Clinical trial NCT05579977
Conditions: Diabetes Mellitus Obesity
Keywords: Diabetes Mellitus Obesity
Sponsor: Pfizer
Start date: 2022-10-27; Completion date: 2023-09-22
Enrollment: 902 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to find out if PF-07081532 ("the active study drug"), is safe and helps treat people with obesity without diabetes to lose weight, and people with diabetes to keep their blood sugar in good control. Individuals diagnosed with diabetes that are on metformin or individuals with obesity without diabetes will be included in the study.

Those participating in the diabetes part of the study, will receive either active study drug, placebo, or an approved treatment called Rybelsus. Those in the obesity part of the study, will receive either active study drug or placebo. The study will last for about 36 weeks except for the first 25% of the participants that enter in which case the study will last for approximately 48 weeks. during this time there will be visits every 4 weeks with phone calls in between.

Detailed description:

Arms: arm 1: PF-07081532 20 mg daily in T2DM arm 2: PF-07081532 40 mg daily in T2DM arm 3: PF-07081532 80 mg daily in T2DM arm 4: PF-07081532 160 mg daily in T2DM arm 5: PF-07081532 260 mg daily in T2DM arm 6: Placebo daily in T2DM arm 7: PF-07081532 80 mg daily in Obesity arm 8: PF-07081532 140 mg daily in Obesity arm 9: PF-07081532 200 mg daily in Obesity arm 10: PF-07081532 200 mg daily in Obesity arm 11: PF-07081532 260 mg daily in Obesity arm 12: Semaglutide 14 mg daily in T2DM arm 13: Placebo in Obesity
Interventions: intervention 1: PF-07081532 intervention 2: Placebo intervention 3: Rybelsus
Intervention descriptions: intervention 1: Oral glucagon-like peptide-1 receptor agonist intervention 2: No drug intervention 3: Oral Semaglutide

Protocol documents:
Prot_000.pdf: 
PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 1
Title Page
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, 
DOSE RANGING, DOSE FINDING, PARALLEL GROUP STUDY TO ASSESS 
EFFICACY AND SAFETY OF PF-07081532, AND OPEN LABEL ORAL 
SEMAGLUTIDE, IN ADULTS WITH TYPE 2 DIABETES MELLITUS (T2DM) 
INADEQUATELY CONTROLLED ON METFORMIN, AND SEPARATELY 
PF-07081532 COMPARED TO MATCHING PLACEBO IN ADULTS WITH 
OBESITY BUT WITHOUT T2DM
Study Intervention Number:
PF-07081532; Oral semaglutide
Study Intervention Name:
NA; Rybelsus
US IND Number:
147045 (PF-07081532)
EudraCT Number:
2022-002834-15
ClinicalTrials.gov ID:
Not available 
Pediatric Investigational Plan Number:
Not applicable 
Protocol Number:
C3991004
Phase:
2
Brief Title:
Trial to Learn About the Study Medicine (PF-07081532) and Rybelsus in People With
T2DM and Separately PF-07081532 in People With Obesity
This document and accompanying materials contain confidential information belonging to Pfizer. Except 
as otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) 
or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 2
Document History
Document
Version Date
Original protocol
13 September 2022


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................18
1.3. Schedule of Activities .............................................................................................19
2. INTRODUCTION ...............................................................................................................23
2.1. Study Rationale .......................................................................................................23
2.2. Background .............................................................................................................23
2.2.1. Type 2 Diabetes Mellitus............................................................................23
2.2.2. Obesity........................................................................................................24
2.2.3. Nonclinical Overview of PF-07081532......................................................24
2.2.4. Clinical Overview of PF-07081532............................................................25
2.2.5. Rybelsus, Internal Reference Standard, Approved in T2DM.....................25
2.3. Benefit/Risk Assessment.........................................................................................26
2.3.1. Risk Assessment.........................................................................................27
2.3.2. Benefit Assessment.....................................................................................30
2.3.3. Overall Benefit/Risk Conclusion................................................................30
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................31
4. STUDY DESIGN.................................................................................................................34
4.1. Overall Design.........................................................................................................34
4.2. Scientific Rationale for Study Design.....................................................................35
4.2.1. Diversity of Study Population ....................................................................38
4.2.2. Choice of Contraception/Barrier Requirements .........................................38
4.3. Justification for Dose ..............................................................................................39
4.3.1. PF-07081532...............................................................................................39
4.3.2. Rybelsus......................................................................................................39
4.4. End of Study Definition ..........................................................................................40
5. STUDY POPULATION......................................................................................................40
5.1. Inclusion Criteria.....................................................................................................40
5.2. Exclusion Criteria....................................................................................................42
5.3. Lifestyle Considerations..........................................................................................46


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 4
5.3.1. Contraception..............................................................................................46
5.3.2. Dietary Restrictions ....................................................................................46
5.3.3. Dietary Counseling.....................................................................................47
5.3.3.1. Stratum 1 (T2DM inadequately controlled with 
metformin).........................................................................................47
5.3.3.2. Stratum 2 (Obesity without T2DM)..........................................47
5.3.4. Physical Activity Counseling .....................................................................48
5.3.5. Alcohol, Caffeine, and Tobacco .................................................................48
5.4. Screen Failures ........................................................................................................48
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................49
6.1. Study Intervention(s) Administered........................................................................49
6.1.1. Administration............................................................................................51
6.1.2. Medical Devices .........................................................................................51
6.2. Preparation, Handling, Storage, and Accountability...............................................52
6.2.1. Preparation and Dispensing........................................................................53
6.3. Assignment to Study Intervention...........................................................................53
6.4. Blinding...................................................................................................................53
6.4.1. Blinding of Participants..............................................................................54
6.4.2. Blinding of Site Personnel..........................................................................54
6.4.3. Blinding of the Sponsor..............................................................................54
6.4.4. Breaking the Blind......................................................................................55
6.5. Study Intervention Compliance...............................................................................55
6.6. Dose Modification...................................................................................................56
6.6.1. Dose Escalation ..........................................................................................56
6.6.2. Considerations for Pausing or Stopping Active Dose(s) Based on 
Observed Safety...............................................................................................56
6.7. Continued Access to Study Intervention After the End of the Study......................57
6.8. Treatment of Overdose............................................................................................57
6.9. Prior and Concomitant Therapy..............................................................................57
6.9.1. Management of Glycemic Control in Stratum 1.........................................58
6.9.1.1. Home Glucose Monitoring........................................................59
6.9.1.2. Management of HAE ................................................................59
6.9.1.3. Management of Hyperglycemia................................................60


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 5
7. DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L ...........................................................................6 1
7. 1. Disc o nti n uati o n of St u d y  Inter ve nti o n .................................................................... 6 1
7. 1. 1. P ote ntial Cases of Ac ute Ki d ne y  Inj ur y ..................................................... 6 2
7. 1. 2. C O VI D -1 9 .................................................................................................. 6 2
7. 2. Partici pa nt Disc o nti n uati o n/ Wit h dra wal Fr o m t he St u d y ....................................... 6 3
7. 2. 1. Wit h dra wal of C o nse nt ............................................................................... 6 3
7. 3. L ost t o F oll o w -U p ................................................................................................... 6 4
8. S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ...............................................................6 4
8. 1. A d mi nistrati ve Pr oce d ures ...................................................................................... 6 4
8. 1. 1. Tele healt h Visits ......................................................................................... 6 5
8. 2. Efficac y  Assess me nts..............................................................................................6 6
8. 2. 1. B o d y wei g ht ................................................................................................ 6 6
8. 2. 2. Waist a n d Hi p Circ u mfere nce a n d Waist -t o-Hi p Rati o .............................. 6 6
8. 3. Safet y Assess me nts ................................................................................................. 7 0
8. 3. 1. P h y sical E xa mi nati o ns ................................................................................ 7 0
8. 3. 2. Vital Si g ns .................................................................................................. 7 0
8. 3. 2. 1. B l o o d Press ure a n d P ulse Rate.................................................. 7 1
8. 3. 3. Electr ocar di o gra ms ..................................................................................... 7 1
8. 3. 4. Cli nical Safet y  La b orat or y Assess me nts.................................................... 7 2
8. 3. 5. Pre g na nc y  Testi n g ......................................................................................7 3
8. 3. 6. S uici dal I deati o n a n d Be ha vi or Ris k M o nit ori n g ....................................... 7 3
8. 3. 6. 1. C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S) –
Strat u m 2 o nl y ................................................................................... 7 3
C CI


P F -0 7 0 8 1 5 3 2 
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Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 6
8. 3. 6. 2. Patie nt Healt h Q uesti o n naire- 9 ( P H Q -9) – Strat u m 2 o nl y ....... 7 4
8. 3. 6. 3. Referral t o a Me ntal Healt h Pr ofessi o nal – Strat u m 2 o nl y ...... 7 4
8. 4. A d verse E ve nts, Seri o us A d verse E ve nts, a n d Ot her Safet y Re p orti n g ................. 7 4
8. 4. 1. Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A E a n d S A E I nf or mati o n....... 7 5
8. 4. 1. 1. Re p orti n g S A Es t o Pfizer Safet y ............................................... 7 5
8. 4. 1. 2. Rec or di n g N o nseri o us A Es a n d S A Es o n t he C R F ................... 7 6
8. 4. 2. Met h o d of Detecti n g A Es a n d S A Es .......................................................... 7 6
8. 4. 3. F oll o w -U p of A Es a n d S A Es ...................................................................... 7 6
8. 4. 4. Re g ulat or y  Re p orti n g Re q uire me nts f or S A Es........................................... 7 7
8. 4. 5. E n vir o n me ntal E x p os ure, E x p os ure D uri n g Pre g na nc y  or 
Breastfee di n g, a n d Occ u pati o nal E x p os ure ..................................................... 7 7
8. 4. 5. 1. E x p os ure D uri n g Pre g na nc y ...................................................... 7 7
8. 4. 5. 2. E x p os ure D u ri n g Breastfee di n g ................................................ 7 9
8. 4. 5. 3. Occ u pati o nal E x p os ure ............................................................. 7 9
8. 4. 6. Car di o vasc ular a n d Deat h E ve nts ...............................................................7 9
8. 4. 7. Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot 
Q ualif yi n g as A Es or S A Es .............................................................................. 8 0
8. 4. 8. A d verse E ve nts of S pecial I nterest ............................................................. 8 0
8. 4. 8. 1. Lac k of Efficac y ........................................................................ 8 0
8. 4. 9. Me dical De vice Deficie ncies ...................................................................... 8 0
8. 4. 9. 1. Ti me Peri o d f or Detecti n g Me dical De vice Deficie ncies ......... 8 0
8. 4. 9. 2. F oll o w -U p of Me dical De vice Deficie ncies.............................. 8 1
8. 4. 9. 3. Pr o m pt Re p orti n g of De vice Deficie ncies t o t he S p o ns or ........ 8 1
8. 4. 9. 4. Re g ulat or y  Re p orti n g Re q uire me nts f or De vice 
Deficie ncies ....................................................................................... 8 1
8. 4. 1 0. Me dicati o n Err ors ..................................................................................... 8 1
8. 5. P har mac o ki netics .................................................................................................... 8 2
8. 6. Ge netics ................................................................................................................... 8 4
8. 6. 2. Retai ne d Researc h Sa m ples f or Ge netics................................................... 8 4
C CI
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 7
8. 8. I m m u n o ge nicit y Assess me nts ................................................................................. 8 4
8. 9. Healt h Ec o n o mics ................................................................................................... 8 5
9. S T A TI S TI C A L C O N SI D E R A TI O N S ................................................................................ 8 5
9. 1. Statistical H y p ot heses ............................................................................................. 8 5
9. 1. 1. Esti ma n ds .................................................................................................... 8 5
9. 1. 1. 1. Pri mar y  Esti ma n ds .................................................................... 8 5
9. 1. 1. 2. Sec o n dar y  Esti ma n ds ................................................................ 8 6
9. 1. 2. M ulti plicit y  A dj ust me nt.............................................................................. 8 7
9. 2. A nal y sis Sets ........................................................................................................... 8 7
9. 3. Statistical A nal y ses ................................................................................................. 8 7
9. 3. 1. Pri mar y  Esti ma n ds A nal ysis ....................................................................... 8 8
9. 3. 1. 1. Se nsiti vit y  A nal yses.................................................................. 8 8
9. 3. 2. Sec o n dar y  Esti ma n ds A nal ysis ................................................................... 8 8
9. 3. 4. Ot her Safet y A nal yses ................................................................................ 8 9
9. 3. 4. 1. Electr ocar di o gra m A nal y ses...................................................... 8 9
9. 4. I nteri m A nal ys es ..................................................................................................... 9 0
9. 4. 1. P K/ P D u n bli n di n g pla n ............................................................................... 9 0
9. 5. Sa m ple Size Deter mi nati o n ..................................................................................... 9 0
1 0. S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S .......................................................................................................... 9 2
1 0. 1. A p pe n di x 1: Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsi derati o ns............... 9 2
1 0. 1. 1. Re g ulat or y a n d Et hical C o nsi derati o ns .................................................... 9 2
1 0. 1. 1. 1. Re p orti n g of Safet y  Iss ues a n d Seri o us Breac hes of t he 
Pr ot oc ol or I C H G C P ......................................................................... 9 2
1 0. 1. 2. Fi na ncial Discl os ure ................................................................................. 9 3
1 0. 1. 3. I nf or me d C o nse nt Pr ocess ........................................................................9 3
1 0. 1. 4. Data Pr otecti o n ......................................................................................... 9 4
1 0. 1. 5. C o m mittees Str uct ure ............................................................................... 9 4
1 0. 1. 5. 1. Data M o nit ori n g C o m mittee ................................................... 9 4
1 0. 1. 6. Disse mi nati o n of Cli nical St u d y  Data ...................................................... 9 4
1 0. 1. 7. Data Q ualit y Ass ura nce ............................................................................ 9 6
1 0. 1. 8. S o urce D oc u me nts .................................................................................... 9 7
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PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 8
10.1.9. Study and Site Start and Closure ..............................................................97
10.1.10. Publication Policy...................................................................................98
10.1.11. Sponsor’s Medically Qualified Individual..............................................99
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................100
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...................................................................102
10.3.1. Definition of AE .....................................................................................102
10.3.2. Definition of an SAE ..............................................................................103
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period..........................................................................104
10.3.4. Reporting of SAEs..................................................................................108
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................109
10.4.1. Male Participant Reproductive Inclusion Criteria..................................109
10.4.2. Female Participant Reproductive Inclusion Criteria...............................109
10.4.3. Woman of Childbearing Potential ..........................................................109
10.4.4. Contraception Methods...........................................................................110
10.5. Appendix 5: Genetics..........................................................................................112
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
and Study Intervention Rechallenge Guidelines .....................................................113
10.7. Appendix 7: Kidney Safety Monitoring Guidelines ...........................................115
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury............................................................................115
10.7.2. Adult Kidney Function Calculation Recommendations.........................115
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .........................................................................................115
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities.................................................................................................115
10.8. Appendix 8: ECG Findings of Potential Clinical Concern .................................116
10.9. Appendix 9: AEs, ADEs, SAEs, SADEs, USADEs, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting in Medical Device Studies ...........................................118
10.9.1. Definition of AE and ADE .....................................................................118
10.9.2. Definition of SAE, SADE, and USADE ................................................118
10.9.3. Definition of Device Deficiency.............................................................119


P F -0 7 0 8 1 5 3 2 
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Pa ge 9
1 0. 9. 4. Rec or di n g/ Re p orti n g a n d F oll o w- U p of Me dical De vice 
Deficie nci es ....................................................................................................1 1 9
1 0. 9. 5. Re p orti n g of S A Es.................................................................................. 1 2 1
1 0. 9. 6. Re p orti n g of S A D Es ............................................................................... 1 2 1
1 0. 1 0. A p pe n di x 1 0: Pr o hi bite d Pri or / C o nc o mita nt Me dicati o ns .............................. 1 2 2
1 0. 1 1. A p pe n di x 1 1: G ui da nce t o I n vesti gat ors – Ma na ge me nt of I n di vi d ual 
Partici pa nts M o A- Base d GI -relate d A Es ................................................................ 1 2 6
1 0. 1 2. A p pe n di x 1 2: G ui da nce t o I n vesti gat ors – Ma na ge me nt of I n di vi d ual 
Par tici pa nts Gl yce mic C o ntr ol ................................................................................ 1 2 7
1 0. 1 3. A p pe n di x 1 3: A b bre viati o ns ............................................................................. 1 2 8
1 1. R E F E R E N C E S ................................................................................................................ 1 3 2
LI S T O F T A B L E S
S o A -Ta ble 1.
St u d y -Relate d Pr oce d ures i n St u d y  C 3 9 9 1 0 0 4 – f or b ot h strata 
u nless ot her wise s pecifie d ........................................................................2 0
S o A -Ta ble 2.
St u d y -Relate d Bl o o d a n d Uri ne C ollecti o ns i n St u d y  C 3 9 9 1 0 0 4 –
f or b ot h strata u nless ot her wise s pecifie d ................................................. 2 2
Ta ble 3.
D o u ble- bli n d, D o u ble -d u m m y  Re gi me ns i n St u d y C 3 9 9 1 0 0 4................. 5 0
Ta ble 5.
Pr ot oc ol -Re q uire d Cli nical La b orat or y  Assess me nts............................. 1 0 0
Ta ble 6.
Pr o hi bite d Me dicati o ns t hat ma y  i nteract (at t he P K le vel) wit h 
P F -0 7 0 8 1 5 3 2........................................................................................... 1 2 2
Ta ble 7.
Ot her Pr o hi bite d Me dicati o ns ................................................................. 1 2 4
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PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 10
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, 
Dose-Finding, Parallel Group Study to Assess Efficacy and Safety of PF-07081532, and 
Open-Label Oral Semaglutide, in Adults with Type 2 Diabetes Mellitus (T2DM) 
Inadequately Controlled on Metformin, and Separately PF-07081532 Compared to Matching 
Placebo in Adults with Obesity but Without T2DM.
Brief Title: Trial to Learn About the Study Medicine (PF-07081532) and Rybelsus in People 
With T2DM and Separately PF-07081532 in People With Obesity
Regulatory Agency Identification Number(s):
US IND Number:
147045  (PF-07081532)
EudraCT Number:
2022-002834-15
ClinicalTrials.gov ID:
Not available 
Pediatric Investigational Plan Number:
Not applicable 
Protocol Number:
C3991004
Phase:
2
Rationale: The current study is the first study in the clinical program with PF-07081532 
powered to evaluate the efficacy of a range of PF-07081532 doses compared to matching 
placebo in adults with T2DM inadequately controlled on metformin and separately adults
with obesity but without T2DM. PF-07081532 is an orally administered, potent and selective 
GLP-1R agonist in development as an adjunct to diet and exercise, to improve glycemic 
control in T2DM, and for chronic weight management in a population that is overweight with 
co-morbidities or who have obesity. The study includes open-label administration of 
Rybelsus (oral semaglutide), an orally administered peptidic GLP-1R agonist, as an internal 
reference standard evaluated in the population with T2DM.
The population enrolled will be stratified as follows:

Stratum 1: participants with T2DM inadequately controlled on metformin

Stratum 2: participants with obesity (defined as BMI ≥30 kg/m2) without T2DM
Additionally, randomization will be further stratified with the aim of randomizing ≥30% 
male (and hence ≤70% female) participants, in each of stratum 1 (T2DM) and stratum 2 
(obesity).


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 11
Objectives, Endpoints, and Estimands: The key primary and secondary endpoints of focus 
in this study include –
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To evaluate the efficacy
of a range of 
PF-07081532 doses 
compared to placebo, in 
participants with T2DM
inadequately controlled 
on metformin 
Placebo-adjusted, change from 
baseline in HbA1C at Week 32
The population average treatment effect on the 
change from baseline in HbA1C at Week 32 of 
PF-07081532 compared to placebo in the absence of 
glycemic rescue medication while on treatment 

Measurements after initiation of glycemic rescue 
medication or discontinuation of study 
intervention will be censored and treated as 
missing data

Missing data due to censoring, study withdrawal 
or other reasons (eg, laboratory failure) will have 
data imputed based on a MAR assumption

Participants with inadequate compliance will 
have their HbA1C values used as-is in the 
analysis

The population-based treatment effect will be the 
difference in the mean change from baseline in 
each PF-07081532 arm compared to placebo
To evaluate the efficacy 
of a range of 
PF-07081532 doses 
compared to placebo, in 
participants with obesity 
but without T2DM
Placebo-adjusted, percent change 
from baseline in body weight at 
Week 32
The population average treatment effect on the 
percent change from baseline in body weight at 
Week 32 of PF-07081532 compared to placebo 
while on treatment 

Measurements after discontinuation of study 
intervention will be censored and treated as 
missing data

Missing data due to censoring, study withdrawal 
or other reasons (eg, equipment failure) will have 
data imputed based on a MAR assumption

Participants with inadequate compliance will 
have their body weight values used as-is in the 
analysis

The population-based treatment effect will be the 
difference in the mean percent change from 
baseline in each PF-07081532 arm compared to 
placebo
Secondary: 
Secondary:
Secondary: 
To assess the effect of a 
range of PF-07081532 
doses compared to 
placebo on various 
parameters, in 
participants with T2DM 
inadequately controlled 
on metformin
Proportion of participants who 
achieve HbA1C <7% 
(<53 mmol/mol) at Week 32
The odds ratio (PF-07081532 relative to placebo) of 
achieving HbA1C <7% (<53 mmol/mol) at Week 32 
in the absence of glycemic rescue medication while 
on treatment 

Measurements after initiation of glycemic rescue 
medication or discontinuation of study intervention
will be censored and treated as missing data

Missing data will not be imputed. Participants with 
inadequate compliance will have their HbA1C 
values used as-is in the analysis

The population-based treatment effect will be the 
odds ratio of PF-07081532 arm relative to placebo


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Protocol C3991004
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Objectives
Endpoints
Estimands
Placebo-adjusted, change from 
baseline in FPG at Week 32
The estimand for placebo-adjusted, change from 
baseline in FPG at Week 32 endpoint will be 
constructed in a similar manner as Placebo-adjusted, 
change from baseline in HbA1C at Week 32
Placebo-adjusted, percent change 
from baseline in body weight at 
Week 32
The estimand for the placebo-adjusted, percent change 
from baseline in body weight at Week 32 endpoint 
will be constructed in a similar manner as Placebo-
adjusted, change from baseline in HbA1C at Week 32
To compare the efficacy
of PF-07081532 and 
Rybelsus relative to 
placebo, in participants 
with T2DM
inadequately controlled 
on metformin
Placebo-adjusted, change from 
baseline in HbA1C at Week 32
The population average treatment effect on the 
change from baseline in HbA1C at Week 32 of each 
arm of PF-07081532 and of Rybelsus compared to 
placebo in the absence of glycemic rescue 
medication while on treatment 

Measurements after initiation of glycemic rescue 
medication or discontinuation of study 
intervention will be censored and treated as 
missing data

Missing data due to censoring, study withdrawal 
or other reasons (eg, laboratory failure) will have 
data imputed based on a MAR assumption

Participants with inadequate compliance will 
have their HbA1C values used as-is in the 
analysis

The population-based treatment effect will be the 
difference in the mean change from baseline in 
each PF-07081532 arm and Rybelsus arm
compared to placebo
To assess the effect of a 
range of PF-07081532
doses compared to 
placebo on various 
parameters in 
participants with obesity 
but without T2DM
Proportion of participants 
achieving ≥5%, ≥10%, and 
≥15% body weight loss at 
Week 32 relative to baseline 
Placebo-adjusted, absolute
change from baseline in waist 
circumference at Week 32 
Placebo-adjusted, absolute
change from baseline in waist-to-
hip ratio at Week 32 
Placebo-adjusted, change from 
baseline in HOMA-IR at 
Week 32
Placebo-adjusted, change from 
baseline in HOMA-S at Week 32

The odds ratio (PF-07081532 relative to placebo) 
of achieving HbA1C <7% (<53 mmol/mol) at 
Week 32 in the absence of glycemic rescue 
medication while on treatment 

Measurements after discontinuation of 
study intervention will be censored and 
treated as missing data

Missing data will not be imputed

Participants with inadequate compliance 
will have their body weight values used 
as-is in the analysis

The population-based treatment effect will 
be the odds ratio of PF-07081532 arm 
relative to placebo

The estimand for each of the continuous 
endpoints will be constructed in a similar manner 
as the primary endpoint Placebo-adjusted, 
percent change from baseline in body weight at 
Week 32
To assess the safety and 
tolerability with a range 
of PF-07081532 doses 
compared to placebo, in 
participants with T2DM
inadequately controlled 
on metformin and 
separately participants 
In each population randomized –
Number (and percent) of 
participants with:
TEAEs
SAEs
AE leading to permanent
discontinuation from study 
intervention or study


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 13
Objectives
Endpoints
Estimands
with obesity but without 
T2DM
Hypoglycemia
AESIs
Clinical laboratory
abnormalities
Vital sign abnormalities
12-lead ECG abnormalities
And TEAEs, presented in 
descending order of frequency 
To assess the safety and 
tolerability with a range 
of PF-07081532 doses 
compared to placebo, in 
participants with obesity 
but without T2DM
Assessment of mental health as 
determined by –

C-SSRS
In all cases, baseline defined as the evaluable result closest prior to dosing on Day 1/Visit 3
Overall Design: This is a multicenter, multinational, randomized, double-blind, 
double-dummy, placebo-controlled, dose-ranging, dose-finding, parallel-group study to 
assess efficacy and safety/tolerability of PF-07081532, and open-label Rybelsus, in adults 
with T2DM inadequately controlled on metformin, and separately PF-07081532 compared to 
matching placebo in adults with obesity but without T2DM. For additional details, refer to 
Schema in Section 1.2.
The study will employ an IRC who will be responsible for ongoing review of unblinded 
safety and tolerability according to an IRC Charter. In addition, an interim analysis to assess 
efficacy and safety/tolerability in the Stratum that achieves PCD early may be performed. 
Number of Participants: Approximately 780 participants (60/arm) will be
enrolled/randomized across 2 populations in the study. 
Note: "Enrolled" means a participant's agreement to participate in a clinical study following 
completion of the informed consent process and randomization. A participant will be 
considered enrolled if the informed consent is not withdrawn prior to participating in any 
study activity. 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. 
Study Population: Key inclusion and exclusion criteria are listed below:
Inclusion Criteria – Participants must meet the following inclusion criteria, for both strata, 
unless otherwise specified, to be eligible for enrollment/randomization into the study:
1. Male or female 18 years or older (or the minimum age of consent in accordance with 
local regulations) and up to 75 years, inclusively, at the Screening Visit;

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants including requirement for pregnancy testing 
(Section 8.3.5); 


PF-07081532 
Protocol C3991004
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CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 14
2. For Stratum 1 only:

Participants diagnosed with T2DM inadequately controlled with metformin at 
doses ≥500 mg/day with metformin dose stable for ≥8 weeks prior to Screening 
Visit;

BMI ≥23.0 kg/m2 (≥20.0 kg/m2 in Japan), at Screening Visit;

HbA1C of 7% to 10% (53-86 mmol/mol), inclusive, at Screening Visit;

FPG ≤270 mg/dL (15 mmol/L); at Screening Visit;
3. For Stratum 2 only: 

Participants with obesity, defined by BMI ≥30.0 kg/m2, at Screening Visit;

HbA1C ≤6.4% (47 mmol/mol), at Screening Visit;

FPG ≤126 mg/dL (7 mmol/L), at Screening Visit;
Exclusion Criteria – Participants with any of the following characteristics/conditions, for 
both strata, unless otherwise specified, will be excluded:
1. Active/current, symptomatic gallbladder disease, history of pancreatitis in the 12-months 
prior to Screening Visit, or history of Type 1 Diabetes Mellitus, or secondary forms of 
diabetes (a history of gestational diabetes that has resolved is allowed), or active liver 
disease, or any condition affecting drug absorption;
2. Previous participation in a clinical study evaluating PF-07081532 (including exposure to 
placebo) or intolerance or hypersensitivity to a GLP-1R agonist;
3. Use of pharmacological agents with approved indication for weight loss (eg, orlistat, 
sibutramine), over-the-counter appetite- stimulant or appetite- suppressant, as 
advertised, within 12 weeks of Screening Visit; or weight loss of >5% in the 12 weeks 
prior to Screening Visit;
4. For Stratum 1 only: 

Use of any pharmacological agent with an approved indication for T2DM (other 
than metformin), or herbal medications, for the explicit purpose of glycemic 
control within 12 weeks of Screening Visit;

History of diabetic ketoacidosis;

Proliferative retinopathy or maculopathy requiring acute treatment; 


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 15
5. For Stratum 2 only: 

Previous or planned (during the study) weight reduction surgery or device use, 
with selected preidentified exceptions;

Diagnosis of Type 2 diabetes mellitus;

Use of pharmacological agent(s) with approved indication for glycemic control;

Major depressive disorder or other severe psychiatric disorders (eg, schizophrenia 
or bipolar disorder) within 2 years prior to Screening Visit or any lifetime history 
of a suicide attempt; or PHQ-9 score ≥15; or response of “yes” to Question 4 or 
5, or on any suicidal behavioral question on the C-SSRS;
6. Clinically significant cardiovascular conditions;
7. Uncontrolled BP defined as ≥160 mmHg (systolic) or ≥100 mmHg (diastolic) –

Participants on an anti-hypertensive medication(s) to treat hypertension should be 
on stable dose(s) for ≥4 weeks prior to Screening Visit;
8. Personal or within first-degree relative family history of MTC or MEN2;
9. Following results reported by sponsor-identified central laboratory, at Screening Visit –

Fasting C-peptide <0.8 ng/mL;

ALT or AST ≥ 2.5x ULN;

Direct bilirubin >ULN or T bili >1.5x ULN except when participants have a 
history of Gilbert syndrome where T bili >1.5x ULN would be eligible provided 
direct bilirubin level is ≤ULN; 

TSH >1.5x ULN or <LLN;

Serum calcitonin >ULN;

Serum amylase or lipase >ULN;

eGFR <45 mL/min/1.73 m2;

Active Hepatitis B, or Hepatitis C;

A positive urine drug test for illicit drugs;
10. Participants requiring concomitant medications excluded based on (potential for) 
PK-based DDI.


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 16
Study Arms and Duration:

In Stratum 1, three interventions, PF-07081532, its matching placebo, and open-label 
Rybelsus, will be evaluated across 7 arms in participants with T2DM on a
background of metformin. 

In Stratum 2, two interventions, PF-07081532 and its matching placebo, will be 
evaluated across 6 arms in participants with obesity.

Across all 12 treatment arms of PF-07081532/ placebo each dose will consist of 
3 tablets. The treatment duration in this study will be 32 weeks for most participants; 
though in the first set of up to 25% randomized participants, treatment interval will 
extend for an additional up to 12 weeks (for a total duration of up to 44 weeks). 
Study Interventions
Intervention Name
Placebo 
PF-07081532 
Rybelsus
Arm Name
(group of participants 
receiving a specific 
treatment or no 
treatment)
Placebo [Stratum 1]
Placebo [Stratum 2]
20 mg QD [Stratum 1]
40 mg QD [Stratum 1]
80 mg QD [Stratum 1 and 2]
140 mg QD [Stratum 2]
160 mg QD [Stratum 1]
200 mg QD [5 steps; Stratum 2]
200 mg QD [4 steps; Stratum 2]
260 mg QD [Stratum 1 and 2]
14 mg QD [Stratum 1]
Unit Dose Strength(s)
Not applicable 
20 mg; 60 mg; 100 mg
3 mg; 7 mg; 14 mg 
Route of Administration
Oral
Oral
Oral 
Use
Placebo
Experimental
Internal reference 
standard [Stratum 1]
IMP or NIMP/AxMP
IMP 
IMP
IMP
Study Arms
Arm Title
Arm Type
Arm Description
Associated 
Intervention Labels
Placebo 
[Stratum 1 and 2]
Placebo 
Participants will receive placebo for up to 
44 weeks
PF-07081532 / 
placebo
PF-07081532 20 mg QD 
[Stratum 1]
Experimental
Participants will receive PF-07081532 20 mg 
QD for up to 44 weeks 
PF-07081532 40 mg QD 
[Stratum 1]
Participants will receive PF-07081532 20 mg 
QD (for 4 weeks) followed by 40 mg QD (for 
up to 40 weeks)
PF-07081532 80 mg QD 
[Stratum 1 and 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 60 mg QD – sequentially, each 
for 4 weeks followed by 80 mg QD (for up to 
32 weeks)
PF-07081532 140 mg QD 
[Stratum 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 60 mg QD, 80 mg QD, 
120 mg QD – sequentially, each for 4 weeks 
followed by 140 mg QD (for up to 24 weeks)
PF-07081532 160 mg QD 
[Stratum 1]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 60 mg QD, 80 mg QD, 
120 mg QD – sequentially, each for 4 weeks 
followed by 160 mg QD (for up to 24 weeks)
PF-07081532 200 mg QD 
[5 steps; Stratum 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 60 mg QD, 100 mg QD, 
160 mg QD – sequentially, each for 4 weeks 
followed by 200 mg QD (for up to 24 weeks)


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 17
Study Arms
Arm Title
Arm Type
Arm Description
Associated 
Intervention Labels
PF-07081532 200 mg QD 
[4 steps; Stratum 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 80 mg QD, 140 mg QD –
sequentially, each for 4 weeks followed by 
200 mg QD (for up to 28 weeks)
PF-07081532 260 mg QD 
[Stratum 1 and 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 80 mg QD, 140 mg QD, 
200 mg QD – sequentially, each for 4 weeks 
followed by 260 mg QD (for up to 24 weeks)
Rybelsus 14 mg QD 
[Stratum 1]
Internal 
reference 
standard 
Participants will receive Rybelsus 3 mg QD, 
7 mg QD –sequentially, each for 4 weeks 
followed by 14 mg QD (for up to 36 weeks)
Rybelsus 
Statistical Methods:
Primary 
estimands:
For the primary estimand in each stratum, the analysis method is an MMRM analysis

The MMRM will include treatment and time as fixed effects, and baseline measure (HbA1C for 
Stratum 1, body weight for Stratum 2) as a covariate with time fitted as a repeated effect and 
participant as a random effect

An unstructured correlation matrix will be used, and the Kenward-Roger approximation will be used 
for estimating degrees of freedom for the model parameters

The MMRM model will be fitted to change from baseline to Weeks 4, 8, 12, 16, 20, 24, 28, and 32

Missing values will be imputed as part of the MMRM model assumptions
Secondary 
Estimands:
For the estimands containing continuous endpoints, the analysis method is an MMRM analysis

The MMRM will include treatment and time as fixed effects, and baseline measure as a covariate 
with time fitted as a repeated effect and participant as a random effect

An unstructured correlation matrix will be used, and the Kenward-Roger approximation will be used 
for estimating degrees of freedom for the model parameters

The MMRM model will be fitted to change from baseline to Weeks 4, 8, 12, 16, 20, 24, 28, and 32

Missing values will be imputed as part of the MMRM model assumptions
For the estimands containing categorical endpoints, the analysis method is a logistic regression analysis

The logistic regression model will include a term for treatment and will include baseline as a 
covariate

No values will be imputed for missing data and missing values will not be included in the model.
No adjustments will be made for multiplicity
Ethical Considerations: The results of 2 completed Phase 1 studies, along with available 
nonclinical data, support the further investigation of PF-07081532 as an adjunct to diet and 
exercise to improve glycemic control in T2DM and for chronic weight management in a 
population that is overweight with co-morbidities or who have obesity. Taking into account 
the measures to minimize risk to participants, the potential risks associated with study 
intervention are justified by the anticipated benefits that may be afforded to participants in 
this study which include –

Participants may experience improvements in glycemic control (Stratum 1) and weight 
management (both strata) during the study and will benefit from more intense monitoring 
and more frequent assessments compared to usual standard of care;

Participants may benefit from contributing to the scientific understanding of the potential 
for efficacy of PF-07081532 in the context of improving glycemic control in adults with 
T2DM, as well as those with obesity without T2DM;


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 18

Based on the experience with marketed peptidic GLP-1R agonists, including Rybelsus, as 
well as previously completed clinical and nonclinical/toxicity studies with PF-07081532, 
the important potential risks with the study interventions include –

Gastrointestinal adverse reactions;

Hypoglycemia;

Increased heart rate;

Other potential risks associated with long-term use of marketed GLP-1R agonists 
including thyroid C-cell tumors, pancreatitis, impairment of renal function, 
diabetic retinopathy complications, and acute gallbladder disease; and suicidal 
ideation/behavior in participants with Obesity.

