Conditions: Diabetes Mellitus, Type 2 Renal Impairment Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 42
Healthy volunteers: yes

Brief summary:
This study will characterize the effect of varying degrees of renal impairment on the pharmacokinetics (PK), safety and tolerability of a single oral dose of PF- 06882961 compared with participants with normal renal function.

Detailed description:

Arms:
arm 1: This arm includes participants with normal renal function who will receive an oral dose of PF-06882961 20 milligrams (mg) on Day 1 arm 2: This arm includes participants with Type 2 Diabetes Mellitus (T2DM) with normal renal function who will receive an oral dose of PF-06882961 20 mg on Day 1 arm 3: This arm includes participants with Type 2 Diabetes Mellitus (T2DM) with mild renal impairment who will receive an oral dose of PF-06882961 20 mg on Day 1 arm 4: This arm includes participants with Type 2 Diabetes Mellitus (T2DM) with moderate renal impairment who will receive an oral dose of PF-06882961 20 mg on Day 1 arm 5: This arm includes participants with Type 2 Diabetes Mellitus (T2DM) with severe renal impairment who will receive an oral dose of PF-06882961 20 mg on Day 1

Interventions: intervention 1: PF-06882961 20 mg
Intervention descriptions: intervention 1: PF-06882961 20 mg single oral dose provided in tablet form administered in a fed state on Day 1

Protocol document:
Prot_000.pdf: 
PF-06882961
Protocol C3421012
Final Protocol, 13 October 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL GROUP STUDY TO 
EVALUATE THE PHARMACOKINETICS OF PF-06882961 IN PARTICIPANTS
WITH TYPE 2 DIABETES MELLITUS WITH VARYING DEGREES OF RENAL 
IMPAIRMENT RELATIVE TO PARTICIPANTS WITHOUT RENAL 
IMPAIRMENT
Investigational Product Number:
PF-06882961
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
C3421012
Phase:
1
Short Title: Pharmacokinetic Study of PF-06882961 in Participants With Type 2 Diabetes 
Mellitus With Varying Degrees of Renal Impairment and Participants Without Renal 
Impairment
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Protocol C3421012
Final Protocol, 13 October 2020
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
13 October 2020
N/A


PF-06882961
Protocol C3421012
Final Protocol, 13 October 2020
PFIZER CONFIDENTIAL
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities (SoA)...................................................................................13
2. INTRODUCTION ...............................................................................................................15
2.1. Study Rationale .......................................................................................................15
2.2. Background .............................................................................................................15
2.2.1. Nonclinical Pharmacology..........................................................................16
2.2.3. Nonclinical Safety ......................................................................................17
2.2.4. Clinical Overview.......................................................................................17
2.2.4.1. Clinical Safety...........................................................................17
2.2.4.2. Clinical Pharmacokinetics.........................................................18
2.3. Benefit/Risk Assessment.........................................................................................19
3. OBJECTIVES AND ENDPOINTS.....................................................................................20
4. STUDY DESIGN.................................................................................................................21
4.1. Overall Design.........................................................................................................21
4.2. Scientific Rationale for Study Design.....................................................................23
4.3. Justification for Dose ..............................................................................................24
4.4. End of Study Definition ..........................................................................................25
5. STUDY POPULATION......................................................................................................25
5.1. Inclusion Criteria.....................................................................................................25
5.1.1. Inclusion Criteria for All Participants.........................................................25
5.1.2. Additional Inclusion Criteria for Healthy Participants with Normal 
Renal Function (Group 1)................................................................................26
5.1.3. Additional Inclusion Criteria for T2DM Participants with Normal 
Renal Function (Group 2)................................................................................26
5.1.4. Additional Inclusion Criteria for T2DM Participants with Impaired 
Renal Function (Groups 3-5) ...........................................................................27
5.2. Exclusion Criteria....................................................................................................27
5.2.1. Exclusion Criteria for All Participants .......................................................27
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5.2.2. Additional Exclusion Criteria for Healthy Participants with Normal 
Renal Function (Group 1)................................................................................30
5.2.3. Additional Exclusion Criteria for T2DM Participants with Normal 
Renal Function (Group 2)................................................................................30
5.2.4. Additional Exclusion Criteria for T2DM Participants with Impaired 
Renal Function (Groups 3-5) only ...................................................................30
5.2.5. Criteria for Dosing on Day 1 ......................................................................31
5.3. Lifestyle Considerations..........................................................................................31
5.3.1. Meals and Dietary Restrictions...................................................................31
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................32
5.3.3. Activity .......................................................................................................32
5.3.4. Contraception..............................................................................................32
5.4. Screen Failures ........................................................................................................33
6. STUDY INTERVENTION..................................................................................................33
6.1. Study Intervention Administered ............................................................................33
6.1.1. Administration............................................................................................33
6.2. Preparation/Handling/Storage/Accountability ........................................................34
6.2.1. Preparation and Dispensing........................................................................35
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................35
6.3.1. Allocation to Investigational Product .........................................................35
6.4. Study Intervention Compliance...............................................................................35
6.5. Concomitant Therapy..............................................................................................35
6.5.1. Rescue Medicine.........................................................................................36
6.6. Dose Modification...................................................................................................36
6.7. Intervention After the End of the Study..................................................................36
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................36
7.1. Discontinuation of Study Intervention ....................................................................36
7.2. Participant Discontinuation/Withdrawal From the Study.......................................37
7.2.1. Withdrawal of Consent...............................................................................37
7.3. Lost to Follow up ....................................................................................................38
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................38
8.1. Efficacy Assessments..............................................................................................39


