meets ANY of the following:

>3 × ULN with at least one total bilirubin value >2 × ULN;

>3 × ULN accompanied by signs or symptoms consistent with hepatic injury 
(eg, new onset elevated PT/INR);

Two sequential AST or ALT elevations >5 × ULN, regardless of total bilirubin or 
accompanying signs or symptoms.
NOTE: See also Appendix 6 for potential cases of drug-induced liver injury.


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7.1.4. Potential Cases of Acute Kidney Injury
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 mol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness.
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 mol/L] in SCr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 mol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants at a given dose level are noted to have 2 consecutive
SCr results of ≥0.3 mg/dL (or ≥26.5 mol/L), an assessment of whether the finding may be 
considered an adverse drug reaction should be undertaken.
7.1.5. Prohibited Medications
Participants who are treated with any prohibited medication during the course of the study 
may require discontinuation. Participants who are administered or take a prohibited 
medication should be discussed with the sponsor for possible withdrawal from the study.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Participants 
may be withdrawn at the discretion of the investigator. Reasons for discontinuation from the 
study may include the following: safety, behavioral, compliance or administrative reasons, or 
if the study is 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. 


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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.
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.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether 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;


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
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.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, banked biospecimens, may 
be used without repeat collection, as appropriate.
Procedures conducted as part of the participant’s routine clinical management (eg, laboratory 
data) 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 


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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.
All efforts will be made to conduct procedures at the exact nominal time relative to dosing. 
Procedures up to and including 10 hours after dose administration that are conducted within 
10% of the nominal time (eg, within 6 minutes of a 60-minute sample) relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the procedure is noted on 
the source document and data collection tool (eg, CRF/DCT). Procedures scheduled more 
than 10 hours after dose administration that are conducted ≤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 procedure is noted on the source document and data collection tool (eg, CRF/DCT). 
When multiple procedures are scheduled at the same time point(s) relative to dosing, the 
following chronology of events should be adhered to, where possible:

ECGs: obtain prior to vital sign measurements and as close as possible to the 
scheduled time, but prior to blood specimen collection (see Section 8.2.3);

Vital Signs (BP and pulse rate): obtain as close as possible to the scheduled time, but 
prior to blood specimen collection (see Section 8.2.2);

Weight: obtain as close as possible to the scheduled time, but prior to eating and 
drinking and prior to dose administration, where applicable (see Section 8.9.3); 

Fasting blood samples: after assessment of 12-lead ECG and vital signs but prior to 
dosing;

PK blood specimens: obtain at the scheduled time (for 0H samples, collect before 
dosing and as close as possible to dosing time, where applicable);

Dosing: must occur at the scheduled nominal time and following predose blood 
sample collection;

Breakfast: provided for consumption following dosing, where applicable (see
Section 5.3.1).
Safety/laboratory/analyte results obtained following 1st dose of the study intervention (Day 1) 
that could unblind the study (ie, glucose, insulin, glucagon, C-peptide, HbA1c, and PK), will 
not be reported to investigative sites or other blinded personnel until the study has been 
unblinded.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.


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The total blood sampling volume for individual participants is approximately, up to 425 mL. 
If participants with obesity are enrolled, approximately, up to 245 mL blood will be 
collected. 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 56 consecutive 
days.
8.1. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms. 
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height will also be measured and recorded per the SoA. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.3.1 to 8.3.3.
8.2.2. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements. When triplicate measurements are obtained, 
they should be collected approximately 2 minutes apart; the average of the triplicate 
measurements at each nominal time point on Day -1 will serve as each participant’s time-
controlled baseline value.
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 


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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.
8.2.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) 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) 
should not be used 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 5 minutes in a supine position. When a meal or snack is 
scheduled at the same time as an ECG, the ECG measurement must be performed prior to the 
meal/snack.
Triplicate 12-lead ECGs will be obtained approximately 3 minutes (±1 minute) 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 value. Any clinically significant 
changes from the baseline/Day 1 ECG may potentially be AEs (Appendix 7) and should be 
evaluated further, as clinically warranted. To ensure safety of the participants, a qualified 
individual at the investigator site will make comparisons to baseline measurements. 
Additional ECG monitoring will occur if a) the mean value from the triplicate measurements 
for any postdose QTcF interval is increased by ≥60 msec from the baseline and is 
>450 msec; or b) an absolute QT value is ≥500 msec for any scheduled ECG. If either of 
these conditions occurs, then a single ECG measurement must be repeated at least hourly 
until QTc values from 2 successive ECGs fall below the threshold value that triggered the 
repeat measurement.
If a) a postdose QTcF interval remains ≥60 msec from the baseline and is >450 msec; or b) 
an absolute QT 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 criteria 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 QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.


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8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
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 3 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention (exception may be made for medically prescribed benzodiazepines, see
Section 5.2).
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers, unexpected safety 
findings or other internal exploratory purposes. These data will not be included in the CSR. 
Samples to be used for this purpose will be shipped to either a Pfizer-approved BBS facility 
or other designated laboratory and retained for up to 1 year following the completion of the 
study.
8.2.4.1. Fasting Fingerstick Blood Glucose (via Glucometer)
Investigators will monitor FSBG using a glucometer at the times specified in the SoA. While 
the participant is confined to the CRU, FSBG measurements should be taken each morning 
before breakfast.
FSBG readings will be maintained at the CRU in source documents, and only the glucose 
results from the laboratory will be reported in the study database. The sites may share the 
FSBG readings with the sponsor, if necessary for the purpose of safety monitoring, but these 


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data will be stored in the CRU source documents unless related to an AE as described in 
Section 8.2.4.2.
If an FSBG result is <70 mg/dL

a second FSBG should be obtained to confirm the glucose value – this is in addition 
to a venous sample that will be sent to the clinical laboratory for confirmation. 

if the value from this second FSBG is also <70 mg/dL, the second value will be 
recorded as a hypoglycemic AE (see Section 8.2.4.2). 

FSBG will continue to be monitored until the glucose value returns to ≥70 mg/dL. 
Samples may be taken more frequently if deemed necessary by the investigator.
FSBG readings from a glucometer are permitted at any time if the investigator or participant 
notes symptoms of hypoglycemia.
8.2.4.2. Hypoglycemia Reporting
Hypoglycemia will be assessed and reported in several categories: severe hypoglycemia, 
documented symptomatic hypoglycemia, asymptomatic hypoglycemia, and probable 
hypoglycemia.
Severe hypoglycemia: In order to be considered severe hypoglycemia all of the following 
3 criteria must be met:
1. The participant had 1 of the following:

Blood glucose <50 mg/dL; or

If blood glucose was not measured, the clinical manifestations were reversed by 
carbohydrate administration.
2. The participant required the assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions.
3. The participant exhibited at least 1 of the following neurological symptoms:

Memory loss;

Uncontrollable behavior;

Irrational behavior;

Unusual difficulty in awakening;

Suspected seizure;

Seizure;


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
Loss of consciousness.
Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by a measured glucose concentration <70 mg/dL.
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with a measured glucose concentration <70 mg/dL.
Probable symptomatic hypoglycemia: An event, during which typical symptoms of 
hypoglycemia are not accompanied by a real time glucose determination, but were 
presumably caused by a plasma glucose concentration <70 mg/dL. The clinical picture must 
include prompt resolution with oral carbohydrates, subcutaneous glucagon, or intravenous 
glucose.
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc.).
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). 
During the active collection period as described in Section 8.3.1, each participant/parent/legal 
guardian/legally authorized representative 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.


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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 permanently 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 information on 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 
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.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
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 or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 


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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 toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study 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.


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
A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion. 

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then exposes his female partner prior to or around the 
time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until at least 5 
terminal half-lives after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
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 in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 


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for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention
by ingestion.
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
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form, regardless of 


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whether there is an associated SAE. Since the information about the occupational exposure
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 must be maintained in the 
investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
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.


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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. Pharmacokinetics 
8.4.1. Plasma for Analysis of PF-07081532
Blood samples of approximately 3 mL, to provide approximately 1 mL of plasma, will be 
collected into appropriately labeled tubes containing K2EDTA for measurement of plasma 
concentrations of PF-07081532 at times 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. Any changes 
in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the 
sponsor and site study files but will not constitute a protocol deviation.
Samples will be used to evaluate the PK of PF-07081532. Samples collected for 
measurement of plasma concentrations of PF-07081532 will be analyzed using a validated 
analytical method in compliance with applicable SOPs.
Samples collected for analyses of PF-07081532 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, or for other internal 
exploratory purposes. Genetic analyses will not be performed on these plasma samples 
(unless consent for this was included in the informed consent). Participant confidentiality 
will be maintained. Any remaining volume may be retained and stored for the duration of the 
study. Upon completion of the study, these retained samples may be used for exploratory 
purposes. Any such data generated will not be included in the CSR. Samples to be used for 
this purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.
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 decide as to whether sample integrity has been 
compromised.


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Drug concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
8.4.2. Plasma for Analysis of 4-β-hydroxycholesterol/cholesterol
Blood samples of approximately 4 mL, to provide plasma volume of approximately 2 mL, 
will be collected into appropriately labeled tubes containing lithium heparin at times 
specified in the SoA. As part of the understanding of the properties of the investigational 
product, these samples may be used for analysis of 4-β-hydroxycholesterol/cholesterol as a 
marker of CYP3A activity, for metabolite identification, evaluation of bioanalytical methods 
and/or other internal exploratory purposes. Data generated from these samples may not be 
included in the CSR. Instructions for the collection and handling of biological samples will 
be provided in the laboratory manual. 
 