Participants will be expected to commit time and may experience some discomfort while 
undergoing study assessments

Female participants of childbearing potential must agree to use appropriate 
contraception methods;

Diet and lifestyle habits suggested, as part of study-related counseling, to aide 
management of body weight are expected to be consistently followed throughout 
the study.
1.2. Schema
The high-level study design is summarized below –


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 19
The dose-escalation scheme to be employed is outlined below –
1.3. Schedule of Activities
The SoA-Table 1 and SoA-Table 2 provides an overview of the protocol visits and 
procedures. Refer to 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 1 and SoA-Table 2, in order to conduct evaluations or assessments required to 
protect the well-being of the participant.


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 2 0
S o A -T a ble 1 . St u d y -Rel ate d Pr oce d ures i n St u d y C 3 9 9 1 0 0 4 – f or b ot h str at a u nless ot her wise s pecifie d
Visit I de ntifier
Scree n
R u n -I n
Tre at m e nt P h ase [all pr oce d ures bef ore m or ni n g d ose of (bli n de d ) st u d y 
i nter ve nti o n ± c o n me ds]
I n first ≤2 5 % 
ra n d o mize d, o nl y
F oll o w -u p
E T
Wee ks
a Rel ati ve t o D osi n g o n D a y 1
≤- 6
- 2
0
2
4
6
8
1 0 1 2
1 4
1 6
1 8
2 0
2 2
2 4
2 6
2 8
3 0
3 2
3 6
4 0
4 4
3 4/ 4 6 b
3 6 / 4 8c
Visit t o Sited or tele p h o ne c o nt act [ T]
1
2
3
4- T
5
6- T
7
8- T 9 1 0 - T 1 1 1 2 - T 1 3 1 4 - T 1 5 1 6 - T 1 7 1 8 - T 1 9
2 0
2 1
2 2
2 0/ 2 3 2 1/ 2 4 - T
I nf or me d c o nse nt, de m o gra p h y , a n d 
dis pe nsati o n of E C C
x
( U p date) Me dical
& Me dicati o n hist or y
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
P h ysical E xa m e
x
C- S S R S ( Str at u m 2)
x
x f
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
x
P H Q -9 ( Str at u m 2)
x
x f
I n fe males, assess c o ntrace pti o n use
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
C o u nseli n g o n diet/e xercise g ui deli nes
x
x
x
x
x
x
x
x
x
x
x
x
Dis pe nse gl uc o meter/s u p plies ( Str at u m 1)
x
Re vie w gl uc ose m o nit ori n g l o g ( Str at u m 1)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
O pe n -e n de d i n q uir y f or a d verse e ve nts 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tri plic at e g s u pi ne 1 2-lea d E C G
x 
x
x h
x
x h
x
x h
x
x h
x
x h
x h
x
x
Tri plic ate g seate d vitals ( B P & p ulse rate)
x 
x
x h
x
x h
x
x h
x
x h
x
x h
x h
x
x
D u plic ate b o d y wei g ht
x
x
x
x
x
x
x
x
x
x
x
x
x
Tri plic ate waist a n d hi p circ u mfere nce 
x
x
x
x
x
x
x
Re gistrati o n of visit i n st u d y ( via I R T) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
x i
x 
x
x
Ra n d o mizati o n i n st u d y ( via I R T)
x
Dis pe ns i n gi ( via I R T) of st u d y i nter ve nti o n
x 
x 
x 
x 
x 
x 
x 
x 
x
x i
x 
x
Wit nesse d o n site d osi n g of st u d y 
i nter ve nti o n
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
C o m plia nce j of ret ur ne d st u d y i nter ve nti o n
via ta blet c o u nt
x f
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
C o nti n ue d a d mi nistrati o n of st u d y 
i nter ve nti o n
x 
x
 
 
 
 

 
 
 
 
 
 
 
 
 

x
 

x
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 2 1
S o A -T a ble 1 . St u d y -Rel ate d Pr oce d ures i n St u d y C 3 9 9 1 0 0 4 – f or b ot h str at a u nless ot her wise s pecifie d
Visit I de ntifier
Scree n
R u n -I n
Tre at m e nt P h ase [all pr oce d ures bef ore m or ni n g d ose of (bli n de d ) st u d y 
i nter ve nti o n ± c o n me ds]
I n first ≤2 5 % 
ra n d o mize d, o nl y
F oll o w -u p
E T
Wee ks
a Rel ati ve t o D osi n g o n D a y 1
≤- 6
- 2
0
2
4
6
8
1 0 1 2
1 4
1 6
1 8
2 0
2 2
2 4
2 6
2 8
3 0
3 2
3 6
4 0
4 4
3 4/ 4 6 b
3 6 / 4 8c
Visit t o Sited or tele p h o ne c o nt act [ T]
1
2
3
4- T
5
6- T
7
8- T 9 1 0 - T 1 1 1 2 - T 1 3 1 4 - T 1 5 1 6 - T 1 7 1 8 - T 1 9
2 0
2 1
2 2
2 0/ 2 3 2 1/ 2 4 - T
a.
Defi ne d at start of gi ve n wee k wit h ± 2 - da y wi n d o w per mitte d f or e ac h visit; f or ex a m ple: Wee k -2 = 1 4 ± 2 da ys bef ore , a n d Wee k 4 = Da y 2 8 ± 2 da ys p ost, Da y 1/ Visit 3
b.
Defi ne d as 1 4 ± 2 da ys p ost last d ose at Wee k 3 2 ( or Wee k 4 4 f or t he first u p t o 2 5 % ra n d o mize d)
c.
Tele p h o ne c o ntact at ≥2 8 - a n d ≤3 5 - da ys p ost last d ose f or f oll o w-u p of o pe n A Es a n d/ or a b n or mal la b orat or y tests, o nly ; if l ocal re g ulati o ns dictate t his t o be a n o n-site visit, 
selecte d pr oce d ures t o be c o m plete d.
d.  
Visit t o be perf or me d i n t he m or ni n g f oll o wi n g a n o ver ni g ht fast ( e xce pt water) of ≥8 h o urs
e. 
F ull P E at Scree n i ncl u di n g ar m circ u mfere nce, a n d hei g ht; ot her wise, brief P E f or o pe n A Es/a b n or mal la b orat or y tests, o nly
f. 
C-S S R S & P H Q -9 q uesti o n naire res p o nses m ust be dee me d acce pta ble, pl us ≥8 0 % a n d ≤ 1 2 0 % c o m plia nce ( wit h si n gle bli n d place b o ta blets), re q uire d t o d ose o n Da y 1
g.
I n t h ose ra n d o mize d t o o pe n-la bel R y bels us i n Strat u m 1, li mite d t o si n gle ( n ot tri plicate) a n d pre-d ose o nl y ( n ot pre - a n d p ost-d ose)
h.
Pr e -d ose assess me nt pl us 1 assess me nt t o occ ur i m me diatel y ( ≤1 0 -mi n) pri or t o p ost d ose P K bl o o d dra w i n P F -0 7 0 8 1 5 3 2/ place b o ar ms i n b ot h Strata
i.
At V 2/ Wee k -2, reflects si n gle -bli n d place b o matc hi n g P F -0 7 0 8 1 5 3 2 t o be d ose d f or 1 4 ± 2 da ys ; st arti n g V 3/ D ay 1 reflects ra n d o mize d re gi me n (eit her d o u ble-bli n d 
P F -0 7 0 8 1 5 3 2/ place b o) or o pe n -la bel R y bels us dis pe nse d e ver y 4 -wee ks; at Wee k 3 2 , I R T re gistrati o n a n d dis pe nsi n g o nly i n t h ose c o nti n ui n g d osi n g u p t o Wee k 4 4 as 
deter mi ne d b y I R T o n Da y 1
j.
Perf or me d at visits w he n st u d y i nter ve nti o n is ret ur ne d, o nly ; partici pa nts will n ot be offere d st u d y i nter ve nti o n p ost last d ose i n t his st u d y
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 2 2
S o A -T a ble 2 . St u d y - Rel ate d Bl o o d a n d Uri ne C ollecti o ns i n St u d y C 3 9 9 1 0 0 4 – f or b ot h str at a u nless ot her wise s pecifie d
Visit I de ntifier
Scree n
R u n -
I n
Tre at m e nt P h ase [m ost pr oce d ures bef ore m or n i n g d ose of ( bli n de d) st u d y 
i nter ve nti o n ± c o n me ds, u nless ot her wise s pecifie d ]
I n first ≤2 5 % 
ra n d o mize d, o nl y
F oll o w -u p
E T
Wee ks
a Rel ati ve t o D osi n g o n D a y 1
≤- 6
- 2
0
2
4
6
8
1 0 1 2
1 4
1 6
1 8
2 0
2 2
2 4
2 6
2 8
3 0
3 2
3 6
4 0
4 4
3 4/ 4 6 b
3 6 / 4 8c
Visit t o Sited or tele p h o ne c o nt act [ T]
1
2
3 4- T
5
6- T
7
8- T 9 1 0 - T 1 1 1 2 - T 1 3 1 4 - T 1 5 1 6 - T 1 7 1 8 - T
1 9
2 0
2 1
2 2
2 0/ 2 3 2 1/ 2 4 - T
Bl o o d c ollecti o n 
( after over ni g ht f ast [exce pt w ater] of ≥ 8 -h o urs) –
N o 
o d or ri n e C ollecti o ns
N o 
o d or ri n e C ollecti o ns
N o 
o d or ri n e C ollecti o ns
N o 
o d or ri n e C ollecti o ns
N o 
o d o
ri n e C ollecti o ns
N o 
o d o
ri n e C ollecti o ns
N o 
o d o
ri n e C ollecti o ns
N o 
o d or ri n e C ollecti o ns
Ser u m F S H & pre g na nc y test (fe males 
o nl y), T S H, He p B, He p C, C -pe pti de
x
He mat ol o g y, c he mistr y i ncl u di n g e G F R
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
x c
x
H b A 1 C, Plas ma Gl uc ose
x 
x e
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
x c
x
Ser u m Li pase a n d A m ylase
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
x c
x
Calcit o ni n
x
x
x
x
x
x
x
x
 Ser u m Li pi d pa nel, 
hs -C R P, Free T 4, t otal bile aci ds
x 
x
x
x
x 
x
x
Pre d ose P F -0 7 0 8 1 5 3 2/ R y bels us P K f
x
x
x
x
x
x
x
x
x
x
x
P ost d ose P F -0 7 0 8 1 5 3 2 / R y bels us P Kf
x
x
x
x
x
x
S p ot uri ne c ollecti o n –
Uri ne dr u g test
x
Uri nar y Al b u mi n: Creati ni ne Rati o
x
x
x
x
x
x
x
x
Uri nal ysis ( +micr osc o p y a n d c ult ure, w he n 
a p pr o pri ate )
x 
x 
x 
x 
x 
x 
x 
x
x 
x
x 
x
x c
x
O n -site pre g na nc y test ( W O C B P o nly )
x e
x g
x g
x g
x g
x g
x g
x g
x g
x g
x g
x g
x
x c
x
a.
Defi ne d at start of gi ve n wee k wit h ± 2 - da y wi n d o w per mitte d f or e ac h visit; f or ex a m ple: Wee k -2 = 1 4 ± 2 da ys bef ore , a n d Wee k 4 = Da y 2 8 ± 2 days p ost, Da y 1/ Visit 3.
b.
Defi ne d as 1 4 ± 2 da ys p ost last d ose at Wee k 3 2 ( or Wee k 4 4 f or t he first u p t o 2 5 % ra n d o mize d) .
c.
Tele p h o ne c o ntact at ≥2 8 - a n d ≤3 5 - da ys p ost last d ose f or f oll o w- u p of o pe n A Es a n d/ or a b n or mal la b orat or y tests, o nly ; if l ocal re g ulati o ns dictate t his t o be a n o n-site visit, 
selecte d pr oce d ures t o be c o m plete d.
d.
Visit t o be perf or me d i n t he m or ni n g f oll o wi n g a n o ver ni g ht fast (e xce pt water) of 8 h o urs .
e.
Test res ults m ust be re vie we d b y me dicall y q ualifie d i n di vi d ual a n d dee me d acce pta ble bef ore pr o gressi o n t o ra n d o mizati o n a n d first d ose of d o u ble- bli n de d st u d y i nter ve nti o n o n 
Da y 1.
f.
Pre d ose/tr o u g h bl o o d sa m ple c ollecti o n t o occ ur at selecte d visits; i n a d diti o n, si n gle bl o o d sa m ple c ollecti o n bet wee n 2 t o 6 h o urs , i ncl usi ve, p ost d ose at s u bset of visits .
g.
At e ac h of t hese visits , t he test res ults m ust be re vie we d b y a me dicall y q ualifie d site staff a n d dee me d acce pta ble t o c o nti n ue partici pati o n i n stu d y.
C CI
C CI
C CI


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 23
2. INTRODUCTION
GLP-1 is a neuroendocrine hormone that is predominantly released from the small intestine 
in response to food intake1. Activation of the GLP-1R stimulates insulin release, inhibits 
glucagon secretion in a glucose-dependent manner, and delays gastric emptying2,3. In 
addition, GLP-1 has been shown to increase satiety and suppress food intake4.
PF-07081532 is an orally administered, potent and selective GLP-1R agonist in development 
as adjunct to diet and exercise, to improve glycemic control in T2DM, and for chronic weight 
management in a population that is overweight with co-morbidities or who have obesity.
2.1. Study Rationale 
The current study is the first study in the clinical program with PF-07081532 powered to 
evaluate the efficacy of a range of PF-07081532 doses compared to matching placebo in 
adults with T2DM inadequately controlled on metformin and separately adults with obesity 
but without T2DM via outpatient dosing, employing 4-week dose-escalation intervals for up 
to 20 weeks (and up to 5 steps), and evaluating once-daily doses up to 260 mg. The study 
includes open-label administration of Rybelsus, an orally administered peptidic GLP-1R 
agonist, as an internal reference standard evaluated in the population with T2DM. The 
population enrolled will be stratified as follows: 

Stratum 1: participants with T2DM inadequately controlled on metformin

Stratum 2: participants with obesity (defined as BMI ≥30 kg/m2) without T2DM
Additionally, randomization will be further stratified with the aim of randomizing ≥30% 
male (and hence ≤70% female) participants, in each of stratum 1 (T2DM) and stratum 2 
(obesity).
2.2. Background
2.2.1. Type 2 Diabetes Mellitus
The increase in the global prevalence of T2DM is largely attributed to rising rates of excess 
body weight and obesity5. T2DM is estimated to affect more than 424 million people 
worldwide6, and the prevalence of T2DM within the US is estimated to range from 12% to 
14%7. The lifetime risk of diabetes may be approximately 40% in both sexes, and above 50% 
in some minority populations8. T2DM is characterized initially 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 failure9. 
Patients with poorly controlled T2DM have an increased risk of developing complications 
associated with both microvascular and macrovascular disease, including nephropathy, 
neuropathy, retinopathy, CV disease, and stroke, and are at 2 to 4 times increased risk of 
mortality than adults who do not have diabetes10 which is associated with years of life lost8. 
While existing pharmacological options for the treatment of diabetes may provide 
satisfactory glycemic control for some patients, there remains a large number of patients who 


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 24
do not achieve targeted HbA1C levels, suggesting a need for additional therapeutic options
which minimize patient burden such as oral therapies.
Currently available GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and CV safety, with several agents having shown a benefit in CV outcomes11. Most 
available GLP-1R agonist treatment options are injected once weekly subcutaneously12,13. 
Injectable therapies are often underutilized due to patient hesitancy, whereas oral options are 
preferred by many patients. Only one GLP-1R agonist (Rybelsus) is currently commercially 
available for oral administration. However, oral semaglutide has strict administration 
requirements (food and water restrictions) and has limitations due to its low bioavailability,14
making it less convenient than an agent without such restrictions. A novel oral small 
molecule GLP-1R agonist that may further improve glucose control, reduce HbA1C levels, 
and decrease food intake and body weight compared to existing oral GLP-1R agonist, 
without any administration restrictions, is expected to be a preferred therapeutic option for 
patients with T2DM and/or obesity and their physicians.
2.2.2. Obesity 
Obesity is a chronic disease that is associated with serious comorbidities, including T2DM, 
dyslipidemia, hypertension, atherosclerosis, obstructive sleep apnea, and certain cancers,15
and is also associated with increased all-cause mortality16. The global burden of obesity is 
high with more than 600 million adults estimated to have obesity worldwide. In addition, the 
prevalence of obesity has doubled in more than 70 countries since 1980 and poses a major 
public health challenge17,18. First line treatment for obesity is lifestyle intervention including 
diet, exercise, and behavioral therapy. While effective in many patients, lifestyle intervention 
is often not sustainable, and many patients regain weight after initial weight loss19.
Pharmacotherapy has been approved for the long-term treatment of obesity and can be a 
useful adjunct to lifestyle intervention to augment and maintain weight loss. However, 
traditional oral anti-obesity agents demonstrate modest clinical weight reduction and can be 
associated with significant safety and tolerability concerns.
GLP-1R agonists, injectable semaglutide and liraglutide have, more recently, been authorized 
in several global regions for chronic weight management in persons with obesity or 
overweight with one or more obesity related comorbidities and at doses higher than those 
approved for glycemic control in T2DM.20,21 Based on this existing clinical history of 
injectable GLP-1R agonists and on Phase 1 data with PF-07081532 in participants with 
T2DM or obesity, oral, small molecule GLP-1R agonists are expected to decrease appetite 
and food intake, resulting in weight loss in patients with obesity and with or without T2DM, 
while avoiding the subcutaneous injection required by currently available peptidic GLP-1R
agonists.
2.2.3. Nonclinical Overview of PF-07081532 
PF-07081532 has been evaluated in a comprehensive nonclinical safety package that includes 
toxicity studies up to 6 months (in rats) and 9 months (in monkeys), as well as reproductive 
and developmental toxicology studies in rats and rabbits.


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 2 5
 
 
 
 
 
 
 
 
 
 
 
 
2. 2. 4. Cli nic al O ver vie w of P F - 0 7 0 8 1 5 3 2 
As of iss ua nce of t his pr ot oc ol, t w o P hase 1 st u dies e val uati n g P F -0 7 0 8 1 5 3 2 ha ve bee n 
c o m plete d. I n t otal, 8 8 partici pa nts ha ve bee n ra n d o mize d i ncl u di n g 2 2 healt h y  a d ult 
partici pa nts, 5 1 a d ult partici pa nts wit h T 2 D M , a n d 1 5 a d ult partici pa nts wit h o besit y. A t otal 
of 7 4 u ni q ue partici pa nts ha ve bee n e x p ose d t o at least 1 d ose of P F- 0 7 0 8 1 5 3 2. T he safet y 
pr ofile of P F - 0 7 0 8 1 5 3 2 was assesse d i n t hese 2 c o m plete d cli nical st u dies a n d, t o date, 
a d mi nistrati o n of P F -0 7 0 8 1 5 3 2 at si n gle d oses u p t o 2 0 0 m g a n d m ulti ple d oses u p t o 1 8 0 m g 
Q D has bee n c o nsi dere d safe, wit h maj orit y of T E A Es bei n g mil d i n i nte nsit y.
O ne P hase 1 st u d y, C 3 9 9 1 0 0 3, rece ntly c o ncl u de d . T his i n patie nt st u d y e nr olle d partici pa nts 
wit h T 2 D M i na de q uately c o ntr olle d o n metf or mi n, a n d partici pa nts wit h o besit y , t o recei ve 
P F -0 7 0 8 1 5 3 2 or place b o Q D f or 4 2 da y s. T he starti n g d ose f or t he first c o h ort of t his st u d y 
was 2 0 m g Q D of P F - 0 7 0 8 1 5 3 2, wit h s u bse q ue nt d ose le vels deter mi ne d base d o n e mer gin g 
data ; t he ma xi m u m d ose a d mi nistere d was 8 0 m g Q D . W hile fi nal cli nical data fr o m t his 
st u d y are n ot yet a vaila ble, as of iss ua nce of t his pr ot oc ol, t here ha ve bee n n o deat hs, S A Es 
or A Es of se vere i nte nsit y  re p orte d. 
2. 2. 5. R y bels us , Inter n al R efere nce S t a n d ar d, Ap pr o ve d i n T 2 D M
I n t his st u dy, R y bels us is bei n g use d as a n i nter nal refere nce sta n dar d i n Strat u m 1. R y bels us, 
se ma gl uti de, is t he o nly orall y  a d mi nistere d G L P-1 R a g o nist, a p pr o ve d f or t he treat me nt of 
T 2 D M .1 4 Se ma gl uti de is a pe pti de a n d is c o -a d mi nistere d wit h salca pr ozate s o di u m, a gastric 
per meati o n e n ha ncer w hic h pr o m otes t he a bs or pti o n of se ma gl uti de fr o m t he gastr oi ntesti nal 
tract. Se ma gl uti de acts i n a mec ha nistically si milar wa y t o P F -0 7 0 8 1 5 3 2 t o pr o m ote 
gl uc ose - de pe n de nt i ns uli n secreti o n a n d re d uce gl uca g o n secreti o n. I n t his st u d y, R ybels us, 
o ral se ma gl uti de, will be a d mi nistere d acc or di n g t o its a p pr o ve d pr o d uct la bel. Se ma gl uti de 
w as de vel o pe d b y N o v o N or dis k first as a n i njecta ble f or m ulati o n u n der t he tra de na me 
Oze m pic ,1 2 f oll o we d b y t he oral f or m ulati o n u n der t he tra de na me R y bels us .1 4
C CI


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 26
For more information on the safety and efficacy of oral semaglutide, see the current approved 
product label for Rybelsus.14
2.3. Benefit/Risk Assessment
While the primary pharmacology (GLP-1R agonism) is well-understood with clinical 
experience of peptidic GLP-1R agonists12,13,14,20,21 given the limited prior clinical experience 
with PF-07081532, a small molecule (not peptidic) GLP-1R agonist, close monitoring of 
randomized participants is envisioned in this first study in the clinical program with 
PF-07081532 powered to assess efficacy. Participants in this study may benefit from 
contributing to the scientific understanding of the potential for efficacy of PF-07081532 in 
the context of improving glycemic control in adults with T2DM, as well as those with obesity 
without T2DM.
A high level summary of the potential risks and well as benefits are offered in Section 2.3.1
and Section 2.3.2.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07081532 may be found in the IB22, which is the SRSD for this study.
The SRSD for Rybelsus is the USPI14.


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 27
2.3.1. Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) PF-07081532 and Rybelsus
Thyroid C-cell tumors

Potential risks are based on product labeling for 
injectable and oral GLP-1R agonists12,13,14,20,21 due 
to dose-dependent and treatment 
duration-dependent thyroid C-cell tumors in 
nonclinical studies in rats and mice at clinically 
relevant exposures

Of note, similar tumors were not seen in rodent 
studies with PF-07081532 likely as PF-07081532 
does not stimulate rodent GLP-1 receptors

Participants with a personal or within first-degree relative family 
history of medullary thyroid carcinoma or Multiple Endocrine 
Neoplasia syndrome type 2 are excluded – refer to Section 5.2

Participants with serum calcitonin >ULN excluded (Section 5.2)
plus serum calcitonin assessment included to monitor for this 
potential effect
Pancreatitis

Potential risks are based on product labeling for 
injectable and oral GLP-1R agonists12,13,14,20,21

Participants with a history of pancreatitis in the 12-months prior to 
Screening Visit are not eligible (Section 5.2)

Participants with serum lipase or serum amylase >ULN excluded
(Section 5.2)

Participants will be monitored for clinical signs of pancreatitis (eg, 
severe abdominal pain), and serum amylase and lipase will be
monitored
Hypoglycemia

Clinical trials with injectable GLP-1R agonists have 
not demonstrated an increased risk for 
hypoglycemia

However, when administered in combination with 
anti-diabetic agents that are known to have an 
increased risk of hypoglycemia (such as insulin or 
sulfonylureas), an increased risk for hypoglycemia 
was observed

Hypoglycemia is listed under “Warning and 
Precautions” for oral semaglutide14 when used in 
combination with an insulin secretagogue or insulin 
therapy

A low overall frequency of generally mild 
hypoglycemia has been reported in the 
PF-07081532 clinical development program to date

Only metformin will be permitted as background anti-hyperglycemic 
treatment - Section 6.9.1

For glycemic rescue, study does –
o
Not permit use of insulin – refer to Section 10.10
o
Plan to offer additional guidance to the participant (and site 
staff) regarding potential for hypoglycemia, if sulfonylurea
is used - Section 6.9.1

Blood glucose will be monitored by finger-stick home monitoring, 
using supplies provided by the Sponsor, and via central lab 
assessments at every onsite visit in this study – refer to Section 6.9.1
and Table 5

Participants will be informed about the signs and symptoms of 
hypoglycemia, and sites will monitor for these symptoms at clinical 
study visits - Section 6.9.1


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 2 8
P ote nti al Ris k of 
Cli nic al Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or Ris k
Miti g ati o n Str ate g y
I mpair m e nt i n re nal 
f u ncti o n

P ote ntial ris ks are base d o n pr o d uct la beli n g f or 
i njecta ble G L P-1 R a g o nists 1 2 ,1 3 ,2 0 ,2 1, a n d 
pre d o mi na ntl y occ ur i n patie nts wit h si g nifica nt 
na usea, v o miti n g, a n d de h y drati o n

P artici pa nts wit h si g nifica nt re nal i m pair me nt ( < 4 5 m L/ mi n/ 1. 7 3 m 2) 
are n ot eli gi ble (Secti o n 5. 2 )

Re nal f u ncti o n will be m o nit ore d at eac h st u d y visit b y t he ce ntral 
la b assessme nts of ser u m B U N, Scr , e G F R, a n d uri nar y 
al b u mi n:creati ni ne rati o - Ta ble 5

H y drati o n will be e nc o ura ge d as part of diet/e xercise c o u nseli n g –
refer t o Secti o n 1 0. 1 1
Gastr oi ntesti nal 
a d verse reacti o ns

P ote ntial ris ks are base d o n pr o d uct la beli n g f or 
i njecta ble a n d oral G L P -1 R a g o nists 1 2 ,1 3 ,1 4 ,2 0 ,2 1 (ie, 
lira gl uti de, e xe nati de, se ma gl uti de, a n d dula gl uti de)

G astr oi ntesti nal A Es, t he maj orit y of w hic h were 
mil d i n se verit y, ha ve bee n o bser ve d i n t he cli nical 
pr o gra m wit h P F -0 7 0 8 1 5 3 2

Partici pa nts will be m o nit ore d d uri n g t he cli nical st u d y visits, via 
b o d y wei g ht, vital si g ns, a n d la b orat or y assess me nts (S o A -Ta ble 1 ), 
t o pre ve nt p ote ntial se q uelae of a n y se vere gastr oi ntesti nal reacti o ns, 
e g, de h y drati o n

D ose escalati o n is li mite d t o o nce e ver y 4 wee ks t o i m pr o ve 
t olera bilit y - refer t o Sc he ma i n Secti o n 1. 2
Dia betic reti n o pat h y 
c o m plicati o ns

P ote ntial ris k is base d o n t he pr o d uct la beli n g f or 
t he i njecta ble G L P -1 R a g o nist, se ma gl uti de1 2 ,1 4 ,2 1
(i ncl u di n g oral se ma gl uti de) i n patie nts wit h T 2 D M

Partici pa nts wit h hist or y of dia betic reti n o pat h y 
w h o are ta ki n g t hese a ge nts s h o ul d be m o nit ore d f or 
pr o gressi o n of dia betic reti n o pat h y, as ra pi d 
i mpr o ve me nt i n gl uc ose c o ntr ol has bee n ass ociate d 
wit h a te m p orar y w orse ni n g of dia betic reti n o pat h y

P ote ntial partici pa nts wit h k n o w n pr oliferati ve reti n o pat h y a n d 
mac ular e de ma re q uiri n g ac ute treat me nt are e xcl u de d (S ecti o n 5. 2 )

Gl yce mic para meters will be m o nit ore d cl osel y , i n Strat u m 1 
( T 2 D M) d uri n g st u d y ( Secti o n 6. 9. 1 ) wi t h resc ue per mitte d w he n 
F P G t hres h ol ds are met (Secti o n 1 0. 1 2 )

F P G,  
 H b A 1 C m o nit ori n g i n t he e ntire st u d y p o p ulati o n at o nsite 
visits - S o A -Ta ble 2
I ncrease i n H R

P ote ntial ris k is base d o n t he pr o d uct la beli n g f or 
t he i njecta ble G L P -1 R a g o nists 1 2 ,2 1 f or T 2 D M a n d 
o besit y

M o dest i ncreases i n H R ha ve bee n n ote d i n t he 
earl y cli nical st u dies wit h P F -0 7 0 8 1 5 3 2 wit h m ost 
val ues wit hi n t he n or mal ra n ge. 
Vital si g ns, i ncl u di n g p ulse rate a n d B P, a n d 1 2 -lea d E C Gs assesse d at 
o n -site visits i n all partici pa nts (S o A -Ta ble 1 ) –

Pri or t o o n -site d osi n g of st u d y i nter ve nti o n 

A n d p ost d ose at i nter val c oi nci di n g wit h T ma x at selecte d visits i n 
t h ose ra n d o mize d t o P F-0 7 0 8 1 5 3 2/ place b o 
Ac ute gall bla d der 
disease

P ote ntial ris k is base d o n t he pr o d uct la beli n g f or 
t he i njecta ble a n d oral G L P -1 R a g o nists 1 2 ,1 4 ,2 1

Partici pa nts wit h acti ve/c urre nt s y m pt o matic gall bla d der disease are 
e xcl u de d (Secti o n 5. 2 )

P artici pa nts will be cl osel y m o nit ore d f or A Es a n d la b orat or y tests 
t hat ma y s u g gest de vel o p me nt of ac ute gall bla d der disease wit h 
a p pr o priate cli nical f oll o w-u p u n derta ke n

Li miti n g cal oric -ric h diet will be e nc o ura ge d as part of diet/e xercise 
c o u nseli n g - refer t o Secti o n 1 0. 1 1
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Suicidal 
ideation/behavior

Potential risk is based on the product labeling for 
the injectable GLP-1R agonists, liraglutide and 
semaglutide for obesity

Suicidal ideation has not been observed in the 
PF-07081532 clinical studies to date
In Stratum 2, participants with major depressive disorder or other severe 
psychiatric disorders, any lifetime history of a suicide attempt, and/or 
clinically significant responses on PHQ-9 or C-SSRS are excluded
(Section 5.2)

With post randomization of C-SSRS undertaken for close monitoring 
of participants – refer to Section 8.3.6
Study Procedures
Use of a placebo arm
Stratum 1: Participants randomized to placebo may not 
experience sufficient glycemic efficacy and/or body 
weight loss
Stratum 2: Participants randomized to placebo may not 
experience sufficient body weight loss
Stratum 1 –

A majority of the randomized study population will receive 
PF-07081532, or Rybelsus, and all participants will receive 
metformin and lifestyle counseling – Section 5.3.3.1

All participants will be eligible for glycemic rescue medication if 
meeting criteria for rescue and deemed necessary by the investigator
– Section 6.9.1.3
Stratum 2 –

A majority of the randomized study population will receive 
PF-07081532, and all participants will receive lifestyle counseling 
and support from study staff throughout the study – Section 5.3.3.2
All participants encouraged to adhere to protocol instructions and 
maintain study participation to maximize potential for weight reduction


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2.3.2. Benefit Assessment
The current study is the first time that PF-07081532 is being administered in an outpatient 
setting to participants with T2DM inadequately controlled on metformin and separately 
adults with obesity without T2DM. For the participants of this study, close monitoring of 
their medical condition and safety will occur as outlined in this protocol –

In Stratum 1 (participants with T2DM inadequately controlled on metformin), for 
every 7 participants randomized, 5 will receive PF-07081532, 1 will receive 
Rybelsus, and 1 will receive PF-07081532 matching placebo;

In Stratum 2 (participants with obesity without T2DM), for every 6 participants 
randomized, 5 will receive PF-07081532, and 1 will receive PF-07081532-matching 
placebo.
Those randomized to active arm (PF-07081532 or Rybelsus) may potentially derive benefit 
from the desired pharmacology, namely, improvement in glycemic control (Stratum 1) and 
weight loss (both Strata). Those randomized to placebo are not expected to obtain any 
specific benefit, beyond close monitoring of their medical condition and safety. All 
participants will receive general, standard-of-care guidance/counseling regarding the overall 
benefits of diet/exercise.
2.3.3. Overall Benefit/Risk Conclusion
In line with the clinical profile of marketed GLP-1R agonists, including Rybelsus, the most 
frequently reported AEs in the 2 completed studies with PF-07081532 administration have 
been in the Gastrointestinal Disorders SOC. In addition, as has been reported for marketed 
GLP-1R agonists, modest increases in heart rate have been observed with PF-07081532 
administration, with most heart rate values within the normal range. Based on available 
clinical data (Section 2.2.4 and current IB22), the dose-range planned for evaluation in this 
study is expected to be safe and well tolerated especially with the planned dose-escalation 
interval of 4 weeks and up to 5 steps to reach the target dose.
Based on the profile of PF-07081532 observed in nonclinical and clinical studies to date and
taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with study intervention are justified by the anticipated benefits that 
may be afforded to participants in this study.