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8.2. Safety Assessments .................................................................................................39
8.2.1. Physical Examinations................................................................................39
8.2.2. Vital Signs ..................................................................................................40
8.2.2.1. Temperature ..............................................................................40
8.2.3. Electrocardiograms.....................................................................................40
8.2.4. Clinical Safety Laboratory Assessments ....................................................41
8.2.5. Glucometer Monitoring of Glucose............................................................41
8.2.6. Management of Hypoglycemia...................................................................42
8.2.6.1. Definition and Severity of Categorization of 
Hypoglycemic Adverse Event (HAE)...............................................42
8.2.7. Management of Hyperglycemia .................................................................43
8.2.8. Pregnancy Testing ......................................................................................44
8.2.9. COVID-19 Specific Assessments...............................................................44
8.3. Adverse Events and Serious Adverse Events..........................................................44
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......44
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................45
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................45
8.3.2. Method of Detecting AEs and SAEs ..........................................................45
8.3.3. Follow-up of AEs and SAEs.......................................................................46
8.3.4. Regulatory Reporting Requirements for SAEs...........................................46
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................46
8.3.5.1. Exposure During Pregnancy......................................................47
8.3.5.2. Exposure During Breastfeeding ................................................47
8.3.5.3. Occupational Exposure .............................................................47
8.3.6. Cardiovascular and Death Events...............................................................47
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................47
8.3.8. Adverse Events of Special Interest.............................................................47
8.3.8.1. Lack of Efficacy........................................................................47
8.3.9. Medical Device Deficiencies......................................................................48
8.3.10. Medication Errors.....................................................................................48


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8.4. Treatment of Overdose............................................................................................48
8.5. Pharmacokinetics ....................................................................................................49
8.5.1. Plasma for Analysis of PF-06882961.........................................................49
8.5.2. Plasma for Determination of PF-06882961 Unbound Fraction..................50
8.5.3. Urine for Analysis of PF-06882961 ...........................................................50
8.6. Pharmacodynamics..................................................................................................51
8.7. Pharmacogenomics..................................................................................................51
8.8. Biomarkers ..............................................................................................................51
8.8.1. Exploratory Biomarker for Measurement of CP-I......................................51
8.9. Health Economics ...................................................................................................52
9. STATISTICAL CONSIDERATIONS ................................................................................52
9.1. Statistical Hypotheses .............................................................................................52
9.2. Sample Size Determination.....................................................................................52
9.3. Populations for Analysis .........................................................................................53
9.4. Statistical Analyses .................................................................................................53
9.4.1. Efficacy Analyses .......................................................................................53
9.4.2. Safety Analyses ..........................................................................................53
9.4.2.1. Electrocardiogram Analyses......................................................54
9.4.3. Other Analyses............................................................................................54
9.4.3.1. Pharmacokinetic Analyses ........................................................54
9.5. Interim Analyses .....................................................................................................57
9.5.1. Data Monitoring Committee.......................................................................57
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................58
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............58
10.1.1. Regulatory and Ethical Considerations ....................................................58
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................58
10.1.2. Financial Disclosure .................................................................................59
10.1.3. Informed Consent Process ........................................................................59
10.1.4. Data Protection .........................................................................................60
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10.1.5. Dissemination of Clinical Study Data ......................................................60
10.1.6. Data Quality Assurance ............................................................................62
10.1.7. Source Documents....................................................................................63
10.1.8. Study and Site Closure..............................................................................63
10.1.9. Publication Policy.....................................................................................64
10.1.10. Sponsor’s Qualified Medical Personnel .................................................65
10.2. Appendix 2: Clinical Laboratory Tests .................................................................66
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................69
10.3.1. Definition of AE .......................................................................................69
10.3.2. Definition of SAE.....................................................................................70
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................71
10.3.4. Reporting of SAEs....................................................................................74
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................76
10.4.1. Male Participant Reproductive Inclusion Criteria....................................76
10.4.2. Female Participant Reproductive Inclusion Criteria.................................76
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................76
10.4.4. Contraception Methods.............................................................................77
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........81
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................83
10.8. Appendix 8: Prohibited Prior/Concomitant Medications......................................85
10.9. Appendix 9: Proposed Chronology of Procedures................................................86
10.10. Appendix 10: Abbreviations ...............................................................................87
11. REFERENCES ..................................................................................................................91
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Final Protocol, 13 October 2020
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LIST OF TABLES
Table 1.
Study Groups ............................................................................................21
Table 2.
Expected Widths of the 90% CIs (with 80% Coverage Probability) 
for Different Possible Estimated Effects ..................................................52
Table 3.
Plasma PK Parameters..............................................................................55
Table 4.
Urine PK Parameters ................................................................................56
Table 5.
Protocol-Required Safety Laboratory Assessments .................................67


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Final Protocol, 13 October 2020
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Page 9
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: Pharmacokinetic Study of PF-06882961 in Participants With Type 2 Diabetes 
Mellitus With Varying Degrees of Renal Impairment and in Participants Without Renal 
Impairment.
Rationale
The purpose of this multi-site, Phase 1, open-label, parallel-group study is to characterize the 
effect of varying degrees of renal impairment on the pharmacokinetics (PK), safety and 
tolerability of a single oral dose of PF-06882961 in participants with type 2 diabetes mellitus 
(T2DM), compared with participants with normal renal function.
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 

To compare the PK of PF-06882961 following 
administration of a single oral dose in adult 
participants with T2DM and varying degrees of 
renal impairment relative to T2DM participants 
without renal impairment.

Plasma: Cmax, AUCinf, AUClast, fu, as data permit.
Secondary: 
Secondary: 

To compare additional PK parameters of 
PF-06882961 following administration of a 
single oral dose in adult participants with 
T2DM and varying degrees of renal impairment 
relative to T2DM participants without renal 
impairment.