 
 
 
 
 
 
 
 
 
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8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
8.9. Pharmacodynamics
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer/vendor SOPs.
The PD samples must be processed and shipped (if needed) as indicated in the instructions 
provided to the investigator site to maintain sample integrity. Any deviations from the PD 
sample handling procedure (eg, sample collection and processing steps, interim storage or 
shipping conditions), including any actions taken, must be documented and reported to the 
sponsor. On a case-by-case basis, the sponsor may make a determination as to whether
sample integrity has been compromised. Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PD effects of PF-07081532, samples may be used for evaluation 
of the bioanalytical method, as well as for other internal exploratory purposes. Any 
remaining volume may be retained and stored for the duration of the study. Upon completion 
of the study, these retained samples may be used for exploratory purposes. Any such data 
generated will not be included in the CSR. Samples to be used for this purpose will be 
shipped to either a Pfizer-approved BBS facility or other designated laboratory and retained 
for up to 1 year following the completion of the study.
8.9.1. Liquid Meal (for MMTT)
A liquid meal consisting of approximately 700 kcal (16 fluid ounces) of Ensure Plus®
(Vanilla) will be administered to the participants as listed in the SoA. The liquid meal will be 
consumed within approximately 10 minutes on all MMTT days. 
8.9.2. Plasma Glucose, Plasma Insulin, C-Peptide, Glucagon and HbA1c 
At each timepoint specified in the SoA, a sufficient amount of blood will be collected for 
analysis of plasma glucose, plasma insulin, C-peptide, glucagon, and HbA1c for MMTT. 
The timing of blood samples for assessment of AUC(0-4) as part of the MMTT will be based 
on the start time of the liquid meal such that the sample for the 15-minute time point is 
collected approximately 5 minutes after completion of the liquid meal.
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Where triplicate FPI is to be measured, the 3 samples should be collected approximately 5 
minutes apart. FPI and FPG values will be used to calculate HOMA-IR (see Section 9.3.4). 
8.9.3. Body Weight
Body weight measurements will be obtained at the time points outlined in the SoA. If 
possible, the same scale should be used for a particular participant for all body weight 
measurements obtained at the CRU. For measuring weight, a scale with appropriate range 
and resolution is used and must be placed on a stable, flat surface. 
Body weight will be measured at outpatient visits to the study site as listed in the SoA under 
the following conditions:

After void of urine;

After removal of shoes, bulky layers of clothing, and jackets so that only light 
clothing remains; 

While remaining still during measurement. 
During admission to the CRU, body weight will be measured at the time points listed in the 
SoA. Measurement will be taken under the following conditions:

In the morning, prior to eating and drinking and prior to dose administration, where 
applicable;

After the participant has been asked to void;

While wearing only a hospital gown and no shoes;

While remaining still during measurement.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
No formal statistical hypothesis testing will be performed in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets (Table 4) are defined:


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Table 4.
Populations to be Analyzed
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 and 
screening. 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. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening.
Full Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.
Safety Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the product they actually received.
PK Concentration Set
The PK concentration population is defined as all randomized 
participants who received at least 1 dose of PF-07081532 and 
in whom at least 1 plasma concentration value is reported.
PK Parameter Set
The PK parameter population is defined as all randomized 
participants that received at least 1 dose of PF-07081532 and 
have at least 1 of the PK parameters of interest calculated.
PD population Set
The PD population set is defined as all randomized 
participants that received at least 1 dose of PF-07081532 and 
have at least 1 of the PD parameters of interest calculated.
9.3. 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.
9.3.1. General Considerations
9.3.2. Primary Endpoint
All participants who received at least 1 dose of study intervention will be included in the 
safety analyses and listings. AEs, ECGs, BP, pulse rate, and safety laboratory data will be 
reviewed and summarized on an ongoing basis during the study to evaluate the safety of 


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participants. Any clinical laboratory, ECG, BP, and pulse rate abnormalities of potential 
clinical concern will be described. Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate.
Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will not be required to be reported, 
unless otherwise noted. However, any untoward findings identified on physical and/or 
neurological examinations conducted during the active collection period will be captured as 
AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data (unless noted below), ECGs, and vital signs, will be considered source data, and will not 
be required to be reported, unless otherwise noted. Demographic data collected at screening 
will be reported. In addition, selected screening laboratory data: free T4, HbA1c, TSH, 
calcitonin, amylase, lipase, TBA and C-peptide will be reported.
9.3.2.1. 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
At the nominal time points, the mean of the triplicate measurements will be used to represent 
a single observation at that time point. If any of the 3 individual ECG tracings has a QTcF 
value 500 msec, but the mean of the triplicates is not >500 msec, the data from the 
participant’s individual tracing will be described in a safety section of the study report in 
order to place the >500 msec value in appropriate clinical context. However, values from 
individual tracings within triplicate measurements that are 500 msec will not be included in 
the categorical analysis unless the average from the triplicate measurements is also 
500 msec.
In addition, an attempt may be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach. The results 
of such analyses will not be included in the CSR.
9.3.3. Secondary Endpoints
The populations for PK concentration and PK parameter analyses are defined in Table 4.


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PK parameters for PF-07081532 following multiple dose administration will be derived from 
the concentration-time profiles using non-compartmental methods as data permit. The PK 
parameters to be assessed in this study, their definition, and method of determination are 
outlined in Table 5. In all cases, actual PK sampling times will be used in the derivation of 
PK parameters. PK samples from placebo samples will not be routinely analyzed. 
The plasma PK parameters will be summarized descriptively by treatment and day. Each 
cohort will be considered as a separate treatment. If data permit, dose-normalized area under 
the plasma concentration time profile from time 0 to 24 hours [AUC24 (dn)] and 
dose-normalized Cmax [Cmax (dn)] may be plotted against treatment for each day (potentially 
on a logarithmic scale depending on the extent of the dose range), and will include individual 
participant values and the geometric means for each treatment. These plots will be used to 
help understand the relationship between the PK parameters and dose.
Plasma concentrations of PF-07081532 will be listed and descriptively summarized by
treatment, day and nominal PK sampling time. Individual participant and median profiles of 
the plasma concentration-time data will be plotted by treatment and day using actual and 
nominal times, respectively. Median profiles will be presented on both linear-linear and log-
linear scales. Each cohort will be considered as a separate treatment.
Table 5
Definition of Plasma PK Parameters for PF-07081532
Parameter
Day 1 (D1) or 
Day 42 (D42)
Definition
Method of Determination
Cmax
D1 and D42
Maximum plasma concentration 
observed from time zero to 
24 hours
Observed directly from data
Tmax
D1 and D42
Time for Cmax
Observed directly from data as time of 
first occurrence
AUC24
D1 and D42
Area under the plasma 
concentration-time profile from 
time zero to time 24 hours
Linear/Log trapezoidal method
t½a
D42
Terminal half-life
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a 
linear regression of the log-linear 
concentration-time curve. Only those 
data points judged to describe the 
terminal log-linear decline will be 
used in the regression.
Cmax(dn)
D1 and D42
Dose normalized Cmax
Cmax/Dose
AUC24(dn)
D1 and D42
Dose normalized AUC24
AUC24/Dose
Cmin
D42
Minimum plasma concentration 
during the dosing interval
Observed directly from data
Cav
D42
Average concentration over 24 
hours
AUC24/24
CL/Fa
D42
Apparent clearance
Dose/AUC24
Vz/Fa
D42
Apparent volume of distribution
Dose/(AUC24 * kel)


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Table 5
Definition of Plasma PK Parameters for PF-07081532
Parameter
Day 1 (D1) or 
Day 42 (D42)
Definition
Method of Determination
PTR
D42
Peak-to-trough ratio
Cmax/Cmin
Rac
D42
Observed accumulation ratio for 
AUC24
Steady State AUC24(dn)/Day 1 
AUC24(dn)
Rac,Cmax
D42
Observed accumulation ratio for 
Cmax
Steady State Cmax(dn)/Day 1 Cmax(dn)
AUClast
D42
Area under the plasma 
concentration-time profile from 
time zero to time of last 
quantifiable concentration
Linear/Log trapezoidal method
AUCinfa
D42
Area under the plasma 
concentration-time profile from 
time zero extrapolated to 
infinite time
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point estimated from the log-
linear regression analysis and kel is the 
terminal phase rate constant 
calculated by a linear regression of the 
log-linear concentration-time curve. 
Only those data points judged to 
describe the terminal log-linear 
decline will be used in the regression.
a.
If data permit
This table includes all PK parameters; AUC24, Cmax, Tmax, t½ are secondary endpoints, all others are 
exploratory.
9.3.4. Other Analyse(s)
The MDG will be computed by AUC24/24 hour. 
The AUC(0-4) for glucose, insulin, glucagon and C-peptide will also be calculated. 
HOMA-IR will be mathematically calculated using FPG and FPI values. 
All exploratory PD endpoints related to glucose, insulin, C-peptide, glucagon, HbA1c, and 
HOMA-IR will be summarized descriptively by treatment, time point and day. Additional 
analyses or summaries of these endpoints will be detailed in the SAP. Analysis of 
exploratory endpoints may not be included in the CSR. 
For body weight, absolute values, CFB, and percent CFB will be summarized descriptively 
by treatment and day where the set of summary statistics will include n, mean, median, SD, 
minimum, and the maximum.
 
 
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Analysis of 4-β-hydroxycholesterol/cholesterol levels in plasma samples, if performed, will 
not be reported in the CSR.
9.4. Interim Analyses
No formal interim analysis will be conducted for this study. As this is a sponsor-open
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating dose selection decisions, facilitating PK/PD 
modeling, and/or supporting clinical development.
9.5. Sample Size Determination
A sufficient number of participants will be screened to achieve an estimated total of 
approximately 12 evaluable participants per cohort (9 PF-07081532:3 placebo). 
The number of participants was selected empirically to provide a sufficient number of 
participants to assess and characterize the safety and tolerability of various doses and dosing  
schemes of PF-07081352.