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Protocol C3991004
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3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To evaluate the efficacy 
of a range of 
PF-07081532 doses 
compared to placebo, in 
participants with T2DM 
inadequately controlled 
on metformin
Placebo-adjusted, change from 
baseline in HbA1C at Week 32
The population average treatment effect on the 
change from baseline in HbA1C at Week 32 of 
PF-07081532 compared to placebo in the absence of 
glycemic rescue medication while on treatment

Measurements after initiation of glycemic 
rescue medication or discontinuation of study 
intervention will be censored and treated as 
missing data

Missing data due to censoring, study 
withdrawal or other reasons (eg, laboratory 
failure) will have data imputed based on a 
MAR assumption

Participants with inadequate compliance will 
have their HbA1C values used as-is in the 
analysis

The population-based treatment effect will be 
the difference in the mean change from 
baseline in each PF-07081532 arm compared to 
placebo
To evaluate the efficacy 
of a range of 
PF-07081532 doses 
compared to placebo, in 
participants with obesity 
but without T2DM
Placebo-adjusted, percent change 
from baseline in body weight at 
Week 32
The population average treatment effect on the 
percent change from baseline in body weight at 
Week 32 of PF-07081532 compared to placebo 
while on treatment 

Measurements after discontinuation of study 
intervention will be censored and treated as 
missing data

Missing data due to censoring, study 
withdrawal or other reasons (eg, equipment 
failure) will have data imputed based on a 
MAR assumption

Participants with inadequate compliance will 
have their body weight values used as-is in the 
analysis

The population-based treatment effect will be 
the difference in the mean percent change from 
baseline in each PF-07081532 arm compared to 
placebo
Secondary: 
Secondary:
Secondary: 
To assess the effect of a 
range of PF-07081532 
doses compared to 
placebo on various 
parameters, in 
participants with T2DM 
inadequately controlled 
on metformin
Proportion of participants who 
achieve HbA1C <7% 
(<53 mmol/mol) at Week 32
The odds ratio (PF-07081532 relative to placebo) of 
achieving HbA1C <7% (<53 mmol/mol) at Week 32 
in the absence of glycemic rescue medication while 
on treatment 

Measurements after initiation of glycemic rescue 
medication or discontinuation of study 
intervention will be censored and treated as 
missing data

Missing data will not be imputed. 

Participants with inadequate compliance will 
have their HbA1C values used as-is in the 
analysis


PF-07081532 
Protocol C3991004
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Page 32
Objectives
Endpoints
Estimands

The population-based treatment effect will be the 
odds ratio of PF-07081532 arm relative to 
placebo
Placebo-adjusted, change from 
baseline in FPG at Week 32
The estimand for placebo-adjusted, change from 
baseline in FPG at Week 32 endpoint will be 
constructed in a similar manner as Placebo-adjusted, 
change from baseline in HbA1C at Week 32
Placebo-adjusted, percent change 
from baseline in body weight at 
Week 32
The estimand for the placebo-adjusted, percent change 
from baseline in body weight at Week 32 endpoint 
will be constructed in a similar manner as Placebo-
adjusted, change from baseline in HbA1C at Week 32
To compare the efficacy 
of PF-07081532 and 
Rybelsus relative to 
placebo, in participants 
with T2DM
inadequately controlled 
on metformin
Placebo-adjusted, change from 
baseline in HbA1C at Week 32
The population average treatment effect on the 
change from baseline in HbA1C at Week 32 of each 
arm of PF-07081532 and of Rybelsus compared to 
placebo in the absence of glycemic rescue 
medication while on treatment 

Measurements after initiation of glycemic 
rescue medication or discontinuation of study 
intervention will be censored and treated as 
missing data

Missing data due to censoring, study 
withdrawal or other reasons (eg, laboratory 
failure) will have data imputed based on a 
MAR assumption

Participants with inadequate compliance will 
have their HbA1C values used as-is in the 
analysis
The population-based treatment effect will be the 
difference in the mean change from baseline in 
each PF-07081532 arm and Rybelsus arm
compared to placebo
To assess the effect of a 
range of PF-07081532
doses compared to 
placebo on various 
parameters in 
participants with obesity 
but without T2DM
Proportion of participants 
achieving ≥5%, ≥10%, and ≥15% 
body weight loss at Week 32 
relative to baseline 
Placebo-adjusted, absolute
change from baseline in waist 
circumference at Week 32
Placebo-adjusted, absolute
change from baseline in waist-to-
hip ratio at Week 32
Placebo-adjusted, change from 
baseline in HOMA-IR at 
Week 32
Placebo-adjusted, change from 
baseline in HOMA-S at Week 32

The odds ratio (PF-07081532 relative to 
placebo) of achieving HbA1C <7% 
(<53 mmol/mol) at Week 32 in the absence of 
glycemic rescue medication while on treatment
Measurements after discontinuation of 
study intervention will be censored and 
treated as missing data
Missing data will not be imputed
Participants with inadequate compliance 
will have their body weight values used 
as-is in the analysis
The population-based treatment effect will 
be the odds ratio of PF-07081532 arm 
relative to placebo

The estimand for each continuous endpoints
will be constructed in a similar manner as the 
primary endpoint Placebo-adjusted, percent 
change from baseline in body weight at 
Week 32
To assess the safety and 
tolerability with a range 
of PF-07081532 doses 
compared to placebo, in 
In each population randomized –
Number (and percent) of 
participants with: 
TEAEs


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 3 3
O bjecti ves
E n d p oi nts
Esti m a n ds
p artici p a nts wit h T 2 D M
i n a de q u ately c o ntr olle d 
o n metf or mi n a n d 
se paratel y p artici p a nts 
wit h o besity b ut wit h o ut 
T 2 D M
S A Es
A E lea di n g t o per ma ne nt
disc o nti n uati o n fr o m st u d y 
i nter ve nti o n or st u d y
H y p o gl yce mia
A E SIs
Cli nical la b orat or y
a b n or malities
Vital si g n a b n or malities
1 2 -lea d E C G a b n or malities
A n d T E A Es, prese nte d i n 
desce n di n g or der of fre q ue nc y 
T o assess t he safet y a n d 
t olera bilit y wit h a ra n ge 
of P F -0 7 0 8 1 5 3 2 d oses 
c o m pare d t o place b o, i n 
p artici p a nts wit h o besity 
b ut wit h o ut T 2 D M
Assess me nt of me ntal healt h as 
deter mi ne d b y –

C- S S R S
Terti ar y: 
Terti ar y:
Terti ar y: 
T o c haracterize P K of –

P F -0 7 0 8 1 5 3 2, i n 
p artici p a nts wit h 
T 2 D M i n a de q u ately 
c o ntr olle d o n 
m e tf or mi n a n d 
se paratel y
I n e ac h p o p ulati o n ra n d o mize d, 
descri pti ve s u m mar y of tr o u g h 
c o nce ntrati o ns of P F - 07 0 8 1 5 3 2 a n d 
R y bels us
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 3 4
O bjecti ves
E n d p oi nts
Esti m a n ds
p artici p a nts wit h 
o besity b ut wit h o ut 
T 2 D M

R y bels us, i n 
p artici p a nts wit h 
T 2 D M i n a de q u ately 
c o ntr olle d o n 
m e tf or mi n
I n all cases, baseli ne defi ne d as t he e val ua ble res ult cl osest pri or t o d osi n g o n Da y 1/ Visit 3
4. S T U D Y D E SI G N
4. 1. O ver all Desi g n
T his is a m ultice nter, m ulti nati o nal, ra n d o mize d, d o u ble -bli n d, d o u ble -d u m m y , 
place b o -c o ntr olle d, d ose-ra n gi n g, d ose-fi n di n g, parallel-gr o u p st u d y t o access efficac y a n d 
safety /t olera bilit y of P F -0 7 0 8 1 5 3 2, a n d o pe n -la bel R y bels us, i n a d ults wit h T 2 D M 
i na de q uately c o ntr olle d o n metf or mi n ( Strat u m 1), a n d se parately P F - 0 7 0 8 1 5 3 2 c o m pare d t o 
matc hi n g place b o i n a d ults wit h o besit y  b ut wit h o ut T 2 D M ( Strat u m 2) – refer t o o verall 
desi g n sc he ma i n Secti o n 1. 2

I n Str at u m 1 , t hree i nter ve nti o ns, P F-0 7 0 8 1 5 3 2, its matc hi n g place b o, a n d o pe n -la bel 
R y bels us, will be e val uate d acr oss 7 ar ms i n partici pa nts wit h T 2 D M o n a 
bac k gr o u n d of metf or mi n. 

I n Str at u m 2 , t w o i nter ve nti o ns, P F-0 7 0 8 1 5 3 2 a n d its matc hi n g place b o, will be 
e val uate d acr oss 6 ar ms i n partici pa nts wit h o besit y. 

Acr oss all 1 2 treat me nt ar ms of P F - 0 7 0 8 1 5 3 2/ place b o eac h d ose will c o nsist of 
3 ta blets. T he treat me nt d urati o n i n t his st u d y will be 3 2 wee ks f or m ost partici pa nts; 
C CI


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Protocol C3991004
Final Protocol, 13 September 2022
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Page 35
though in the first set of up to 25% randomized participants, treatment interval will 
extend for an additional up to 12 weeks (for a total duration of up to 44 weeks). 

Dosing across the 12 arms of placebo/PF-07081532 (including dose-escalation, 
maintenance, and extension (in up to first 25% randomized) – refer to dose-escalation 
schema in Section 1.2 – is accommodated via administration of 3 tablets per dose QD, 
and planned using dispensation of 3 bottles (1 tablet per bottle) – refer to Table 3.
Once confirmed to be eligible based on assessments performed at the Screening Visit, 
participants will transition to Run-In/Visit 2 and receive single-blind PF-07081532-matching 
placebo for 14 ± 2 days. On Day 1/Visit 3, participants who meet randomization criteria will 
be randomly assigned to receive double-blinded, double-dummy, PF-07081532 or placebo 
(and in Stratum 1, open-label Rybelsus).

For the majority of participants, a total of 21 visits (from Screening to second
Follow-up Visit) including 12 on-site plus 9 telephone contacts are planned – with the 
total duration of participation in study ranging from 40 to 44 weeks;

For up to the first 25% of participants randomized, an additional 3 on-site visits are 
planned with the duration of participation extended by 12-weeks with the total 
duration of participation in study, hence, ranging from 52 to 56 weeks.
Approximately 780 participants (60/arm) will be enrolled (ie, randomized) in the study to 
ensure approximately 650 participants (51/arm) offer evaluable data for the primary 
endpoint. Across each of the two populations, approximately 420 participants (60/arm) with 
T2DM inadequately controlled on metformin plus approximately 360 (60/arm) with obesity 
but without T2DM, will be enrolled – refer to Section 9.5.
4.2. Scientific Rationale for Study Design
The current study is the first study with PF-07081532 powered to assess the efficacy of the 
agent on glycemic control and weight. A range of doses of PF-07081532 are being evaluated, 
via outpatient dosing and dose-escalation once every 4 weeks, in participants with T2DM 
inadequately controlled on metformin and separately in adults with obesity without T2DM. 
Duration of stable dose of metformin prior to Screening Visit set at ≥8-weeks such that by 
the time of baseline assessment of HbA1C, metformin would have been administered at a 
stable dose for ≥12-weeks. The treatment phase is proposed as at least 32 weeks (including 
up to 20 weeks for dose-escalation) to permit an evaluation of near nadir for glycemic effect 
and a clear trajectory for weight loss effect. In up to the first 25% of the total sample size 
randomized, an extension phase of up to 12 weeks has been added to permit sparse collection 
of endpoints beyond the primary timepoint (Week 32). These additional data along with 
model-based-meta-analysis of data from other GLP-1R agonists will permit extrapolation 
beyond the current study duration and better identification of doses to take forward into 
future clinical development. 
A priori, to permit an evaluation of efficacy on glycemic control and in parallel assess effect 
on body weight, this study employs stratification based on population – T2DM inadequately 


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 3 6
c o ntr olle d o n metf or mi n a n d se paratel y a d ults wit h o besit y wit h o ut T 2 D M. I n a d diti o n, t his 
st u d y will e nr oll re prese ntati ve p o p ulati o n via a n a d diti o nal stratificati o n, b y se x, a n d ai m t o 
ra n d o mize ≥3 0 % males a n d he nce ≤7 0 % fe males, i n eac h p o p ulati o n strat u m.
Partici pa nts wit h T 2 D M e nr olle d i n t his st u d y ( Strat u m 1) will be i na de q uatel y c o ntr olle d o n 
metf or mi n al o ne at d oses ≥5 0 0 m g/ da y  (a n d u p t o t he hi g hest a p pr o ve d d ose i n c o u ntr y). A 
cli nical D DI st u d y wit h metf or mi n has n ot bee n c o n d ucte d si nce base d o n assess me nt usi n g 
i n vitr o data a n d a ph y si ol o gically rele va nt static mec hanist ic m o del , P F -0 7 0 8 1 5 3 2 , is n ot 
e x pecte d t o i m pact t he P K of metf or mi n a n d as s uc h t he ris k of a cli nical i nteracti o n is 
dee me d ne gli gi ble. Gi ve n t he c o ntri b uti o n of C Y P 3 A i n t he meta b olis m of P F- 0 7 0 8 1 5 3 2 a n d 
t he fact t hat P F - 0 7 0 8 1 5 3 2 is e x pecte d t o be cleare d via he patic O A T P u pta ke, str o n g C Y P 3 A 
i n hi bit ors or C Y P 3 A i n d ucers a n d cli nically si g nifica nt O A T P i n hi bit ors will be pr o hi bite d i n 
t his st u d y (A p pe n di x 1 0 ). A d diti o nall y , b ase d o n t he pre dicte d D DI lia bilities ( usi n g i n vitr o 
data a n d a p h ys i ol o gicall y rele va nt static mec ha nistic m o del) of P F- 0 7 0 8 1 5 3 2, certai n 
se nsiti ve s u bstrates f or w hic h i n hi biti o n of U G T 1 A 1 a n d C Y P 2 C 1 9 pat h wa ys w o ul d be 
e x pecte d t o cli nicall y si g nifica ntly alter t heir safet y or efficac y will n ot be per mitte d i n t his 
st u d y (A p pe n di x 1 0 ). 
T he i ncl usi o n of R y bels us will pr o vi de a n i nter nal sta n dar d f or t he st u d y t o better cali brate 
st u d y perf or ma nce a n d i nter pret fi n di n gs wit h P F-0 7 0 8 1 5 3 2 i n a d ults wit h T 2 D M 
i na de q uately c o ntr olle d o n metf or mi n. W hile R y bels us is o pe n -la bel, use d acc or di n g t o its 
a p pr o ve d d osi n g i nstr ucti o ns, pre vi o us o pe n- la bel st u dies of oral se ma gl uti de (e g, 
PI O N E E R - 42 3 a n d - 72 4) ha ve yi el de d si milar gl yc e mic efficac y a n d t olera bility res ults as 
t h ose o bser ve d i n d o u ble-bli n d st u d y (e g, PI O N E E R - 22 5). I n Strat u m 2 ( O besit y), assess me nt 
of C -S S R S ( S o A -Ta ble 1 ) pl us P H Q 9 at Scree ni n g Visit a n d Da y 1 incl u de d gi ve n ris k of 
me ntal healt h/s uici dalit y  i n t his p o p ulati o n; b ut n ot i n t h ose wit h T 2 D M i na de q uately 
c o ntr olle d o n metf or mi n ( Strat u m 1) – t his a p pr oac h is c o nsiste nt wit h t his differe nce i n ris k 
i n t he la bel f or se ma gl uti de i n T 2 D M vers us O besit y – refer t o Secti o n 2. 3. 1 .
Be y o n d t he pri mar y  assess me nt of H b A 1 C (i n T 2 D M) a n d b o dy wei g ht (i n o besit y wit h o ut 
T 2 D M ), t he c urre nt st u d y als o u n derta kes assess me nt f or p ote ntial i m pr o ve me nt o n ot her 
meas ures of gl yc e mia ( F P G,
 H O M A-I R, H O M A-S, as well as ot her c o nti n u o us a n d 
cate g orical data), wei g ht l oss ( waist circ u mfere nce, waist- t o-hi p rati o), a n d fasti n g li pi d 
para meters ( H D L -C, direct L D L -C, T G, t otal c h olester ol), t o per mit c o m paris o n t o p u blis he d 
data wit h pe pti dic G L P- 1 R a g o nists. W hile tra diti o nal ba n ki n g of plas ma/ser u m/ w h ole bl o o d 
is n ot pla n ne d, 
. T his st u d y  i ncl u des 1 2- lea d E C G assess me nts b ot h pre -
a n d p ost- P F -0 7 0 8 1 5 3 2/ place b o d osi n g t o e x pl ore a n y p ote ntial relati o ns hi p bet wee n
e x p os ure a n d Q T - Secti o n 9. 3. 4. 1 .
C CI
C CI
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 3 7
 
 
 
 
 
W hile t he cli nical e x perie nce wit h P F - 0 7 0 8 1 5 3 2 is li mite d t o ma xi m u m of 6 wee ks, 
tra nsiti o n t o t he c urrent st u d y  of u p t o 4 4 wee ks of d osi n g is dee me d t o be acce pta ble gi ve n: 
(a) prece d e nte d pri mar y  p har mac ol o g y ( G LP- 1 R a g o nis m) wit h cli nical e x perie nce of 
pe pti dic G L P- 1 R a g o nists ; ( b) c hr o nic t o xicit y st u dies wit h P F - 0 7 0 8 1 5 3 2 i n rats ( u p t o 
6 m o nt hs) a n d m o n ke y s ( u p t o 9 m o nt hs) dis pla y  n o e vi de nce of off-tar get p har mac ol o g y 
wit h mar gi ns of 4 0 x ( C ma x ) a n d 2 9 x (A U C 2 4) relati ve t o N O A E L i n 6-m o nt h rat st u d y  a n d 
5. 2 x ( Cma x ) a n d 4. 6 x (A U C 2 4) relati ve t o N O A E L i n 9-m o nt h m o n ke y  st u d y; a n d (c) si n gle 
( u p t o 2 0 0 m g) a n d re peate d d oses ( u p t o 1 8 0 m g Q D) u p t o 6 wee ks were c o nsi dere d safe 
a n d were de m o nstrate d t o ha ve a t olera bilit y  pr ofile c o nsiste nt wit h t he mec ha nis m of acti o n. 
Des pite t his safet y pr ofile, gi ve n t he tra nsiti o n t o t he pr o p ose d u p t o 4 4 wee ks of d osi n g i n 
t his st u d y, meas ures t o e ns ure partici pa nt safety are i ncl u de d – ( a) eli gi bilit y criteria a n d 
safety m o nit ori n g strate g y ai me d at mi ni mizi n g ris k – refer t o Secti o n 2. 3. 1 ; ( b) fre q ue nt 
(e ver y 2 wee k), visits wit h site staff eit her as o ut patie nt visits or tele p h o ne c o ntact, u p t o 
Wee k
3 2 / Visit 1 9 wit h pr o visi o ns f or u n pla n ne d visits f or f oll o w- u p of A Es ( refer t o 
Secti o n 8. 4. 3 ) a n d cli nicall y si g nifica nt la b orat or y res ults; (c) as m uc h as pr actic ally d o a ble , 
t he use of sa me-d a y  s hi pme nt of safet y-relate d bl o o d/ uri ne sa m ples t o s p o ns or- i de ntifie d 
ce ntral la b orat or y wit h ra pi d t ur n-ar o u n d of safet y- relate d res ults a n d ma na ge me nt of o verall 
gl yc e mic c o ntr ol (A p pe n di x 1 2 ); ( d) use of a n IR C (refer t o Secti o n 9. 4 a n d Secti o n 1 0. 1. 5. 1 )
t o u n derta ke u n bli n de d re vie w of data p ost ra n do mizati o n, at a mi ni m u m, of a p pr o xi matel y  
2 5 %, 5 0 %, 7 5 % a n d 1 0 0 % of pla n ne d t otal sa m ple size; a n d (e) peri o dic bli n de d re vie w of 
safety b y t he s p o ns ors’ cli nical tea m me m bers t o assess f or p ote ntial tri g ger f or a d diti o nal 
I R C u n bli n de d re vie w(s) of c u m ulati n g safet y data w hile t he st u d y  is o n-g oi n g.
A c o m paris o n of e x p os ures of P F- 0 7 0 8 1 5 3 2 a d mi nistere d u n der faste d a n d fe d c o n diti o ns
i n dicate t hat P F-0 7 0 8 1 5 3 2 ma y  be a d mi nistere d wit h o ut re gar d t o f o o d. T he cli nical P K a n d 
o bs er ve d half -life of P F-0 7 0 8 1 5 3 2 (ra n gi n g bet wee n 2 0. 7 t o 2 6. 5 h o urs f oll o wi n g m ulti ple 
d osi n g) are s u p p orti ve of o nce dail y a d mi nistrati o n. T h us, a d mi nistrati o n of 
P F -0 7 0 8 1 5 3 2/ place b o i n t his st u d y will be re q ueste d t o occ ur wit h t he m or ni n g meals – gi ve n 
the i m p orta nce of re g ular meals t o t he sta n dar d -of -care diet c o u nseli n g f or t he pla n ne d 
p o p ulati o n.
F or all partici pa nts dee me d eli gi ble after Scree ni n g Visit , tra nsiti o n t o Visit 2 / R u n-I n is 
ma n dat or y  f or a fi xe d, si n gle-bli n d, 2- wee k peri o d (ie, Visit 2/ R u n- I n t o 1-da y  pri or t o 
Visit 3 / Da y 1). T his is i ncl u de d wit h t he e x plicit p ur p ose of fa miliarizi n g t he partici pa nts 
wit h t he d osi n g i nstr ucti o ns f or t he st u d y  i nter ve nti o n (refer t o Ta ble 3 ), a n d t o e xcl u de 
partici pa nts w h o are n ot c o m plia nt wit h t he si n gle -bli n d place b o pri or t o ra n d o mizati o n i n a n 
atte m pt t o mi ni mize me dicati o ns err ors p ost ra n d o mizati o n.
C CI


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4.2.1. Diversity of Study Population
Diversity of study population in this protocol applies to sites in US only. This diversity 
strategy will include high-performing sites with the potential to support the recruitment of 
diverse populations. Reasonable attempts will be made to enroll participants that are 
representative of the patient population that will be treated with PF-07081532 in clinical 
practice. The following strategies may be explored in support of diverse recruitment efforts:

Inclusion of diversity questions into the Feasibility Survey and Pre-Trial Assessment 
to identify sites with access to diverse patient populations

Selecting sites that have access to diverse participants within their locale

Discussion with investigator sites during pre-trial assessment to assess preparedness, 
mitigation strategies for reaching diversity goals, and active inclusion

Encouragement of investigator sites to complete the Investigator Site Recruitment 
Plan

Have proactive discussions with investigator sites throughout the enrollment period to 
assess and reevaluate site specific strategies as needed to best position each site for 
the most diverse representation enrollment outcomes

Collaboration with patient advocacy groups

Monitor diverse enrollment to identify potential opportunities to include diverse 
populations
4.2.2. Choice of Contraception/Barrier Requirements 
Both women of childbearing potential, as well as those who are of non-childbearing 
potential, may be enrolled given the availability of EFD nonclinical toxicity studies with 
PF-07081532. However, measures will be taken to limit the risk of pregnancy in the female 
population of childbearing potential enrolled (see SoA-Table 1, SoA-Table 2, and 
Appendix 4).
The potential risk of exposure to PF-07081532 in a sexual partner of a male participant in 
this study via ejaculate is low, and therefore no contraception (condom) use in male 
participants is warranted. The calculated safety margin is ≥100-fold between the estimated 
partner exposure due to seminal transfer and the NOAEL for serious manifestations of 
developmental toxicity in nonclinical studies. The safety margin of 100-fold is based on 
applying a 10-fold safety factor for interspecies extrapolation and a 10-fold safety factor for 
susceptible populations.40


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4.3. Justification for Dose
4.3.1. PF-07081532 
The dose range selected (refer to dose-escalation schema in Section 1.2) for this study is
based on observed safety, tolerability, PK, and PD data in completed Phase I clinical studies 
along with data obtained in nonclinical toxicity studies.
In Stratum 1 (T2DM inadequately controlled on metformin), this study is designed to 
evaluate the dose-response of PF-07081532 from low doses, predicted to have sub-maximal 
effects on HbA1C up to doses expected to have greater HbA1C lowering efficacy, while still 
having an adequate tolerability profile. Based on preliminary dose-response analysis of mean 
daily glucose data following repeated dose data in participants with T2DM and translation to 
HbA1C efficacy via semi-mechanistic modeling,28 the proposed PF-07081532 targeted dose 
levels, in Stratum 1, of 20, 40, 80, 160, and 260 mg QD are expected to result in HbA1C
lowering that is 26%, 40%, 56%, 71% and 80% of the maximal response, respectively.
In Stratum 2 (Obesity without T2DM), planned doses will be different than Stratum 1 with
the lowest planned targeted dose in the former being 4-fold higher (80 mg QD). This 
acknowledges that with peptidic GLP-1R agonists, higher doses are needed to observe 
clinically meaningful weight loss compared to improvement in glycemic control. Based on 
the available Phase 1 data with PF-07081532, it is anticipated that the dose range tested in 
Stratum 2 (from 80 to 260 mg QD) will adequately bracket the efficacious dose needed to 
achieve comparable weight loss to that of approved injectable GLP-1R agonists, while still 
having an adequate tolerability profile. Escalation of PF-07081532 to the target dose of 
200 mg QD will be assessed via different dose steps in two different arms of the study to 
investigate impact of the dose escalation scheme on tolerability.
Single doses up to 200 mg and multiple doses up to 180 mg QD of PF-07081532 have been 
shown to be safe, with no clinically relevant dose-related adverse trends and a tolerability 
profile consistent with the mechanism of action. The duration of repeat dosing in the 
completed multiple ascending dose study was limited to 6 weeks with rapid escalation over 
5 weeks before reaching the top dose (180 mg QD). In the current study, PF-07081532 doses 
will be escalated over a period of up to 20 weeks with escalation steps of every 4 weeks, 
which, in line with other marketed GLP-1R agonists, is expected to further improve 
tolerability and mitigate the adverse MoA-based GI side effects11,29. The lowest dose of 
20 mg QD, in Stratum 1, is expected to be well tolerated without the need for escalation and 
thus will be dosed at the same dose level for the entire duration. The predicted PF-07081532 
exposure at the highest 260 mg QD dose is lower than the exposure observed at the NOAEL 
in the pivotal 9-month toxicology study in monkeys, after accounting for differences in 
plasma protein binding between species. Therefore, this dose level is not anticipated to pose 
an undue safety risk. Based on the above, PF-07081532 doses up to 260 mg QD are viewed 
as appropriate for assessment in this study with an expected acceptable safety and tolerability 
profile. 
4.3.2. Rybelsus
The highest approved dose (14 mg QD) of Rybelsus, the only currently approved oral 
GLP-1R agonist, for the treatment of T2DM, was selected to be evaluated in this study as a 


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within-study benchmark of the efficacy and tolerability profiles observed with PF-07081532. 
The dose escalation scheme that will be employed in this study is in line with Rybelsus
prescribing information14.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit in the study (ie, second Follow-up 
Visit shown in SoA-Table 1, SoA-Table 2) for the last participant in the study globally.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the second Follow-up Visit shown in SoA-Table 1, SoA-Table 2.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
pre-screening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. 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.
Pfizer will review eligibility criteria verified by the investigator or qualified designee to 
confirm that participants meet study eligibility criteria before they are enrolled/randomized
into the study. The enrollment/randomization approval process will be initiated for a 
participant after an informed consent document has been signed and the investigator or 
qualified designee has assessed the participant as eligible. The enrollment/randomization 
approval will be based on review of CRF/system data.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1.
Male or female 18 years or older (or the minimum age of consent in accordance 
with local regulations) and up to 75 years, inclusively, at the Screening Visit.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and 
female (Section 10.4.2) participants including requirement for pregnancy 
testing (Section 8.3.5);


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Disease Characteristics:
2. For Stratum 1 only:

Participants diagnosed with T2DM inadequately controlled with metformin at 
doses ≥500 mg/day (and up to the highest approved, in country dose) with 
metformin dose stable for ≥8 weeks prior to Screening Visit;

BMI ≥23.0 kg/m2 (≥20.0 kg/m2 in Japan), using the average of the duplicate 
body weight assessment at Screening Visit, and with 1 other assessment of 
BMI via duplicate body weight assessment permitted, on a different day, to 
assess eligibility;

HbA1C of 7% to 10% (53-86 mmol/mol), inclusive, at Screening Visit, with 
result as assessed using a method that is NGSP certified and standardized to 
the DCCT assay, by the sponsor-identified central laboratory, with a single 
repeat permitted to assess eligibility;

FPG ≤270 mg/dL (15 mmol/L) at Screening Visit, with a single repeat 
permitted to assess eligibility;
3. For Stratum 2, only:

Participants with obesity, defined by BMI ≥30.0 kg/m2, using the average of 
the duplicate body weight assessment at Screening Visit, and with 1 other 
assessment of BMI via duplicate body weight assessment permitted, on a 
different day, to assess eligibility;

HbA1C ≤6.4% (47 mmol/mol), at Screening Visit, with result as assessed 
using a method that is NGSP certified and standardized to the DCCT assay, by 
the sponsor-identified central laboratory, with a single repeat permitted to 
assess eligibility;

FPG ≤126 mg/dL (7 mmol/L) at Screening Visit, with a single repeat 
permitted to assess eligibility;
Other Inclusion Criteria:
4. At the Screening Visit, participants willing to adhere to dose-escalation and 
MoA-based GI AEs mitigation strategies – refer to Section 10.11.