Plasma: Cmax,u, AUCinf,u, AUClast,u, CL/F, CLu/F, 
Vz/F, Vz,u/F, Tmax, t1/2, as data permit.

To evaluate the safety and tolerability of a 
single oral dose of PF-06882961 in T2DM 
participants with varying degrees of renal 
impairment and in participants with normal 
renal function.

Incidence and severity of treatment-emergent 
AEs, clinical laboratory abnormalities, vital signs 
(blood pressure and pulse rate), 12-lead 
electrocardiogram (ECG) parameters (heart rate, 
QT, QTcF, PR and QRS intervals).
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To compare urine PK parameters of 
PF-06882961 following administration of a 
single oral dose in adult participants with 
T2DM and varying degrees of renal impairment 
relative to T2DM participants without renal 
impairment.

Urine: CLr, Ae24, Ae24%.

To compare the PK of PF-06882961 following 
administration of a single oral dose in adult 
participants with T2DM and normal renal 
function relative to healthy participants with 
normal renal function.

Plasma: Cmax, Tmax, AUCinf, AUClast, CL/F, Vz/F, 
t1/2, fu, as data permit;

Urine: CLr, Ae24, Ae24%.


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Protocol C3421012
Final Protocol, 13 October 2020
PFIZER CONFIDENTIAL
Page 10

To explore the relationship of markers of innate 
organic anion transporting polypeptide (OATP)
activity in adult participants with T2DM and 
varying degrees of renal impairment relative to 
participants with normal renal function.

Coproporphyrin I (CP-I) concentration.

To enable exploratory research through 
collection of banked biospecimens, unless 
prohibited by local regulations or ethics 
committee decision.

Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study).
Overall Design
This Phase 1, open-label, single-dose, parallel group, multi-site study will assess the effect of 
varying degrees of renal impairment on the PK, safety and tolerability of PF-06882961 after 
a single oral dose of 20 mg administered in a fed state (Section 5.3.1).
Number of Participants
Approximately 40 participants will be enrolled in the study. All participants assigned to 
investigational product (IP) and who take at least 1 dose of IP will be evaluable.  Participants 
who discontinue from the study before completing all assessments may be replaced at the 
discretion of the investigator and sponsor.
Intervention Groups and Duration
Participants with T2DM and varying degrees of renal impairment (Group 3: T2DM with mild 
renal impairment, Group 4: T2DM with moderate renal impairment, Group 5: T2DM with 
severe renal impairment) will be recruited and enrolled first.  An average value for age and 
weight for these groups will be determined and participants in Groups 1-2 (Group 1: healthy 
with normal renal function, Group 2: T2DM with normal renal function) will be recruited last 
to match the average demographics (at a minimum, age and weight, and, as much as 
practically possible, gender) across the pooled Groups 3-5.  Approval from the sponsor must 
be garnered before proceeding with dosing participants in Groups 1 and 2. All participants 
will receive a single oral dose of IP in the fed state.
Screening will occur within 28 days of the first dose of study medication.  All participants 
will provide informed consent and undergo Screening evaluations to determine their 
eligibility. For individual participants, the total duration of participation from the Screening 
Visit to the Follow-up Contact will be a minimum of approximately 5 weeks and a maximum 
of approximately 10 weeks.
Data Monitoring Committee: No
Statistical Methods
Linear regression will be used to characterize the potential relationship between appropriate 
PK parameters (CL/F, CLu/F and CLr) for PF-06882961 and renal function (eGFR). 


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Final Protocol, 13 October 2020
PFIZER CONFIDENTIAL
Page 11
A one-way analysis of variance (ANOVA) will be used to compare the natural log 
transformed AUCinf (if data permit), AUClast, Cmax and fu of PF-06882961 for each of the 
T2DM renal impairment groups (Test, Groups 3, 4, 5) to the T2DM normal renal function 
group (Reference, Group 2). Also, the T2DM normal renal function group (Test, Group 2) 
will be compared to the healthy normal renal function group (Reference, Group 1). The 
ANOVA model will include all groups (ie, both T2DM and healthy participants from the 
5 groups). Estimates of the adjusted mean differences (Test-Reference) and corresponding 
90% confidence intervals (CIs) will be obtained from the model. The adjusted mean 
differences and 90% CIs for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and corresponding 90% CIs. If 
substantial differences in demographic characteristics between healthy (Group 1), T2DM 
normal (Group 2) and T2DM renal impairment function participants (Groups 3, 4, 5) are 
observed, covariates such as weight and age may be explored.
The PK parameters for PF-06882961 will also be summarized descriptively by renal function 
group and population (healthy vs. T2DM). 
For summary statistics and median/mean plots by sampling time, the nominal PK sampling 
time will be used. For individual participant plots by time, the actual PK sampling time will 
be used.