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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, 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.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation 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 GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (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. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant or his/her legally authorized representative and answer 
all questions regarding the study. The participant or his/her legally authorized representative 
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 or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant or his or her legally authorized representative 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 or his or her 
legally authorized representative.
The participant or his or her legally authorized representative must be informed that his/her 
medical records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants or his or her legally authorized representative must be reconsented to the most 
current version of the ICD(s) during their participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.


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Participants who are rescreened are required to sign a new ICD.
10.1.3. 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 ID. 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.
10.1.3.1. Data Monitoring Committee 
This study will not use a DMC.
10.1.4. 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 
which the study was conducted.
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.


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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 data from these trials available 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.5. 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.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.


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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, including definition of study critical data items and 
processes (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, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory retain 
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.
10.1.6. 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.


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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.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes source data and its origin can be found in the investigator site 
file, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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 guidelines, and all applicable regulatory requirements.
10.1.7. 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 the ICH GCP 
guidelines;


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
Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. 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.
10.1.9. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study team on demand (SToD).
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 
the time of informed consent. The ECC contains, at a minimum, (a) protocol and study 
intervention identifiers, (b) participant’s study identification number, (c) site emergency 
phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number.


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The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. 
Unscheduled clinical laboratory measurements and/or reflex testing may be obtained at any 
time during the study at the discretion of the investigator to assess any perceived safety 
issues.
Table 6.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry/Other
Urinalysis
At specified times 
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/Urea 
Serum Creatininea
Plasma Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST
ALT
Total bilirubin
Direct bilirubin
Indirect bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total Bile Acids
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyb
At screening only:

FSHc

HBsAg

HCVAb

HBcAb

HBsAb

HIV

C-peptided
At times specified in the SoA:

Urine drug screeninge

Free T4

TSH

Calcitonin

Amylase

Lipase

Lipid profile (ie, total 
cholesterol, triglycerides, 
direct HDL, direct LDL)
a.
GFR will be calculated using the MDRD equation: GFR (ml/min/1.73m2) = 175 × standardized Serum Creatinine-
1.154 × age-0.203 × 1.212 [if Black] × 0.742 [if female].
b.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
c.
For confirmation of postmenopausal status in female participants only.
d.
C-peptide is collected as part of safety laboratory tests at Screening (collected as part of MMTT at other times 
indicated in Table 1and Table 2).
e.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, and 
amphetamines (others are site and study specific).
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.
Safety/laboratory/analyte results obtained following first dose of the study intervention (Day 
1) that could unblind the study (ie, glucose, insulin, glucagon, C-peptide, HbA1c, and PK), 


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will not be reported to investigative sites or other blinded personnel until the study has been 
unblinded.


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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 condition 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 or 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 that 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 an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
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 admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.


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d. Results in persistent or significant 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), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a 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 participant 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.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant
medical events that 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.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious 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 


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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, 
All AEs or SAEs 
associated with exposure 
during pregnancy or 
breastfeeding
Note:  Instances of EDP or 
EDB not associated with an 
AE or SAE are not 
captured in the CRF.
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE). **
Environmental or 
occupational exposure to 
the product under study to 
a non-participant (not 
involving EDP or EDB).
None. Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report 
Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or Occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form. 

When an AE or 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 or 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 or SAE CRF page.


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
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 or SAE.
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: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.

Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 

Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self 
care ADL. Self care ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden. 

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 or SAE. The investigator will use clinical 
judgment to determine the relationship.

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.

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.


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
The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
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 submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.


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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
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 and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention.

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.
In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly effective 
methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding and is not 
a WOCBP (see definitions below in Section 10.4.3).
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.


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For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion (eg, bilateral tubal ligation).
5. Vasectomized partner.

A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.


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Highly Effective Methods That Are User Dependent 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;
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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CCI


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” 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).
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. 


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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 Hy’s law
cases, 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, or 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, 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, 21 October 2021
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free 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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10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI
The prohibited concomitant medications listed below should not be taken with PF-07081532
for the period of time at least equal to the required washout period listed in the table, and 
throughout the conduct of the study. 
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgement on the ongoing 
participation of any participant with prohibited medication use during the study.
This list of drugs prohibited for potential DDI concerns with the IMP may be revised during 
the course of the study with written notification from sponsor, to include or exclude specific 
drugs or drug categories for various reasons (eg, emerging DDI results for the IMP, 
availability of new information in literature on the DDI potential of other drugs). 
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.
Drug Category 
Drugs (Therapeutic Class)
Washout Period 
Requirement Prior to the 
First Dose of Study 
Intervention
CYP3A 
Inhibitor 
(strong)
Boceprevir (Antiviral),
Ceritinib (Kinase Inhibitor),
Clarithromycin (Antibiotic),
Cobicistat (Pharmacokinetic Enhancer),
Conivaptan (Diuretic),
Danoprevir and Ritonavir (Antiviral),
Elvitegravir and Ritonavir (Treatment of 
AIDS),
Grapefruit juice (Food Product),
Idelalisib (Kinase Inhibitor),
Indinavir (Protease Inhibitor),
Indinavir and Ritonavir (Protease Inhibitor),
Itraconazole (Antifungal),
Ketoconazole (Antifungal),
LCL161 (Cancer Treatment),
Lopinavir and Ritonavir (Protease Inhibitor),
Mibefradil (Calcium Channel Blocker),
Mifepristone (Antiprogestin),
Nefazodone (Antidepressant),
Nelfinavir (Protease Inhibitor),
Posaconazole (Antifungal),
Ribociclib (Kinase Inhibitor),
Ritonavir (Protease Inhibitor),
Saquinavir (Protease Inhibitor),
Saquinavir and Ritonavir (Protease Inhibitor),
Telaprevir (Antiviral),
Telithromycin (Antibiotic),
5 half-lives plus 14 days


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Final Protocol, 21 October 2021
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Page 94
Drug Category 
Drugs (Therapeutic Class)
Washout Period 
Requirement Prior to the 
First Dose of Study 
Intervention
Tipranavir and Ritonavir (Protease Inhibitor),
Troleandomycin (Antibiotic),
Tucatinib (Kinase Inhibitor),
Viekira Pak (Antiviral),
Voriconazole (Antifungal)
CYP3A 
Inducer 
(strong)
Apalutamide (Antiandrogen),
Avasimibe (Antilipemic),
Carbamazepine (Anticonvulsant),
Enzalutamide (Antiandrogen),
Ivosidenib (Cancer Treatment),
Lumacaftor (Cystic Fibrosis Treatment),
Mitotane (Antineoplastic),
Phenobarbital (Anticonvulsant),
Phenytoin (Anticonvulsant),
Rifampin (Antibiotic),
Rifapentine (Antibiotic),
St. John’s wort extract (Herbal Medication)
5 half-lives plus 14 days
OATP 
(1B1/1B3) 
Inhibitor
Atazanavir and Ritonavir (Protease Inhibitor),
Clarithromycin (Antibiotic),
Cyclosporine (Immunosuppressant),
Erythromycin (Antibiotic),
Gemfibrozil (Fibric Acid Derivative),
Lopinavir and Ritonavir (Protease Inhibitor),
Rifampin (Antibiotic),
Simeprevir (Antiviral)
2 weeks or 5 half-lives,
whichever is longer
CYP2C19 
Substrate
BMS-823778 (Diabetes Treatment),
Clobazam (Benzodiazepine),
Clopidogrel (Antiplatelet),
Diazepam (Benzodiazepine),
Gliclazide (Sulfonylurea),
Hexobarbital (Hypnotic – Sedative),
Lansoprazole (Proton Pump Inhibitor),
Mephobarbital (Anticonvulsant),
Omeprazole (Proton Pump Inhibitor),
Pantoprazole (Proton Pump Inhibitor),
Proguanil (Antimalarial),
Rabeprazole (Proton Pump Inhibitor),
S-mephenytoin (Anticonvulsant),
Tilidine (Treatment of Pain & Inflammation),
Voriconazole (Antifungal)
2 weeks or 5 half-lives,
whichever is longer
Investigators should consult the SRSD for active comparator for information regarding 
medication that is prohibited for concomitant use.
Investigators should consult the product label for any other medication used during the study 
for information regarding medication that is prohibited for concomitant use. 


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10.9. Appendix 9: Prohibited Medications Not Permitted From Screening
Drug class/Name
Duration Not Permitted 
from Screening
TZDs: eg, pioglitazone; rosiglitazone
Within 3 Months of 
Screening
Subcutaneously administered agents for glycemic control: eg, insulin,
exenatide, liraglutide, pramlintide
Other oral anti-diabetic medications:

Sulfonylureas: eg, acetohexamide, chlorpropamide, 
tolazamide, tolbutamine;

Glimepiride, glipizide, glyburide;

Meglitinide analogues, eg, repaglinide, nateglinide;

DPP-4i eg, sitagliptin, saxagliptin;

Vildagliptin;

α-glucosidase inhibitors, eg, acarabose, miglitol;

SGLT2 inhibitors, eg, canagliflozin.
Within 4 Weeks of 
Screening
Systemic glucocorticoids, eg, prednisone, dexamethasone, 
triamcinolone, budesonide, betamethasone. Note: As an exception, 
steroid-containing inhalers, nasal sprays, and topical formulations are 
permitted.
Immunosuppressants, eg, cyclosporine and tacrolimus.
Appetite- or weight-modifying medications, including non-
prescription or herbals.
Pharmacological agents with approved indication for weight loss, eg, 
orlistat and sibutramine.
(Medical-grade) marijuana, regardless of medical indication.
Anti-psychotic medications, eg olanzapine, risperidone.
Antidepressant medications, eg tricyclic agents, selective serotonin 
reuptake inhibitors, and serotonin/norepinephrine reuptake inhibitors.
Coumarin-type anticoagulants or other anticoagulants (eg, 
dabigatran).
Anticonvulsants, if prescribed for a seizure disorder.
Opioids.
Antiarrhythmics.
Non-selective β-blockers.
Thiazide diuretics >25 mg per day.
Sympathomimetic agents.