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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Any of the following clinically significant medical conditions –

Active/current, symptomatic gallbladder disease;

History of pancreatitis in the 12-months prior to Screening Visit;

History of Type 1 Diabetes Mellitus, or secondary forms of diabetes 
(NOTE: a history of gestational diabetes that has resolved is allowed);

Any condition affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, or any area of intestinal resection, active inflammatory bowel
disease or pancreatic insufficiency); 

Known medical history of active liver disease (other than non-alcoholic 
hepatic steatosis), including active hepatitis, primary biliary cirrhosis, ascites;
2. Use of pharmacological agents with approved indication for weight loss (eg, orlistat, 
sibutramine, GLP-1R agonists), over-the-counter appetite- stimulant or appetite-
suppressant, as advertised, within 12 weeks of Screening Visit; or weight loss of >5% 
in the 12 weeks prior to Screening Visit, based on participants medical records or as 
reported by the participant;
3. For Stratum 1 only: 

Use of any pharmacological agent with an approved indication for T2DM 
(other than metformin), or herbal medications, for the explicit purpose of 
glycemic control within 12 weeks of Screening Visit;

History of diabetic ketoacidosis unless this was the presentation leading to 
diagnosis of T2DM without recurrence since initial presentation;

Proliferative retinopathy or maculopathy requiring acute treatment; 
4. For Stratum 2 only: 

Previous or planned (during the study) weight reduction surgery or device use, 
with the following exceptions so long as body weight has stabilized

Liposuction and/or abdominoplasty;

Lap banding if band has been removed;


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
Intragastric balloon if balloon removed; 

Duodenal-jejunal bypass sleeve if removed;

Diagnosis of T2DM;

Use of pharmacological agent(s) with approved indication for glycemic 
control except metformin when used for the explicit sole purpose of managing
PCOS;

Any of the following –

Major depressive disorder or other severe psychiatric disorders (eg, 
schizophrenia or bipolar disorder) within 2 years prior to Screening Visit;

Any lifetime history of a suicide attempt; 

PHQ-9 score ≥15 – at the Screening Visit or Day 1/Visit 3; 

Response of “yes” to Question 4 or 5, or on any suicidal behavioral 
question on the C-SSRS – at the Screening Visit or Day 1/Visit 3;
5. Clinically significant cardiovascular conditions defined by either of the following –

Myocardial infarction, stroke, hospitalization for unstable angina, or transient 
ischemic attack within 12 weeks prior to Screening Visit;

Presentation of unstable angina or congestive heart failure (NYHA class III or 
IV) or significant edema managed with diuretics with or without evidence of 
ascites, at Screening Visit; 
6. Uncontrolled blood pressure defined as average of triplicate assessment being 
≥160 mmHg (systolic) or ≥100 mmHg (diastolic), at Screening Visit
(Section 8.3.2.1), with 1 other assessment of average BP via triplicate assessment
permitted, on a different day, to assess eligibility; or on Day 1/Visit 3

Participants on anti-hypertensive medication(s) to treat hypertension should be 
on a stable dose ≥4 weeks prior to Screening Visit;
7. Personal or within first-degree relative family history of MTC or MEN2;
8. Other medical or psychiatric condition including recent or active suicidal 
ideation/behavior or laboratory abnormality that may increase the risk of study 


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participation or, in the investigator’s judgment, make the participant inappropriate for 
the study including –

Recent (within 5 years of Screening Visit) systemically administered 
treatments for malignancy including (but not limited to) the use of 
chemotherapy, radiotherapy, or immunotherapy; or any other active 
malignancy (within 3 years of Screening Visit), except for adequately treated 
basal cell or squamous cell skin cancer, or carcinoma in situ.
Prior/Concomitant Therapy:
9.
Current use of any prohibited concomitant medication(s) or participants
unwilling/unable to use a permitted concomitant medication(s) - refer to Section 6.9
and Section 10.10;
Prior/Concurrent Clinical Study Experience:
10. Participants noted to be non-compliant (based on tablet count and defined as 
compliance of <80% or >120%) with incorrect self-administration (ie, deviating from 
1 tablet from each bottle daily) with the single-blind placebo administered from 
Run-In/Visit 2 to 1 day before Day 1/Visit 3, inclusive;
11. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose on Day 1/Visit 3 in this study (whichever is longer);

Investigational products which are strong CYP3A inducers are prohibited 
within 14 days plus 5 half-lives preceding the first dose of study intervention
refer to Section 10.10;
12. Previous participation in a clinical study evaluating PF-07081532 (including exposure 
to placebo) or intolerance or hypersensitivity to a GLP-1R agonist;
Diagnostic Assessments:
13. Results as reported by sponsor-identified central laboratory, at Screening Visit, as 
below, with a single repeat permitted to assess eligibility:

Fasting C-peptide <0.8 ng/mL;

ALT or AST ≥2.5x ULN;

Direct bilirubin >ULN or T Bili >1.5x ULN except when participants have a 
history of Gilbert syndrome where total bilirubin >1.5x ULN would be 
eligible provided direct bilirubin level is ≤ULN; 

TSH >1.5x ULN or <LLN;


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
Serum calcitonin >ULN;

Serum amylase or serum lipase >ULN;

eGFR (using CKD-EPI-Scr-Scys Combined <45 ml/min/1.73 m2 – refer to 
Section 10.7.2.1;

Active Hepatitis B, or Hepatitis C;

A positive urine drug test for illicit drugs –

Participants who have been medically prescribed controlled/scheduled 
drugs and report the use of these drugs to the investigator at Screening 
Visit may be allowed to participate with notification to the sponsor; 

This one laboratory-based assessment not permitted to be repeated to 
confirm eligibility.
14. At Screening Visit, average of triplicate assessment of standard 12-lead ECGs
(Section 8.3.3) that demonstrates clinically relevant abnormalities that may affect 
participant safety or interpretation of study results (eg, QTcF >450 ms, 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 the Screening Visit, average of triplicate assessment, uncorrected QT 
interval is >450 ms, this interval should be rate corrected using the Fridericia 
method only and the resulting QTcF should be used for decision making and 
reporting;

If average of triplicate assessment of QTcF exceeds 450 ms, or QRS exceeds 
120 ms, 1 other assessment of average cardiac conduction intervals (QTcF and 
QRS) via triplicate assessment is permitted on a different day, to determine 
the participant’s eligibility;

Computer-interpreted ECGs should be overread by medically qualified 
individual (either site or central reader) experienced in reading ECGs before 
excluding a participant.
Other Exclusion Criteria:
15. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and 
sponsor delegate employees directly involved in the conduct of the study and their 
family members.


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5.3. Lifestyle Considerations
The following sections describe guidelines for diet, physical activity, alcohol, caffeine and 
tobacco use and contraception requirements that are to be followed throughout the study.
5.3.1. Contraception 
In females of child-bearing potential, the investigator or their designee, in consultation with 
the participant, will confirm that the participant is utilizing an appropriate method of 
contraception for the individual participant from the permitted list of contraception methods 
(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed in 
its consistent and correct use. At time points indicated in the SoA-Table 1, the investigator or 
designee will inform the participant of the need to use acceptable effective contraception 
consistently and correctly and document the conversation and the participant’s affirmation in 
the participant’s chart. Participants need to affirm their consistent and correct use of at least 1
of the selected methods of contraception, considering that their risk for pregnancy may have 
changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Dietary Restrictions

Participants must abstain from all food and drink (except water) for ≥8 hours prior to 
all pre-dose procedures outlined in SoA-Table 1, SoA-Table 2;

Water may be consumed as desired (ad libitum) up to 2 hours prior to pre-dose blood 
sampling;

PF-07081532/placebo must be administered QD in the morning; and with the 
morning meal as much as possible; 

Stratum 1 only: Rybelsus must be administered QD in the morning ≥30 minutes 
before the first meal/beverage, or other oral medications with ≤4 oz (120 mL) water;

On scheduled on-site visits (SoA-Table 1, SoA-Table 2), participants should be 
instructed to arrive following an overnight fast of ≥8 hours (without having 
consumed any food/beverage [except water]) and without self-administration of study 
intervention;

Note: Participants, other than the Rybelsus group, may take their morning dose of 
their background medications before their visit per their usual routine, if 
applicable.


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
On the mornings of scheduled on-site visits (SoA-Table 1, SoA-Table 2), the study 
intervention will be administered at the site –

The morning meal during site visits will be either provided by the site or the 
participant provided a voucher [or similar] by the site to purchase the meal before 
arriving at the site for each visit with caloric content of approximately 
300 calories and macronutrient composition commensurate to dietary counseling 
(Section 5.3.3);

Participants will be counseled on appropriate dietary (Section 5.3.3) and physical 
activity (Section 5.3.4) guidelines, at the times listed in SoA-Table 1, and asked to 
maintain these guidelines throughout participation in the study; of note, initiation of 
participation in formal weight loss program(s) should be avoided after Day 1/Visit 3
and until the completion of the first follow-up visit.
5.3.3. Dietary Counseling
At times listed in the SoA-Table 1, participants will receive dietary counseling29 by 
appropriate site staff and asked to follow these guidelines throughout the treatment phase 
(and up to Week 44). In addition, suggested dietary modifications are outlined in 
Section 10.11.
5.3.3.1. Stratum 1 (T2DM inadequately controlled with metformin)
Participants will be counseled on appropriate dietary and lifestyle guidelines for T2DM.
Counseling on dietary guidelines should be in accordance with local medical standards of 
care for patients with T2DM. 
5.3.3.2. Stratum 2 (Obesity without T2DM)
Consistent with the expected background of diet and exercise, participants in Stratum 2, as 
part of dietary counseling will receive instructions that encourage an energy deficit of
≥500 kcal/day30.
Individual participants energy deficit determined based on the participant’s TEE, in 
accordance with guidelines, using the formula below:

TEE = REE x activity factor.
For all participants, an activity factor of 1.3 (to match a sedentary activity level) will be used.
The REE for each participant will be calculated with the Harris Benedict formula31 for men 
and women, using the participant’s body weight, height, and age obtained at Screening Visit, 
as listed below:

For women: REE (kcal/d) = 655.0955 + [9.5634 x weight (kg)] + [1.8496 x height (cm)] –
[4.6756 x age (years)].

For men: REE (kcal/d) = 66.4730 + [13.7516 x weight (kg)] + [5.0033 x height (cm)] –
[6.7550 x age (years)].


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5.3.4. Physical Activity Counseling
At times listed in SoA-Table 1, participants will be encouraged to maintain physical activity 
for ≥150 minutes per week (≥30 minutes per day most days of the week) in accordance with 
guidelines30.
5.3.5. Alcohol, Caffeine, and Tobacco

Intake of alcohol is permitted in moderation defined by alcohol consumption of up to
7 drinks/week for female participants or 14 drinks/week for male participants 
(1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces 
[45 mL] of hard liquor);

Caffeine containing products will be permitted during the study with the following 
restrictions: caffeine containing products may not be consumed within 1 hour prior to 
measuring post dose vital signs and ECGs;

Use of nicotine-containing products is permitted in this study with the following 
restrictions: nicotine-containing products may not be used within 1 hour prior to 
measuring post dose vital signs and ECGs.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently 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, and any SAE.
For this study, rescreening may only be permitted under specific circumstances and only 
after contact with a Sponsor Clinical Representative –

This may be permitted, for example, for a participant who qualified for this study but 
did not enroll within the protocol prescribed interval of 6 weeks (from Screening 
Visit to Day 1/Visit 3) due to logistical constraints or for administrative reasons;

Re-screening may be appropriate, at Investigator and Sponsor discretion, following 
mild intercurrent illness (eg, infection) after the condition has resolved;

Re-screening may be appropriate, at Investigator and Sponsor discretion, after
medical decompensation has been successfully managed (eg, BP ≥160 (SBP) or 
≥100 (DBP) mmHg appropriately controlled via optimization of background BP 
medications/diet counseling in particular related to salt intake);
Otherwise, individuals who do not meet the eligibility criteria for participation in this study 
(screen failure) cannot be re-screened. 


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In case of re-screening, reconsent is required and all screening procedures must be repeated. 
The participant will be assigned a new Screening number. It must be confirmed that 
participant meet all eligibility criteria under the new Screening number before progressing to 
randomization/Day 1.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational products, medical devices, and other 
interventions (eg, surgical and behavioral) intended to be administered to the study 
participants during the study conduct.
For the purposes of this protocol, study intervention refers to –

PF-07081532 

Placebo, matching PF-07081532 

Open-label Rybelsus (ie, oral semaglutide)
6.1. Study Intervention(s) Administered
Study Intervention(s)
Intervention Name
Placebo 
PF-07081532 
Rybelsus
Arm Name
(group of participants 
receiving a specific 
treatment or no 
treatment)
Placebo [Stratum 1]
Placebo [Stratum 2] 
20 mg QD [Stratum 1]
40 mg QD [Stratum 1]
80 mg QD [Stratum 1 and 2]
140 mg QD [Stratum 2]
160 mg QD [Stratum 1]
200 mg QD [5 steps; Stratum 2]
200 mg QD [4 steps; Stratum 2]
260 mg QD [Stratum 1 and 2]
14 mg QD [Stratum 1]
Type 
Drug 
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Tablet 
Unit Dose Strength(s)
Not Applicable
20 mg; 60 mg; 100 mg
3 mg; 7 mg; 14 mg 
Dosage Level(s)
0 mg 
Refer to Arm Description below 
Refer to Arm 
Description below
Route of Administration
Oral
Oral
Oral 
Storage conditions
Refrigerated
(2-8°C)
Refrigerated
(2-8°C)
Room temperature 
(15-25°C)
Use
Placebo
Experimental
Internal reference 
standard [Stratum 1]
IMP or NIMP/AxMP
IMP 
IMP
IMP
Sourcing 
Provided centrally by the sponsor. Refer to the IPM
Packaging and Labeling 
Study intervention 
will be provided in
34 count bottles
Each bottle will be
labeled as required 
per country
requirement
Blinded labels will 
be utilized for
placebo run-in, dose-
escalation, and 
Study intervention will be 
provided in 34 count bottles
Each bottle will be labeled as 
required per country
requirement;
Blinded labels will be utilized 
for dose-escalation, and 
maintenance dosing bottles
Study intervention will 
be provided in over-
labeled 30 count
commercial bottles (US 
Sourced) and over-
labeled 30 count
commercial blister 
packs (EU Sourced)
Unblinded labels will 
be utilized for dose-
escalation, and 


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Study Intervention(s)
maintenance dosing 
bottles
maintenance bottles or
blister packs
Current/Former Name(s) 
or Alias(es)
Placebo
PF-07081532 
Rybelsus/oral 
semaglutide
Study Arms
Arm Title
Arm Type
Arm Description
Associated 
Intervention Labels
Placebo 
[Stratum 1 and 2]
Placebo 
Participants will receive placebo for up to
44 weeks
PF-07081532 / 
placebo
PF-07081532 20 mg QD 
[Stratum 1]
Experimental
Participants will receive PF-07081532 20 mg 
QD for up to 44 weeks 
PF-07081532 40 mg QD 
[Stratum 1]
Participants will receive PF-07081532 20 mg 
QD (for 4 weeks) followed by 40 mg QD (for 
up to 40 weeks)
PF-07081532 80 mg QD 
[Stratum 1 and 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 60 mg QD – sequentially, each 
for 4 weeks followed by 80 mg QD (for up to 
32 weeks)
PF-07081532 140 mg QD 
[Stratum 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 60 mg QD, 80 mg QD, 
120 mg QD – sequentially, each for 4 weeks 
followed by 140 mg QD (for up to 24 weeks)
PF-07081532 160 mg QD 
[Stratum 1]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 60 mg QD, 80 mg QD, 
120 mg QD – sequentially, each for 4 weeks 
followed by 160 mg QD (for up to 24 weeks)
PF-07081532 200 mg QD 
[5 steps; Stratum 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 60 mg QD, 100 mg QD, 
160 mg QD – sequentially, each for 4 weeks 
followed by 200 mg QD (for up to 24 weeks)
PF-07081532 200 mg QD 
[4 steps; Stratum 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 80 mg QD, 140 mg QD –
sequentially, each for 4 weeks followed by 
200 mg QD (for up to 28 weeks)
PF-07081532 260 mg QD 
[Stratum 1 and 2]
Participants will receive PF-07081532 20 mg 
QD, 40 mg QD, 80 mg QD, 140 mg QD, 
200 mg QD – sequentially, each for 4 weeks 
followed by 260 mg QD (for up to 24 weeks)
Rybelsus 14 mg QD 
[Stratum 1]
Internal 
reference 
standard 
Participants will receive Rybelsus 3 mg QD, 
7 mg QD –sequentially, each for 4 weeks 
followed by 14 mg QD (for up to 36 weeks)
Rybelsus 
Across the 12 arms involving administration of varying doses of PF-07081532 or placebo, 
double-blind, double-dummy design will be retained as outlined in Table 3 – using 
4 identical-looking tablet strengths and each dose consisting of 3 tablets.
Table 3.
Double-blind, Double-dummy Regimens in Study C3991004
PF-07081532 doses
Number of tablets 
Placebo
20 mg 
60 mg 
100 mg 
Total 
Placebo
3
-
-
-
3
20 mg QD
2
1
-
-
3
40 mg QD
1
2
-
-
3
80 mg QD
1
1
1
-
3
120 mg QD
1
1
-
1
3


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Table 3.
Double-blind, Double-dummy Regimens in Study C3991004
PF-07081532 doses
Number of tablets 
Placebo
20 mg 
60 mg 
100 mg 
Total 
140 mg QD
-
2
-
1
3
160 mg QD
1
-
1
1
3
200 mg QD
1
-
-
2
3
260 mg QD
-
-
1
2
3
Open-label Rybelsus across the planned 2-step dose-escalation to target dose of 14 mg QD 
(ie, 3 mg QD, 7 mg QD, and 14 mg QD) consists of 1 tablet per dose.
Study intervention may be shipped courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the study 
intervention. Pfizer does not permit the shipment of study intervention by mail. The tracking 
record of shipments, including temperature monitoring data, and the chain of custody 
of study intervention must be kept in the participant’s source documents/medical records.
6.1.1. Administration
Participants will swallow the study intervention whole and will not manipulate or chew the 
study intervention prior to swallowing.

Each dose of PF-07081532/ placebo consists of 3 identical looking tablets – 1 from 
each of the 3 identical looking bottles dispensed;

In addition, as a means to reinforce dosing instructions, at each on-site visit, 
dosing of PF-07081532/ placebo with the morning meal on site should include 
site staff watching each participant remove 1 tablet from each bottle, and 
self-administering the dose of 3 tablets;

Each dose of Rybelsus consists of 1 tablet from the single bottle or blister pack;

Refer to Section 5.3.2 for instructions on dosing of PF-07081532/placebo and 
Rybelsus – while considering dietary restriction;

Additional dosing instructions will be offered as part of the dosing diary – including 
management of isolated cases when dosing in the morning is missed;
6.1.2. Medical Devices

The manufactured medical devices provided for use in this study, for participants in 
Stratum 1 only include glucometer and associated ancillary supplies to permit 
participants to undertake self-monitoring of fingerstick glucose as per local 
standard-of-care guidance 

Instructions for medical device use are provided as part of the instructions related to 
hypoglycemia.


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
All medical device deficiencies (including malfunction, use error, and inadequate 
labeling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.4.9) and appropriately managed by the sponsor.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) 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, prepare, and/or administer study intervention. 
3. 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 upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to labeled storage conditions, 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 excursion definition and information to
report for each excursion will be provided to the site in the IPM.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. Site staff will instruct participants on the proper storage 
requirements for take-home study intervention. See the IPM for storage conditions of 
the study intervention.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record. All study intervention that is taken home by the participant, both used 
and unused, must be returned to the investigator by the participant. Returned study 
intervention must not be re-dispensed to the participants.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IPM. All destruction must be adequately 


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documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM.
6.2.1. Preparation and Dispensing
A qualified staff member will dispense the study intervention via an IRT system using unique 
container numbers on the bottles or blister packs provided, in quantities appropriate 
according to the SoA-Table 1. A second staff member will verify the dispensing. The 
participant should be instructed to maintain the product in the bottle or blister pack provided 
throughout the course of dosing and return the bottle or blister pack to the site at the next 
study visit.
6.3. Assignment to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system
for –

Single-blind placebo administered starting at Run-In/Visit 2 through 1 day prior to 
Day 1/Visit 3;

Double-blind, double-dummy PF-07081532/matching placebo starting Day 1/Visit 3 
and up to Week 44;

and open-label Rybelsus starting Day 1/Visit 3 and up to Week 44;
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s ID and password, the protocol number, 
and the participant number. The site personnel will then be provided with a randomization 
number corresponding to the assigned treatment group, and DU or container number(s) when 
study intervention is being supplied via the IRT system. The IRT system will provide a 
confirmation report containing the participant number, randomization number, and DU or 
container number assigned. The confirmation report must be stored in the site’s files. 
Study intervention will be dispensed at the study visits summarized in the SoA-Table 1.
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
6.4. Blinding
This is a double-blind study with administration of PF-07081532 or matching placebo in 
12 of the 13 arms in this 2 strata study. One of the 13 arms includes the internal reference 
standard, Rybelsus, as an open-label arm in Stratum 1, only. 


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 5 4
6. 4. 1. Bli n di n g of P artici p a nts
Partici pa nts will be –

bli n de d t o a d mi nistrati o n of si n gle -bli n d place b o d uri n g t he R u n -I n Peri o d (ie, 
Visit 2/ R u n -I n t o 1 da y pri or t o Visit 3/ Da y 1);

bli n de d t o t heir ra n d o mize d assi g n me nt of P F -0 7 0 8 1 5 3 2 or place b o i ncl u di n g 
d ose -escalati o n ste ps starti n g o n Da y  1;

u n bli n de d t o t heir ra n d o mize d assi g n me nt of R ybels us i ncl u di n g d ose-escalati o n 
ste ps starti n g o n Da y 1. 
6. 4. 2. Bli n di n g of Site Pers o n nel
I n vesti gat ors a n d ot her site staff will be –

u n bli n de d t o a d mi nistrati o n of place b o d uri n g t he R u n -I n Peri o d (ie, Visit 2/ R u n -I n 
t o 1 da y pri or t o Visit 3/ Da y 1);

bli n de d t o ra n d o mize d assi g n me nt of P F-0 7 0 8 1 5 3 2 or place b o i ncl u di n g 
d ose -escalati o n ste ps starti n g o n Da y  1;

u n bli n de d t o ra n d o mize d assi g n me nt of Ry bels us i ncl u di n g d ose-escal ati o n ste ps 
starti n g o n Da y 1;

bli n de d t o f oll o wi n g la b orat or y res ults as re p orte d b y s p o ns or-i de ntifie d ce ntral 
la b orat or y –

H b A 1 C res ults o n D a y  1; a n d after Da y  1 u nless res ult is > 1 0 % (8 6 m m ol/ m ol) ;

F P G res ults o n Da y  1; a n d after Da y 1 u nless res ult is –

> 2 7 0 m g/ d L ( 1 5 m m ol/ L) u p t o 1 da y  pri or t o Wee k 1 6/ Visit 1 1;

> 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) after Wee k 1 6/ visit 1 1 a n d u p t o 
Wee k
4 4 / Visit 2 2;

or < 7 0 m g / d L (3. 9 m m ol/ L ) at a n y ti me ;
6. 4. 3. Bli n di n g of t he S p o ns or

S p o ns or staff i nterfaci n g wit h t he sites will mai ntai n t he sa me le vel of bli n di n g as site 
pers o n nel a n d o utli ne d i n Secti o n 6. 4. 2;
C CI


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
Additional Sponsor staff, not involved in day-to-day conduct of the study will have 
access to blinded information as outlined in the PK-PD unblinding plan 
(Section 9.4.1).
6.4.4. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the study medical monitor prior to 
unblinding a participant’s treatment assignment unless this could delay further management 
of the participant. If a participant’s treatment assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
6.5. Study Intervention Compliance
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit as per SoA-Table 1. Compliance will be assessed 
by direct questioning, counting returned tablets during the applicable on-site visits and 
documented in the source documents and CRF. Deviation(s) from the prescribed dosage 
regimen should be recorded in the CRF.
A record of the number of PF-07081532/placebo or Rybelsus tablets dispensed to and taken 
by each participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention delays 
and/or temporary pause in dosing, will also be recorded in the CRF.
Compliance with study intervention will be defined as –

≥80% and ≤120% of tablets in each bottle of study-supplied single-blind placebo 
consumed from Visit 2/Run-In to 1 day prior to Visit 3/Day 1 – with 
self-administration correctly as defined by 1 tablet from each of the 3 bottles 
dispensed each day; 

For example: If duration of dosing was 12 days (of the permitted 14±2 days), 
participant can miss a maximum of 2 doses (or take a maximum of 2 extra 
doses) to remain qualified for randomization 


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
≥80% (and ideally, up to 100%) of tablets in each bottle or blister pack of study-
supplied intervention from Visit 3/Day 1 through up to Visit 22/Week 44, inclusive,
are expected to be consumed

Investigators must closely monitor non-compliant participants in order to 
enhance participants adherence to the study intervention;

Post randomization, at each dispensation visit (refer to SoA-Table 1), 
participants who are <80% compliant must be re-educated on the importance of 
daily self-administration of study intervention;

Overall aim: maintain ≥80% compliance over the duration of dosing with 
randomized study intervention.
Deviation(s) from the prescribed dosage regimen should be recorded in the CRF.
6.6. Dose Modification
6.6.1. Dose Escalation
A fixed dose escalation scheme is planned to be used for each PF-07081532 or Rybelsus 
study intervention dosing arm in this study as described in Section 1.2. Each dosing regimen 
will be provided in prefilled bottles (and blister packs in the case of Rybelsus for some 
region(s) as necessary based on source of this commercially available supply) –

The protocol does not permit dose adjustment – refer to Section 10.11;

However, participant education, expectations, and avenues to manage the temporary 
MoA-based GI-related AEs including permitting dosing to be temporarily paused for 
a maximum of 2 days is permitted – refer to Section 10.11;

Whenever possible, attempts must be made to avoid temporary pause in dosing in the 
7 days immediately prior to on-site visit 
6.6.2. Considerations for Pausing or Stopping Active Dose(s) Based on Observed Safety
The decision to stop dosing for 1 or more active dose(s) of PF-07081532 may be considered 
based on recommendations from the IRC (Section 9.4) according to their review of 
unblinded, study-level emerging, observed safety data, for reasons such as the following:

More than 50% of participants develop a moderate or severe AE in the 
gastrointestinal SOC not responsive to symptomatic management;

Additional details included in the IRC Charter finalized prior to initiation of 
randomization in this study.


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6.7. Continued Access to Study Intervention After the End of the Study
This is the first study powered to assess efficacy of PF-07081532 with an evaluation of a 
range of doses to enable identification of efficacious dose(s) upon study completion (not at 
start of the study). Hence, no study intervention will be provided to participants at the end of 
their study participation. It is expected that participants will be treated as required with 
standard-of-care treatments, as advised by their usual care physician.
6.8. Treatment of Overdose
For this study, any dose of PF-07081532 greater than 16 tablets taken from 1 bottle within a 
24-hour time period will be considered an overdose. This reflects a dose of 1.6 g assuming
overdose with the bottle containing the highest strength tablets (ie, 100 mg) in any 1 bottle. A 
single dose of 1.6 g is projected to result in exposure that will exceed that observed at the 
NOAEL in the pivotal 9-month toxicology study in monkeys, after accounting for species 
differences in plasma protein binding. 
The SRSD for Rybelsus does not identify a specific dose (mg) as overdose14. In the event of 
overdose, appropriate supportive treatment should be initiated according to the patient’s 
clinical signs and symptoms. A prolonged period of observation and treatment for these 
symptoms may be necessary, taking into account the long half-life of Rybelsus of 
approximately 1 week.
There is no specific treatment for an overdose with PF-07081532 or Rybelsus.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the study medical monitor within 24 hours.
2.
Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up.
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 study 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 study medical monitor as needed based on the clinical evaluation of the 
participant.
6.9. Prior and Concomitant Therapy
Details regarding prohibited concomitant medications as well as medications with 
timeframes for restriction prior to Screening or first dose of study intervention are provided 


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in Section 10.10. Sites are encouraged to contact the Sponsor should there be any questions 
as to whether a medication is permitted or prohibited. 
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants per details in Appendix 4 and in Stratum 1 (T2DM) specific restrictions are set 
regarding agents for glycemic control – refer to Section 6.9.1.
OTC medications are permitted during this study, unless specified as prohibited in 
Section 10.10. The use of herbal supplements and other natural products (including 
Traditional Chinese Medicine) should be discouraged. Participants should be instructed not
to initiate new supplements or natural products during the study.
All concomitant treatments (both prescription and OTC) taken during the study must be 
recorded with indication and start and stop dates of administration. All participants will be 
questioned about concomitant treatment at each visit. In Stratum 1, details regarding daily 
dose of metformin will be captured in the CFR to permit an assessment of changes in this 
required background medication.
Medications started before, or ongoing, on Day 1/Visit 3 will be documented as prior
medications. Medications started after dosing with randomized study intervention on 
Day 1/Visit 3 and until the second Follow-up Visit, inclusive, will be documented as 
concomitant medications.
Given the duration of the dosing phase in this study (ie, up to 44 weeks), it is likely that 
changes in background medications will be needed as part of standard-of-care to manage 
concomitant medical conditions. Guidance offered herein is requested to be considered when 
determining how best to maintain control. 
6.9.1. Management of Glycemic Control in Stratum 1
Participants are required to be on a stable dose of metformin of ≥500 mg/day and up to the 
highest in-country approved dose for ≥8 weeks prior to Screening Visit and until first
on-site Follow-up Visit

Use of any other country-specific approved classes of agents for glycemic control 
including other biguanides, DPPIV inhibitors, SGLT2 inhibitors, 
thiazolidinediones/PPAR, sulphonylureas, -glucosidase inhibitors, meglitinide 
analogues, GLP-1R agonists, short or long-acting insulin – is not permitted within 
12 weeks prior to Screening Visit (Table 7);

Of note, short-term (ie, ≤7 days) of insulin administration is permitted if 
participant is hospitalized; 

In participants meeting FPG thresholds for addition of new agent (Section 10.12), any 
of the above mentioned classes of orally administered agents can be considered 
except –

GLP-1R agonist, DPPIV inhibitors, thiazolidinediones/PPAR


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
Other agents with an inherent risk of HAE (for example: amylin analogues, 
sulphonylureas, and insulin) to limit added risk of hypoglycemia 
(Section 2.3.1).
FSBG (assessed via glucometers) and FPG (assessed by sponsor-identified central 
laboratory) will be routinely monitored during participation in the study. Based on this 
information, as well as review of the results reported by the central laboratory, an assessment 
of any symptomatic and asymptomatic occurrence of hypo- or hyper- glycemia must be 
undertaken.
6.9.1.1. Home Glucose Monitoring

To aide in management of their T2DM, all participants in Stratum 1 will be provided 
home glucose monitoring supplies, including a Sponsor provided glucometer, 
instructions on the use of the glucometer, and accompanying supplies – SoA-Table 1.

The Investigator will review the readings stored in the glucometer device at each 
on-site visit after dispensation of the device.

Participants can use their own glucometer, provided that the daily glucose values 
stored in the glucometer device can be reviewed by the Investigator at each on-site 
visit.

Home glucose monitoring logs, either via results saved on the glucometer or results 
transcribed into a hard copy glucose monitoring diary, will be maintained by
participants and brought to each on-site visit to enable monitoring of compliance with 
the home glucose monitoring requirement by the site staff.

Participants should be instructed to self-perform home glucose monitoring at least 
3 times weekly, on separate, nonconsecutive days, following a fast of ≥8 hours 
(except water).

In addition, home glucose monitoring should be performed upon experiencing 
symptoms of HAE.
6.9.1.2. Management of HAE
Any episode of HAE must be captured on the AE eCRF with details captured on the HAE 
details eCRF.
Participants noted to have a fasting fingerstick blood glucose value (during home glucose 
monitoring) meeting the definition of HAE must be instructed to repeat the measurement the 
next day (following a fast of ≥8 hours except water). If the second measurement also meets 
the definition of HAE, participants must be asked to return to the site within 1 to 3 days
(following a fast of ≥8 hours except water) and have blood collected and sent to the central 
laboratory for analysis of FPG.
Based on review of the home glucose monitoring logs, either via results saved on the 
glucometer or results transcribed into a hard copy glucose monitoring diary, at each on-site 
visit per SoA-Table 1, as well as results reported by the central laboratory, the Investigator 
must assess the glucose values as well as any symptoms documented. 


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HAE will be defined using the classification published by the ADA as follows –
Severe HAE (all 3 required): 

Participant was unable to treat him/herself due to neurological impairment (not age) and 
require assistance of another person.

At least one neurological symptom of memory loss, confusion, uncontrolled behavior, 
irrational behavior, unusual difficulty in awakening, documented or suspected seizure, or 
loss of consciousness.

Either documented blood glucose ≤54 mg/dL (2.7 mmol/L) or, if blood glucose not 
measured, documented reversal of clinical symptoms by administration of oral 
carbohydrates, SC glucagon, or IV glucose.
Events that do not meet all of the criteria above for severe HAE are characterized as mild or 
moderate in severity. 
Documented symptomatic HAE:
An event during which typical symptoms of an HAE are accompanied with a plasma/blood 
glucose value <70 mg/dL (3.9 mmol/L) using a glucometer or Sponsor-identified central 
laboratory and the clinical picture includes prompt resolution with oral food/carbohydrate 
intake, SC glucagon, or IV glucose.
Probable symptomatic HAE:
An event during which symptoms of an HAE are not accompanied by a plasma glucose 
determination but was presumably caused by a plasma glucose concentration <70 mg/dL 
(3.9 mmol/L), and the clinical picture includes prompt resolution with food intake, SC 
glucagon, or IV glucose.
Asymptomatic HAE:
An event not accompanied by typical symptoms of an HAE, but a plasma/blood glucose 
value of <70 mg/dL (3.9 mmol/L) is reported using a glucometer or sponsor-identified 
central laboratory.
6.9.1.3. Management of Hyperglycemia
Hyperglycemia (refer to Section 10.12) is defined as the following:

Fasting blood/plasma glucose >270 mg/dL (15.0 mmol/L) from Week 4 to 1 day 
prior to Week 16;

Fasting blood/plasma glucose >240 mg/dL (13.3 mmol/L) from Week 16 and up to 
Week 44;
After randomization, participants noted to have a fasting blood glucose value (during home 
glucose monitoring) meeting the above definition of hyperglycemia must be instructed to 
repeat the measurement the next day (following a fast of ≥8 hours except water). If the 
second measurement also meets the above definition, participants must be asked to return to 
the site as soon as possible but within 7 days of the repeat home glucose assessment 


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(following a fast of ≥8 hours except water) and have blood collected for FPG (and shipped to 
the central laboratory for analysis).
The Investigator should determine if the participant collected the samples after an adequate 
fasting period and if the participant is following recommended dietary guidelines. Proper 
dietary and collection procedures should be reinforced with the participant.
If the results of the central laboratory confirm the glucometer readings, the participant should 
be offered glycemic rescue medication at the discretion of the Investigator. 