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1.2. Schema
*Screening period is ≤28 days from dosing on Day 1.
S1 and S2 are outpatient 
visits separated by at least 
72 hours.
Screening
Visit 1
(S1)
Screening
Visit 2
(S2)
Day -1
Admission 
FU
Contact
(28-35 days) 
post IP dose
Day 2
Day 1
IP Dosing
Day 3
Discharge 
from CRU
Inpatient Study Period (Day -1 to Day 3)


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1.3. Schedule of Activities (SoA)
The SoA table provides an overview of the protocol visits and procedures.  Refer to STUDY ASSESSMENTS AND PROCEDURES
Section 8.2 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, to conduct evaluations or assessments 
required to protect the well-being of the participant.
Visit Identifier (for proposed chronology of 
procedures refer to Appendix 9; for abbreviations 
refer to Appendix 10)
Screening
Study Period
Follow-
upb
ET
S1a
S2a
Study Day 
≤-28
-1
1
2
3
28-35
Hours Post Dose
--
--
--
0
1
2
3
4
5
6
8
10
12
16
24
36
48
Informed consent & demography 
X
Adverse event monitoring
X
X
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
X
Outpatient visit 
X
X
Xb
X
COVID-19 symptoms and risk assessment
X
X
COVID-19 testing
Xc
X
Inpatient stay at Clinical Research Unit 
X
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Eligibility assessment 
X
X
Medical history
X
X
Alcohol/tobacco & contraception use
X
X
Review contraception use (females only)
X
X
X
Prior/concomitant treatments
X
X
X
Physical exam (height and body weight at S1, only)d
X
X
X
X
Alcohol breath teste
X
X
Single, supine 12-lead ECG
X
X
X
X
Single, seated vital sign assessmentf
X
Xg
X
X
X
X
Glucometer measurementh
X
X
X
X
Standard mealsi
X
X
X
X
X
X
Investigational product administrationj
Xj
Blood Sampling for: 
Safety laboratory tests - after ≥8-hr fast (incl. eGFR)k,l
X
Xl
X
X
X
Serum FSH (females only), HbA1C, C-peptide
X
Serum pregnancy test (WOCBP only)l,m
X
X
X
X
Exploratory plasma for coproporphyrin-I
X
PF-06882961 PK 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PF-06882961 unbound fraction for protein binding
X
X
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Visit Identifier (for proposed chronology of 
procedures refer to Appendix 9; for abbreviations 
refer to Appendix 10)
Screening
Study Period
Follow-
upb
ET
S1a
S2a
Study Day 
≤-28
-1
1
2
3
28-35
Hours Post Dose
--
--
--
0
1
2
3
4
5
6
8
10
12
16
24
36
48
Urine Sampling for: 
Urine drug testo
X
Urinalysis (and microscopy, if needed)p
X
X
X
X
On-site pregnancy test (WOCBP only)m
X
PF-06882961 PKq
X
→
→
→
→
→
X
→
→
X
→
X
a.
Screening visits S1 and S2 should be separated by at least 72 hours. S2 is optional only for participants with dialysis.
b.
Visit to be performed as telephone contact and must occur 28 to 35 days from administration of the final dose of investigational product.  A clinic visit may be performed in 
place of telephone contact, if deemed necessary by the investigator.
c.
COVID-19 viral test to occur between Day -5 and Day -2 to permit availability of test result prior to admission on Day -1.
d.
Full physical examination (PE) will be performed at Screening visit S1; at all other time points, a brief physical examination is performed and may be performed at 
non-specified visits if there are findings during the previous exam or new/open AEs, if appropriate and at investigator discretion.
e.
Alcohol breath test may be conducted at investigator discretion.
f.
Includes blood pressure, temperature and pulse rate.
g.
On Day -1, only temperature is required on admission.
h.
Glucometer measures will be taken before breakfast in participants with T2DM on all days while inpatient.  Additional measurements may be made at the discretion of the 
investigator.
i.
Meals/snacks will occur on all days while inpatient as per Section 5.3.1.  While inpatient, mealtimes should match nominal time of approximately 0H, 4H, 10H relative to 
dosing on Day 1.
j.
Dosing will occur within approximately 10 minutes of completion of breakfast on Day 1.
k.
The eGFR determination will be performed by the central lab. 
l.
Only serum creatinine and eGFR (along with pregnancy testing) should be collected at S2. 
m.
Test result must be reviewed and deemed acceptable (ie, negative) to continue participation in the study. For a participant on dialysis who is anuric only, an alternative 
method (eg, blood) for urine pregnancy testing may be used.
o.
For a participant on dialysis who is anuric only, an alternative method (eg, saliva) for drug testing may be used.
p.
For a participant on dialysis who is anuric only, urinalysis is not required to be collected.
q.
Blank pre-dose urine sample to be collected within 24H prior to dosing and urine should be collected at intervals of 0-6, 6-12 and 12-24 hours after dosing. If participant is on 
dialysis and has no urine output, no urine PK sample will be collected.
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2. INTRODUCTION
Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone that is predominantly 
released from the small intestine in response to food intake.1 GLP-1 activation of the GLP-1 
receptor (GLP-1R) stimulates insulin release, inhibits glucagon secretion in a 
glucose-dependent manner, and delays gastric emptying.2,3  In addition, GLP-1 has been 
shown to increase satiety and suppress food intake.4  PF-06882961 is an orally administered, 
small molecule GLP-1R agonist that has been demonstrated, in nonclinical models, to 
stimulate glucose-dependent insulin release and suppress food intake with equivalent efficacy 
to an injectable peptide GLP-1R agonist approved for the treatment of type 2 diabetes 
mellitus (T2DM).
2.1. Study Rationale
The purpose of this multi-site, Phase 1, open-label, parallel-group study is to characterize the 
effect of varying degrees of renal impairment on the PK, safety and tolerability of a single 
oral dose of PF-06882961 in participants with T2DM, compared with participants with 
normal renal function.
2.2. Background
The increase in the global prevalence of T2DM is largely attributed to rising rates of excess 
body weight and obesity.5  T2DM is estimated to affect more than 424 million people 
worldwide,6 and the prevalence of T2DM within the United States (US) is estimated to range 
from 12 to 14%.7  T2DM is characterized by insulin resistance, a disorder in which cells do 
not respond effectively to insulin, resulting in higher blood glucose levels.  Elevated blood 
glucose levels and increasing severity of insulin resistance result in the need for more insulin 
over time, eventually resulting in progressive pancreatic -cell failure.8  Patients with poorly 
controlled T2DM have an increased risk of developing complications associated with both 
microvascular and macrovascular disease, including nephropathy, neuropathy, retinopathy, 
cardiovascular disease and stroke; and are at 2 to 4 times increased risk of mortality than 
adults who do not have diabetes.9  While existing pharmacological options for the treatment 
of diabetes may provide satisfactory glycemic control for some patients, there remains a large 
number of patients who do not achieve target glycated hemoglobin (HbA1c) levels, 
suggesting a need for additional therapeutic options.
Marketed injectable GLP-1R agonists have demonstrated robust glycemic efficacy, weight 
loss, and cardiovascular safety, with some agents demonstrating cardiovascular benefit.10  
Based on the clinical history of injectable GLP-1R agonists, an oral GLP-1R agonist is 
expected to improve glucose control and reduce HbA1c levels in patients with T2DM, while 
decreasing food intake and body weight and avoiding the subcutaneous injection required by 
currently available peptidic GLP-1R agonists.