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Final Protocol, 21 October 2021
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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
%CV
percent coefficient of variation
Abs
absolute
ADL
activities of daily living
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time profile from time 0 to the time of 
the last quantifiable concentration
AUC(0-4)
area under the curve from 0 to 4 hours 
AUC24
area under the concentration-time curve over 24 hours
AUCinf
area under the concentration-time curve to infinity
AV
atrioventricular
BBS
Biospecimen Banking System
BCRP
Breast Cancer Resistance Protein
BMI
body mass index
BP
blood pressure
Bpm
beats per minute
BUN
blood urea nitrogen
cAMP
3’-5’-cyclic adenosine monophosphate
CFB
change from baseline
CFR
Code of Federal Regulations
CI
confidence interval 
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL
clearance
CL/F
apparent clearance
CLp
plasma clearance
Cav
average concentration
Cmin
minimum observed concentration
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial


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Abbreviation
Term
CV
co-efficient of variation
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DPP-4i
dipeptidyl peptidase-4 inhibitors 
DU
dispensable unit
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FPG
fasting plasma glucose
FPI
fasting plasma insulin
FSBG
fingerstick blood glucose
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GLP-1
glucagon-like peptide-1 
GLP-1R
glucagon-like peptide-1 receptor
H
hour
HbA1c
Glycated hemoglobin
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HOMA-IR
homeostatic model assessment of insulin resistance
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document


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Abbreviation
Term
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ID
identification
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product 
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous(ly)
IVGTT
intravenous glucose tolerance test
K2EDTA
dipotassium ethylenediaminetetraacetic acid
kel
terminal phase rate constant
kg
kilogram
Ki
mean binding inhibition constant
LBBB
left bundle branch block
LDL
low density lipoprotein
LFT
liver function test
Loge
natural logarithm with the base e
MATE
multi-drug and toxin extrusion protein 
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDG
mean daily glucose
MEN2
multiple endocrine neoplasia syndrome type 2
mg/dL
milligram(s) per deciliter
µmol/L
micromole per liter
MDRD
modification of diet in renal disease 
min
minute; minimum
MMTT
mixed meal tolerance test
msec
millisecond
MTC
medullary thyroid cancer
MTD
maximum tolerated dose
MDR1
multidrug resistance protein 1
N/A
Not applicable
N
total number
NC
not calculated
NHP
non-human primate 
nM
nanomolar
NOAEL
no observed adverse effect level
NSAID
non-steroidal anti-inflammatory drug
OAT 
organic anion transporter 
OATP
organic anion transporting polypeptide


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Abbreviation
Term
OCT
organic cation transporter
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
PI
Principal Investigator
PK
pharmacokinetic(s)
PT
prothrombin time
PTR
peak-to-trough ratio 
PVC
premature ventricular contraction
QD
once daily
QT
duration of ventricular depolarization and subsequent repolarization. 
Duration resides between beginning of QRS complex to end of the 
T wave
QTc
corrected QT
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
Rac
accumulation ratio based on AUC (observed)
Rac,Cmax
Cmax accumulation ratio 
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCr
serum creatinine
SD
standard deviation
SGLT2
sodium-glucose cotransporter-2
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SS
steady state
SSID
single subject identifier
SToD
Study Team on Demand
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal phase half life
T2DM
type 2 diabetes mellitus
T4
free thyroxine
TBD
to be determined
TBA
total bile acids
TBili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
Tmax
time to reach Cmax
TSH
thyroid stimulating hormone
TZD
thiazolidinedione
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal


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Abbreviation
Term
US
United States
Vss
steady-state volumes of distribution 
Vz/F
apparent volume of distribution for extravascular dosing
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of non-childbearing potential


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11. REFERENCES
1.
Orskov 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.
IDF Diabetes Atlas 8th Edition. Available from:.http://www.idf.org/diabetesatlas.
Accessed: 20 September 2021.
6.
Menke A, Casagrande S, Geiss L, et al. Prevalence of and trends in diabetes among 
adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-9.
7.
Hu FB. Globalization of diabetes: the role of diet, lifestyle and genes. Diabetes Care.
2011;34(6):1249-57.
8.
DeFronzo RA. From the triumvirate to the omnious octet: a new paradigm for the 
treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-95.
9.
Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular 
and microvascular complications of type 2 diabetes (UKPDS 35): prospective 
observational study. BMJ. 2000;321(7258):405-12.
10.
Drucker, DL. The ascending GLP-1 road from clinical safety to reduction of 
cardiovascular complications. Diabetes. 2018;67:1710-9.
11.
Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon-like peptide-1 
receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16(1):6.
12.
Victoza (liraglutide) US prescribing information. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022341s031lbl.pdf.
Accessed: 17 September 2021.
13.
American Diabetes Association. Pharmacologic approaches to glycemic treatment: 
standards of medical care in diabetes—2019 American Diabetes Association. Diabetes 
Care. 2019; 42 (Suppl.1):S90-S102.
14.
Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes 
Care. 2004;27(6)(Jun):1487-95.