In order to ensure appropriate glycemic control, per local/in-country standard-of-care, 
and considering the duration of dosing with study intervention (ie, up to 44 weeks), it 
may be necessary to adjust the dose of metformin for glycemic control post 
randomization and/or add a new agent – refer to Section 6.9.1 and Section 10.12.
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 –

Criteria for a potential Hy’s law case are met – refer to Section 10.6;

Intent to become pregnant or pregnancy confirmed via -hCG testing;

Safety or tolerability concern arises, including MoA-based GI-related AEs, in 
particular if intolerable to the participant despite persistent best efforts to minimize 
symptoms, dosing with study intervention may be permanently stopped in an 
individual participant at the discretion of the investigator – refer to Section 10.11; 

Based on mental health assessment must be discontinued from dosing or from study, 
as outlined in Section 8.3.6.3.
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is permanently discontinued, the participant should remain in the study 
to be evaluated for at least the primary endpoint. See SoA-Table 1 and SoA-Table 2 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.
It is strongly recommended that the investigator discuss permanent discontinuation of study 
intervention with the study medical monitor or sponsor clinician before progressing with
discontinuation. 


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7.1.1. Potential Cases of Acute Kidney Injury
Increase in Scr concurrent with presence or absence of an increase in urea (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 that warrants 
additional assessment. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in Scr 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 of Scr (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] 
in Scr relative to the participant’s own baseline) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study intervention 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 the 
increased 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. 
7.1.2. COVID-19 
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Study treatment should continue 
unless the investigator/treating physician is concerned about the safety of the participant, in 
which case temporary or permanent discontinuation of study intervention may be required.
Temporary discontinuation of the study intervention may be medically appropriate until the 
participant has recovered from COVID-19 –

If management of COVID-19 infection includes use of Paxlovid (ritonavir-boosted 
nirmatrelvir), and participant is randomized to PF-07081532/placebo, switch 
administration of study intervention to every other day while taking Paxlovid and for 
up to 2 days post last dose of Paxlovid – as a means to manage the potential PK DDI 
(refer to Table 6 in Section 10.10) with coadministration is necessary;

If management of COVID-19 infection includes use of remdesivir or monoclonal 
antibodies (eg, bebtelovimab), temporary pause (for up to 2 days) in dosing of 
PF-07081532/placebo may be medically appropriate (eg, in the setting of GI related 
AEs if participant is struggling to remain adequately hydrated).


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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:

Reasons outlined in Section 7.1;

Refused further follow-up;

Lost to follow-up;

Death;

Study termination by sponsor;

Discretion of the investigator or sponsor for safety or behavioral reasons, or the 
inability of the participant to comply with protocol-required schedule of study visits 
or procedures at a given site.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See SoA-Table 1 and SoA-Table 2 for assessments to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed.
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, they 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 will be performed and no 
additional data will 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 them 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 


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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 the participant 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;

Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures (Section 10.1.3).
Study procedures and their timing are summarized in SoA-Table 1 and SoA-Table 2. 
Protocol waivers or exemptions are not allowed.
Adherence to the study design requirements, including those specified in SoA-Table 1 and 
SoA-Table 2, is essential and required for study conduct.
All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a Screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
Screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 


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circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have 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.
Laboratory test results related to glycemic parameters (refer to Section 6.4.2) that have been 
collected for the purposes of this study and could unblind the study will not be reported to 
investigative sites or other blinded personnel (Section 6.4.3) until the study has been 
unblinded.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is up to 
approximately 285 mL. The actual collection times of blood sampling may change. 
Additional blood samples may be taken for safety assessments at times specified by Pfizer, 
provided the total volume taken during the study does not exceed 550 mL during any period 
of 56 consecutive days.
8.1.1. Telehealth Visits 
Telehealth visits may be used to assess participant safety and collect data points. Telehealth 
includes the exchange of healthcare information and services via telecommunication 
technologies (eg, audio, video, videoconferencing software) remotely, allowing the 
participant and the investigator to communicate on aspects of clinical care, including medical 
advice, reminders, education, and safety monitoring. The following assessments must be 
performed during a telehealth visit (see SoA-Table 1):

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.4.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Section 10.4. 
Study participants must be reminded to promptly notify site staff about any change in their 
health status.


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 6 6
8. 2. Effic ac y Assess me nts
Assess me nts t o e val uate efficac y  (S o A -Ta ble 1 a n d S o A -Ta ble 2 ), i ncl u de –

H b A 1 C , F P G,
as assesse d b y t he s p o ns or i de ntifie d- ce ntral la b orat or y –
Secti o n 1 0. 2 ;

Wit h H O M A -I R a n d H O M A-S pr o gra m maticall y deri ve d b y t he s p o ns or ;

B o d y wei g ht – Secti o n 8. 2. 1 ;

Waist a n d hi p circ u mfere nce (f or e n d p oi nt of waist circ u mfere nce a n d w aist-t o-hi p 
rati o) – Secti o n 8. 2. 2 ;
8. 2. 1. B o d y wei g ht
B o d y wei g ht will be meas ure d i n d u plicate as i n dicate d i n S o A -Ta ble 1 wit h t he sec o n d 
wei g ht meas ure me nt s h o ul d be o btai ne d at le ast 2 mi n utes after t he first meas ure me nt.

Wei g ht will be rec or de d usi n g a cali brate d scale ( wit h t he sa me scale use d as m uc h as 
practicall y p ossi ble f or t he d urati o n of t he st u d y) ;

Wei g hi n g scale ca n re p ort wei g ht i n eit her p o u n ds (l b) or kil o gra ms ( k g), b ut m ust 
ha ve a n acc urac y t o t he nearest 0. 2 l b ( or 0. 1 k g); ie, t he de vice m ust be a ble t o 
disti n g uis h a differe nce bet wee n 1 5 0. 4 l b ( 6 8. 4 k g) vers us 1 5 0. 2 l b ( 6 8. 3 k g);

Wit h t he
wei g hi n g scale place d o n a sta ble, flat s urface, wei g ht meas ure me nt ca n be 
ta ke n u n der t he f oll o wi n g c o n diti o ns:

Part ici pa nt is i n faste d state; 

After t he partici pa nt has v oi de d uri ne (ie, f orce d v oi d); 

After t he partici pa nt has re m o ve d s h oes a n d b ul k y la yers of cl ot hi n g a n d 
jac kets, s o t hat o nl y li g ht cl ot hi n g ( wit h e m pty p oc kets) or a h os pital g o w n , 
re mai ns; 

Wit h t he partici pa nt sta n di n g still w hile o n t he scale.
8. 2. 2. W aist a n d Hi p C irc u mfere nce a n d W aist -t o- Hi p R ati o
Waist a n d hi p circ u mfere nce will be meas ure d as i n dicate d i n S o A -Ta ble 1 a n d s h o ul d be 
ta ke n u n der t he f oll o wi n g c o n diti o ns:

Waist circ u mfere nce s h o ul d be meas ure d at mi d p oi nt, bet wee n l o wer mar gi n of last 
pal pa ble ri b a n d t o p of iliac crest ( ~ 1 i nc h [ 2. 5 4 c m] a b o ve t he na vel);

T he hi p circ u mfere nce is defi ne d as t he circ u mfere nce ar o u n d t he wi dest p orti o n of 
t he b utt oc ks;
C CI
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 6 7

Partici pa nt s h o ul d be li g htl y  cl ot he d a n d i n a faste d state;

Meas ure me nts s h o ul d be ta ke n after t he partici pa nt has bee n as ke d t o v oi d of uri ne 
(ie, f orce d v oid);

Meas ure me nts s h o ul d be ta ke n wit h ta pe t o uc hi n g t he s ki n ( n ot cl ot hi n g) f or waist 
meas ure me nts, a n d t he ta pe t o uc hi n g t he s ki n, if p ossi ble, f or hi p meas ure me nts.
T he meas ure me nts s h o ul d be ta ke n wit h t he f oll o wi n g ste ps:

Ste p 1: As k t he partici pa nt t o sta n d wit h t heir feet cl ose t o get her a n d ar ms at t heir 
si de wit h t heir b o d y wei g ht e ve nl y distri b ute d

Ste p 2: As k t he partici pa nt t o rela x a n d breat he n or mall y

Ste p 3: Meas ure me nts s h o ul d be rec or de d at t he e n d of a n or mal e x pirati o n
T hese meas ure me nts wi ll be o btai ne d usi n g a n a nt hr o p o metric ta pe (stretc h-resista nt). T he 
ta pe s h o ul d be s n u g ar o u n d t he b o d y, b ut n ot p ulle d s o ti g ht t hat it is c o nstricti n g. T he ta pe 
s h o ul d be i n t he h oriz o ntal all ar o u n d t he b o dy, parallel t o t he fl o or at t he le vel at w hic h t he 
meas ure me nt is ma de a n d a v oi di n g t wists i n t he ta pe. T he waist a n d hi p circ u mfere nce will 
be meas ure d i n tri plicate 3 4, wit h a brief i nter val (at least 1 -2 mi n utes) bet wee n s uccessi ve 
meas ure me nts. All 3 meas ure me nts will be rec or de d i n i nc hes or c m, r o u n de d t o t he nearest 
1/ 1 6 t h i nc h or 0. 1 c m.
 
 
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 6 8
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 6 9
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 7 0
8. 3. S afet y Assess me nts
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n S o A -Ta ble 1 a n d S o A -Ta ble 2 .
U nsc he d ule d safety meas ure me nts m a y  be o btai ne d at a n y ti me d uri n g t he st u d y t o assess 
a n y percei ve d safety iss ues.
8. 3. 1. P h ysic al E x a mi n ati o ns
A c o m plete p h ys ical e xa mi nati o n will be perf or me d b y a me dicall y q ualifie d or a p pr o priatel y 
dele gate d site staff (e g , P As, N Ps, or si milar) . A c o m plete p h ysical e xa mi nati o n i ncl u des, at a
mi ni m u m, assess me nts of t he car di o vasc ular, res pirat or y, gastr oi ntesti nal , a n d n e ur ol o gical
s yste ms. Ar m circ u mfere nce, waist circ u mfere nce, a n d h ei g ht will als o be meas ure d a n d 
rec or de d.
A brief p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, l u n gs, 
car di o vasc ular s ys te m, a n d a b d o me n (li ver a n d s plee n).
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
P h y sical e xa mi nati o n fi n di n gs c ollecte d d uri n g t he st u d y will be c o nsi dere d s o urce data a n d 
will n ot be re q uire d t o be re p orte d, u nless ot her wise n ote d. A n y u nt o war d p h y sical 
e xa minati o n fi n di n gs t hat are i de ntifie d d uri n g t he acti ve c ollecti o n peri o d a n d meet t he 
defi niti o n of a n A E or S A E (A p pe n di x 3 ) m ust be re p orte d acc or di n g t o t he pr ocesses i n 
Secti o ns 8. 4. 1 t o 8. 4. 3 .
8. 3. 2. Vit al Si g ns
A n y  u nt o war d vital si g n fi n di n gs t hat are i de ntifie d d uri n g t he acti ve c ollecti o n peri o d a n d 
meet t he defi niti o n of a n A E or S A E ( A p pe n di x 3 ) m ust be re p orte d acc or di n g t o t he 
pr ocesses i n Secti o ns 8. 4. 1 t o 8. 4. 3 .
C CI


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8.3.2.1. Blood Pressure and Pulse Rate
In this study, assessment of vital signs (including seated blood pressure, and pulse rate) will
occur at the nominal time points specified in the SoA-Table 1 per the following 
specifications:

At the Screening Visit, the participants’ arm circumference should be measured (using 
a flexible anthropometric tape) at the midpoint of the length of the upper arm and the
appropriate cuff selected and used throughout the study to measure BP/PR via an 
automated device using an oscillometric method (not auscultation):

Participants with arm circumference greater than the largest cuff size available at
each site are not eligible.

Triplicate (in PF-07081532/placebo arms) and single (in Rybelsus arm) seated
BP/PR will be measured with the participant’s arm supported at the level of the heart, 
and recorded to the nearest mm Hg, with a rest of ≥ 5-minutes before the first of 
3 measurements is obtained with continued seated rest till third of 3 measurements is 
obtained; each of the 3 consecutive readings will be recorded on the CRF.

As much as practically possible, same arm (preferably the dominant arm) will be used 
for blood pressure/pulse rate assessment throughout the study.
8.3.3. Electrocardiograms
Standard 12-lead ECGs, as provided by the sponsor-identified central vendor, utilizing limb 
leads (with a 10-second rhythm strip) should be collected at times specified in SoA-Table 1
using an ECG machine that automatically calculates the HR and measures PR interval, 
QT interval, QTc (ideally, QTcF), 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 ≥10 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 (in PF-07081532/placebo arms) and single (in Rybelsus arm) supine 12-lead 
ECGs will be obtained with a rest of ≥10-minutes before the first of 3 ECGs is obtained with 
continued supine rest till 3rd of 3 ECGs is obtained. Assessment of eligibility must be made by 
site-based medically qualified individual or central reader. The average of the triplicate ECG 
measurements collected pre-dose on Day 1/Visit 3 will serve as baseline for each participant
and each of the 3 consecutive readings databased (via the central vendor reviewing 12-lead 
ECGs in randomized participants).
If a) a post dose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QTcF value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner,
at the discretion of the investigator); or c) QTcF values get progressively longer, the 
participant should undergo continuous ECG monitoring. A cardiologist should be consulted 


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if QTcF values do not return to less than the criteria listed above after 8 hours of monitoring 
(or sooner, at the discretion of the investigator).
ECG tracings will be submitted to sponsor-identified central vendor for measurement. The 
final ECG report from the sponsor-identified central vendor should be maintained in the 
participant’s source documentation and be the final interpretation of the ECG recording. Any 
clinically significant changes from the baseline/Day 1 ECG may potentially be AEs 
(Appendix 8) and should be evaluated further, as clinically warranted. 
The cardiac conduction intervals as assessed by the sponsor-identified central vendor will 
undergo concentration-QT analysis – refer to Section 9.3.4.1.
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 8.
8.3.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and SoA-
Table 2 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 
SoA-Table 2. 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 significant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory test findings are those that 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 significant and abnormal during 
participation in the study or within 14 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 study 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 
DILI.


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See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
8.3.5. Pregnancy Testing 
A serum pregnancy test is required at screening. Following screening, pregnancy tests may 
be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. Pregnancy tests 
will be performed in WOCBP at the times listed in SoA-Table 2. Following a negative 
pregnancy test result at screening, appropriate contraception must be commenced and a 
second negative pregnancy test result will be required at Day 1/Visit 3 prior to the 
participant’s receiving the study intervention. Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected) and at the end of the study. Pregnancy tests may also be repeated if 
requested by IRBs/ECs or if required by local regulations. If a urine test cannot be confirmed 
as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the 
participant must be excluded if the serum pregnancy result is positive.
8.3.6. Suicidal Ideation and Behavior Risk Monitoring 
8.3.6.1. Columbia Suicide Severity Rating Scale (C-SSRS) – Stratum 2 only 
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behavior.32 The “baseline/screening” version of the C-SSRS will be administered at 
Screening Visit. The “since last visit” version of the C-SSRS will be administered at the 
other visits specified in SoA-Table 1. The C-SSRS will be administered by study site staff 
who have completed training in its administration. Participants who respond “yes” to 
questions 4 or 5 (indicating suicidal ideation), or to any suicidal behavioral question on the 
C-SSRS at Screening Visit or Day 1/Visit 3 will not be permitted in the study (refer to 
Section 5.2).
8.3.6.1.1. Rater Qualifications 
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
participants in this study. The minimum qualifications a rater must meet for each study rating 
assessment will be outlined in the training materials provided to each participating site. The 
level of experience with the target population (or equivalent), specific scale experience (or 
equivalent), and certification required (if applicable) will be listed and used to determine 
whether a rater is approved for a given assessment. The rater must become certified to 
perform selected study assessments before they can participate in the conduct of the study. 
For specifically defined assessments, rater training and standardization exercises may be 
conducted, and written documentation will be provided by the site for each rater’s 
certification. In return, each site will be provided written documentation outlining each 
rater’s certification for specific study assessments. Recertification may be required at 
periodic intervals during the study. The raters who administer specific study assessments will 
be documented in a centralized location and all site staff who administer ratings will be 
verified in the site study documentation during the conduct of the study.


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8.3.6.2. Patient Health Questionnaire-9 (PHQ-9) – Stratum 2 only
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms33. The 
PHQ-9 will be completed by participants and reviewed by site staff at the pre-defined time 
points outlined in SoA-Table 1. A PHQ-9 score of ≥15 at Screening Visit or Day 1/Visit 3
indicates clinically significant depression and serves as an exclusion criterion for this study 
(refer to Section 5.2).
8.3.6.3. Referral to a Mental Health Professional – Stratum 2 only
A participant must be referred to a MHP for the following reasons:

Response of “yes” to question 4 or 5, or on any suicidal behavioral question on the 
C-SSRS;

A score of ≥15 on the PHQ-9;

In the investigator’s judgment a risk assessment or exclusion is required.
A clinically-qualified MHP is a MHP with appropriate training in the assessment of suicide 
risk, according to local clinical practice standards and regulations, who would normally 
evaluate the risk for suicidal ideation and behavior in a patient.
After Day 1/Visit 3, for any participant in study, meeting any of the above reasons, risk 
assessment by a clinically-qualified MHP must be performed to determine whether it is safe 
for a participant to continue to participate in the study. 
Participants who have recurrent suicidal ideation or behavior during the study should be 
discontinued from the study and treated appropriately. If a study participant endorses a 4 or 5 
on the ideation subscale or any suicidal behavioral item of the C-SSRS on 2 or more 
occasions and is confirmed to have active suicidal ideation or behavior on both occasions by 
a risk assessment conducted by a qualified MHP, then the participant should be discontinued 
from the study and treated appropriately.
Participants who meet criteria for referral to a MHP, but refuse evaluation and/or treatment 
by a MHP, should be discontinued from dosing or from the study. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Appendix 9. Device deficiencies are covered in Section 8.4.9.
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).


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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 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. 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 undergoing any study-related procedure and/or receiving study 
intervention, through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant 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 they consider 
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.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 


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Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
8.4.1.2. 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 8.4.1, 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.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
Reporting of AEs and SAEs for participants who fail Screening are subject to the CRF 
requirements as described in Section 5.4.
8.4.2. 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.
8.4.3. 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 
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 provided in Appendix 3.


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8.4.4. 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.
8.4.5. 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 EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of 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.


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
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then inseminates 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/participant’s partner the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental 
Form, regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until 28 days after 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 
pre-procedure 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 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

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. 


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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.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB 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 EDB 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 EDB 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 EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. 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
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.
8.4.6. Cardiovascular and Death Events
Not applicable. 


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8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable. 
8.4.8. Adverse Events of Special Interest
AESIs are examined as part of routine safety data review procedures throughout the clinical 
study and as part of signal detection processes. Should an aggregate analysis indicate that 
these prespecified events occur more frequently than expected, eg, based on epidemiological 
data, literature, or other data, then this will be submitted and reported in accordance with 
Pfizer’s safety reporting requirements. Aggregate analyses of safety data will be performed 
on a regular basis per internal SOPs. 
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.4.1 through 8.4.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form.
8.4.8.1. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE.
8.4.9. Medical Device Deficiencies
Medical devices being provided for use in this study are those listed in Section 6.1.2. In order 
to fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of device deficiency that occur 
during the study with such devices.
The definition of a medical device deficiency can be found in Appendix 9.
Note: AEs and/or SAEs that are associated with a medical device deficiency will follow the 
same processes as other AEs or SAEs, as outlined in Sections 8.4.1 through 8.4.4 and 
Appendix 3 of the protocol.
8.4.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
Importantly, reportable device deficiencies are not limited to problems with the device itself 
but also include incorrect or improper use of the device and even intentional misuse, etc. 
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such deficiency is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiencies is provided in Appendix 9.


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8.4.9.2. Follow-Up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on a follow-up form with all changes signed 
and dated by the investigator.
8.4.9.3. Prompt Reporting of Device Deficiencies to the Sponsor
When a device deficiency occurs: 
1.
The investigator notifies the sponsor by telephone or email within 1 business day 
of determining that the incident meets the protocol definition of a medical device 
deficiency.
2.
The device deficiency must be recorded on the Medical Device Complaint form.
3.
If an AE (either serious or nonserious) associated with the device deficiency
occurs, then the AE must be entered into the AE section of the CRF.
4.
If an SAE associated with the device deficiency is brought to the attention of the 
investigator, the investigator must immediately notify Pfizer Safety of the SAE (see 
Section 8.4.1.1). All relevant details related to the role of the device in the event 
must be included in the CT SAE Report Form as outlined in Sections 8.4.1.1 and
8.4.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
8.4.9.4. Regulatory Reporting Requirements for Device Deficiencies
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/EC.
8.4.10. 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.


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Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
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;

Administration of expired study intervention;

Administration of an incorrect study intervention;

Administration of an incorrect dosage (ie, not 1 tablet for each of the 3 separate 
bottles in the case of dosing with PF-07081532/placebo);

Administration of study intervention that has undergone temperature excursion from 
the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use.
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.
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.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics 
Blood samples of approximately 3 mL to provide a minimum of 1 mL plasma will be 
collected for measurement of plasma concentrations of PF-07081532 (Stratum 1 and 2) as 
specified in SoA-Table 2. 


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Blood samples of approximately 6 mL to provide a minimum of 3 mL matrix will be 
collected for measurement of concentrations of Rybelsus (Stratum 1, only) as specified in 
SoA-Table 2.
The actual date and time of the on-site dosing with study intervention and of the blood 
collections related to PK (both pre- and post-dose samples) should be captured by site 
personnel in the eCRF. The actual date and time of the previous two doses of study 
intervention prior to each on-site visit that includes blood draws for PK should be noted in a 
dosing diary (or similar) by the participants and captured by site personnel in the eCRF.

The PK samples must be processed and shipped as indicated in the study-specific
laboratory manual provided to the site, prior to initiation of study, to maintain sample
integrity:

Any deviations from the PK sample handling procedure (eg, sample collection
and processing steps, interim storage or shipping conditions), including any
actions taken, must be documented and reported to the sponsor;

On a case-by-case basis, the sponsor may make a determination as to whether 
sample integrity has been compromised;

Any deviation from the specified sample handling procedure resulting in 
compromised sample integrity will be considered a protocol deviation;

Any of the following errors in scheduled collection of blood samples for PK 
(refer to SoA-Table 2) will be captured as protocol deviations even if results are
deemed to be evaluable and included in analyses

Predose collection (ie, Ctrough) obtained post dose;

Post dose PK sample not collected within collection window following
morning dose;

PK sample (pre- or post- dose) not collected.
Samples will be used to evaluate the PK of PF-07081532 (Stratum 1 and 2) and Rybelsus 
(Stratum 1, only). Each matrixed sample will be divided into 2 aliquots. 
Samples collected for analyses of PF-07081532 (Stratum 1 and 2) and Rybelsus (Stratum 1, 
only) concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study, for metabolite identification and/or evaluation of 
the bioanalytical method, or for other internal exploratory purposes.
Genetic analyses will not be performed on these samples. Participant confidentiality will be 
maintained.


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 8 4
Sa m ples c ollecte d f or meas ure me nt of c o nce ntrati o ns of P F -0 7 0 8 1 5 3 2 ( Strat u m 1 a n d 2) a n d 
R y bels us ( Strat u m 1, o nl y ) will be a nal yz e d usi n g a vali date d a nal ytical met h o d i n 
c o m plia nce wit h a p plica ble S O Ps. P ote ntial meta b olites ma y  be a naly ze d wit h eit her 
vali date d or e x pl orat or y  met h o ds.
Dr u g c o nce ntrati o n i nf or mati o n t hat w o ul d u n bli n d t he st u d y  will n ot be re p orte d t o 
i n vesti gator sites or bli n de d pers o n nel u ntil t he st u d y  has bee n u n bli n de d.
8. 6. Ge netics
I n t he e ve nt of D N A e xtracti o n fail ure, a re place me nt ge netic bl o o d sa m ple ma y be re q ueste d 
fr o m t he partici pa nt.
See Secti o n 1 0. 5 f or inf or mati o n re gar di n g ge netic researc h. Details o n pr ocesses f or 
c ollecti o n a n d s hi p me nt of t hese sa m ples ca n be f o u n d i n la b orat or y ma n ual pr o vi de d b y t he 
s p o ns or-i de ntifie d ce ntral la b orat or y. 
8. 6. 2. Ret ai ne d Rese arc h S a m ples f or Ge netics
N ot pla n ne d.
8. 8. I m m u n o ge nicit y Assess me nts
I m m u n o ge nicity assess me nts are n ot i ncl u de d i n t his st u d y .
C CI
C CI


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8.9. Health Economics
Health economics/medical resource utilization and health economics parameters including 
inpatient/outpatient/emergency department visits that take place between scheduled visits 
will be collected at each clinic visit.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the 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.
Other than where expressly stated, there are no planned analyses that will combine strata. All 
statistical analyses will be performed separately for each stratum.
9.1. Statistical Hypotheses
9.1.1. Estimands
Estimands described below as “in the absence of glycemic rescue medication while on 
treatment” for Stratum 1 (T2DM inadequately controlled on metformin) and “while on 
treatment” for Stratum 2 (Obesity without T2DM) represent hypothetical or treatment 
product estimands.
9.1.1.1. Primary Estimands
For Stratum 1 (T2DM): The primary estimand will be the population average treatment 
effect on the change from baseline in HbA1C at Week 32 of PF-07081532 compared to 
placebo in the absence of glycemic rescue medication while on treatment. Measurements 
after initiation of glycemic rescue medication or discontinuation of study intervention will be
censored and treated as missing data. Missing data due to censoring, study withdrawal or
other reasons (eg, laboratory failure) will have data imputed based on a MAR assumption. 
Participants with inadequate compliance will have their HbA1C values used as-is in the 
analysis. The population-based treatment effect will be the difference in the mean change 
from baseline in each PF-07081532 arm compared to placebo.
For Stratum 2 (Obesity): The primary estimand will be the population average treatment 
effect on the percent change from baseline in body weight at Week 32 of PF-07081532
compared to placebo while on treatment. Measurements after discontinuation of study 
intervention will be censored and treated as missing data. Missing data due to censoring, 
study withdrawal or other reasons (eg, equipment failure) will have data imputed based on a 
MAR assumption. Participants with inadequate compliance will have their body weight 
values used as-is in the analysis. The population-based treatment effect will be the difference 
in the mean percent change from baseline in each PF-07081532 arm compared to placebo.


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9.1.1.2. Secondary Estimands
For Stratum 1 (T2DM): For each of the continuous secondary endpoints evaluating 
PF-07081532: the population average treatment effect on the change from baseline in at each 
specified timepoint of PF-07081532 compared to placebo in the absence of glycemic rescue 
medication while on treatment. Measurements after initiation of glycemic rescue medication 
or discontinuation of study intervention will be censored and treated as missing data. Missing 
data due to censoring, study withdrawal or other reasons (eg, laboratory failure) will have 
data imputed based on a MAR assumption. Participants with inadequate compliance will 
have their observed values used as-is in the analysis. The population-based treatment effect 
will be the difference in the mean change from baseline in each PF-07081532 arm compared 
to placebo.
For the continuous secondary endpoint comparing Rybelsus to placebo: the population 
average treatment effect on the change from baseline in at each specified timepoint of 
Rybelsus compared to placebo in the absence of glycemic rescue medication while on 
treatment. Measurements after initiation of glycemic rescue medication or discontinuation of 
Rybelsus will be censored and treated as missing data. Missing data due to censoring, study 
withdrawal or other reasons (eg, laboratory failure) will have data imputed based on a MAR
assumption. Participants with inadequate compliance will have their observed values used 
as-is in the analysis. The population-based treatment effect will be the difference in the mean 
change from baseline in the Rybelsus arm compared to placebo.
For each of the categorical secondary endpoints: The odds ratio (PF-07081532 relative to 
placebo) at Week 32 in the absence of glycemic rescue medication while on treatment. 
Measurements after initiation of glycemic rescue medication or discontinuation of study 
intervention will be censored and treated as missing data. Missing data will not be imputed. 
Participants with inadequate compliance will have their observed values used as-is in the 
analysis. The population-based treatment effect will be the odds ratio of PF-07081532 arm 
relative to placebo.
For Stratum 2 (Obesity): For each of the continuous secondary endpoints: the population 
average treatment effect on the change from baseline in at each specified timepoint of 
PF-07081532 compared to placebo while on treatment. Measurements after discontinuation 
of study intervention will be censored and treated as missing data. Missing data due to 
censoring, study withdrawal or other reasons (eg, equipment failure) will have data imputed 
based on a MAR assumption. Participants with inadequate compliance will have their 
observed values used as-is in the analysis. The population-based treatment effect will be the 
difference in the mean change from baseline in each PF-07081532 arm compared to placebo.
For each of the categorical secondary endpoints: The odds ratio (PF-07081532 relative to 
placebo) at Week 32 while on treatment. Measurements after discontinuation of study 
intervention will be censored and treated as missing data. Missing data will not be imputed. 
Participants with inadequate compliance will have their observed values used as-is in the 
analysis. The population-based treatment effect will be the odds ratio of PF-07081532 arm 
relative to placebo.


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9.1.2. Multiplicity Adjustment
In this study, the 2 main strata (T2DM and Obesity) are defined as administrative strata and 
will not be adjusted for in statistical analyses. Unless expressly stated, all analyses will be 
performed for each stratum separately.
No adjustments will be made for multiple comparisons.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Defined Population 
for Analysis
Description
Enrolled
All participants who sign the ICD and are randomized

A participant will be considered enrolled if informed consent is 
not withdrawn prior to participating in any study activity;

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 
Randomly assigned 
to investigational 
product
All participants randomly assigned to study intervention regardless 
of whether or not study intervention was administered.
Evaluable
All participants randomly assigned to study intervention and who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the randomized 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
All participants randomly assigned to study intervention and who 
take at least 1 dose of PF-07081532 or Rybelsus and in whom at 
least one concentration value is reported.
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
The primary statistical method of MMRM will apply to continuous endpoints.
Statistical efficacy comparisons will be made between each dose of PF-07081532 and 
placebo for primary and secondary endpoints, respectively. Placebo-adjusted LS mean 
difference, 95% CI and p-value will be presented.