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2.2.1. Nonclinical Pharmacology
In vitro primary pharmacodynamics (PD) studies demonstrated that, in cells expressing 
recombinant human and cynomolgus monkey GLP-1R, PF-06882961 dose-dependently 
promotes 3’-5’-cyclic adenosine monophosphate (cAMP) production.  In vivo, PF-06882961 
potentiated glucose-stimulated insulin secretion during an intravenous glucose tolerance test 
(IVGTT) in cynomolgus monkeys in a dose and concentration dependent manner.  
PF-06882961 was also shown to reduce food intake in cynomolgus monkeys.  In all in vivo 
studies, efficacious plasma levels were consistent with the in vitro potency.  
Refer to the Investigator’s Brochure (IB) for more details on the nonclinical pharmacology of 
PF-06882961.
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2.2.3. Nonclinical Safety
General toxicology studies have been completed in cynomolgus monkeys up to 6 months in 
duration (with a 3-week lead-in and 1-month recovery) and in rats up to 6 months in duration 
(with a 1‑month recovery).  The exposure limits for plasma concentrations of PF-06882961 
for clinical studies are based on the exposure at the no observed adverse effect level 
(NOAEL) dose of 250 mg/kg/day in the 6-month with 1-month recovery toxicology study in 
rats, due to the fact that findings in monkeys such as decreased food intake and body weight 
loss are reversible and monitorable in a clinical setting.  In the 6-month toxicity study in rats 
with 1-month recovery, the NOAEL was 250 mg/kg/day based on species-specific toxicity at 
a higher dose. 
Embryo-fetal developmental studies were completed in rats and rabbits. Based on the lack of 
maternal toxicity or adverse effects on embryo-fetal development, the NOAEL for maternal 
and developmental toxicity in rats was 500 mg/kg/day (highest dose evaluated). In 
embryo-fetal studies conducted in rabbits, the NOAEL for maternal and developmental 
toxicity was 250 mg/kg/day.
PF-06882961 was negative in genetic toxicity testing and photosafety endpoints.  A risk 
assessment of the target organ toxicities noted in the repeat-dose toxicity studies is provided 
in the IB.  
Refer to the IB for more details on the nonclinical safety of PF-06882961.
2.2.4. Clinical Overview
Three clinical studies, C3421001, C3421002 and C3421003 have completed dosing with 
PF-06882961. In C3421001 and C3421003, single oral doses of PF-06882961 up to 300 mg 
(or matching placebo) were generally safe and well tolerated in healthy adult participants.  In 
the multiple dose study C3421002, PF-06882961 doses up to 120 mg BID (or matching 
placebo) for 28 days were generally safe and well-tolerated in adult participants with T2DM 
on a background of metformin therapy, and safety results from this study are provided in 
Section 2.2.4.1. Refer to the IB for more details on these studies and the known drug class 
effects of marketed injectable GLP-1R agonists.
2.2.4.1. Clinical Safety
Clinical data from the completed C3421001, C3421002, and C3421003 studies are provided 
in the IB for PF-06882961.
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In study C3421002, PF-06882961 doses ranging from 10 mg BID to 120 mg BID were 
generally safe and well tolerated. A total of 98 participants with T2DM on a background of 
metformin were randomized to receive PF-06882961 or matching placebo in a 
3:1 randomization ratio, and 92 participants completed the study. Six participants 
discontinued from the study, of which 2 discontinuations were due to treatment-related 
TEAEs, and 4 withdrew during the treatment or follow-up period for non-treatment related 
reasons.
A total of 319 all-causality treatment-emergent adverse events (TEAEs) were reported in 
these participants, of which a majority (294 or 92%) were mild in intensity, 23 (or 7%) were 
moderate, and 2 (or 1%) were severe in intensity. 
The total number of TEAEs generally increased with higher daily doses of PF-06882961. 
The most frequently reported TEAEs (by number of occurrences) in these cohorts have been 
nausea (48), dyspepsia (32), vomiting (26), diarrhea (24), headache (23), constipation (20), 
and decreased appetite (19). In addition, there was one symptomatic hypoglycemic AE 
reported in 1 participant in the 120 mg BID group. This AE was non-fasting, mild in 
severity, and of limited duration (15 minutes). No deaths occurred in the C3421002 study.
Two participants experienced 2 severe TEAEs during the study, 1 of which occurred in the 
dosing period and was considered treatment related, the other occurred during the follow-up 
period and was not considered treatment related. One participant experienced 
2 non-treatment-related SAEs, 1 of which occurred in the follow-up period and the other 
occurred outside of the study reporting period.
In C3421002, there were isolated values for laboratory tests, vital signs and ECG intervals 
outside of the reference ranges; however, no clear adverse trends were apparent in these 
parameters.  As has been reported for marketed GLP-1R agonists11 increases in heart rate 
were observed, with mean increases ranging from 5 to 15 beats per minute (bpm) across 
doses administered, and with most heart rate values within the normal range.  
2.2.4.2. Clinical Pharmacokinetics
The clinical PK of PF-06882961 in healthy adult participants have been evaluated in 
3 completed studies: C3421001, C3421002 and C3421003.  The results of these completed 
studies are summarized in the PF-06882961 IB.  
In study C3421001, following a single, oral dose administration of PF-06882961 to healthy 
participants at doses ranging from 3 mg to 300 mg under fasted conditions, median Tmax
ranged from 2.0 to 6.0 hours post dose.  Mean t½ values ranged from 4.3 to 6.1 hours.  
Plasma exposure, as assessed by dose-normalized geometric mean AUCinf and Cmax values, 
appeared to increase in a dose proportional manner across the 3 mg to 300 mg doses.  
Variability in PF-06882961 exposure based on geometric percent coefficient of variation 
(%CV) ranged from 50% to 91% for Cmax and 28% to 60% for AUCinf across the 3 mg to 
300 mg dose range.  