SAP_001.pdf: 
Protocol C3991003 (PF-07081532) 
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1 of 29
Protocol C3991003
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY, TOLERABILITY,
AND PHARMACOKINETICS OF MULTIPLE ORAL DOSES OF PF-07081532 IN 
ADULT PARTICIPANTS WITH TYPE 2 DIABETES MELLITUS
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
29 Jul 2022
NOTE: Italicized text within this document has been taken verbatim from the Protocol
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Statistical Analysis Plan
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Modifications to the Analysis Plan Described in the Protocol..................................6
2.2. Study Objectives, Endpoints, and Estimands............................................................6
2.2.1. Primary Estimand(s).....................................................................................7
2.2.2. Secondary Estimand(s).................................................................................7
2.2.3. Additional Estimand(s).................................................................................7
2.3. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint(s) ..................................................................................................9
3.1.1. Adverse Events.............................................................................................9
3.1.1.1. Hypoglycemia Monitoring and Reporting ..................................9
3.1.2. Safety Laboratory Tests..............................................................................10
3.1.3. Vital Signs ..................................................................................................10
3.1.4. Electrocardiograms.....................................................................................10
3.2. Secondary Endpoint(s) ............................................................................................11
3.3. Other Endpoint(s)....................................................................................................12
3.3.1. Change from Baseline in Insulin, Glucagon and C-Peptide AUC0-4..........12
3.3.2. Change from Baseline in Fasting Plasma Glucose, Fasting Plasma 
Insulin and HOMA-IR .....................................................................................12
3.3.3. Change from Baseline in HbA1c................................................................13
3.3.4. Change from Baseline in TSH....................................................................13
3.3.5. Change from Baseline in FreeT4, Calcitonin, Amylase, Lipase, and 
Lipids ...............................................................................................................13
3.3.6. Change from Baseline in Body Weight......................................................13
3.3.7. Baseline Variables ......................................................................................13
3.4. Other Safety Endpoints ...........................................................................................13
3.4.1.1. Adverse events of interest .........................................................13
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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................14
5.1. Hypotheses and Decision Rules ..............................................................................14
5.2. General Methods .....................................................................................................14
5.2.1. Analyses for Continuous Endpoints ...........................................................14
5.2.2. Analyses for Categorical Endpoints ...........................................................14
5.2.3. Longitudinal Analysis using Mixed Model Repeated Measures 
(MMRM) model...............................................................................................14
5.2.4. Analysis of Covariance (Raw Scale)..........................................................15
5.2.5. Analysis of Covariance (Log Scale)...........................................................15
5.2.6. Cumulative Incidence Plots........................................................................16
5.3. Methods to Manage Missing Data ..........................................................................16
5.3.1. Pharmacokinetic Concentrations Below the Limit of Quantification.........16
5.3.2. Deviations, Missing Concentrations and Anomalous Values.....................16
5.3.3. Pharmacokinetic Parameters.......................................................................16
5.3.4. 4-β-hydroxycholesterol/cholesterol ratio....................................................17
5.3.5. Pharmacodynamic Parameters....................................................................17
6. ANALYSES AND SUMMARIES ......................................................................................17
6.1. Baseline Variables...................................................................................................17
6.2. Primary Endpoint ....................................................................................................17
6.2.1. Safety Analysis ...........................................................................................17
6.2.1.1. Demographic and Physical Examination Data..........................18
6.2.1.2. Discontinuation(s) .....................................................................18
6.2.1.3. Adverse Events..........................................................................18
6.2.1.4. Hypoglycemia ...........................................................................19
6.2.1.5. Laboratory Data.........................................................................19
6.2.1.6. Vital Signs Data ........................................................................19
6.2.1.7. Electrocardiograms Data...........................................................20
6.3. Secondary Endpoint(s) ............................................................................................21
6.3.1. PF-07081532 PK Parameters......................................................................21
6.4. Other Endpoint(s)....................................................................................................23
6.4.1. Change from Baseline in Insulin, Glucagon and C-Peptide AUC0-4..........23
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6.4.2. Change from Baseline in Fasting Plasma Glucose, Fasting Plasma 
Insulin and HOMA-IR .....................................................................................23
6.4.3. Change from Baseline in HbA1c................................................................24
6.4.4. 4-β-hydroxycholesterol/Cholesterol Ratio..................................................24
6.5. Subset Analyses.......................................................................................................24
6.6. Baseline and Other Summaries and Analyses.........................................................24
6.6.1. Baseline Summaries....................................................................................24
6.6.2. Study Conduct and Participant Disposition................................................25
6.6.4. Concomitant Medications and Nondrug Treatments..................................25
6.6.5. Discontinuations .........................................................................................25
6.7. Safety Summaries and Analyses .............................................................................25
7. INTERIM ANALYSES.......................................................................................................25
7.1. Introduction .............................................................................................................25
7.2. Interim Analyses and Summaries............................................................................25
8. REFERENCES ....................................................................................................................25
APPENDICES .........................................................................................................................26
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
PF-07081532 PK Parameters....................................................................12
Table 3.
PF-07081532 PK Parameters to be Summarized Descriptively...............21
LIST OF FIGURES
Figure 1.
Dose Titration Scheme ...............................................................................8
APPENDICES
Appendix 1. Statistical Methodology Details..........................................................................26
Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....27
Appendix 3. List of Abbreviations...........................................................................................28
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
14th Jan 2022 N/A
•
Original protocol 
N/A
2
28th Jul 2022
N/A
•
Based on data review
before database release, 
SQE (#PR2205605) was 
opened regarding 
confirmed aberrant 
glucose values reported 
by the site. SAP 
amendment is supported 
by DMB02 SOP and 
QMS-01 SOP
•
Repeated wording
for summarization of 
change from baseline on 
safety laboratories
•
Listings of laboratory 
parameter of interest 
should only be listed/ 
Alignment with 
C3991002 outputs using 
Pfizer standards for 
reporting
•
Physical examination 
data is not collected in 
this study
Impacted sections of SAP V1:
Section 3.3.1: reference to 
glucose AUC0-4 removed
Section 3.3.4 - Change from 
baseline in MDG - removed
Section 5.3.5: reference to 
glucose AUC0-4 and AUC24
removed
Section 6.3.1: reference to 
glucose AUC0-4 removed
Section 6.3.4: entire section 
removed
Section 3.4.1.2 removed
Section 6.7.1: Focused 
Laboratory Summaries on 
Endpoints of Interest 
removed
Section 6.7.2: Entire section
removed
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2. INTRODUCTION
This statistical analysis plan amendment (SAP) provides the detailed methodology for 
summary and statistical analyses of the data collected in Study C3991003 issued on 
September, 21st 2021.  
2.1. Modifications to the Analysis Plan Described in the Protocol
The following endpoints
•
The MDG will be computed by AUC24/24 hour. 
•
The AUC(0-4) for glucose will also be calculated. 
as described in Section 9.3.4 of the protocol has been removed due to aberrant glucose values 
(see Version History).
2.2. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Primary: 
Primary:
•
To evaluate the safety and tolerability of multiple 
doses of PF-07081532, administered orally, in adult 
participants with inadequately controlled T2DM on 
metformin and if enrolled, in non-diabetic participants 
with obesity.
• Assessment of AEs, safety laboratory 
tests, vital signs and 12-lead ECGs.
Secondary: 
Secondary:
•
To characterize plasma PK of PF-07081532 
following multiple doses administered orally, in adult 
participants with inadequately controlled T2DM on 
metformin and if enrolled, in non-diabetic 
participants with obesity.
• PF-07081532 plasma PK 
parameters AUC24, Cmax, Tmax on 
Day 1 and Day 42 and t½ on Day 42, 
as data permit.
Tertiary/Exploratory: 
Tertiary/Exploratory:
•
To characterize the PD effect on glucose, insulin, 
glucagon, and C-peptide excursions after a MMTT
following multiple doses of PF-07081532, 
administered orally, in adult participants with 
inadequately controlled T2DM on metformin.
• CFB in response to MMTT at all 
postdose timepoints as specified in 
the SoA for AUC(0-4) for glucose, 
insulin, glucagon, and C-peptide.
•
To explore the PD effect on MDG*, HbA1c*, plasma 
glucose, plasma insulin, and HOMA-IR following 
multiple doses of PF-07081532, administered orally, 
in adult participants with T2DM inadequately 
controlled on metformin and, if enrolled, in non-
diabetic participants with obesity.
•
CFB at all post-dose timepoints as 
specified in the SoA for: 
o
Fasting plasma glucose;
o
Fasting plasma insulin;
o
HOMA-IR;
o
HbA1c*;
o
MDG*.
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Objectives
Endpoints
•
To assess the PD effect on body weight changes 
following multiple doses of PF-07081532, 
administered orally, in adult participants with T2DM 
inadequately controlled on metformin and if enrolled, 
in non-diabetic participants with obesity.
• CFB in body weight at all post-dose 
timepoints as specified in the SoA.
•
To further characterize plasma PK of PF-07081532 
following multiple doses administered orally, in adult 
participants with inadequately controlled T2DM on 
metformin and if enrolled, in non-diabetic 
participants with obesity.
• Additional PF-07081532 plasma PK 
parameters following multiple dose 
administration including, as data 
permit: AUC24(dn), AUCinf, AUClast,  
Cav, CL/F, Cmax(dn), Cmin, Rac, 
Rac,Cmax, PTR, Vz/F
* not analyzed in non-diabetic population with obesity, if enrolled
2.2.1. Primary Estimand(s)
Not applicable because C3991003 is a Phase 1 study with no estimands on safety endpoints
2.2.2. Secondary Estimand(s)
Not applicable because C3991003 is a Phase 1 study with no estimands on PK parameters
2.2.3. Additional Estimand(s)
Not applicable because C3991003 is a Phase 1 study with no estimands on exploratory or 
tertiary endpoints
2.3. Study Design
The purpose of this study is to evaluate the safety, tolerability, and PK of multiple doses of  
PF-07081532 in participants with T2DM, inadequately controlled on metformin. The study 
may also enroll non-diabetic participants with obesity. 
The study will also assess the effect on PD biomarkers, including MDG.
This is a randomized, double-blind (investigator- and participant- blind), sponsor-open, 
placebo-controlled, multiple oral dose-escalating study of PF-07081532. 
In this study, adult participants with T2DM inadequately controlled on metformin will be 
enrolled and will receive PF-07081532 or placebo daily, for 42 days. 
•
Enrollment in 3 cohorts is planned with approximately 12 participants (9 
PF-07081532: 3 placebo) per cohort. 
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A sample dosing scheme is provided below. Dosing in Cohort 1 will be conducted as shown. 
Increments in doses and duration of dosing at each step for subsequent cohorts, as well as 
the number of cohorts conducted, may be adjusted based on emerging data. The dosing 
scheme for each cohort will be provided in writing prior to its initiation. 
Figure 1.
Dose Titration Scheme
If a participant does not tolerate dose increment to the next dose level, as determined by the 
investigator and with notification to the sponsor, the participant may be reverted to the 
previously tolerated dose level. Following this dose modification, 2 separate attempts at 
increasing the dose to the next dose level are permitted, per investigator discretion. If, per
investigator assessment, unacceptable intolerance (eg, severe vomiting) occurs shortly 
following dose administration, the dose will not be re-administered on the same day, and the 
participant may resume dosing at the current dose level at the next scheduled dosing time. 
Participants whose dose level is tolerability-limited may continue in the study for the 
intended duration of their assigned cohort at their own individual MTD, as judged to be 
appropriate by the PI and sponsor.
The planned cohorts in the study (Cohorts 1-3) may be conducted concurrently, partially 
overlapping or sequentially. The sponsor may decide not to conduct all planned cohorts, if it 
is judged that study objectives have been met. Up to 3 additional cohorts may be enrolled if 
judged necessary to meet the study objectives. One or more of the study cohorts may be 
conducted in non-diabetic participants with obesity.  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
Baseline is defined as the assessments performed on Day -1 for all endpoints,  unless 
otherwise specified.
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3.1. Primary Endpoint(s)
The safety endpoints which will be measured during the study constitute the primary 