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The primary statistical method of logistic regression will apply to categorical endpoints.
Statistical efficacy comparisons will be made between each dose of PF-07081532 and 
placebo. Odds ratios, 95% CI and p-value will be presented.
Since this study is exploratory in nature, no multiplicity adjustment of endpoints nor 
adjustments for multiple comparisons to placebo will be made. Sensitivity analyses and 
supplementary analyses are defined in the SAP.
9.3.1. Primary Estimands Analysis
For the primary estimand in each stratum, the analysis method is an MMRM analysis. The 
MMRM will include treatment and time as fixed effects, and baseline measure (HbA1C for 
Stratum 1, body weight for stratum 2) as a covariate with time fitted as a repeated effect and 
participant as a random effect. An unstructured correlation matrix will be used, and the 
Kenward-Roger approximation will be used for estimating degrees of freedom for the model 
parameters. The MMRM model will be fitted to change from baseline to Weeks 4, 8, 12, 16, 
20, 24, 28, and 32.
Missing values will be imputed as part of the MMRM model assumptions.
A Bayesian Emax dose-response model will also be estimated. This model will be utilized to 
characterize the dose response across all PF-07081532 doses, to estimate the mean response 
(and 95% CI) for each dose studied, and to estimate the placebo-adjusted response for each 
dose (and 95% CI). If an Emax dose-response model cannot be fitted to the data, then other 
models that allow dose response to be estimated will be fitted, ie, linear, log-linear or 
exponential. No adjustments will be made for multiplicity.
For the estimands containing continuous endpoints, the analysis method is an MMRM 
analysis. The MMRM will include treatment and time as fixed effects, and baseline measure
as a covariate with time fitted as a repeated effect and participant as a random effect. An 
unstructured correlation matrix will be used, and the Kenward-Roger approximation will be 
used for estimating degrees of freedom for the model parameters. The MMRM model will be 
fitted to change from baseline to Weeks 4, 8, 12, 16, 20, 24, 28, and 32. Missing values will 
be imputed as part of the MMRM model assumptions.
No adjustments will be made for multiplicity.
9.3.1.1. Sensitivity Analyses
Sensitivity analyses will be detailed in the SAP prior to database lock.
9.3.2. Secondary Estimands Analysis
For the estimands containing continuous endpoints, the analysis method is an MMRM 
analysis. The MMRM will include treatment and time as fixed effects, and baseline measure
as a covariate with time fitted as a repeated effect and participant as a random effect. An 
unstructured correlation matrix will be used, and the Kenward-Roger approximation will be 
used for estimating degrees of freedom for the model parameters. The MMRM model will be 


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 8 9
fitte d t o c ha n ge fr o m baseli ne t o Wee ks 4, 8, 1 2, 1 6, 2 0, 2 4, 2 8, a n d 3 2. Missi n g val ues will 
be i m p ute d as part of t he M M R M m o del ass u m pti o ns.
F o r t he esti ma n ds c o ntai ni n g cate g orical e n d p oi nts, t he a nalys is met h o d is a l o gistic 
re gressi o n a nalys is. T he l o gistic re gressi o n m o del will i ncl u de a ter m f or treat me nt a n d will 
i ncl u de baseli ne as a c o variate. N o val ues will be i m p ute d f or missi n g data , an d missi n g 
val ues will n ot be i ncl u de d i n t he m o del .
N o a dj ust me nts will be ma de f or m ulti plicit y .
9. 3. 3. Terti ar y/ E x pl or at or y E n d p oi nt(s) A n al ysis
Pre - d ose (tr o u g h) P K c o nce ntrati o ns will be s u m marize d descri pti vel y b y treat me nt gr o u p 
( P F-0 7 0 8 1 5 3 2 or R y bels us), d ose a n d visit. P ost -d ose P K c o nce ntrati o ns will o nl y be liste d. 
A nal y ses 
 le vels will be 
s pecifie d i n t he S A P.
P K data ma y  be use d f or p o p ulati o n P K a n d/ or P K/ P D a nal y ses – i ncl u di n g b ot h t he e n d p oi nt 
at Wee k 3 2 a n d li mite d data ac q uire d i n t h ose e nr olle d i n e xte nsi o n t o u p t o Wee k
4 4. T he 
o bjecti ve of s uc h a nal ys es, if c o n d ucte d, w o ul d ai m t o e x pl ore t he relati o ns hi p bet wee n
c o nce ntrati o ns of P F -0 7 0 8 1 5 3 2 or R y bels us a n d e ffect o n e n d p oi nts of i nterest a n d als o 
i de ntificati o n of p ote ntial de m o gra p hic deter mi na nts (e g, a ge, se x, a n d wei g ht) i nfl ue nci n g 
t he o bser ve d P K a n d/ or P D. T hese a nalys es if c o n d ucte d, will be re p orte d se paratel y  fr o m t he 
mai n C S R.
9. 3. 4. Ot her S afet y A n al yses
T he safet y data will be s u m marize d i n acc or da nce wit h Pfizer Data Sta n dar ds. All 
partici pa nts w h o recei ve at least o ne d ose of r a n d o mize d st u d y i nter ve nti o n (safety 
p o p ulati o n) will be i ncl u de d i n t he safet y a nal ys es. All safet y data will be s u m marize d 
de scri pti vel y t hr o u g h a p pr o priate data ta b ulati o n, descri pti ve statistics, cate g orical 
s u m maries, a n d gra p hical prese ntati o ns. Safety e n d p oi nts f or t he st u d y are refere nce d i n
Secti o n 3 .
9. 3. 4. 1. Electr oc ar di o gr a m A n al yses
C ha n ges fr o m baseli ne f or t he E C G para meters H R, Q Tc F, P R i nter val, a n d Q R S c o m ple x 
will be s u m marize d b y  treat me nt a n d ti me. T he fre q ue nc y of u nc orrecte d Q T val ues a b o ve 
5 0 0 ms will be ta b ulate d. T he n u m ber ( %) of partici pa nts wit h ma xi m u m p ost d ose Q Tc F 
val ues a n d ma xi m u m i ncreases fr o m baseli ne i n t he f oll o wi n g cate g ories will be ta b ulate d b y  
treat me nt: 
S afet y Q Tc F Assess me nt
De gree of Pr ol o n g ati o n
Mil d ( ms)
M o der ate ( ms)
Se vere ( ms)
A bs ol ute val ue
> 4 5 0 ‑ 4 8 0
> 4 8 0 ‑ 5 0 0
> 5 0 0
I ncrease fr o m baseli ne
N/ A
3 0 ‑ 6 0
> 6 0
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 9 0
 
9. 4. I nteri m A n al yses
I nteri m a nalys es will be perf or me d t o assess s afety /t oler a bility, at a mi ni m u m, after 
a p pr o xi matel y 2 5 %, 5 0 %, 7 5 % a n d 1 0 0 % of pla n ne d t otal sa m ple size, has bee n ra n d o mize d 
i n t he st u d y. T hese a nal ys es ma y i ncl u de f utilit y a nal ysis f or i nt olera ble M o A-base d GI A E 
pr ofile – partic ularl y rate of disc o nti n uati o n of st u d y i nter ve nti o n e xcee di n g 5 0 % i n a n y 
gi ve n P F -0 7 0 8 1 5 3 2 ar m bas e d o n u n bli n de d re vie w of t he data. I nteri m a nal ysis res ults ma y 
be use d f or i nter nal b usi ness decisi o ns re gar di n g f ut ure st u d y  pla n ni n g, o r a da pti n g t he 
safety -relate d e n d p oi nts i n t he st u d y after t he i nteri m a nal ysis. Partici pa nts ma y  be 
disc o nti n ue d fr o m t he st u d y as a res ult of t he i nteri m a nal ysis, as descri be d i n Secti o n 7 . 
I n a d diti o n, s h o ul d t here be m ore t ha n 1 2- wee k se parati o n i n f orec aste d P C D bet wee n 
Strat u m 1 vers us Strat u m 2 (f or e xa m ple: 1 strat u m c o m pletes e nr oll me nt/ra n d o miz ati o n of 
t he pla n ne d sam ple size m uc h faster t ha n t he ot her strata), a n i nteri m a nal ysis ma y  be 
perf or me d t o assess effic acy a n d s afety/t oler a bility i n t he Strat u m t hat ac hie ves P C D early. 
I n or der t o mai ntai n t he bli n d w hile t he st u d y is o n g oi n g, t he res ults of a ny i nter i m a nal ys es 
will be discl ose d t o get her wit h t he P C D a nal y ses wit hi n 1 year after e n d of t he st u d y as 
defi ne d i n Secti o n 4. 4 . 
Bef ore a n y i nteri m a nal ysis is perf or me d , t he details of t he o bjecti ves, decisi o n criteria,
disse mi nati o n pla n , a n d met h o d of mai ntai ni n g t he st u d y  bli n d (if a p plica ble) as per Pfizer ’s 
S O Ps will be d oc u me nte d a n d a p pr o ve d i n a n I RC c harter. I n a d diti o n, t he a nalys is details 
will be d oc u me nte d a n d a p pr o ve d i n t he S A P .
9. 4. 1. P K/ P D u n bli n di n g pl a n
T he S p o ns or staff i nterfaci n g wit h t he site will mai ntai n t he sa me le vel of bli n di n g as site 
pers o n nel ( o utli ne d i n Secti o n 6. 4. 3 ). H o we ver, a li mite d n u m ber of i n di vi d uals n ot o n t he 
st u d y tea m ma y be u n bli n de d acc or di n g t o S p o ns or S O Ps wit h t he p ur p ose of c o m p osi n g P K,
P K/ P D data sets a n d c o n d ucti n g p o p ulati o n P K a n d/ or P K/ P D a nal y ses t hat will be ma de 
a vaila ble t o t he st u d y tea m f oll o wi n g data base l oc k. T hese data ma y i ncl u de P K, H b A 1 C , 
vitals, E C Gs, b o d y  wei g ht, a n d p ote ntiall y ot her P D mar kers / bi o mar kers a n d A Es of
i nterest.
9. 5. S a m ple Size Deter mi n ati o n
T he sa m ple size is base d o n t he nee d t o ha ve a n a de q uatel y size d safet y data base of 
partici pa nts o n P F -0 7 0 8 1 5 3 2 f oll o wi n g p hase 2 cli nical de vel o p me nt. A p pr o xi matel y  
7 8 0 partici pa nts will be e nr olle d/ ra n d o mize d, wit h t he p o p ulati o n e nr olle d stratifie d wit h 
a p pr o xi matel y 4 2 0 wit h T 2 D M i na de q uately c o ntr olle d o n metf or mi n a n d a p pr o xi matel y 
3 6 0 wit h O besit y  b ut wit h o ut T 2 D M. Wit hi n eac h strat u m, a 1: 1 all ocati o n acr oss treat me nts 
gr o u ps at t he strat u m le vel will be u se d. T he R y bels us gr o u p (e xisti n g wit hi n t he T 2 D M 
strat u m o nl y) a d mi nistrati o n will be o pe n-la bel. A d diti o nall y , ra n d o mizati o n will be f urt her 
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 9 1
stratifie d wit h t he ai m of ra n d o mizi n g ≥3 0 % male (a n d he nce ≤7 0 % fe male) partici pa nts, i n 
e ac h of strat u m 1 ( T 2 D M ) a n d strat u m 2 ( o besit y ).
Partici pa nts w h o wit h dra w fr o m t he st u d y or treat me nt after ra n d o mizati o n will n ot be 
re place d.
T he pri mar y  a nalys is f or t his st u d y is base d o n t he pri mar y e n d p oi nts wit hi n eac h strat u m, 
na mel y  t he C F B i n H b A 1 C at Wee k 3 2 f or t he T 2 D M Strat u m a n d perce nt C F B i n b o d y  
w ei g ht f or t he O besit y strat u m. 
F or t he T 2 D M str at u m , t he effect size was ass u me d t o be -0. 7 % wit h a n S D of 1. 1. Base d o n 
t hese ass u m pti o ns, 5 1 c o m pleters per treat me nt ar m w o ul d pr o vi de at least 9 0 % p o wer usi n g 
a 1-si de d t-test at a 5 % le vel t o detect a differe nce bet wee n eac h d ose of acti ve treat me nt 
ar ms a n d place b o i n C F B i n H b A 1 C .
F or t he O besity str at u m , t he effect size was ass u me d t o be -4 % wit h a S D o n t he l o g-scale of 
0. 0 8. Base d o n t hese ass u m pti o ns, 5 1 ra n d o mize d partici pa nts per treat me nt ar m w o ul d 
pr o vi de at least 9 0 % p o wer usi n g a 1- si de d t-test at a 5 % le vel t o detect a differe nce bet wee n 
eac h d ose of acti ve treat me nt ar ms a n d place b o i n perce nt c ha n ge fr o m baseli ne i n b o d y  
wei g ht.
It is a ntici pate d t hat u p t o 1 5 % of partici pa nts ma y n ot be e val ua ble or disc o nti n ue 
pre mat urel y bef ore Wee k 3 2, res ulti n g i n a fi nal ra n d o mize d sa m ple size of a p pr o xi matel y  
6 0 partici pa nts per treat me nt ar m.
 
C CI


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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, European Medical Device Regulation 2017/745 for 
clinical device research, 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. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the study.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data. 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about their
right to access and correct their personal data and to withdraw consent for the processing of 
their 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 must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations.


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A copy of the ICD(s) must be provided to the participant.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their 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.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will use an IRC. The IRC is independent of the study team and includes only
internal members. The IRCcharter describes the role of the IRC in more detail.
The IRC will be responsible for ongoing monitoring of the safety of participants in the study 
according to the charter. The recommendations made by the IRC will be forwarded to the 
appropriate authorized Pfizer personnel for review and final decision. Pfizer will 
communicate such decisions, which may include summaries of aggregate analyses of safety 
data to regulatory authorities and investigators, as appropriate. 
10.1.6. 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/CTIS, and/or 


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www.pfizer.com, and other public registries and websites 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 study results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted. These 
results are submitted for posting in accordance with the format and timelines set forth by US 
law.
EudraCT/CTIS
Pfizer posts clinical study results on EudraCT/CTIS for Pfizer-sponsored interventional 
studies in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-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 studies available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
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 


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be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. 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.
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.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
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.


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
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 Source 
Document Locator, 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.
The sponsor or designee will perform monitoring 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.
10.1.9. 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.


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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, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. 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 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;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
For multicenter studies, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 


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submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer 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-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.11. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the supporting study documentation/study portal or other electronic 
system.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from non-study healthcare professionals, participants are provided 
with an 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.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they will be directed back to the investigator site.


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 0 0
1 0. 2. A p pe n di x 2: Cli nic al L a b or at or y Tests
T he f oll o wi n g safet y la b orat or y  tests will be perf or me d at ti mes defi ne d i n S o A -Ta ble 2 . 
A d diti o nal la b orat or y  res ults ma y be re p orte d o n t hese sa m ples as a res ult of t he met h o d of 
a nal ys is or t he t ype of a nal y zer use d b y t he cli nical la b orat or y, or as deri ve d fr o m calc ulate d 
val ues. T hese a d diti o nal tests w o ul d n ot r e q uire a d diti o nal c ollecti o n of bl o o d. U nsc he d ule d 
cli nical la b orat or y meas ure me nts ma y be o btai ne d at a n y ti me d uri n g t he st u d y t o assess a n y 
percei ve d safet y  iss ues.
T a ble 5.
Pr ot oc ol -Re q uire d Cli nic al L a b or at or y Assess me nts
H e m at ol o g y
C he mistr y
Uri n al ysis
•
H e m o gl o bi n
•
H e m at ocrit
•
R B C c o u nt
•
Platelet c o u nt
•
W B C c o u nt
•
T otal ne utr o p hils ( A bs)
•
E osi n o p hils ( A bs)
•
M o n oc ytes ( A bs)
•
Bas o p hils ( A bs)
•
L y m p h oc ytes ( A bs)
• Urea ( B U N)
•
Scr
• Ser u m C ystati n C
• e G F R a
• S o di u m
• P otassi u m
• P h os p hate/ p h os p h or us
• Calci u m
• A S T
• A L T
• T otal bilir u bi n
• Dir e ct bilir u bi n
• I n dir e ct bilir u bi n
• Al kali ne p h os p hatase
• Al b u mi n
• T otal pr otei n
• Fasti n g pl as m a gl uc ose
• p H
• Gl uc ose ( q ual)
• Pr otei n ( q ual)
• Bl o o d ( q ual)
• Ket o nes
• Nitrites
• Le u k oc yte esterase
• Uri nar y al b u mi n:creati ni ne rati o
• Micr osc o p y a n d c ult ure
b
At Scree ni n g Visit o nly
At s pecific visits o utli ne d i n S o A -Ta ble 2 –
• Ser u m F S H c
• Pre g na nc y test ( β -h C G) d
• He patitis B s urface a nti ge n
• He patitis C a nti b o d y (a n d if p ositi ve, refle x H C V R N A)
• Fasti n g C- pe pti de
• T S H
• Uri ne dr u g testi n g e
• H b A 1 C
• Ser u m li pase
• Ser u m a m ylase
• Fasti n g ser u m li pi d pa nel ( H D L -C, direct 
L D L -C, T G, t otal c h olester ol)
• hs C R P
• Free T 4
• T otal bile aci ds
• Calcit o ni n
• Pre d ose P F -0 7 0 8 1 5 3 2/ R y bels us P K
• P ost d ose P F -0 7 0 8 1 5 3 2/ R y bels us P K
a.
A ssess e G F R usi n g C K D-E PI Scr -Sc ys c o m bi ne d per Secti o n 1 0. 7
b.
O nl y if U T I is s us pecte d a n d uri ne di pstic k is p ositi ve f or nitrites or le u k oc yte esterase or b ot h
c.
F or c o nfir mati o n of p ost me n o pa usal s tat us o nly
d.
I n fe male partici pa nts of c hil d beari n g p ote ntial, se r u m h C G (at Scree ni n g Visit ) wit h uri ne h C G 
(at all ot her visits usi n g kits pr o vi de d b y s p o ns or-i de ntifie d ce ntral la b orat or y) 
e.
At Scree ni n g Visit wit h t his test n ot per mitte d t o be re peate d a n d mi ni m u m re q uire me nt f or uri ne dr u g 
scree n a n d refle xe d c o nfir mat or y testi n g ( w he n d o ne) i ncl u di n g c ocai ne, o piates/ o pi oi ds, 
be nz o diaze pi nes , a n d a m p heta mi nes
C CI
C CI
C CI


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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Laboratory parameters related to efficacy (refer to Section 6.4.2) that could unblind the study 
and have been collected for the purpose of the study will not be reported to investigator 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 an 
increase in either 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
a. 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.
b. 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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c.
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.
d. Is a congenital anomaly/birth defect
e.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or nonpathogenic
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.
f.
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. 


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It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with EDP or EDB
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 nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
nonparticipant 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 the 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: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing discomfort,
but poses no significant or permanent risk of harm to the research participant.

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
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.

The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment.


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
For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have 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 their 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 DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT.

If the electronic system is unavailable, then the site will use the paper SAE DCT
(see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT 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 DCT 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 the 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, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, 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
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definition in Section 10.4.3).
OR

Is a WOCBP and agrees to use a highly effective contraceptive method (failure rate of 
<1% per year) during the intervention period and for at least for 28 days after the last 
dose of study intervention, which corresponds to the time needed to eliminate any 
reproductive safety risk of the study intervention(s). If a highly effective, 
user-dependent method is chosen, she agrees to concurrently use an effective barrier 
method of contraception.  The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;


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
Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above (eg, 
mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to use 
one of the highly effective non-estrogen hormonal contraception methods if she
wishes to continue her HRT during the study. Otherwise, she 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 studies.
The following contraceptive methods are appropriate for this study:
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.
5.
Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the WOCBP and the absence of sperm 
has been confirmed. If not, an additional highly effective method of 


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contraception should be used. The spermatogenesis cycle is approximately 90 
days.
6.
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation:

Oral + barrier*

Intravaginal** + barrier*

Transdermal** + barrier*
7.
Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral** + barrier*

Injectable** + barrier*
8.
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.
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:

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).
**Not approved in Japan.


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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 8.6.1) will be stored for up to 
3 years or other period as per local requirements.

Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site. 


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments and 
Study Intervention Rechallenge Guidelines
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 T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be elevated within 
the same laboratory sample). In rare instances, by the time T bili 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 T bili 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 T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili 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 T bili 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 T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN
(whichever is smaller).


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Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili 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 
T bili 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.


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 1 5
1 0. 7. A p pe n di x 7: Ki d ne y S afet y M o nit ori n g G ui deli nes
1 0. 7. 1. L a b or at or y Assess me nt of C h a n ge i n Ki d ne y F u ncti o n a n d Detecti o n of Ki d ne y 
I nj ur y
Sta n dar d ki d ne y  safet y m o nit ori n g re q uires assess me nt of baseli ne a n d p ost baseli ne ser u m 
creati ni ne (Scr meas ure me nt t o e G F R [ Scr-base d e G F R ] or [e Cr Cl]). Baseli ne a n d 
p ost baseli ne Sc y s ma kes it feasi ble t o disti n g uis h A KI fr o m ot her ca uses of Scr i ncrease. If 
Scr i ncrease is c o nfir me d after baseli ne, t he n refle x meas ure me nt of Sc y s is i n dicate d t o 
esti mate t he c o m bi ne d Scr-S c y s e G F R calc ulati o n (f or a d ults o nly).
Re gar dless of w het her ki d ne y  f u ncti o n m o nit ori n g tests are re q uire d as a r o uti ne safety 
m o nit ori n g pr oce d ure i n t he st u d y , if t he i n vesti gat or or s p o ns or dee ms it necess ar y t o f urt her 
assess ki d ne y safet y a n d q ua ntif y ki d ne y f u ncti o n, t he n t hese test res ults s h o ul d be ma na ge d 
a n d f oll o we d per sta n dar d of care.
1 0. 7. 2. A d ult Ki d ne y F u ncti o n C alc ul ati o n Rec o m me n d ati o ns
1 0. 7. 2. 1. A d ults ( 1 8 Y e ars a n d A b o ve) — 2 0 2 1 C K D- E P I E q u ati o ns
2 0 2 1 C K D -
E P I Scr-Sc ys 
C o m bi ne d 4 1
Scr
( m g/ d L)
S c ys
( m g/ L)
Rec o m me n de d e G F R E q u ati o n
Fe male
if ≤
0. 7
if ≤
0. 8
e G F R = 1 3 0 × ( Scr/ 0. 7) -0. 2 1 9 ×
( Sc ys/ 0. 8)-0. 3 2 3 ×
( 0. 9 9 6 1)A ge
Fe male
if ≤
0. 7
if > 0. 8
e G F R = 1 3 0 × ( Scr/ 0. 7) -0. 2 1 9 ×
( Sc ys/ 0. 8)-0. 7 7 8 ×
( 0. 9 9 6 1)A ge
Fe male
if > 0. 7
if ≤
0. 8
e G F R = 1 3 0 × ( Scr/ 0. 7) -0. 5 4 4 ×
( Sc ys/ 0. 8)-0. 3 2 3 ×
( 0. 9 9 6 1)A ge
Fe male
if > 0. 7
if > 0. 8
e G F R = 1 3 0 × ( Scr/ 0. 7) -0. 5 4 4 ×
( Sc ys/ 0. 8)-0. 7 7 8 ×
( 0. 9 9 6 1)A ge
Male
if ≤
0. 9
if ≤
0. 8
e G F R = 1 3 5 × ( Scr/ 0. 9) -0. 1 4 4 ×
( Sc ys/ 0. 8)-0. 3 2 3 ×
( 0. 9 9 6 1)A ge
Male
if ≤
0. 9
if > 0. 8
e G F R = 1 3 5 × ( Scr/ 0. 9) -0. 1 4 4 ×
( Sc ys/ 0. 8)-0. 7 7 8 ×
( 0. 9 9 6 1)A ge
Male
if > 0. 9
if ≤
0. 8
e G F R = 1 3 5 × ( Scr/ 0. 9) -0. 5 4 4 ×
( Sc ys/ 0. 8)-0. 3 2 3 ×
( 0. 9 9 6 1)A ge
Male
if > 0. 9
if > 0. 8
e G F R = 1 3 5 × ( Scr/ 0. 9) -0. 5 4 4 ×
( Sc ys/ 0. 8)-0. 7 7 8 ×
( 0. 9 9 6 1)A ge
1 0. 7. 3. A d verse E ve nt Gr a di n g f or Ki d ne y S afet y L a b or at or y A b n or m alities
A E gra di n g f or decli ne i n ki d ne y  f u ncti o n (ie, e G F R or e Cr Cl) will be acc or di n g t o K DI G O
criteria.


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10.8. Appendix 8: 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 ms.

New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms 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 ms.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB (QRS complex >120 ms).

New-onset right bundle branch block (QRS complex >120 ms).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR
<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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10.9. Appendix 9: AEs, ADEs, SAEs, SADEs, USADEs, and Device Deficiencies:
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting in 
Medical Device Studies
Definitions of a Medical Device Deficiency
The definitions and procedures detailed in this appendix are in accordance with ISO 14155
and the European MDR 2017/745 for clinical device research (if applicable). 
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.2 for the list of sponsor 
medical devices).
10.9.1. Definition of AE and ADE
AE and ADE Definition

An AE is defined in Appendix 3 (Section 10.3.1).

An ADE is defined as an AE related to the use of an investigational medical device. 
This definition includes any AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device as well as any event resulting 
from use error or from intentional misuse of the investigational medical device.
10.9.2. Definition of SAE, SADE, and USADE
SAE Definition

An SAE is defined in Appendix 3 (Section 10.3.2).
SADE Definition

An SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE.

Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate.


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USADE Definition

A USADE (also identified as UADE in US Regulations 21 CFR 813.3) is a SADE
that by its nature, incidence, severity, or outcome has not been identified in the 
current version of the risk analysis management file.
10.9.3. Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequate information supplied by the 
manufacturer.
10.9.4. Recording/Reporting and Follow-Up of Medical Device Deficiencies
Device Deficiency Recording

When a device deficiency 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 device deficiency information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice and will also capture the required information on the Medical Device 
Complaint form.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of following the reporting process described 
in the Medical Device Complaint form.

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.

If the investigator determines that the medical device deficiency may have injured 
the participant (ie, the medical device deficiency is associated with an AE or SAE), 
then the investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis will be documented in the participant’s medical record and recorded as 
the AE or SAE rather than the individual signs/symptoms. Requirements for 
recording and reporting an AE or SAE are provided in Appendix 3 (Section 10.3.3)


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Page 120

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent 
recurrence.
Assessment of Causality Occurring in Conjunction With a Medical Device Deficiency

If an AE or SAE has occurred in conjunction with a medical device deficiency, the 
investigator must assess the relationship between each occurrence of the AE or 
SAE and the medical device deficiency. 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.

The investigator will also consult the IB for PF-07081532 and/or product 
information, for Rybelsus in their assessment.

For each device deficiency, the investigator must document in the medical notes 
that they have reviewed the device deficiency and have 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 their 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.


PF-07081532 
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PFIZER CONFIDENTIAL
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Page 121
Follow-Up of Medical Device Deficiency

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 device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

New or updated information regarding the nature of the device deficiency will be 
recorded in the originally completed Medical Device Complaint form.

New or updated information regarding any SAE that was potentially associated 
with the medical device deficiency will be submitted to Pfizer Safety on the CT
SAE Report Form within 24 hours of receipt of the information, according to the 
requirements provided in Appendix 3.
10.9.5. Reporting of SAEs
Reporting of an SAE to Pfizer Safety must be performed according to the processes 
described in Appendix 3 (Section 10.3.4).
10.9.6. Reporting of SADEs
SADE Reporting to Pfizer Safety
Note: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs (ie, an SADE) that must fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.

Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency.

The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 2 2
1 0. 1 0. A p pe n di x 1 0 : Pr o hi bite d Pri or / C o nc o mit a nt Me dic ati o ns
T he me dicati o ns liste d i n Ta ble 6 m a y  i nteract (at t he P K le vel) wit h P F-0 7 0 8 1 5 3 2 a n d t h us 
are pr o hi bite d f or t he pr o vi de d ti mefra me of restricti o n ( Ta ble 6) a n d u ntil first F oll o w -u p 
Visit . A d diti o nall y , t he me dicati o ns liste d i n Ta ble 7 are als o pr o hi bite d f or t he pr o vi de d 
ti mefra me of restricti o n (Ta ble 7 ) a n d u ntil first F oll o w -u p Visit .
T he Pfizer st u d y  tea m is t o be n otifie d of a n y pro hi bite d me dicati o ns ta ke n d uri n g t he st u d y . 
After c o ns ulti n g wit h t he s p o ns or, t he i n vesti gat or will ma ke a j u d g me nt o n t he o n g oi n g 
partici pati o n of a n y partici pa nt wit h pr o hi bite d me dicati o n use d uri n g t he st u d y.
T his list of dr u gs pr o hi bite d f or p ote nti al D DI c o ncer ns wit h t he I M P ma y  be re vise d d uri n g 
t he c o urse of t he st u d y wit h writte n n otificati o n fr o m s p o ns or, t o i ncl u de or e xcl u de s pecific 
dr u gs or dr u g cate g ories f or vari o us reas o ns (e g, e mer gi n g D DI res ults f or t he I M P, 
a vaila bilit y of ne w i nf or mati o n i n literat ure o n t he D DI p ote ntial of ot her dr u gs).
T his is n ot a n all -i ncl usi ve list. Site staff s h o ul d c o ns ult wit h t he s p o ns or or desi g nee wit h 
a n y q uesti o ns re gar di n g p ote ntial D DI.
I n vesti gat ors s h o ul d c o ns ult t he S R S D f or R y bels us f or i nf or mati o n re gar di n g me dicati o n 
t hat is pr o hi bite d f or c o nc o mita nt use. R y bels us dela y s gastric e m ptyi n g. W he n 
c o-a d mi nisteri n g oral me dicati o ns i nstr uct patie nts t o cl osel y  f oll o w Ry bels us a d mi nistrati o n 
i nstr ucti o ns. C o nsi der i ncrease d cli nical or la b orat or y m onit ori n g f or me dicati o ns t hat ha ve a 
narr o w t hera pe utic i n de x or t hat re q uire cli nical m o nit ori n g.
I n vesti gat ors s h o ul d c o ns ult t he pr o d uct la bel f or a n y ot her me dicati o n use d d uri n g t he st u d y 
f or i nf or mati o n re gar di n g me dicati o n t hat is pr o hi bite d f or c o nc o mita nt use. 
T a ble 6.
Pr o hi bite d Me dic ati o ns t h at m a y i nter act 
) wit h 
P F -0 7 0 8 1 5 3 2 
Dr u g C ate g or y 
Dr u gs ( T her a pe utic Cl ass)
Ti mefr a me of Restricti o n
C Y P 3 A I n hi bit ors 
(str o n g)
B oce pre vir ( A nti viral),
Ceriti ni b ( Ki nase I n hi bit or),
Clarit hr o m yci n ( A nti bi otic),
C o bicistat ( P har mac o ki netic E n ha ncer),
C o ni va pta n ( Di uretic),
Da n o pre vir a n d Rit o na vir ( A nti viral),
El vite gra vir a n d Rit o na vir ( Treat me nt of AI D S),
Gra pefr uit j uice ( F o o d Pr o d uct),
I delalisi b ( Ki nase I n hi bit or),
I n di na vir ( Pr otease I n hi bit or),
I n di na vir a n d Rit o na vir ( Pr otease I n hi bit or),
Itrac o naz ole ( A ntif u n gal),
J osa m yci n ( A nti bi otic),
Ket oc o naz ole ( A ntif u n gal),
L C L 1 6 1 ( Ca ncer Treat me nt),
L o nafar ni b ( Misc a ge nt; Rare diseases),
L o pi na vir a n d Rit o na vir ( Pr otease I n hi bit or),
Mi befra dil ( Calci u m C ha n nel Bl oc ker),
2 w ee ks or 5 half -li ves,
w hic he ver is l o n ger, pri or t o 
t he first d ose of st u d y 
i nter ve nti o n
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 2 3
T a ble 6.
Pr o hi bite d Me dic ati o ns t h at m a y i nter act 
) wit h 
P F -0 7 0 8 1 5 3 2 
Dr u g C ate g or y 
Dr u gs ( T her a pe utic Cl ass)
Ti mefr a me of Restricti o n
Mife prist o ne ( A nti pr o gesti n),
Nefaz o d o ne ( A nti de pressa nt),
Nelfi na vir ( Pr otease I n hi bit or),
O m bitas vir a n d Parita pre vir a n d Rit o na vir a n d 
Dasa b u vir ( A nti viral),
P osac o naz ole ( A ntif u n gal),
Ri b ocicli b ( Ki nase I n hi bit or),
Rit o na vir ( Pr otease I n hi bit or) a,
Sa q ui na vir ( Pr otease I n hi bit or),
Sa q ui na vir a n d Rit o na vir ( Pr otease I n hi bit or),
Tela pre vir ( A nti viral),
Telit hr o m yci n ( A nti bi otic),
Ti pra na vir a n d Rit o na vir ( Pr otease I n hi bit or),
Tr olea n d o m yci n ( A nti bi otic),
T ucati ni b ( Ki nase I n hi bit or),
V oric o naz ole ( A ntif u n gal)
C Y P 3 A I n d ucers 
(str o n g)
A pal uta mi de ( A ntia n dr o ge n),
A vasi mi be ( A ntili pe mic),
Car ba maze pi ne ( A ntic o n v ulsa nt),
E nzal uta mi de ( A ntia n dr o ge n),
I v osi de ni b ( Ca ncer Treat me nt),
L u macaft or ( C ystic Fi br osis Treat me nt),
Mit ota ne ( A nti ne o plastic), 
P he n yt oi n ( A ntic o n v ulsa nt),
Rifa m pi n ( A nti bi otic),
Rifa pe nti ne ( A nti bi otic),
St. J o h n’s wort e xtract ( Her bal Me dicati o n)
5 half -li ves pl us 1 4 da ys 
pri or t o t he first d ose of 
st u d y i nter ve nti o n
O A T P ( 1 B 1/ 1 B 3) 
I n hi bit ors
Ataza na vir a n d Rit o na vir ( Pr otease I n hi bit or),
B oce pre vir ( A nti viral),
Clarit hr o m yci n ( A nti bi otic),
Eltr o m b o pa g ( T h r o mb o p oieti n rece pt or a g o nist),
Er yt hr o m yci n ( A nti bi otic),
Fal da pre vir ( A nti viral),
Ge mfi br ozil ( Fi bric Aci d Deri vati ve),
Graz o pre vir ( A nti viral),
Itrac o naz ole ( A ntif u n gal),
Leter m o vir ( A nti viral),
L o pi na vir a n d Rit o na vir ( Pr otease I n hi bit or),
Rifa m pi n, si n gle d ose ( A nti bi otic),
Si me pre vir ( A nti viral), 
Tela pre vir ( A nti viral),
Vel patas vir ( A nti viral)
2 w ee ks or 5 half -li ves,
w hic he ver is l o n ger, pri or t o 
t he first d ose of st u d y 
i nter ve nti o n
C Y P 2 C 1 9 
S u bstr ates 
( Se nsitive) b
B M S -8 2 3 7 7 8 ( Dia betes treat me nt),
Cl o baza m ( Be nz o diaze pi ne),
Cl o pi d o grel ( A nti platelet) c,
Diaze pa m ( Be nz o diaze pi ne),
Gliclazi de ( S ulf o n yl urea),
Pr o hi bite d p ost 
ra n d o mizati o n
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 2 4
T a ble 6.
Pr o hi bite d Me dic ati o ns t h at m a y i nter act 
) wit h 
P F -0 7 0 8 1 5 3 2 
Dr u g C ate g or y 
Dr u gs ( T her a pe utic Cl ass)
Ti mefr a me of Restricti o n
He x o bar bital ( H y p n otic – Se dati ve),
Me p h o bar bital ( A ntic o n v ulsa nt),
Pr o g ua nil ( A nti malarial),
S- me p he n yt oi n ( A ntic o n v ulsa nt ),
Tili di ne ( Treat me nt of Pai n & I nfla m mati o n),
Val pr oic aci d ( A ntic o n v ulsa nt)
U G T 1 A 1 
S u bstr ates 
( Se nsiti ve)
Beli n ostat ( Hist o ne Deacet ylase I n hi bit or),
Iri n oteca n ( T o p ois o merase I n hi bit or)
Pr o hi bite d p ost 
ra n d o mizati o n
a.
Nir m atrel vir + Rit o na vir ( Pa xl o vi d) is per mitte d; s pecial i nstr ucti o ns pr o vi de d i n Secti o n 7. 1. 2
b.
T he P PIs de xla ns o praz ole, la ns o praz ole, o me praz ole, pa nt o praz ole a n d ra be praz ole, alt h o u g h c o nsi dere d 
se nsiti ve C Y P 2 C 1 9 s u bstrates, are n ot pr o hi bite d d ue t o wi de t hera pe utic i n de x a n d n o a ntici pate d 
i mpact o n t heir efficac y or safet y
c.
T he P K i nteracti o n bet w ee n P F-0 7 0 8 1 5 3 2 a n d cl o pi d o grel has bee n cli nicall y a ssesse d (see 
P F -0 7 0 8 1 5 3 2 I B). O ut of a b u n da nce of ca uti o n, u ntil f urt her cli nical or m o del -base d assess me nt of 
w het her t he m o dest c ha n ges o bser ve d i n t he e x p os ure of t he acti ve meta b olite of cl o pi d o grel 
( H 4-cl o pi d o grel) ca n elicit a n y cli nicall y mea ni n gf ul i mpact o n efficac y/safet y, c o -a d mi nistrati o n of 
P F -0 7 0 8 1 5 3 2 w it h cl o pi d o grel is pr o hi bite d
T a ble 7.
Ot her Pr o hi bite d Me dic ati o ns
Dr u g Cl asses a n d/ or Dr u gs 
Ti mefr a me of Restricti o n 
T Z Ds (ie, / P P A Rs uc h as pi o glitaz o ne a n d r osi glitaz o ne.