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In study C3421002, following 28 days of dosing to participants with T2DM, accumulation 
was modest for the BID IR formulation treatments, with mean ratios based on dose 
normalized AUC24 (Rac) values ranging from 1.203‑2.009.  Day 28 plasma exposure as 
measured by geometric mean AUC24 values appeared to increase in an approximate dose 
proportional manner across all IR treatments. Urinary recovery of PF-06882961 was low, 
with <0.1% of the dose recovered unchanged in urine on Day 28. Mean t½ values on Day 28 
across all treatments ranged between 4.681 to 8.090 hours, and no apparent trends were 
observed across various treatments, regimens, or doses administered. Inter-participant 
variability for PF-06882961 exposure was based on geometric mean was 31%-87% for 
AUC24 and 32%-94% for Cmax and on Day 28 across all treatments and cohorts. 
2.3. Benefit/Risk Assessment
A single dose of PF-06882961 administered in this study is not expected to provide any 
clinical benefit to healthy participants or T2DM participants with or without renal 
impairment.  This study is designed primarily to characterize the effect of varying degrees of 
renal impairment on the PK of PF-06882961.  Results from this study will be used in 
conjunction with collective safety, efficacy, and PK/PD data from other PF-06882961 studies 
to provide recommendations on dosing for participants with varying degrees of renal 
impairment.
In line with the clinical profile of marketed GLP-1R agonists,12-14 the most frequently 
reported AEs with PF-06882961 administration have been nausea, diarrhea, dyspepsia, 
headache, and vomiting.  In addition, as has been reported for marketed GLP-1R agonists,
increases in heart rate have been observed with PF-06882961 administration, with most heart 
rate values within the normal range. Based on current Phase 1 data with PF-06882961, a 
20 mg dose is anticipated to be well tolerated, even if plasma concentrations are higher with 
renal impairment.  
Considering all available clinical and nonclinical data, the benefit-risk profile of 
PF-06882961 supports continued clinical development in patients with T2DM.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06882961 may be found in the IB which is the single reference safety 
document (SRSD) for this study. 
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3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To compare the PK of PF-06882961 following 
administration of a single oral dose in adult 
participants with T2DM and varying degrees of 
renal impairment relative to T2DM participants 
without renal impairment.

Plasma: Cmax, AUCinf, AUClast, fu, as data permit.
Secondary:
Secondary: 

To compare additional PK parameters of 
PF-06882961 following administration of a 
single oral dose in adult participants with 
T2DM and varying degrees of renal impairment 
relative to T2DM participants without renal 
impairment.

Plasma: Cmax,u, AUCinf,u, AUClast,u, CL/F, CLu/F,
Vz/F, Vz,u/F, Tmax, t1/2, as data permit.

To evaluate the safety and tolerability of a 
single oral dose of PF-06882961 in T2DM
participants with varying degrees of renal
impairment and in participants with normal 
renal function.

Incidence and severity of treatment-emergent 
AEs, clinical laboratory abnormalities, vital signs 
(blood pressure and pulse rate), ECG parameters 
(heart rate, QT, QTcF, PR and QRS intervals).
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To compare urine PK parameters of 
PF-06882961 following administration of a 
single oral dose in adult participants with 
T2DM and varying degrees of renal impairment 
relative to T2DM participants without renal 
impairment.

Urine: CLr, Ae24, Ae24%.

To compare the PK of PF-06882961 following 
administration of a single oral dose in adult 
participants with T2DM and normal renal 
function relative to healthy participants with 
normal renal function.

Plasma: Cmax, Tmax, AUCinf, AUClast, CL/F, Vz/F, 
t1/2, fu, as data permit;

Urine: CLr, Ae24, Ae24%.

To explore the relationship of markers of innate 
OATP activity in adult participants with T2DM 
and varying degrees of renal impairment 
relative to participants with normal renal 
function.

CP-I concentration.

To enable exploratory research through 
collection of banked biospecimens, unless 
prohibited by local regulations or ethics 
committee decision.

Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study).