endpoints.  Where applicable, details of the endpoints to be derived and definition of baseline 
are also provided.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
Adverse events;
•
Laboratory data;
•
Vital signs data;
•
ECG results.
3.1.1. Adverse Events
An adverse event is considered treatment emergent (TEAE) relative to a given treatment if:
•
the event starts during the effective duration of treatment (i.e. starting after or on the first 
dose but before the last dose plus lag time)
The effective duration of treatment is determined by the lag time. Any event occurring within 
the lag time, whether this occurs during a break in treatment or at the end of treatment, is 
attributed to the corresponding treatment period. The lag time is defined by the Pfizer 
Standard of 365 days post last dose of IP.
Adverse events occurring up to the first dose of active treatment on Day 1 will be considered 
non-treatment emergent.
A 3-tier approach for summarizing AEs will not be used for this study as there is a low number of 
subjects planned to be enrolled per treatment group, although risk differences and related 
summaries for AEs of interest will be presented as defined in 3.4.1.1.
3.1.1.1. Hypoglycemia Monitoring and Reporting
Hypoglycemia AEs will be recorded in the AE Case Report Form (CRF) with details of the 
event captured on the Hypoglycemic Event Details CRF. Details of when these will be 
recorded are given in the protocol (Section 8.2.4.2).
For programming purposes, the hypoglycemic AE categories are based on the following:
•
Severe Hypoglycemia: Severe is checked in the severity criteria of the CRF. This 
assessment will be made by the PI based on the protocol definition.
•
Documented Symptomatic Hypoglycemia: If (2 – Did the participant have symptoms 
of hypoglycemia?) Yes and (3 – Was the blood glucose measured?) Yes and result 
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<70 mg/dL (or <3.9 mmol/L) on the CRF, but hypoglycemia is not classified as 
severe.
•
Asymptomatic Hypoglycemia: If (2) No and (3) Yes and result <70 mg/dL (or <3.9 
mmol/L) on the CRF, but hypoglycemia is not classified as severe.
•
Probable Symptomatic Hypoglycemia: If (2) Yes and (3) No and (3a – If blood 
glucose was not measured, did symptoms resolve when treated with carbohydrate or 
glucagon?) Yes on the CRF, but hypoglycemia is not classified as severe.
3.1.2. Safety Laboratory Tests
Safety laboratory tests (hematology, chemistry, urine testing and other clinical laboratory 
tests) will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the safety tests 
will be assessed against the criteria specified in the sponsor reporting standards. The 
assessment will take into account whether each participant’s baseline test result is within or 
outside the laboratory reference range for the particular laboratory parameter.
Baseline for all laboratory measurements will be defined as the result assessed on Day -1.
3.1.3. Vital Signs
Vital sign measurements (systolic blood pressure, diastolic 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 collected at each appropriate assessment time will be calculated 
for each vital sign parameter. 
Baseline will be defined as the result assessed on Day -1 per SoA, where “result” refers to the 
average of a triplicate measurement.
Changes from baseline for supine systolic and diastolic blood pressure and pulse rate will be 
calculated for each post baseline measurement.
The time-matched double difference in supine blood pressures and pulse rate measurements 
is calculated in the following steps: (1) subtract the average of the triplicate predose values 
on Day 1 from all postdose values; (2) subtract the value at 0 hours on Day -1 from all other 
values on Day -1; (3) take the difference between the adjusted postdose value in (1) and its 
time-matched value in (2).
3.1.4. Electrocardiograms
Standard 12-lead ECG (including heart rate, QT, QTcF, PR and QRS interval) 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.
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ECG endpoints include heart rate, QT interval, PR interval and QRS interval. If not supplied 
QTcF will be derived using Fridericia’s heart rate correction formula: 
QTcF = QT / (RR)^(1/3), where RR = 60/HR (if RR is not provided).  
Baseline will be defined as the result assessed on Day -1 per SoA, where “result” refers to the 
average of a triplicate measurement.
Change from baseline for heart rate, QT, QTcF, PR and QRS interval will be calculated for 
each post baseline measurement.
The time-matched double difference in heart rate, QT, QTcF, PR and QRS measures is 
calculated in the following steps: (1) subtract the average of the triplicate predose values 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)
3.2. Secondary Endpoint(s)
Blood samples for PK analysis of PF-07081532 will be taken according to the Schedule of 
Activities given in the protocol. 
Plasma PF-07081532 PK parameters following single or multiple dose administration of PF-
07081532 will be derived using standard noncompartmental methods, as data permit, for 
each treatment and day (as appropriate), from the concentration time profiles as follows:
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Table 2.
PF-07081532 PK Parameters
Parameter
Analysis Scale
PF-07081532
Assessment Day
AUC24
Ln
D
D1 and D42
AUC24(dn)
Ln
D
D1 and D42
Cmax
Ln
D
D1 and D42
Cmax(dn)
Ln
D
D1 and D42
Tmax
R
D
D1 and D42
t1/2*
R
D
D42
PTR
Ln
D
D42
Rac
Ln
D
D42
Cav
Ln
D
D42
Cmin
Ln
D
D42
Rac,Cmax
Ln
D
D42
CL/F*
Ln
D
D42
VZ/F*
Ln
D
D42
AUCinf*
Ln
D
D42
AUClast
Ln
D
D42
Key: D=displayed with descriptive statistics, Ln=natural-log transformed, R=raw (untransformed), *=if data 
permits.
3.3. Other Endpoint(s)
3.3.1. Change from Baseline in Insulin, Glucagon and C-Peptide AUC0-4
Baseline for Insulin, Glucagon and C-Peptide AUC0-4 following MMTT will be defined as 
the AUC0-4 assessed on Day -1.  
Change from baseline, percent change from baseline and relative change from baseline at the 
end of the study (ie Day 42 for Insulin, Glucagon and C-Peptide AUC0-4) as specified in the 
schedule of activities will be calculated.
Note: Relative Change from Baseline = Post-dose timepoint Value / Baseline Value
3.3.2. Change from Baseline in Fasting Plasma Glucose, Fasting Plasma Insulin and 
HOMA-IR
The change from baseline to all post-dose timepoints as specified in the schedule of activities 
will be calculated.
Remark: Where triplicate fasting plasma insulin (FPI) are assessed, the average of the three 
measurements will be calculated to be reported at each timepoint and used to derive 
HOMA-IR. When three assessements are performed at baseline, FPI baseline will be the 
average of the three values.
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3.3.3. Change from Baseline in HbA1c
Baseline for HbA1c will be defined as the Day -1. The change from baseline to all post-dose 
timepoints as specified in the schedule of activities will be calculated.
3.3.4. Change from Baseline in TSH 
Baseline for TSH will be defined as the Day -1, 0H time point. The change from baseline to 
all post-dose timepoints as specified in the schedule of activities will be calculated.
3.3.5. Change from Baseline in FreeT4, Calcitonin, Amylase, Lipase, and Lipids
Baseline for freeT4, calcitonin, amylase, lipase, and lipids will be defined as the Day -1, 0H 
time point. The change from baseline to all post-dose timepoints as specified in the schedule 
of activities will be calculated.
3.3.6. Change from Baseline in Body Weight
Baseline for body weight will be defined as the pre-dose measure on Day 1. The change from 
baseline and percent change from baseline to all post-dose timepoints as specified in the 
schedule of activities will be calculated.
3.3.7. Baseline Variables
Baseline measures will be included as a covariate in all applicable statistical.
3.4. Other Safety Endpoints
3.4.1.1. Adverse events of interest
The TEAEs of interest for additional reporting are: nausea, vomiting and diarrhoea (as 
defined based on preferred term). Based on emerging blinded data reviews, other AEs of 
interest may be added to this list, which would be documented with a SAP amendment or 
documented in the changes to planned analysis section in the CSR.  
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
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 and 
screening. 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. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening.
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Participant Analysis Set
Description
Full Analysis Set 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.
Safety Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the product they actually received.
PK Concentration Set
The PK concentration population is defined as all randomized 
participants who received at least 1 dose of PF-07081532 and 
in whom at least 1 plasma concentration value is reported.
PK Parameter Set
The PK parameter population is defined as all randomized 
participants that received at least 1 dose of PF-07081532 and 
have at least 1 of the PK parameters of interest calculated.
PD population Set
The PD population set is defined as all randomized participants 
that received at least 1 dose of PF-07081532 and have at least 
1 of the PD parameters of interest calculated.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
Not applicable
5.2. General Methods
5.2.1. Analyses for Continuous Endpoints
Continuous endpoints and relevant safety endpoints will be presented using summary 
statistics: number of observations, arithmetic mean, standard deviation, median, minimum 
and maximum values.
5.2.2. Analyses for Categorical Endpoints
Categorical endpoints and relevant safety endpoints will be presented using summary statistics: 
number of observations, counts and percentages.
5.2.3. Longitudinal Analysis using Mixed Model Repeated Measures (MMRM) model
MMRM models will include the change from baseline of the relevant endpoints as specified 
in  Section 6  as the dependent variable and will include treatment, baseline, day, 
baseline*day interaction and the day*treatment interaction, with day fitted as a repeated 
effect, and participant as a random effect.
An unstructured covariance matrix will be used to estimate the variances and covariance 
within participant across time points.  If convergence is not obtained or model fit is not 
adequate then other covariance structures (eg CS)  will be investigated as necessary.  The 
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Kenward-Roger approximation will be used for estimating degrees of freedom for the model 
parameters.  Missing values will be imputed as part of the MMRM model assumptions.
The Least Squares Means (LSMeans) together with 90% confidence intervals and standard 
errors will be obtained for each treatment and day.  Differences in LSMeans between each 
treatment and placebo, together with 90% confidence intervals and standard errors, will also 
be obtained.
Standard SAS output will be provided to support the main statistical summary table for the 
models.
5.2.4. Analysis of Covariance (Raw Scale)
The ANCOVA model will include the change from baseline of the relevant endpoint as 
specified in Section 6  as the dependent variable and will include treatment as a fixed effect 
and baseline as a covariate.
Missing values will not be imputed.
The Least Squares Means (LSMeans) together with 90% confidence intervals and standard 
errors will be obtained for each treatment.  Differences in LSMeans between each treatment 
and placebo, together with 90% confidence intervals and standard errors, will also be 
obtained.
Standard SAS output will be provided to support the main statistical summary table for the 
models.
Example SAS code is provided in the Appendices.
5.2.5. Analysis of Covariance (Log Scale)
The ANCOVA model will include the natural logarithmic transformed of relative change 
from baseline of the relevant endpoint as specified in Section 6  as the dependent variable 
and will include treatment as a fixed effect and log(baseline) as a covariate.
Missing values will not be imputed.
The adjusted geometric Least Squares Means (LSMeans) together with 90% confidence 
intervals and standard errors will be obtained for each treatment.  Differences in adjusted 
geometric LSMeans between each treatment and placebo, together with 90% confidence 
intervals and standard errors, will also be obtained.
Standard SAS output will be provided to support the main statistical summary table for the 
models.
Example SAS code is provided in the Appendices.
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5.2.6. Cumulative Incidence Plots
Cumulative Incidence Plots will be produced based on the time to the event of interest 
(starting from the time of start of dosing on Day 1) for each treatment group separately and 
will be plotted on the same graph. This will be based on plotting the cumulative incidence 
function (with no competing risks), which will be presented as a % on the y-axis. No 
statistical testing for differences between treatment groups will be considered.
Details of censoring are included in Section 6.2.1.2 and example SAS code is provided in the 
Appendices.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
5.3.1. Pharmacokinetic 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/clinical team.
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 dose with ≥3 evaluable measurements.
If a participant receives a dose that was not assigned based on the randomized titration 
scheme (for example due to a down-titration), the PK data from that Day will not be included 
in the calculation of summary statistics but will be included in listings.
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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.
5.3.4. 4-β-hydroxycholesterol/cholesterol ratio
Rules described in Section 5.3 will be used  to manage concentrations below limit of 
quantification, deviations, missing concentrations and anomalous values.
5.3.5. Pharmacodynamic Parameters
For baseline AUC0-4 calculations, if participants have a missing baseline (ie, Day -1) 0 hour 
value, no imputation will be made. No imputation will be made for other missing values. 
AUC0-4 will only be calculated in any participant with at least the first, last, and 75% of the 
total number of samples within the given interval available. Nominal times will be used in 
the calculation.  No imputation for missing values will be conducted for these PD endpoints.  
If the concentrations are below the limits of quantification such values will be truncated at 
the limit of quantification for all summaries and analyses, and will appear as reported in all 
listings. 
The same principles apply to the analyses of all other PD endpoints.
6. ANALYSES AND SUMMARIES
Data collected before baseline will only be listed , unless otherwise stated.
In case of additional cohorts with non-diabetic participants with obesity, for all relevant 
analyses, the placebo arm will be presented as two separate treatment groups for the T2DM 
participants and non-diabetic participants with obesity.
6.1. Baseline Variables
Not applicable
6.2. Primary Endpoint
6.2.1. Safety Analysis
•
Estimand strategy: Not applicable
•
Analysis set: Safety set  
A set of summary tables split by treatment will be produced to evaluate any potential risk 
associated with the safety and toleration of administering PF-07081532.
No formal analyses are planned for safety data.  The safety and other endpoints detailed in 
Section 3.1 will be listed and summarized in accordance with sponsor reporting standards, 
Disposition of Subjects
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Subject evaluation groups will show end of study subject disposition.  Frequency counts will 
be supplied for subject discontinuation(s) by treatment.
Data will be reported in accordance with the sponsor reporting standards.
6.2.1.1. Demographic and Physical Examination Data
A breakdown of demographic data will be provided for age, gender, race, and ethnicity
(T2DM and non-diabetic obesity, summarized separately). The physical measurement -