I n Str at u m 1 – i n 1 2 w ee ks
pri or t o Scree ni n g Visit

I n Str at u m 2 – a n y ti me 
S u bc uta ne o usl y a d mi nistere d a ge nts f or gl yce mic c o ntr ol (e g, i ns uli n, 
e xe nati de, lira gl uti de, d ula gl uti de, se ma gl uti de, tirze pati de, a m yli n 
a nal o g ues s uc h as pr a m li nti de). 
N ote: S h ort -ter m (ie, ≤7 da ys) of i ns uli n a d mi nistrati o n is per mitte d if 
partici pa nt is h os pitalize d.

I n Str at u m 1 – i n 1 2 wee ks 
pri or t o Scree ni n g Visit 

I n Str at u m 2 – a n y ti me
Oral a nti -dia betic me dicati o ns, i ncl u di n g
Bi g ua ni des s uc h as p he nf or mi n. N ote : metf or mi n, a bi g ua ni de, is a 
re q uire d bac k gr o u n d me dicati o n i n all partici pa nts i n Strat u m 1 
S ulf o n yl ureas s uc h as acet o he xa mi de, c hl or pr o pa mi de, t olaza mi de, 
t ol b uta mi de, gli me piri de, gli pizi de, gl y b uri de. 
Me gliti ni de a nal o g ues s uc h as re pa gli ni de, nate gli ni de.
D P PI Vi s uc h as sita gli pti n, sa xa gli pti n, li na gli pti n, vil da gli pti n.
α- gl uc osi dase i n hi bit ors s uc h as acar b ose, mi glit ol.
S G L T 2 i n hi bit ors s uc h as ca na glifl ozi n, e m pa glifl ozi n, da pa glifl ozi n, 
ert u glifl ozi n. 
Oral G L P -1 R a g o nists ( oral se ma gl uti de). N ote: Oral se ma gl uti de is 
t he i nter nal refere nce sta n dar d ar m ( R y bels us) of t he st u d y.
A nti -h y per gl yce mic me dicati o ns, i ncl u di n g br o m o cri pti ne a n d 
c olese vela m.

I n Str at u m 1 – i n 1 2 wee ks
pri or t o Scree ni n g Visit –
t h o u g h s o me of t hese a ge nts 
(refer t o Secti o n 6. 9. 1. 3 ) ca n 
be use d t o ma na ge gl yce mic 
c o ntr ol (A p pe n di x 1 2 )

I n Str at u m 2 – a n y ti me
C CI


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Page 125
Table 7.
Other Prohibited Medications
Drug Classes and/or Drugs 
Timeframe of Restriction 
Herbal medications for the explicit purpose of glycemic control.
In Both Strata
Pharmacological agents with approved indication for weight loss such as 
liraglutide, semaglutide, orlistat and sibutramine.
Appetite or weight modifying medications, including nonprescription or 
herbals and medical grade marijuana.
12 weeks prior to Screening 
Visit
Systemic glucocorticoids such as prednisone, dexamethasone, 
triamcinolone, budesonide, betamethasone. Note: As an exception, 
steroid-containing inhalers, nasal sprays and topical formulations are 
permitted. Note: Intercurrent treatment with systemic corticosteroids 
during participation in the study may be permitted if treatment does/will 
not exceed 7 days.
8 weeks prior to Screening Visit
Immunosuppressants such as cyclosporine, tacrolimus, TNF-alpha 
inhibitors (eg, etanercept, infliximab, adalimumab), IL-6 receptor 
antagonists (eg, tocilizumab, sarilumab), JAK inhibitors (eg, tofacitinib).
8 weeks prior to Screening Visit
Anti-psychotic medications such as olanzapine, risperidone.
8 weeks prior to Screening Visit
Coumarin type anticoagulants or other anticoagulants (eg, dabigatran, 
apixaban, edoxaban, rivaroxaban, fondaparinux).
8 weeks prior to Screening Visit
Anticonvulsants if prescribed for seizure disorder.
8 weeks prior to Screening Visit
(with some medications 
prohibited post randomization –
refer to Table 6)
Antiarrhythmic medications whose primary mechanism of action is 
sodium or potassium channel blockade (eg, procainamide, phenytoin, 
quinidine, propafenone; as well as amiodarone, dofetilide, sotalol). Note:
β-adrenergic receptor blocking agents (eg, atenolol, metoprolol) and 
calcium channel blockers (eg, diltiazem, amlodipine, nifedipine) are 
permitted.
8 weeks prior to Screening Visit
Sympathomimetic agents. Note: Inhaled β-adrenergic receptor agonists 
(e.g., albuterol) are permitted. Methylphenidate and amphetamine 
medications for ADHD that are at a stable dose for at least 12 weeks
prior to Screening Visit are permitted.
8 weeks prior to Screening Visit
Systemically administered treatments for malignancy including (but not 
limited to) the use of chemotherapy, radiotherapy, or immunotherapy
5 years prior to Screening Visit 
An investigational product (drug or vaccine)
30 days (or as determined by 
local requirements) or 5 half-
lives prior to Day 1/Visit 3
Previous participation in a study evaluating PF-07081532 (including 
exposure to placebo) or intolerance/hypersensitivity to GLP-1R agonist
Any time 


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
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Page 126
10.11. Appendix 11: Guidance to Investigators – Management of Individual 
Participants MoA-Based GI-related AEs
Adapted from Postgraduate Medicine 2022;134(1):14-1929


PF-07081532 
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Page 127
10.12. Appendix 12: Guidance to Investigators – Management of Individual 
Participants Glycemic Control 
Sites are blinded to FPG results as reported by sponsor-identified central laboratory, starting 
on Day 1/Visit 3, unless above mentioned thresholds are met as outlined in Section 6.4.2; 
refer to Section 6.9.1.3 for guidance on agents permitted to serve as rescue.


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
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Page 128
10.13. Appendix 13: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
A1 
albuminuria (KDIGO albuminuria severity standardization)
Abs
absolute
ADA
American Diabetes Association
ADE
adverse device effect
ADHD
attention deficit hyperactivity disorder
ADL
activity/activities of daily living
AE
adverse event
AESI
adverse event of special interest
AKI
acute kidney injury
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC24
area under the concentration-time curve from time 0 to 24 hours
AV
atrioventricular
AxMP
auxiliary medicinal product
β hCG
β-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
C-cell
Calcitonin-producing cells
CFB
change from baseline
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology 
Cmax 
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTIS
Clinical Trial Information System
Ctrough
predose concentration
CV
cardiovascular
CYP
cytochrome P450
DBP
diastolic blood pressure
DBili
Direct Bilirubin
DCCT
Diabetes Control and Complications Trial
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DPPIV
dipeptidyl peptidase IV
DPPIVi
dipeptidyl peptidase IV inhibitors
DU
dispensable unit
EC
ethics committee
ECC
emergency contact card


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 2 9
A b bre vi ati o n
Ter m
E C G
electr ocar di o gra m or electr ocar di o gra p h y
e Cr Cl
esti mate d creati ni ne cleara nce
e C R F
electr o nic case re p ort f or m
E D B
e x p os ure d uri n g breastfee di n g
E D P
e x p os ure d uri n g pre g na nc y
E F D
e mbr y o -fetal de vel o p m e nt
e G F R
esti mate d gl o mer ular filtrati o n rate
E ma x
ma xi mal effect
e S A E
electr o nic seri o us a d verse e ve nt
E T
E arl y T er mi nati o n
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n U ni o n Dr u g Re g ulati n g A ut h orities Cli nical Trials ( E ur o pea n Cli nical Trials 
Data base)
F D A
F o o d a n d Dr u g A d mi nistrati o n
F P G
fasti n g plas ma gl uc ose
F S B G
fi n gerstic k bl o o d gl uc ose 
F S H
f ollicle-sti m ulati n g h or m o ne
G C P
G o o d Cli nical Practice
G G T
ga m ma -gl uta m yl tra nsferase
GI
gastr oi ntesti nal
G L P -1
gl uca g o n -li ke pe pti de-1
G L P -1 R
gl uca g o n -li ke pe pti de-1 rece pt or
H A E
h y p o gl yce mic a d verse e ve nt
H b A 1 C
gl ycate d he m o gl o bi n
H C V
he patitis C vir us
H D L -C
hi g h -de nsit y li p o pr otei n c h olester ol
He p B
he patitis B
He p C
he patitis C
H O M A -I R
H o m e ostatic M o del Assess me nt f or I ns uli n Resista nce 
H O M A -S
H o m e ostatic M o del Assess me nt f or I ns uli n Se nsiti vit y
H R
heart rate
H R T
h or m o ne re place me nt t hera p y
hs -C R P
hi g h -se nsiti vit y C-reacti ve pr otei n
Ht
hei g ht
I B
I n vesti gat or’s Br oc h ure
I C D
i nf or me d c o nse nt d oc u me nt
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har m ace uticals f or H u ma n Use
I D
i de ntificati o n
I M P
i n vesti gati o nal me dici nal pr o d uct
I N D
In vesti gati o nal N e w Dr u g
I N R
i nter nati o nal n or malize d rati o
I P A L
I n vesti gati o nal Pr o d uct Acc o u nta bilit y L o g
I P M
i n vesti gati o nal pr o d uct ma n ual
I R B
Instit uti o nal R e vie w B oar d
I R C
i nter nal re vie w c o m mittee
I R T
I nteracti ve Res p o nse Tec h n ol o g y
I S O
I nter nati o nal Or ga nizati o n f or Sta n dar dizati o n
I V
i ntra ve n o us(l y)
C CI
C CI
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 3 0
A b bre vi ati o n
Ter m
K DI G O
Ki d ne y Disease: I m pr o vi n g Gl o bal O utc o mes
k g
kil o gra m
l b
p o u n d
L B B B
left b u n dle bra nc h bl oc k
L D L -C
l o w-de nsit y li p o pr otei n
L F T
li ver f u ncti o n test
L L N
l o wer li mit of n or mal
L S
least s q uare
M A R
m issi n g at ra n d o m
M D R
me dical de vice re g ulati o n
M E N 2
M ulti ple E n d ocri ne Ne o plasia T y pe 2
M H P
Me ntal Healt h Pr ofessi o nal
mI U
milli -i nter nati o nal u nit
M M R M
Mi xe d M o del Re peate d Meas ures
M o A
mec ha nis m of acti o n
M QI
me dicall y q ualifie d i n di vi d ual
ms
millisec o n d
M T C
Me d ullar y T h yr oi d Carci n o ma
n
n u m ber (s u b gr o u p or s u b p o p ulati o n)
N
t otal n u m ber
N G S P
Nati o nal Gl yc o he m o gl o bi n Sta n dar dizati o n Pr o gra m
NI M P
n o n -in vesti gati o nal me dici nal pr o d uct
N O A E L
n o o bser ve d a d verse effect le vel
N P
N urse practiti o ner 
N Y H A
N e w  Y or k Heart Ass ociati o n
O A T P
or ga nic a ni o n tra ns p orti n g p ol y pe pti de
O T C
o ver -t he-c o u nter
P A
P h y sicia ns’ assista nt
P B O
place b o
P C D
pri mar y c o m pleti o n date
P C O S
p ol yc ystic o var y s y n dr o me
P D
p har mac o d y na mic(s)
P E
p h ysical e xa m
P H Q -9
Patie nt Healt h Q uesti o n naire -9
P K
p har mac o ki netic(s)
P P A R 
per o xis o me pr oliferat or -acti vate d rece pt or - y
P PI
pr ot o n p u m p i n hi bit or
P R
p ulse rate
P S S A
Pfizer's Seri o us A d verse E ve nt S u b missi o n Assista nt
P T
P r othr o m bi n T i me
P V C
pre mat ure ve ntric ular c o ntracti o n
Q D
o nce dail y
Q T c
c orrecte d Q T i nter val
Q Tc F
Q Tc c orrecte d usi n g Fri dericia’s f or m ula
Q T L
q ualit y t olera nce li mit
C CI
C CI
C CI
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 3 1
A b bre vi ati o n
Ter m
q ual
q ualitati ve
R B C
re d bl o o d cell
R E E
resti n g e ner g y e x pe n dit ure
R N A
ri b o n ucleic aci d
S A D E
seri o us a d verse de vice effect
S A E
seri o us a d verse e ve nt
S A P
S tatistical A nal ysis Pla n
S B P
s yst olic bl o o d press ure
S C
s u bc uta ne o us(l y)
Scr
ser u m creati ni ne
Sc ys
ser u m c ystati n C
S D
sta n dar d de viati o n
S G L T 2
s o di u m gl uc ose c otra ns p orter 2
S o A
sc he d ule of acti vities
S O C
s yste m or ga n class
S O P
sta n dar d o perati n g pr oce d ure
S R S D
Si n gle Refere nce Safet y D oc u me nt
S T -T
S T se g me nt t o T w a ve c ha n ges o n 1 2 -lea d E C G
S U S A R
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n
T
tele p h o ne c o ntact
T 2 D M
t ype 2 dia betes mellit us
T 3
t otal trii o d ot h yr o ni ne
T 4
t otal t h yr o xi ne
T bili
t otal bilir u bi n
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T E E
t otal e ner g y e x pe n dit ure
T G
tri gl yceri de
T ma x 
ti me t o reac h Cma x
T S H
t h yr oi d-sti m ulati n g h or m o ne
T Z D
t hiaz oli di ne di o ne
U A D E
u na ntici pate d a d verse de vice effect
U G T
uri di ne 5’ -di p h os p h o -gl uc ur o n os yltra nsferase
U L N
u p per li mit of n or mal
U S
U nite d States
U S A D E
u na ntici pate d seri o us a d verse de vice effect
U S PI
U nite d States Prescri bi n g I nf or mati o n
U TI
uri nar y tract i nfecti o n
V
visit
W
wee k
W B C
w hite bl o o d cell
W O C B P
w o ma n/ w o me n of c hil d beari n g p ote ntial
C CI
C CI


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 132
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.
Hu FB. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care 
2011;34:1249-57.
6.
International Diabetes Federation. IDF Diabetes Atlas, 10th Ed. Brussels, Belgium.
Available from: http://www.idf.org/diabetesatlas.Accessed: 14 Aug 2022.
7.
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.
8.
Gregg EW, Zhuo X, Cheng YJ, et al. Trends in lifetime risk and years of life lost due to 
diabetes in the USA, 1985-2011: a modelling study. Lancet Diabetes Endocrinol 
2014;2:867-74.
9.
DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the 
treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95.
10.
Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular 
and microvascular complications of type 2 diabetes (UKPDS 35): prospective 
observational study. BMJ 2000;321:405-12.
11.
Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 
2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102. 
doi:10.1016/j.molmet.2020.101102.
12.
Ozempic (semaglutide). US Prescribing Information (USPI). Plainsboro, NJ: Novo 
Nordisk Inc; 2017. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf. Accessed:
14 Aug 2022.
13.
Victoza (liraglutide) US Prescribing Information (USPI). Plainsboro, NJ. Novo Nordisk
Inc; 2017. Available from: 


PF-07081532 
Protocol C3991004
Final Protocol, 13 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 133
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022341s027lbl.pdf. 
Accessed: 14 Aug 2022.
14.
Rybelsus (semaglutide) US Prescribing Information (USPI). Plainsboro, NJ. Novo 
Nordisk Inc; 2022. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213051s011lbl.pdf. 
Accessed: 30 Aug 2022.
15.
Guh DP, Zhang W, Bansback N, et al. The incidence of co-morbidities related to 
obesity and overweight: a systematic review and meta-analysis. BMC Public Health 
2009;9:88.
16.
Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with overweight 
and obesity using standard body mass index categories: a systematic review and 
meta-analysis. JAMA 2013;309(1):71-82.
17.
GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 
195 countries over 25 years. N Engl J Med 2017;377(1):13-27.
18.
Ogden CL, Carroll MD, Kit BK, et al. Prevalence of childhood and adult obesity in the 
United States, 2011-2012. JAMA 2014;311(8):806-14.
19.
Anderson JW, Konz EC, Frederich RC, et al. Long-term weight-loss maintenance: a 
meta-analysis of US studies. Am J Clin Nutr 2001;74(5):579-84.
20.
Saxenda (liraglutide [rDNA origin] injection), US Prescribing Information (USPI). 
Plainsboro, NJ. Novo Nordisk Inc; 2014. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206321Orig1s000lbl.pdf.
Accessed: 14 Aug 2022.
21.
Wegovy (semaglutide) US Prescribing Information (USPI). Plainsboro, NJ. Novo 
Nordisk Inc; 2021. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf.
Accessed: 14 Aug 2022.
22.
Pfizer. Investigator’s Brochure PF-07081532. Data on File. 
23.
Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide 
and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a 
trial. Lancet 2019;394:39-50.
24.
Pieber TR, Bode B, Mertens A, et al. Efficacy and safety of oral semaglutide with 
flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a 
multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol 
2019;7:528-39.


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 3 4
2 5.
R o d bar d H W, R ose nst oc k J, Ca na ni L H, et al. Oral se ma gl uti de vers us e m pa glifl ozi n i n 
patie nts wit h t y pe 2 dia betes u nc o ntr olle d o n metf or mi n: T he PI O N E E R -2 trial. 
Dia betes Care 2 0 1 9; 4 2( 1 2): 2 2 7 2- 8 1.
2 6.
Kr o gsta d V, Peric A, R o bertse n I, et al. C orrelati o n of b o d y  wei ght a n d c o m p ositi o n 
wit h he patic acti vities of c y t oc hr o me P 4 5 0 e nz ymes. J o ur nal of P har mace utical 
Scie nces 2 0 2 1; 1 1 0 : 4 3 2-3 7.
2 7.
R o dri g uez -M orat o J, G o da y  A, La n g o hr K, et al. S h ort- a n d me di u m-ter m i m pact of 
bariatric s ur ger y  o n t he acti vities of C Y P 2 D 6, C Y P 3 A 4, C Y P 2 C 9, a n d C Y P 1 A 2 i n 
m or bi d o besit y . Sci Re p 2 0 1 9; 9: 2 0 4 0 5 . d oi: 1 0. 1 0 3 8/s 4 1 5 9 8 - 0 1 9- 5 7 0 0 2- 9
2 8.
Lle d o -Garcia R, Mazer N A, Karlss o n M O. A se mi -mec ha nistic m o del of t he 
relati o ns hi p bet wee n a vera ge gl uc ose a n d H b A 1 C i n healt h y a n d dia betic s u bjects. 
J P har mac o k i net P har mac o d yn. 2 0 1 3; 4 0( 2): 1 2 9 -1 4 2. 
2 9.
W hart o n S, Da vies M, Dic ker D, et al. Ma na gi n g t he gastr oi ntesti nal si de effects of 
G L P- 1 rece pt or a g o nists i n o besit y : rec o m me n dati o ns f or cli nical practice. P ost gra d 
Me d
2 0 2 2; 1 3 4 ( 1):1 4 - 1 9. 
3 0.
A merica n C olle ge of Car di ol o g y / A merica n Heart Ass ociati o n Tas k F orce o n Practice 
G ui deli nes, O besit y  E x pert Pa nel, 2 0 1 3. E x pert Pa nel Re p ort: g ui deli nes ( 2 0 1 3) f or t he 
ma na ge me nt of o ver wei g ht a n d o besit y  i n a d ults. O besit y ( Sil ver S pri n g) 
2 0 1 4; 2 2 (S u p pl 2 ):S 4 1 - 4 1 0.
3 1.
Fra n k e nfiel d D C, M ut h E R, R o we W A . T he Harris -Be ne dict St u dies of H u ma n Basal
M eta b olis m: Hist or y a n d Li mitati o ns. J A m Diet Ass oc. 1 9 9 8; 9 8:4 3 9- 4 5.
3 2.
P os ner K, Br o w n G K, Sta nle y  B, et al. T he C ol u m bia– S uici de Se verit y  Rati n g Scale: 
i nitial vali dit y a n d i nter nal c o nsisten c y  fi n di n gs fr o m t hree m ultisite st u dies wit h 
a d olesce nts a n d a d ults. A m J Ps y c hiatr y 2 0 1 1; 1 6 8( 1 2): 1 2 6 6– 7 7. 
3 3.
Kr oe n ke K, S pitzer R L , Willia ms J B. T he P H Q-9: vali dit y  of a brief de pressi o n se verit y 
meas ure. J Ge n I nter n Me d 2 0 0 1; 1 6( 9): 6 0 6 - 1 3.
3 4.
W orl d Healt h O r ga nizati o n. Waist circ u mfere nce a n d w aist- hi p rati o: re p ort of a W H O 
ex pert co ns u ltati o n. Ge ne va, S witzerla n d: W orl d Healt h Or ga nizati o n; 2 0 0 8 : 1-4 7.
C CI


P F -0 7 0 8 1 5 3 2 
Pr ot oc ol C 3 9 9 1 0 0 4
Fi nal Pr ot oc ol, 1 3 Se pte m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate P hase 1 2 3 4 ( 0 1 A pril 2 0 2 2)
Pa ge 1 3 5
4 0.
Ba n h olzer M L, Wa n del C, Barr o w P, et al. Cli nical trial c o nsi derati o ns o n male 
c o ntrace pti o n a n d c ollecti o n of pre g na nc y  i nf or mati o n fr o m fe male part ner: u p date.
Cli n Tra nsl Me d 2 0 1 6; 5( 1): 2 3- 3 7.
4 1.
I n ker MA, E nea n ya N D, C ores h J, et al. Ne w Creati ni ne- a n d C ystati n C-Base d 
E q uati o ns t o Esti mate G F R wit h o ut Race. N EJ M 2 0 2 1; 3 8 5: 1 7 3 7 - 4 9.
C CI

SAP_001.pdf: 
Protocol C3991004 (
) Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022 
PFIZER  CONFIDENTIAL  
TMF Doc ID: 98.03 
Page 1  
 
 
 
Protocol C3991004 
 
 
 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, DOSE 
RANGING, DOSE FINDING, PARALLEL GROUP STUDY TO ASSESS EFFICACY 
AND SAFETY OF 
, AND OPEN LABEL ORAL SEMAGLUTIDE, IN 
ADULTS WITH TYPE 2 DIABETES MELLITUS (T2DM) INADEQUATELY 
CONTROLLED ON METFORMIN, AND SEPARATELY 
 COMPARED 
TO MATCHING PLACEBO IN ADULTS WITH OBESITY BUT WITHOUT T2DM 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
3 
Date:  
27SEP2023 
 


Protocol C3991004 (
) Statistical Analysis Plan
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022
PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3 
LIST OF FIGURES ...................................................................................................................4 
APPENDICES ...........................................................................................................................4 
1. VERSION HISTORY............................................................................................................5 
2. INTRODUCTION .................................................................................................................7 
2.1. Modifications to the Analysis Plan Described in the Protocol..................................7 
2.2. Study Objectives, Endpoints, and Estimands............................................................8 
2.2.1. Primary Estimands......................................................................................14 
2.3. Study Design ...........................................................................................................15 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................16 
3.1. Primary Endpoint(s) ................................................................................................16 
3.2. Secondary Endpoint(s) ............................................................................................16 
3.4. Baseline Variables...................................................................................................19 
3.5. Safety Endpoints......................................................................................................19 
3.5.1. Adverse Events ...........................................................................................19 
3.5.2. Laboratory Data..........................................................................................20 
3.5.3. Vital Signs Data..........................................................................................21 
3.5.4. Electrocardiogram Data ..............................................................................21 
3.5.5. Columbia Suicide Severity Rating Scale (C-SSRS) Data ..........................21 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................22 
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................23 
5.1. Hypotheses and Decision Rules ..............................................................................23 
5.2. General Methods .....................................................................................................24 
5.2.1. Analyses for Binary Endpoints...................................................................24 
5.2.2. Analyses for Continuous Endpoints ...........................................................24 
5.2.3. Analyses for Time-to-Event Endpoints ......................................................24 
5.3. Methods to Manage Missing Data...........................................................................25 
6. ANALYSES AND SUMMARIES ......................................................................................25 
6.1. Primary Endpoint(s) ................................................................................................25 
6.1.1. Main Analysis.............................................................................................25 


Protocol C3991004 (
) Statistical Analysis Plan
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022
PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
Page 3
6.1.2. Figures ........................................................................................................26 
6.2. Secondary Endpoint(s) ............................................................................................26 
6.2.1. Binary Secondary Endpoints ......................................................................26 
6.2.1.1. Main Analysis............................................................................26 
6.2.2. Continuous Secondary Endpoints...............................................................26 
6.2.2.1. Main Analysis............................................................................27 
6.2.2.2. Figures.......................................................................................27 
6.4. Pharmacokinetic Endpoints.....................................................................................27 
6.6. Subset Analyses.......................................................................................................28 
6.7. Baseline and Other Summaries and Analyses.........................................................28 
6.7.1. Baseline Summaries....................................................................................28 
6.7.2. Concomitant Medications and Nondrug Treatments ..................................28 
6.7.3. Treatment Compliance................................................................................28 
6.7.4. Discontinuations .........................................................................................28 
6.8. Safety Summaries and Analyses .............................................................................28 
6.8.1. Adverse Events ...........................................................................................28 
6.8.2. Laboratory Data..........................................................................................29 
6.8.3. Vital Signs ..................................................................................................30 
6.8.4. Electrocardiograms .....................................................................................30 
7. INTERIM ANALYSES.......................................................................................................31 
8. APPENDICES .....................................................................................................................31 
LIST OF TABLES
Table 1. 
Summary of Changes..................................................................................5 
Table 2. 
Objectives, Endpoints, and Estimands........................................................8 
Table 3. 
Laboratory Abnormalities.........................................................................20 
Table 4. 
Analysis Sets.............................................................................................23 
Table 5. 
Vital Signs Change from Baseline............................................................30 
Table 6. 
Safety QTcF Assessment..........................................................................31 
Table 7. 
Categories for PR and QRS ......................................................................31 


Protocol C3991004 (
) Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022 
PFIZER  CONFIDENTIAL  
TMF Doc ID: 98.03 
Page 4  
LIST OF FIGURES 
Figure 1. 
High Level Study Design..........................................................................15 
Figure 2. 
Dose Escalation Scheme ...........................................................................16 
APPENDICES 
Appendix 1. Data Derivation Details .......................................................................................31 
Appendix 2. List of Abbreviations...........................................................................................37 
 
 


Protocol C3991004 (
) Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022 
PFIZER  CONFIDENTIAL  
TMF Doc ID: 98.03 
Page 5  
1. VERSION HISTORY 
Table 1. 
Summary of Changes 
Version/
Date 
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1 
26APR2023 
Original 
21SEP2022 
N/A 
N/A 
2 
16AUG2023 
Original 
21SEP2022 
Analysis 
reduction due to 
program 
termination 
Planned analyses were reduced in scope to 
align with study and program reporting 
needs following study termination: 
 MMRM analyses are limited to the 
following (Sections 3.1, 3.2, and 5.2.2):
 Primary endpoint for Cohort 1 
(T2DM): placebo-adjusted, change 
from baseline in HbA1C (%) at 
Week 32 for Cohort 1 (T2DM)  
 Primary endpoint for Cohort 2 
(Obesity): placebo-adjusted, percent 
change from baseline in body 
weight (kg) at Week 32 for Cohort 
2 (Obesity) 
 Secondary endpoint for Cohort 1 
(T2DM): placebo-adjusted, percent 
change from baseline in body 
weight (kg) at Week 32 for Cohort 
1 (T2DM) 
MMRM will be limited to visits up to 
and including Week 16 for Cohort 1 
(T2DM) and Week 20 for Cohort 2 
(Obesity) 
 Extension population and analyses of 
Extension data have been removed 
 Box plots planned for continuous 
endpoints were removed and will not 
be produced (previously included in 
Sections 4,5.2, 5.2.1, 5.2.2, 6.1.1, 
6.2.1.1, 6.2.2.1, and 6.4) 


Protocol C3991004 (
) Statistical Analysis Plan
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022
PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
Page 6
Endpoints defined as categories of 
continuous endpoints (Section 3.2 and 
6.2.1.1) will not be summarized nor
modeled.  These endpoints will not be 
summarized but will be derived and 
included in the ADaM datasets: 
Proportion of participants who 
achieve HbA1C <7% (<53 
mmol/mol) at Week 32 
Proportion of participants achieving 
weight loss at Week 32 relative to 
baseline
Plots of vital sign and ECG data will 
not be produced
3 Tier Aes and AESIs will not be 
summarized separately from standard 
AE reporting


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3
27SEP2023 
Original 
21SEP2022 
Analysis 
clarifications 
 In Section 5.2.2, MMRM models have 
been updated to include a baseline*time 
interaction term  
 Conventions for handling non-fasting 
lab values and values below the level of 
quantification have been added to 
Section 3.5.2 
 Spaghetti plots of Total Bile Acids 
(TBA) have been added in Section 
6.8.2 
 Summary of recurrence of TEAEs has 
been added to Section 6.8.1 
 Fasting glucagon was removed from 
Section 6.7.1 
 QT has been added as an ECG 
parameter and ECG listings have been 
added to Section 6.8.4 
 
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C3991004. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
Due to termination of the PF-07081532 program and premature termination of study 
C3991004: 
 Planned analyses were modified or reduced to align with the updated planned study 
report; 
 MMRM models have been updated to include a baseline*time interaction term 
 These changes will not be reflected in a protocol amendment. 


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2.2. Study Objectives, Endpoints, and Estimands 
Table 2. 
Objectives, Endpoints, and Estimands 
Objectives
Endpoints 
Estimands 
Primary: 
Primary: 
Primary:  
To evaluate the 
efficacy of a range of 
 doses 
compared to placebo, 
in participants with 
T2DM inadequately 
controlled on 
metformin  
Placebo-adjusted, change from 
baseline in HbA1C at Week 32 
Population: All treated participants 
with T2DM inadequately controlled on 
metformin  
Variable: Placebo-adjusted, change 
from baseline in HbA1C at Week 32  
Intercurrent events:   
 
An On Treatment strategy will be 
used: Measurements after initiation of 
glycemic rescue medication or 
discontinuation of study intervention 
are considered as intercurrent events, 
which will be censored and treated as 
missing data. The missing data due to 
censoring, study withdrawal or other 
reasons (e.g., laboratory failure) will 
have data imputed based on a MAR 
assumption. Participants with 
inadequate compliance will have their 
HbA1C values used as-is in the 
analysis  
Population-level summary measure: 
The population-based treatment effect 
will be the difference in the mean 
change from baseline in each 
 arm compared to placebo 
To evaluate the 
efficacy of a range of 
 doses 
compared to placebo, 
in participants with 
obesity but without 
T2DM 
Placebo-adjusted, percent 
change from baseline in body 
weight at Week 32 
Population: All treated participants 
with obesity but without T2DM   
Variable: Placebo-adjusted, percent 
change from baseline in body weight at 
Week 32  
Intercurrent events:   
 
An On Treatment strategy will be 
used: Measurements after 
discontinuation of study 
intervention are considered as 
intercurrent events, which will be 
censored and treated as missing 
data. The missing data due to 
censoring, study withdrawal or 
other reasons (e.g., equipment 
failure) will have data imputed 
based on a MAR assumption. 
Participants with inadequate 
compliance will have their body 
weight values used as-is in the 
analysis  


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Table 2. 
Objectives, Endpoints, and Estimands 
Objectives
Endpoints 
Estimands 
Population-level summary measure: 
The population-based treatment effect 
will be the difference in the mean 
percent change from baseline in each 
 arm compared to placebo 
Secondary:  
Secondary: 
Secondary:  
To assess the effect of 
a range of 
 doses 
compared to placebo 
on various parameters, 
in participants with 
T2DM inadequately 
controlled on 
metformin 
Proportion of participants who 
achieve HbA1C <7% (<53 
mmol/mol) at Week 32 
Population: All treated participants with 
T2DM inadequately controlled on 
metformin   
Variable: Proportion of participants who 
achieve HbA1C <7% (<53 mmol/mol) at 
Week 32  
Intercurrent events:   
 
An On Treatment strategy will be 
used: Measurements after initiation of 
glycemic rescue medication or 
discontinuation of study intervention 
are considered as intercurrent events 
which will be censored and treated as 
missing data. Missing data will not be 
imputed. Participants with inadequate 
compliance will have their HbA1C 
values used as-is in the analysis.  
Population-level summary measure: The 
population-based treatment effect will be the 
odds ratio of achieving HbA1c < 7% in a 
 arm relative to placebo  
Placebo-adjusted, change from 
baseline in FPG at Week 32 
The estimand for placebo-adjusted, change from 
baseline in FPG at Week 32 endpoint will be 
constructed in a similar manner as Placebo-
adjusted, change from baseline in HbA1C at 
Week 32 
Placebo-adjusted, percent 
change from baseline in body 
weight at Week 32 
The estimand for the placebo-adjusted, percent 
change from baseline in body weight at Week 32 
endpoint will be constructed in a similar manner 
as Placebo-adjusted, change from baseline in 
HbA1C at Week 32 
To compare the 
efficacy of 
 and 
Rybelsus relative to 
placebo, in 
participants with 
T2DM inadequately 
controlled on 
metformin 
Placebo-adjusted, change from 
baseline in HbA1C at Week 32 
Population: All treated participants with 
T2DM inadequately controlled on metformin 
Variable: Placebo-adjusted, change from 
baseline in HbA1C at Week 32  
Intercurrent events:   
 
An On Treatment strategy will 
be used: Measurements after 
initiation of glycemic rescue 
medication or discontinuation 
of study intervention are 
considered as intercurrent 
events, which will be censored 
and treated as missing data. 