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4. STUDY DESIGN
4.1. Overall Design
This Phase 1, open-label, single-dose, parallel group, multi-site study will assess the effect of 
varying degrees of renal impairment on the PK, safety and tolerability of PF-06882961 after 
a single oral dose of 20 mg administered in a fed state (Section 5.3.1).
Approximately 40 participants will be enrolled in the study. Refer to Table 1 below for 
details of study groups. Due to the potential difficulty in recruiting T2DM patients with 
estimated glomerular filtration rate (eGFR) <30 mL/min, the number of participants to be 
enrolled in this group is flexible (6 to 8 participants).
This study will permit enrollment of 2-4 participants on dialysis, as part of the severe renal 
impairment group, to assist in recruitment of patients with more advanced renal impairment
and to permit assessment of the PK of PF-06882961 in participants with the highest degree of 
renal impairment. 
dialysis is not expected to significantly impact the clearance 
of PF-06882961 and therefore the dialysis clearance of PF-06882961 will not be 
characterized in this study.  Thus, Day 1 (per the SoA) will occur in dialysis patients on a day 
in which dialysis is not administered.
Table 1.
Study Groups
Group
Disease State
Renal Impairment
No. of 
Participants
eGFRa
(mL/min)
1
None (healthy)
None (Normal Renal 
Function)
8
≥90
2
T2DM
None (Normal Renal 
Function)
8
≥90
3
T2DM
Mild
8
60-89
4
T2DM
Moderate
8
30-59
5
T2DM
Severe 
6-8b
<30
a.
Estimate of eGFR based on the SCr-based CKD-Epi equation.  The eGFR will be multiplied by each participant’s 
ratio of BSA/1.73 to obtain the BSA-unnormalized eGFR value.  The average of the 2 unnormalized eGFR values
from S1 and S2 will be used for study enrollment and group placement.  Note: participants on dialysis will be placed 
in Group 5 regardless of unnormalized eGFR from S1 and S2.
b.
This includes approximately 4 participants not on dialysis and 2-4 participants on dialysis.
Screening will occur within 28 days of the first dose of study intervention on Day 1.  All 
participants will provide informed consent and undergo Screening evaluations to determine 
their eligibility.  All participants who are not on dialysis must have stable renal function to 
enter the study, defined as ≤25% difference between 2 measurements of BSA-unnormalized 
eGFR obtained from the 2 screening visits, S1 and S2 as listed in the SoA.
As indicated in Table 1, the estimate of eGFR will be based on the SCr-based CKD-Epi 
equation:15
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
eGFR (mL/min/1.73m2) = 141 × min (SCr /κ, 1)α × max(SCr /κ, 1)-1.209 × 0.993Age × 
1.018 [if female] × 1.159 [if Black].
where: 

SCr is serum creatinine in mg/dL (based on the standardized assay);

κ is 0.7 for females and 0.9 for males;

is -0.329 for females and -0.411 for males;

Min indicates the minimum of SCr /κ or 1;

Max indicates the maximum of SCr /κ or 1;

Age is in years.
The eGFR value will be multiplied by each participant’s ratio of BSA/1.73 to obtain the 
BSA-unnormalized eGFR value as shown below:

eGFR (mL/min) = eGFR (mL/min/1.73m2) * [BSA (m2) / 1.73].
The BSA of an individual will be calculated using the following equation:16
BSA (m2) = [Weight(kg)0.425 × Height(cm)0.725] × 0.007184
Participants with T2DM and varying degrees of renal impairment (Groups 3-5) will be 
recruited and enrolled first.  An average value for age and weight for these groups will be 
determined and participants in Groups 1-2 will be recruited to match the average 
demographics (at a minimum, age and weight, and as much as practically possible gender) 
across the pooled Groups 3-5.  Recruitment for participants in Groups 1-2 may start when 
approximately 75% of total participants across Groups 3-5 (ie, approximately 17-18) have 
been dosed.  Approval from the sponsor must be garnered before proceeding with dosing 
participants in Groups 1 and 2.
Refer to Section 1.2 for study schema.  For individual participants, the total duration of 
participation from the Screening Visit to the Follow-up Contact will be a minimum of 
approximately 5 weeks and a maximum of approximately 10 weeks.
Participants who discontinue from the study before completing all assessments may be 
replaced at the discretion of the investigator and sponsor.