height; weight; body mass index; duration of T2DM (for T2DM participants only) - at 
baseline will also be summarized.  Each will be summarized by treatment and ‘All Subjects’ 
in accordance with the sponsor reporting standards.
An additional table listing the screening data of free T4, TSH, calcitonin, amylase, lipase, C-
peptide and HbA1c will be produced as above.
6.2.1.2. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.
6.2.1.3. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
Incidence and severity of treatment emergent adverse event (TEAE) tables will additionally 
be produced (‘All causality’ and ‘Treatment related’, separately) to summarise the total 
number of adverse events by preferred term, which will be reported by treatment group and 
overall.
A set of individual profile plots will be produced separately for each TEAE of interest. Each 
plot will include horizontal bars by participant which will represent if/when a participant 
experienced the TEAE of interest (measured in days). The x-axis will represent time and the 
bars will be colored by severity, with the plots paged by treatment group. Multiple events for 
the same participant of the same TEAE would therefore be represented by multiple 
horizontal bars.
Time to the first occurrence of TEAEs of interest will be produced using Cumulative 
Incidence Plots as described in Section 5.2.6. Participants who discontinue from the study, 
discontinue from IP will be censored at the discontinuation/initiation date.
A separate plot for each TEAE will be produced separately.
The above will also be produced separately for the time to the first recurrence of the TEAEs 
of interest. There will be a separate line for each treatment group.
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6.2.1.4. Hypoglycemia 
Any hypoglycemic AEs will be listed in a separate table and summarized categorically by
treatment as per Section 5.2.2.
6.2.1.5. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 3.
6.2.1.6. Vital Signs Data
Average of the triplicate measurements (where applicable) will be used in analyses. 
Unless specified otherwise, for non-maximum summaries unplanned assessments will not be 
considered.
Absolute values and changes from baseline in supine systolic and diastolic blood pressure
and pulse rate will be summarized by treatment group and time point, according to sponsor
reporting standards. Tables will be paged by parameter. 
Baseline is as defined in Section 3 .
Mean changes from baseline for systolic and diastolic blood pressure and pulse rate will be
plotted against time point.  On each plot there will be 1 line for each treatment group with all 
treatments on the same plot.
For baseline subtracted supine systolic and diastolic blood pressure and pulse rate, the
differences between each treatment group of PF-07081532and placebo (treatment – placebo, 
using the placebo from the respective population) will be summarized (N, mean, 90% CI) 
and plotted (mean, 90% CI) for each treatment group of PF-07081532and time point.  
Participants with absolute values and changes from baseline for vital signs (over all post-dose 
measurements) meeting categories as defined in the Appendix 2 will also be summarized 
descriptively by treatment group. Numbers and percentages of participants meeting the 
categorical criteria will be provided. All planned and unplanned post-dose time points will be 
counted in these categorical summaries.  All values meeting the criteria of potential clinical 
concern will be listed.
Maximum decrease and increase from baseline for supine systolic and diastolic blood
pressures, and maximum increase from baseline for supine pulse rate will be summarized by
treatment group, according to sponsor reporting standards.
Data from all cohorts will be plotted on the same figure using a single line for the placebo 
group(s).  Corresponding individual plots of change from time-matched baseline will also be 
produced for each treatment.
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The time-matched double differences in vital signs obtained following the Day 1 treatment, 
as defined in Section 3 , will be summarized (N, mean, 90% confidence interval) for each 
treatment and time point.  In addition, the time-matched double differences between each 
treatment and placebo will be summarized (N, mean, 90% confidence interval) for each 
treatment, time post-dose and day.
Mean time-matched double differences in vital signs will be plotted against time post-dose
for each Day as defined in the SoA separately. On each plot there will be 1 line for each 
treatment and a single line for the placebo group(s).  Corresponding individual plots of 
time-matched double differences will also be produced for each treatment.  The mean plots 
will similarly be produced for the time-matched double differences between each treatment 
and placebo.
6.2.1.7. Electrocardiograms Data
Average of the triplicate measurements (where applicable) will be used in analyses. 
Unless specified otherwise, for non-maximum summaries unplanned assessments will not be 
considered.
Absolute values and changes from baseline in QT interval, heart rate, QTcF interval, PR and 
QRS will be summarized by treatment group and time point using sponsor reporting 
standards.  Tables will be paged by parameter.  Baseline is as defined in Section 3 .
Mean changes from baseline in QT interval, heart rate and QTcF will be plotted against time 
point.  On each plot there will be 1 line for each treatment group with all treatments included 
on the same plot. 
In addition for baseline subtracted QT, heart rate and QTcF, the differences between each 
treatment group of PF-07081532 and placebo (treatment – placebo, using the placebo from 
the respective population) will be summarized (N, mean, 90% CI) and plotted (mean, 90% 
CI) for each treatment group of PF-07081532 and time point.
Participants with ECG endpoints and changes from baseline (QTcF, PR and QRS) meeting 
categories as defined in the Appendix 2 (for QTcF these correspond to the Pfizer Guidance
[2]) will also be summarized descriptively by treatment group.  Numbers and percentages of 
participants meeting the categorical criteria will be provided.  All planned and unplanned 
post-dose time points will be counted in these categorical summaries.  All values meeting the 
criteria of potential clinical concern will be listed.
Maximum absolute value (post-dose) and the maximum increase from baseline for QTcF, PR 
and QRS will be summarized by treatment group according to sponsor reporting standards. 
Listings of participants with any single post-dose value > 500 msec will also be produced for 
QTcF.
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Mean change from time-matched baseline in ECG parameters will be plotted against day.  
On each plot there will be 1 line for each treatment and a single line for the placebo group(s).  
Corresponding individual plots of change from time-matched baseline will also be produced 
for each treatment.
The time-matched double differences in QT, QTcF, PR, QRS intervals and heart rate
measures obtained following the Day 1 treatment, as defined in Section 3.1, will be 
summarized (N, mean, 90% confidence interval) for each treatment and time point.  In 
addition, the differences between each treatment and placebo will be summarized (N, mean, 
90% confidence interval) for each treatment, time postdose and day.
Mean time-matched double differences in ECG parameters will be plotted against time 
postdose for each Days as defined in the SoA separately.  On each plot there will be 1 line for 
each treatment and a single line for the placebo group(s).  Corresponding individual plots of 
time-matched double differences will also be produced for each treatment.  The mean plots 
will similarly be produced for the time-matched double differences between each treatment 
and placebo.
The time-matched double differences in QTcF will be plotted against PF-07081532
concentration.  This will be a scatter plot for all observations where QTcF and drug 
concentration are recorded.  Placebo data will also be included (with drug concentration set 
to zero).  Different symbols will be used for each treatment.  
6.3. Secondary Endpoint(s)
6.3.1. PF-07081532 PK Parameters
•
Estimand strategy:  Not applicable
•
Analysis set:  PF-07081532 Concentration and  Pharmacokinetic Parameter Set 
To assess the pharmacokinetics of PF-07081532, the PK parameters detailed in Section 3.2
will be listed and summarized for participants in the PK analysis set (as defined in Section 4).  
Missing values will be handled as detailed in Section 5.3 along with handling of values 
where participants received a dose that was not assigned based on the titration scheme). Each 
PK parameter will be summarized by treatment (eg differentiating different doses and dosing 
frequencies as required), and Study Day (Day 1, and 42, as applicable). 
The parameters will include the set of summary statistics as specified in the table below:
Table 3.
PF-07081532 PK Parameters to be Summarized Descriptively
Parameter
Matrix
Summary Statistics
AUC24, AUC24(dn), Cmax, 
Cmax(dn), PTR, Rac, Cav, Cmin, 
Rac,Cmax,, , CL/F, Vz/F, AUCinf, 
AUClast
Plasma
N, arithmetic mean, median, cv%, 
standard deviation, minimum, 
maximum, geometric mean and 
geometric cv%.
Tmax
Plasma
N, median, minimum, maximum.
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t1/2
Plasma
N, arithmetic mean, median, cv%, 
standard deviation, minimum, 
maximum.
There will be one summary table presenting all PK parameters. The treatment subheading 
will include the analyte, matrix, dose information and day (Day 1, or Day 42).  As per 
Section 5.3.3, data collected on days that participants received anything other than the 
assigned dose based on the titration scheme will only be listed and not summarized as part of 
the summary table.
To assess the relationship between the PK parameters and dose for PF-07081532, dose 
normalized AUC24 and Cmax will be plotted against treatment (using a logarithmic scale) for 
Day 1, and Day 42 separately and will include individual participant values and the 
geometric means for each dose.  Geometric means will have a different symbol than the 
individual values.  The values will be dose normalized (to a 1 mg dose) by dividing the 
individual values and raw geometric means by dose. A footnote will be added to the plots to 
indicate that geometric means are presented.
The observed accumulation ratio for AUC24 and Cmax will be analyzed after natural log 
transformation using a one-way analysis of variance with a single term for dose.  The means 
and 90% confidence intervals (CIs) obtained from the model will be back-transformed to
provide means and 90% CIs for the accumulation for each dose.
Supporting data from the estimation of t½ will be listed where applicable:  terminal phase 
rate constant (kel); goodness of fit statistic from the log-linear regression (r2); and the first, 
last, and number of time points used in the estimation of kel. This data may be included in 
the clinical study report.
Presentations for PF-07081532 concentrations will include:
•
a listing of all concentrations sorted by participant ID, treatment, day and nominal 
time postdose.  The concentration listing will also include the actual times.  
Deviations from the nominal time will be given in a separate listing.
•
a summary of concentrations by treatment, day and nominal time postdose, where the 
set of statistics will include n, mean, median, standard deviation, coefficient of 
variation (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 treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose), for Day 1 and Day 42 . 
•
mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose), for Day 1 and Day 42.
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•
individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment
per scale), paged by day (and also equivalent plots spanning the entire study duration
– not paged by day).
•
Median trough concentrations time plots (on both linear and semi-log scales) against 
nominal time post dose by treatment, spanning the entire study duration, i.e. not 
paged by day (all treatments on the same plot per scale, based on the summary of 
concentrations by treatment and time postdose)
The length of time used for the x-axes of these plots will be decided on review of the data, 
and will depend on how long PF-07081532 concentration is quantifiable in the matrix.
For summary statistics, median and 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.
6.4. Other Endpoint(s) 
6.4.1. Change from Baseline in Insulin, Glucagon and C-Peptide AUC0-4
•
Estimand strategy: Not applicable
•
Analysis set: Pharmacodynamic Population Set
•
The natural log-transformed of the relative change from baseline at the end of the study
will be included in an ANCOVA model, as described in Section 5.2.5, for each measure 
separately. The adjusted geometric LSMeans and adjusted geometric LSMean differences 
to placebo (with 90% confidence intervals) will be calculated and plotted.
Absolute values and percent change from baseline will be summarized descriptively by 
treatment and day as described in Section 5.2.1.
6.4.2. Change from Baseline in Fasting Plasma Glucose, Fasting Plasma Insulin and 
HOMA-IR
•
Estimand strategy:  Not applicable
•
Analysis set: Pharmacodynamic Population Set
Absolute values and change from baseline will be summarized descriptively by treatment and 
timepoint (when applicable) as described in Section 5.2.1.
The change from baseline over time for FPG will be included in an MMRM model as 
described in Section 5.2.3. The LSMeans and LSMean differences to placebo (with 90% 
confidence intervals) will also be plotted.
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The change from baseline over time for FPI and HOMA-IR will be included in an ANCOVA 
model, as described in Section 5.2.4, for each measure separately. The LSMeans and 
LSMean differences to placebo (with 90% confidence intervals) will also be plotted.
6.4.3. Change from Baseline in HbA1c
•
Estimand strategy:  Not applicable
•
Analysis set:  Pharmacodynamic Population Set
Absolute values and change from baseline will be summarized descriptively by treatment and 
timepoint as described in Section 5.2.2
The change from baseline over time will be included in an MMRM model as described in 
Section 5.2.3.  The LSMeans and LSMean differences to placebo for each timepoint (with 
90% confidence intervals) will be plotted.
6.4.4. 4-β-hydroxycholesterol/Cholesterol Ratio 
The percent change from baseline to all post-dose timepoints as specified in the SoA will be 
calculated.
•
Estimand strategy:  Not applicable
•
Analysis set: PD Population Set
Absolute values, and percent change from baseline will be summarized descriptively by 
treatment and day as per Section 5.2.1.
The percent change from baseline over time will be analyzed with an ANCOVA model as 
described in Section 5.2.5. The LSMeans and LSMean differences to placebo (with 90% 
confidence intervals) will be plotted. Results of this analysis may be not included in the CSR.
6.5. Subset Analyses
Not applicable
6.6. Baseline and Other Summaries and Analyses
Where relevant, data will be reported in accordance with the sponsor reporting standards.
6.6.1. Baseline Summaries
A baseline table (or separate tables, as required) summarizing the following will be produced 
by treatment group and overall (T2DM and non-diabetic obesity, summarized separately): 
HbA1c; fasting plasma glucose; systolic blood pressure; diastolic blood pressure; pulse rate; 
and metformin total daily dose (for T2DM participants only).
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6.6.2. Study Conduct and Participant Disposition
Participant evaluation groups will show participant disposition for each phase of the study 
(screening, double-blind treatment and follow-up) and will additionally show which 
participants were analyzed for safety, for PK and for tertiary endpoints. Frequency counts 
and percentages will be supplied for participant discontinuation(s) by treatment group and 
overall. 
 