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Table 2. 
Objectives, Endpoints, and Estimands 
Objectives
Endpoints 
Estimands 
The missing data due to 
censoring, study withdrawal or 
other reasons (eg, laboratory 
failure) will have data imputed 
based on a MAR assumption. 
Participants with inadequate 
compliance will have their 
HbA1C values used as-is in 
the analysis  
Population-level summary measure: The 
population-based treatment effect will be the 
difference in the mean change from baseline 
in each 
 arm and Rybelsus arm 
compared to placebo   
To assess the effect of 
a range of 
 doses 
compared to placebo 
on various parameters 
in participants with 
obesity but without 
T2DM 
 Proportion of participants 
achieving 5%, 10%, and 
15% body weight loss at 
Week 32 relative to baseline 
 Placebo-adjusted, absolute 
change from baseline in waist 
circumference at Week 32  
 Placebo-adjusted, absolute 
change from baseline in 
waist-to-hip ratio at Week 32 
 Placebo-adjusted, change 
from baseline in HOMA-IR 
at Week 32
 Placebo-adjusted, change 
from baseline in HOMA-S at 
Week 32 
Population: All treated participants 
with obesity but without T2DM  
Variables: Proportion of participants 
weight loss at Week 32 relative to 
baseline  
Intercurrent events:   
 
An On Treatment strategy will be 
used: Measurements after initiation 
of glycemic rescue medication or 
discontinuation of study 
intervention are considered as 
intercurrent events, which will be 
censored and treated as missing 
data. Missing data will not be 
imputed. Participants with 
inadequate compliance will have 
their body weight values used as-is 
in the analysis  
Population-level summary measure: The 
population-based treatment effect will be the 
odds ratio of 
arm relative to 
placebo  
 
The estimand for each of the continuous 
endpoints will be constructed in a similar 
manner as the primary endpoint Placebo-
adjusted, percent change from baseline in 
body weight at Week 32  
To assess the safety 
and tolerability with a 
range of 
 
doses compared to 
placebo, in 
participants with 
T2DM inadequately 
controlled on 
metformin and 
In each population randomized 
  
 Number (and percent) of 
participants with:  
 TEAEs 
 SAEs 


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Table 2. 
Objectives, Endpoints, and Estimands 
Objectives
Endpoints 
Estimands 
separately
participants with 
obesity but without 
T2DM 
 AE leading to permanent 
discontinuation from study 
intervention or study 
 Hypoglycemia 
 Clinical laboratory 
abnormalities 
 Vital sign abnormalities 
 12-lead ECG abnormalities
 And TEAEs, presented in 
descending order of frequency 


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Table 2.
Objectives, Endpoints, and Estimands
Objectives
Endpoints
Estimands
To assess the safety 
and tolerability with a 
range of 
doses compared to 
placebo, in 
participants with 
obesity but without 
T2DM
Assessment of mental health as 
determined by 
C-SSRS
Tertiary: 
Tertiary:
Tertiary: 


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Table 2.
Objectives, Endpoints, and Estimands
Objectives
Endpoints
Estimands
To characterize PK of 
, in 
participants with 
T2DM 
inadequately 
controlled on 
metformin and 
separately
participants with 
obesity but 
without T2DM
Rybelsus, in 
participants with 
T2DM 
inadequately 
controlled on 
metformin
In each population randomized, 
descriptive summary of trough 
concentrations of 
and Rybelsus
In all cases, baseline is defined as the evaluable result closest prior to dosing on Day 1/Visit 3
Efficacy assessments will be assessed by the On Treatment estimand. Study termination 
occurred after the study was fully randomized and prior to any participant achieving Week 
32, and thus, efficacy analyses will be limited through Week 16 for Cohort 1 (T2DM) and 
through Week 20 for Cohort 2 (Obesity).


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2.2.1. Primary Estimands 
Cohort 1 (T2DM) 
The On Treatment strategy estimates the effect if all patients maintain their randomized
treatment and adhere to the protocol.  It includes the following attributes:  
 Treatment condition:  The randomized treatment under the scenario where initiation 
of glycemic rescue medication or discontinuation of study intervention has not 
occurred. Observations after that will be censored and treated as missing data; 
 Population:  All treated patients with T2DM inadequately controlled on metformin;  
 Variable:  Placebo-adjusted, change from baseline in HbA1C at Week 32; 
 Population-level summary:  Difference of variable means between 
and 
placebo.  
Cohort 2 (Obesity) 
The On Treatment strategy estimates the effect if all patients maintain their randomized 
treatment and adhere to the protocol.  It includes the following attributes:  
 Treatment condition:  The randomized treatment under the scenario where initiation 
of glycemic rescue medication or discontinuation of study intervention has not 
occurred. Observations after that will be censored and treated as missing data 
 Population:  All treated patients with obesity but without T2DM;  
 Variable:  Placebo-adjusted, percent change from baseline in body weight at Week 
32; 
 Population-level summary:  Difference of variable means between 
and 
placebo. 
The On Treatment strategy  estimates the effect if all patients maintain their randomized 
treatment and adhere to the protocol.  It includes the following attributes:  
 Treatment condition:  The randomized treatment under the scenario where initiation 
of glycemic rescue medication or discontinuation of study intervention has not 
occurred. Observations after that will be censored and treated as missing data; 
 Population:  All treated patients with T2DM inadequately controlled on metformin;  
 Variable:  Placebo-adjusted change from baseline in FPG (mg/dL, mmol/L) at Week 
32, Placebo-adjusted percent change from baseline in body weight (kg) through Week 
32; 


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 Population-level summary:  Difference of variable means between 
and 
placebo. 
2.3. Study Design 
This is a multicenter, multinational, randomized, double-blind, double-dummy, placebo-
controlled, dose-ranging, dose-finding, parallel-group study to assess efficacy and 
safety/tolerability of 
, and open-label Rybelsus in Cohort 1 (T2DM), and 
separately 
 compared to matching placebo in Cohort 2 (Obesity). 
The study will employ an IRC who will be responsible for ongoing review of unblinded 
safety and tolerability according to an IRC Charter. In addition, an interim analysis to assess 
efficacy and safety/tolerability in the Cohort that achieves PCD early may be performed. 
Number of Participants: Approximately 780 participants (60/arm) will be 
enrolled/randomized across 2 populations in the study. 
Study Arms and Duration: 
 In Cohort 1 (T2DM), three interventions, 
, its matching placebo, and 
open-label Rybelsus, will be evaluated across 7 arms in participants with T2DM on a 
background of metformin.  
 In Cohort 2 (Obesity), two interventions, 
 and its matching placebo, 
will be evaluated across 6 arms in participants with obesity.  
 The treatment duration in this study will be 32 weeks for most participants; though in 
the first set of up to 25% randomized participants, treatment interval will extend for 
an additional up to 12 weeks for a total duration of up to 44 weeks.  
The high-level study design is summarized below. 
Figure 1. High Level Study Design 
 


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The dose-escalation scheme to be employed is outlined below. 
Figure 2. Dose Escalation Scheme 
 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
In Cohort 1 (T2DM) the primary efficacy endpoint is, the placebo-adjusted, change from 
baseline in HbA1C (%) at Week 32. 
In Cohort 2 (Obesity) the primary efficacy endpoint is, the placebo-adjusted, percent change 
from baseline in body weight (kg) at Week 32. 
3.2. Secondary Endpoint(s) 
Cohort 1 (T2DM)  
 Proportion of participants who achieve HbA1C <7% (<53 mmol/mol) at Week 32  
 Placebo-adjusted, change from baseline in FPG (mg/dL, mmol/L) at Week 32 
 Placebo-adjusted, percent change from baseline in body weight (kg) at Week 32  
 Placebo-adjusted, change from baseline in HbA1C (%) in the Rybelsus arm at Week 
32 
Cohort 2 (Obesity) 


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body weight loss at
Week 32 relative to baseline
Placebo-adjusted, absolute change from baseline in waist circumference (cm) at 
Week 32
Placebo-adjusted, absolute change from baseline in waist-to-hip ratio at Week 32
Placebo-adjusted, change from baseline in HOMA-IR at Week 32
HOMA-IR is calculated as: ([FPI] × FPG)/405
Placebo-adjusted, change from baseline in HOMA-S at Week 32
HOMA-S% is calculated as (22.5/[FPI] × FPG))*100
Safety Endpoints Analyzed in both Cohort 1 (T2DM) and Cohort 2 (Obesity) separately
Number (and percent) of participants with:
TEAEs
SAEs
AE leading to permanent discontinuation from study intervention or study
Hypoglycemia
Clinical laboratory abnormalities
Vital sign abnormalities
12-lead ECG abnormalities
Assessment of mental health as determined in Cohort 2 (Obesity) by C-SSRS


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Descriptive summary of trough concentrations of
and Rybelsus
Descriptive summary of trough concentrations of 
and Rybelsus


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3.4. Baseline Variables
In all cases, baseline is defined as the evaluable result closest prior to dosing on Day 1/Visit 
3. Baseline measures will be included as a covariate in all applicable statistical models. The 
statistician may conduct further exploratory analyses into the effect of covariates and factors 
(such as gender, age and strata) on the efficacy endpoints. If conducted, and considered 
relevant to the CSR, the methods will be fully justified and discussed within the report.
Focused change from baseline summaries (including both absolute changes from baseline 
and percent change from baseline, calculated separately) of the following safety laboratory 
endpoints will be assessed:
Change from baseline in calcitonin to all post-dose time points as per the SOA
Change from baseline in amylase to all post-dose time points as per the SOA
Change from baseline in lipase to all post-dose time points as per the SOA
Change from baseline in hs-CRP to all post-dose time points as per the SOA
Change from baseline in Urinary Albumin:Creatinine Ratio to all post-dose time 
points as per the SOA
Change from baseline in free thyroxine (free T4) to all post-dose time points as per 
the SOA
Change from baseline in lipid profile (total cholesterol, direct LDL-C, HDL-C and 
TG) to all post-dose time points as per the SOA
Change from baseline in liver function tests (ALT, AST, alkaline phosphatase, total 
bilirubin, and total bile acid) to all post-dose time points as per the SOA
Change from baseline in eGFR to all post-dose time points as per the SOA
3.5. Safety Endpoints
The safety endpoints included as part of secondary endpoints are listed in the Section 3.2.
Some additional details are provided in this section.
3.5.1. Adverse Events
AEs are considered TEAEs relative to a given treatment if the event starts during the 
effective duration of treatment (i.e. starting on or after the first dose but before the last dose 
plus lag time).
The effective duration of treatment is determined by the lag time. Any event occurring within 
the lag time, whether this occurs during a break in treatment or at the end of treatment, is 
attributed to the corresponding treatment period. The lag time is defined by the Pfizer 
Standard of 365 days post last dose of study intervention. 


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Adverse events occurring during the placebo run-in period (i.e. starting from Day -14, 
inclusive, up to and before the first dose of active treatment on Day 1) will be considered 
non-treatment emergent.
3.5.2. Laboratory Data 
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 abnormality criteria. The assessment will take into account 
range for the particular laboratory parameter. 
Baseline for all laboratory measurements will be defined as the result closest prior to dosing 
at Visit 3 (Day 1).  
For the specific laboratory parameters listed in the table below, the following endpoints will 
be derived:  
.  
Table 3. 
Laboratory Abnormalities 
Parameter
Flag Level
Alert Level
Conventional Units
Amylase   
> ULN  
- 
 U/L 
Calcitonin
> ULN
-
Ng/L
Lipase
> ULN
-
U/L
HbA1C  
-  
>10  
%  
Fasting Plasma 
Glucose   
-  
< 70  
mg/dL  
-
> 270
mg/dL
-
>240
mg/dL
Alanine 
aminotransferase  
> ULN  
- 
U/L  
  
- 
U/L  
> 3x ULN
-
U/L
> 5x ULN
>8x ULN
U/L
> 5x ULN 
>10x ULN  
U/L  
> 5x ULN 
>20x ULN  
U/L  
Aspartate 
aminotransferase  
> ULN
-
U/L
  
- 
U/L  
> 3x ULN 
- 
U/L  
> 5x ULN
>8x ULN
U/L
> 5x ULN
>10x ULN
U/L
> 5x ULN 
>20x ULN  
U/L  
Alkaline Phosphatase  
  
- 
U/L  
> 3x ULN
-
U/L
>5x ULN
-
U/L
Creatinine   
baseline  
baseline  
mg/dL  
Total Bilirubin
>3x ULN
mg/dL
Direct and Indirect 
Bilirubin  
> ULN  
- 
mg/dL  
All flag level changes are cumulative from baseline (defined as result closest prior to dosing at Visit 3 (Day 1); 
ULN upper limit of normal as determined by the central laboratory 


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These endpoints will be derived using both pre and post-dose data separately. Post-dose will 
include all post-baseline data including unplanned readings and pre-dose will include all data 
from the placebo run-in defined by including all values from Visit 1 to pre-dose, including 
the baseline measurement and unplanned readings. Note, both pre- and post-dose populations 
will be from the safety analysis set (defined in Section 4). In cases where lab results are 
reported as below the level of quantification, results will be imputed as 0.1 units below the 
level of quantification.
In cases where fasting status impacts interpretability of results, results will be excluded from 
summary tables and excluded lab parameters will be stated in a footnote.  
3.5.3. Vital Signs Data 
Vital sign measurements (blood pressure and pulse rate) will be taken as detailed in the 
Schedule of Activities given in the protocol. The average of the triplicate measurements 
collected at each appropriate assessment time will be calculated for each vital sign parameter.  
Participants randomized to Rybelsus will have a single measurement instead of triplicate 
measurements and the single measurement will be used as is. 
Baseline will be defined as the average of the triplicate measurements at the visit closest 
prior to dosing at Visit 3 (Day 1).  
Changes from baseline for seated SBP and DBP and pulse rate will be calculated for each 
post baseline measurement.  
3.5.4. Electrocardiogram Data 
Standard 12-lead ECG (including HR, 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 centrally read tracings collected at each appropriate assessment time will be 
calculated for each ECG parameter.  Participants randomized to Rybelsus will have a single 
measurement instead of triplicate measurements and the single measurement will be used as 
is. 
Baseline will be defined as the average of the triplicate measurements at the visit closest 
prior to dosing at Visit 3 (Day 1).  
Change from baseline for HR, QT, QTcF, PR and QRS interval will be calculated for each 
post baseline measurement.  
3.5.5. Columbia Suicide Severity Rating Scale (C-SSRS) Data
C-SSRS data will be mapped to C-CASA per Guidance for Industry: Suicidal Ideation and 
Behavior: Prospective Assessment of Occurrence in Clinical Trials  
The 
   
 Suicidal Behavior  


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 Suicidal Ideation  
 Suicidal Behavior or Ideation  
Suicidal behavior:  A participant is said to have suicidal behavior if the participant has 
experienced any of the following events (C-CASA event codes 1-3):   
 Completed suicide;  
 Suicide attempt; or  
 Preparatory acts toward imminent suicidal behavior.  
Suicidal ideation:  Any observed suicidal ideation maps to a single C-CASA category.  
Depending on the scale used, more granularity of observed ideation (sub-categories of C-
CASA category 4) may be displayed.  The C-SSRS, for example, includes five ideation 
questions (that map to C-CASA category 4) with increasing severity.      
Suicidal data is collected at screening for two time intervals.  Any suicidal ideation at any 
point in lifetime as well as suicidal ideation within the past year or suicidal behavior within 
the last 5 years.  Baseline/day of randomization includes details of suicidality since the 
screening assessment, and study visits post-baseline includes details of suicidality since the 
previous visit.   
A participant listing of C-CASA categories as well as the underlying scale data will be 
provided.  In addition, a summary table with the number and percent of participants with a 
positive response within each C-CASA category by treatment group at screening, baseline, 
and at any time post-baseline will be provided.    
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. 
Participants who are randomized to the wrong cohort, in error, will have the incorrect cohort 
assignment remain in Impala 2.0 but the clinical database will include the correct cohort. As 
the treatment groups are not the same for the two cohorts, participants cannot be analyzed as 
treated; participants will be analyzed as randomized.  
Participants enrolled in the same study multiple times will be reported and documented as a 
protocol deviation. Data for applicable participants will be excluded for all planned efficacy 
and safety analyses unless decided otherwise upon clinical review.  Blinded participant safety 
data will be listed for the clinical review, and a data reporting decision will be made before 
the database release 
The analysis populations for reporting are below: 
For purposes of analysis, the following analysis sets are defined: 


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Table 4.
Analysis Sets 
Population  
Description 
Enrolled
All participants who sign the ICD and are randomized 
 A participant will be considered enrolled if informed consent is 
not withdrawn prior to participating in any study activity; 
 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  
Randomly assigned 
to investigational 
product 
All participants randomly assigned to study intervention regardless 
of whether or not study intervention was administered. 
Evaluable 
All participants randomly assigned to study intervention and who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the randomized 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 All participants randomly assigned to study intervention and who 
take at least 1 dose of 
 or Rybelsus and in whom at 
least one concentration value is reported. 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
This study was terminated prior to observation of Week 32, and prior to reaching a 
maintenance dose in most participants.  Statistical analyses will be limited to visits with 
sufficient data and interpretation may be limited. 
For each cohort separately, statistical inference will be based on the primary endpoint in each 
respective cohort: change from baseline in HbA1c at Week 32 for Cohort 1 (T2DM) and 
percent change from baseline in body weight at Week 32 for Cohort 2 (Obesity).  
The null hypothesis is that there is no difference between 
 and placebo on the 
primary endpoints. The alternative hypothesis is that 
 is superior (i.e. greater 
reduction) to placebo on the primary endpoints.  


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The Type I error rate (
level) used for the statistical inference will be 5% (1-sided). Each 
dose of 
 will be tested separately compared to placebo.  
No adjustment for multiple comparisons will be made.  
5.2. General Methods 
The efficacy analyses will be based on the appropriate population for analysis (see Section 
4).  Analysis using the Evaluable set is aligned with the objectives and endpoints of this 
study.   
In this study, the Cohort 1 (T2DM) and Cohort 2 (Obesity) are defined as administrative 
strata and will not be adjusted for in statistical analyses. Unless expressly stated, all analyses 
will be performed for each cohort separately.  Randomization was also stratified by gender 
(Male, Female) which will be included in statistical models.  Since this study is exploratory 
in nature, no multiplicity adjustment of endpoints nor adjustments for multiple comparisons 
to placebo will be made.  
Additional details regarding data derivation statistical methods will be included in the ARP 
or in amendment to this SAP. 
5.2.1. Analyses for Binary Endpoints 
Binary variables will be presented using summary statistics: number of observations, counts 
and percentages. 
5.2.2. Analyses for Continuous Endpoints 
Continuous variables will be presented using summary statistics: number of observations, 
arithmetic mean, SD, median, minimum and maximum values.  
MMRM analyses will be used. The MMRM will include treatment, strata, time, 
baseline*time and treatment*time as fixed effects, and baseline as a covariate with time fitted 
as a repeated effect and participant as a random effect. An unstructured correlation matrix 
will be used, and the Kenward-Roger approximation will be used for estimating degrees of 
freedom for the model parameters. In the case where an unstructured correlation matrix 
cannot converge, a first order autoregressive matrix will be attempted, followed by a 
compound symmetry correlation matrix.  The MMRM model will be fitted to change from 
baseline to each planned study visit that is estimable. Planned study visits are Weeks 4, 8, 12, 
16, 20, 24, 28, and 32. Due to scarcity of data at later visits at the time of study termination, 
MMRM analyses will be limited to Week 16 for Cohort 1 (T2DM) and Week 20 for Cohort 2 
(Obesity).  Missing values up to Week 16 for Cohort 1 (T2DM) and up to Week 20 for 
Cohort 2 (obesity) will be imputed as part of the MMRM model assumptions.
5.2.3. Analyses for Time-to-Event Endpoints 
Time-to-event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically when appropriate.  Graphs will describe the 
number of participants at risk over time.  The median, quartiles, and probabilities of an event 
at particular points in time will be estimated by the Kaplan-Meier method.  Confidence 
intervals for medians and quartiles are based on the Brookmeyer-Crowley method.  


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Confidence intervals for the estimated probability of an event at a particular time point will 
be generated using the Greenwood formula.
5.3. Methods to Manage Missing Data
For applicable continuous endpoints modelled with an MMRM, missing/censored values will 
be imputed as part of the analysis method.
The average of the duplicate body weight readings collected at each assessment time will be 
calculated prior to summaries/analysis. If one of the two duplicates are missing, the non-
missing value will be used, and missing values will not be imputed. Both the absolute change 
and percent change from baseline in body weight will be calculated. If all duplicate values 
are missing, body weight will not be imputed and will be set to missing.
In all PK data presentations (except listings), concentrations BLQ will be set to zero. In 
listings,
for the LLQ.
6. ANALYSES AND SUMMARIES
Scarcity of data at later visits limits some analysis and interpretation of study data.  All 
available safety and efficacy data 
will be summarized.
Statistical models of efficacy data will be limited to Week 16 for Cohort 1 (T2DM) and 
Week 20 for Cohort 2 (Obesity).
Tabular displays will be ordered with placebo as the left most column, followed by ascending 
total maintenance dose of PF-07081532 and Rybelsus® as the right most column.
6.1. Primary Endpoint(s)
Placebo-adjusted change from Baseline in HbA1c at Week 32 for Cohort 1 (T2DM)
Placebo-adjusted percent change from baseline in and Body Weight at Week 32 for
Cohort 2 (Obesity)
6.1.1. Main Analysis
Estimand strategy: On Treatment (Section 2.2.1)
Analysis Set: Evaluable (Section 4).
Analysis methodology: MMRM (Section 5.2.2)
Intercurrent Events and Missing Data: As per estimands (Section 2.2.1)
Absolute values and change from baseline will be summarized descriptively by 
treatment and time point as described in Section 5.2.2. Tables will present all data 
from the screening (visit 1, absolute tables only), beginning of the placebo run-in 
(visit 2, absolute tables only), baseline and post-baseline time points 


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 MMRM for the Evaluable set for Cohort 1 (T2DM) through Week 16 and Cohort 2 
(Obesity) through Week 20 
6.1.2. Figures 
Profile plots of the LS Means (including 90% confidence intervals) over time, with a separate 
line for each treatment. 
6.2. Secondary Endpoint(s) 
6.2.1. Binary Secondary Endpoints 
The following secondary endpoints are binary categories derived from observed continuous 
measurements: 
 Proportion of Participants who Achieve HbA1c <7% (<53 mmol/mol) at Week 32 for 
Cohort 1 (T2DM) 
 Proportion of Participants who Achieve 
body weight loss at 
Week 32 relative to Baseline for Cohort 2 (Obesity)  
6.2.1.1. Main Analysis 
These endpoints will not be summarized but will be derived and included in ADaM datasets. 
6.2.2. Continuous Secondary Endpoints 
The secondary endpoint of placebo-adjusted, percent change from baseline in body weight 
(kg) at Week 32 in Cohort 1 (T2DM) will be analyzed as described for the primary 
continuous endpoints. 
The following secondary endpoints are continuous and will summarized as described in 
Section 5.2.2, and no modeling will be performed: 
 Placebo-adjusted, change from baseline in FPG (mg/dL, mmol/L) at Week 32 in 
Cohort 1 (T2DM)  
 Placebo-adjusted, change from baseline in HbA1C (%) in the Rybelsus arm at Week 
32 in Cohort 1 (T2DM)  
 Placebo-adjusted, absolute change from baseline in waist circumference (cm) at 
Week 32 in Cohort 2 (Obesity) 
 Placebo-adjusted, absolute change from baseline in waist-to-hip ratio at Week 32 in 
Cohort 2 (Obesity) 
 Placebo-adjusted, change from baseline in HOMA-IR at Week 32 in Cohort 2 
(Obesity) 
 Placebo-adjusted, change from baseline in HOMA-S at Week 32 in Cohort 2 
(Obesity) 


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6.2.2.1. Main Analysis
Estimand strategy:  On Treatment (Section 2.2.1)
Analysis Set: Evaluable (Section 4).
Analysis methodology: MMRM (Section 5.2.2) for percent change from baseline in 
body weight (kg) at Week 32 in Cohort 1 (T2DM) only
Intercurrent Events and Missing Data: As per estimands (Section 2.2.1)
Absolute values and change from baseline will be summarized descriptively by 
treatment and time point as described in Section 5.2.2. Tables will present all data 
from the screening (visit 1, absolute tables only), beginning of the placebo run-in 
(visit 2, absolute tables only), baseline and post-baseline time points
MMRM for the Evaluable set for percent change from baseline in body weight (kg) in 
Cohort 1 (T2DM) through Week 16
6.2.2.2. Figures
Profile plots of the LS Means (including 90% confidence intervals) over time, with a separate 
line for each treatment.
6.4. Pharmacokinetic Endpoints
PK data may be used for population PK and/or PK/PD analyses. The objective of such 
analyses, if conducted, would aim to explore the relationship between concentrations of 
or Rybelsus and effect on endpoints of interest and also identification of 
potential demographic determinants (eg, age, sex, and weight) influencing the observed PK 
and/or PD. These analyses if conducted, will be reported separately from the main CSR.


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6.6. Subset Analyses 
Subset analyses added for other efficacy and/or safety endpoints if required for the CSR 
would be included as part of an update to this SAP with an amendment prior to database lock 
or documented in the CSR under changes to planned analysis.  
6.7. Baseline and Other Summaries and Analyses 
6.7.1. Baseline Summaries 
A baseline table (or separate tables, as required) summarizing the following will be produced 
for Cohort 1 (T2DM) and Cohort 2 (Obesity) separately by treatment and overall: age; 
gender; race; ethnicity; height; weight; body mass index; waist circumference; waist-to-hip 
ratio; duration of T2DM; stratification factor; country; HbA1c; FPG; SBP; DBP; as well as 
duration of metformin for Cohort 1 (T2DM). 
6.7.2. Concomitant Medications and Nondrug Treatments 
All prior and concomitant medication(s) by incident transaminitis and overall will be 
reported as described in Section 5.2.1. 
Baseline concomitant metformin dose 
500 mg - 
1000 
mg) will be reported as described in Section 5.2.1.   
A separate table listing the use of rescue medication will be produced. The use of rescue 
medication (grouped by class of medication) will be summarized descriptively by treatment 
and overall as described in Section 5.2.1. The classes will be defined based on medications 
used in the study.  
6.7.3. Treatment Compliance 
A summary table of treatment compliance (by treatment and overall) will be produced 
according to Section 5.2.2.  
6.7.4. Discontinuations 
Participant discontinuations and temporary discontinuations from study and from treatment 
due to AEs will be detailed and summarized by treatment and overall as described in Section 
5.2.1.  
6.8. Safety Summaries and Analyses 
Safety analyses will be performed using the safety analysis set (Section 4).  All summaries 
will be performed separately by cohort. 
6.8.1. Adverse Events 
An AE is considered TEAE relative to a given treatment if the event starts during the 
effective duration of treatment (i.e. starting on or after the first dose but before the last dose 
plus lag time).   
The effective duration of treatment is determined by the lag time. Any event occurring within 
the lag time, whether this occurs during a break in treatment or at the end of treatment, is 


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attributed to the corresponding treatment period. The lag time is defined by the Pfizer 
Standard of 365 days post last dose of study intervention.    
AEs occurring during the placebo run-in period (i.e., starting from Day -14, inclusive, up to 
and before the first dose of active treatment on Day 1) will be considered non-treatment 
emergent.  
AEs will be summarized by treatment and overall and in accordance with sponsor reporting.   
Incidence and severity of TEAE tables will be summarized by SOC and PT, by treatment and 
overall.  Incidence and severity of TEAE 
 will be summarized by PT, 
by treatment and overall.  In addition, incidence and severity of TEAE tables will be 
produced by PT by dosing regimen as well as by titration step.    
TEAEs, related TEAEs, and SAEs will be reported by PT. The subset of TEAEs occurring in 
at least 2% of participants will be shown in a separate table. 
The prevalence of TEAEs of each nausea, vomiting, and diarrhea will be shown in separate 
figures. Recurrence of these TEAEs, defined as an observed TEAE that has ended and then a 
new instance of the same TEAE occurs, will be summarized. 
The timing and duration of TEAEs of PTs 
will be plotted per TEAE per participant.  The figure for each included PT will display each 
participant on the y-axis and a line connecting the study days of the start and end date of the 
TEAE.  
 Additional AE summaries will include those listed below:  
 Events of hypoglycemia 
 TEAEs (and SAEs) leading to temporary discontinuation of treatment  
 TEAEs (and SAEs) leading to permanent discontinuation and withdrawal of treatment 
and of study  
 Cumulative discontinuation from treatment over time displayed in a figure  
6.8.2. Laboratory Data 
Laboratory data will be listed and summarized as outlined in Sections 5.2.1 and 5.2.2. 
Spaghetti plots will be shown for each of the following separately by cohort and treatment, 
observations expressed as a function of the upper limit of normal: 
 Individual ALT Versus Time 
 Individual AST Versus Time  
 Individual Alkaline Phosphatase Versus Time  


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 Individual Total Bilirubin Versus Time
 Individual Direct Bilirubin Versus Time 
 Individual Total Bile Acids Versus time, including both central lab and local lab 
values as well as scheduled and unplanned observations 
eDISH plots of Maximum ALT or AST Versus Total Bilirubin will be shown. 
6.8.3.  Vital Signs 
Absolute values and changes from baseline in seated SBP and DBP and pulse rate will be 
summarized by treatment and time point, as described in Section 5.2.2. Tables will be paged 
by parameter. Baseline is as defined in Section 3.5.3. 
Maximum absolute values and maximum changes from baseline for vital signs, over all 
measurements taken post dose will also be tabulated by treatment using categories as defined 
below.  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 seated SBP and DBP, and maximum 
increase from baseline for seated pulse rate will be summarized by treatment, as described in 
Section 5.2.2.  
Table 5. 
Vital Signs Change from Baseline 
Parameter
Flag Level
Conventional Units
SBP (seated) I 
< 90, >200  
mm Hg  
DBP (seated)  
< 40, >100  
mm Hg  
Pulse rate (seated)  
<40  
Bpm
> 110  
Bpm
6.8.4. Electrocardiograms 
Changes from baseline for the ECG parameters HR, QT, QTcF, PR interval, and QRS 
complex will be summarized by treatment and time as described in Section 5.2.2. The 
frequency of uncorrected QT values above 500 ms will be tabulated. The number (%) of 
participants with maximum post dose QTcF values and maximum increases from baseline in 
the following categories will be tabulated by treatment as described in Section 5.2.1. 
A listing of all ECG results as well as a listing subset to those with abnormal findings will be 
produced. 


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Table 6. 
Safety QTcF Assessment  
Degree of Prolongation  Mild (ms)  
Moderate (ms)  Severe (ms)  
Absolute value  
>450-480  
>480-500  
>500  
Increase from baseline  
N/A  
30-60  
>60  
  
Note: For purposes of reporting study-level results, QTcF interval will be derived using
 heart rate correction formula applied to databased QT interval, and RR interval.  
Table 7.
Categories for PR and QRS 
ECG Parameter
Increase Categories
Decrease Categories
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 
  
7. INTERIM ANALYSES 
Interim analyses and summaries are provided in the IRC Charter. 
8. APPENDICES 
Appendix 1. Data Derivation Details 
C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events and Codes 


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Event 
Code
C-CASA Event
C-SSRS Response
Suicidal Ideation
1
Passive
2
Active: Nonspecific (no method, intent, or plan)
Non-Specific Active 
Suicidal Thoughts
3
Active: Method, but no intent or plan
Active Suicidal Ideation 
with Any Methods (Not Plan) without 
Intent to Act
4
Active: Method and intent, but no plan
Active Suicidal Ideation 
with Some Intent to Act, without 
Specific Plan
5
Active: Method, intent, and plan1
Active Suicidal Ideation 
with Specific Plan and Intent
Suicidal Behavior
1
Completed suicide
2
Suicide attempt
Actual Attempt
3
Interrupted attempt 
Interrupted attempt
4
Aborted attempt
Aborted attempt
5
Preparatory actions toward imminent suicidal 
behaviors
Preparatory Acts or 
Behavior
Self-injurious behavior, no suicidal intent
Self-injurious behavior, no suicidal intent
Non-suicidal Self-


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Appendix 2. List of Abbreviations
Abbreviation
Term
ADaM
analysis data model
AE
adverse event
ALT
alanine aminotransferase
ARP
analysis & reporting plan
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
Bpm
beats per minute
C-CASA
Columbia classification algorithm for suicide assessment
Cavg
average concentration
cm
centimeter
CSR
clinical study report
C-SSRS
Columbia suicide severity rating scale
CYP3A
cytochrome P450 3A
DBP
diastolic blood pressure
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
FPG
fasting plasma glucose
FPI
fasting plasma insulin
GI
gastro intestinal
HbA1C
glycated hemoglobin
HDL-C
high-density lipoprotein cholesterol
HOMA-IR
homeostatic model assessment for insulin resistence
HOMA-S
homeostatic model assessment for insulin sensitivity
HR
heart rate
hs-CRP
high-sensitivity C-reactive protein
ICD
informed consent document
IRC
internal review committee
kg
kilogram
LDL-C
low-density lipoprotein
LLQ
lower limit of quantitation
LS
least-squares
MAR
missing at random
mg/dL
milligram per deciliter
mm Hg
millimeters of mercury
mmol/L
millimoles per liter
mmol/mol
millimoles per mole


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Abbreviation
Term
MMRM
mixed-effects model with repeated measures
ms
milliseconds
N/A
not applicable
Ng/L
nanograms per liter
PCD
primary completion date
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PT
preferred term
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SOA
schedule of activities
SOC
system organ class
T2DM
Type 2 diabetes mellitus
TEAE
treatment emergent adverse event
TG
triglyceride
U/L
units per liter
ULN
upper limit of normal