6.6.4. Concomitant Medications and Nondrug Treatments
All prior and concomitant medication(s) as well as non-drug treatment(s) will be reported 
according to current sponsor reporting standards.
6.6.5. Discontinuations
Participant discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment group and overall.
Data will be reported in accordance with the sponsor reporting standards.
6.7. Safety Summaries and Analyses
Not applicable
7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study. As this is a sponsor-open 
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating dose selection decisions, facilitating PK/PD 
modeling, and/or supporting clinical development.
7.2. Interim Analyses and Summaries
Not applicable.
8. REFERENCES
3. ICH Harmonised Guideline E9 (R1); Estimands and Sensitivity Analysis in Clinical 
Trials; 16 June 2017.
4. Pfizer Guidance for Evaluation of QT / QTc Interval Prolongation and Proarrhythmic 
Potential for Non-antiarrhythmic Drugs; Members of the Cardiovascular Safety & 
Advisory Council (CVSAC); January 26, 2018.
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APPENDICES
Appendix 1. Statistical Methodology Details
Example SAS code for MMRM Model:
proc mixed data = dataset method=reml;
class subject treatment time;
model cfb = treatment base time base*time time*treatment / ddfm=kr residual 
outp=resid_out;
repeated time /subject=subjid type = un;
lsmeans treatment*time/diff cl alpha=0.1;
ods output lsmeans=lsmeans_out;
ods output diffs=diffs_out;
run;
Example SAS code for Cumulative Incidence Plots:
proc lifetest data = dataset method=km plots=cif(test) outcif=cifatrisk intervals=0 to 20 by 2; 
strata treatment;
time day*censor(1)/eventcode=0;
run; 
NOTE: the censor variable has a value = 1 when the related time is censored and has a value 
= 0 when the event of interest occurs. There should be no other values available for this 
censored variable in this dataset (including missing values). If required, missing observations 
should be removed prior to analysis.
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Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Absolute value of QTcF
(msec)
>450 and ≤480
>480 and ≤500
>500
Increase from baseline in QTcF
(msec)
>30 and ≤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
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Appendix 3. List of Abbreviations
Abbreviation
Term
Abs
Absolute
AE
adverse event
ANCOVA
analysis of covariance
ANOVA
analysis of variance
ATC
Anatomic Therapeutic Chemical
AUC
area under the curve
BA
Bioavailability
BE
Bioequivalence
BLQ
below the limit of quantitation
BOCF
baseline observation carried forward
BP
blood pressure
CDARS
Clinical Data Analysis and Reporting System (of US Food and Drug 
Administration)
CI
confidence interval
Cmax
maximum observed concentration
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CSR
clinical study report
DMC
data monitoring committee
EAC
event adjudication committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
FAS
full analysis set
FDA
Food and Drug Administration (United States)
GCP
Good Clinical Practice
GLIMMIX
generalized linear mixed-effects model with repeated measures
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMR
geometric mean ratio
GMT
geometric mean titer
ICD
informed consent document
ICH
International Council for Harmonisation
IRC
internal review committee
IST
independent statistical team
ITT
intent-to-treat
LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LOD
limit of detection
LS
least-squares
LSM
least-squares mean
MAR
missing at random
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Abbreviation
Term
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMRM
mixed-effects model with repeated measures
MNAR
missing not at random
N/A
not applicable
NNB
number needed to benefit
NNH
number needed to harm
NNT
number needed to treat
NOAEL
no-observed-adverse-effect level
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
per-protocol
PPAS
per-protocol analysis set
PRO
patient-reported outcome
PT
preferred term
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RCDC
reverse cumulative distribution curve
RR
relative risk
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SGS
Statistical Guidance Standards
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TA
therapeutic area
ULN
upper limit of normal
WHO 
World Health Organization
WHODD
World Health Organization Drug Dictionary
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