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4.2. Scientific Rationale for Study Design
The purpose of this study is to characterize the effect of varying degrees of renal impairment 
on the PK, safety and tolerability of PF-06882961. PF-06882961 is an oral GLP-1R agonist 
that is currently being investigated as chronic therapy to improve glycemic control in adult 
participants with T2DM.  Chronic kidney disease (CKD) occurs in 20-40% of patients with 
diabetes and may be present at the time of diagnosis of T2DM.17
Renal impairment can affect drug metabolism and transport in other organs (such as the 
liver), which may lead to clinically relevant changes in non-renal clearance (where OATP 
substrates may be affected).18-20  Based on this, and since patients with T2DM may 
experience varying stages of CKD, a full-range study design including participants with no, 
mild, moderate and severe renal impairment (including participants requiring dialysis) will be 
conducted.  Consistent with the recommendation in the draft FDA Guidance for Industry 
“Pharmacokinetics in Patients with Impaired Renal Function: Study Design, Data Analysis, 
and Impact on Dosing and Labelling”21 that the participants should be representative of a 
typical patient population, T2DM participants will be the primary population.  Healthy 
participants with normal renal function will be enrolled to enable comparison of PK 
parameters between the age, weight, and gender of healthy participants, T2DM participants
with varying degrees of renal impairment, and T2DM participants with normal renal 
function.  
 Therefore, to compare exposures directly in 
this study, both T2DM and healthy participants with normal renal function are included.  
Renal impairment classification will be based on the eGFR according to the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation which has been used in renal 
outcome studies.22,23,24
Based on the draft FDA Guidance for Industry, plasma and urine samples will be analyzed
for PF-06882961.  As PF-06882961 was observed to have a t½ of approximately 4-8 hours, 
plasma sampling up to 48 hours will be collected.  Since PF-06882961 is highly protein 
bound, to assess the in vivo protein binding of PF-06882961 with varying degrees of renal
impairment, the fraction unbound (fu) of PF-06882961 will be determined at approximately 
the expected Tmax in each participant.  To explore the relationship between OATP activity 
and CKD, the endogenous biomarker, coproporphyrin I (CP-I), will be measured prior to 
dosing. CP-I has been reported to be a potential marker of OATP activity. In this study, a 
single dose of PF-06882961 will be administered with a standard breakfast to reflect the 
conditions for anticipated use of PF-06882961 in the target T2DM population.  Additionally, 
in study C3421001 in healthy participants, variability based on geometric %CV for Cmax was 
lower following administration with a high-fat meal (23% in the fed state, compared to 91% 
in the fasted state). The adjusted geometric mean Cmax was 57% lower (90% CI: 28%, 74%) 
in the fed state compared to the fasted state, while mean AUCinf values were similar 
(approximately 12% lower in the fed state [90% CI: -5%, 26%]).
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While GLP-1R agonists typically are not associated with hypoglycemia unless 
co-administered with anti-diabetic agents that can cause hypoglycemia (such as insulin or 
sulfonylureas), blood glucose concentrations will be monitored throughout the study via 
glucometer, and monitoring of symptomatic HAEs will be performed.  As is typical for 
studies with renally impaired participants, vital signs will be obtained in the seated position. 
In addition, COVID-19 specific assessments have been incorporated to minimize the risks of 
COVID-19 related complications to participants and the study site personnel.
Both females of childbearing potential as well as those who are of non-childbearing potential 
will be enrolled given the availability of embryo fetal developmental (EFD) toxicity studies 
with PF-06882961.  However, as marketed GLP-1R agonists are listed as contraindicated in 
pregnancy, measures will be taken to limit the risk of pregnancy in the female population 
enrolled (see SoA and Section 10.4).
The potential risk of exposure to PF-06882961 in a sexual partner of a male participant in 
this study via ejaculate is low, and therefore no contraception (condom) use in male 
participants is warranted.  The calculated safety margin is ≥100-fold between the estimated 
partner exposure due to seminal transfer and the NOAEL for serious manifestations of 
developmental toxicity in nonclinical studies.  The safety margin of 100-fold is based on 
applying a 10-fold safety factor for interspecies extrapolation and a 10-fold safety factor for 
susceptible populations.25
4.3. Justification for Dose
Based on data available from the completed C3421001 study, a single dose of PF-06882961 
20 mg is expected to be safe and well tolerated and will provide data to meet the objectives 
of this study.  This dose selection also takes into account safety considerations for patients 
with varying degrees of renal impairment in whom an increase in plasma concentration of 
PF-06882961 may be observed in this study. Based on current Phase 1 data, a 20 mg dose is 
anticipated to be well tolerated, even if exposures are approximately 2-fold higher with renal 
impairment and approximately 1.7-fold higher in T2DM versus healthy participants.  
Additionally, a 20 mg dose will allow for adequate characterization of the plasma PK profile
out to 48 hours and therefore it is suggested to choose the highest single dose that is 
anticipated to be well tolerated (ie, 20 mg).  Since the exposure of PF-06882961 is 
approximately dose-proportional over the range of clinical doses (up to single dose of 
300 mg and up to 120 mg BID), the results of this study can be extrapolated to understand 
the effect of renal impairment on the PK of PF-06882961 over the range of clinical doses 
planned for future studies.
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4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last scheduled procedure shown in the SoA
for the last participant in the trial.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
5.1.1. Inclusion Criteria for All Participants
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Stable renal function (for participants not on dialysis) defined as ≤25% difference 
between 2 measurements of eGFR (as calculated by the sponsor-identified central 
laboratory using the CKD-EPI equation)1 obtained at Screening visits S1 and S2.  The 
average of the 2 eGFR values obtained from S1 and S2 will be used for study 
enrollment and assignment to appropriate renal function group (see Table 1). Note: 
participants on dialysis will be placed in Group 5 regardless of eGFR from S1 and S2
(S2 is optional for dialysis participants only).
Age and Sex:
2. Male and female participants must be ≥18 years of age, inclusive, at the time of 
signing the informed consent document (ICD).

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures, including 
the ability to perform self-monitoring blood glucose at a frequency deemed 
appropriate by the investigator.


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Weight:
4. Body mass index (BMI) of ≥18.0 kg/m2 and <45.4 kg/m2; and a total body weight 
>50 kg (110 lb).
Informed Consent:
5. Capable of giving signed informed consent as described in Appendix 1 (Section 
10.1), which includes compliance with the requirements and restrictions listed in the 
ICD and in this protocol.
5.1.2. Additional Inclusion Criteria for Healthy Participants with Normal Renal 
Function (Group 1)
1. No clinically relevant abnormalities identified by a detailed medical history, full 
physical examination, including blood pressure (BP) and pulse rate measurement, 
standard 12-lead ECG and clinical laboratory tests.
2. Normal renal function (mean eGFR ≥90 mL/min) based on an average of measures 
from Screening visits S1 and S2.
3. Demographically comparable to participants with impaired renal function:
a.
A body weight within ±15 kg of the mean body weight of the pooled renal 
impairment groups (Groups 3, 4, and 5), as provided by sponsor;
b. An age within ±10 years of the mean age of the pooled renal impairment groups
(Groups 3, 4 and 5), as provided by sponsor;
c.
Attempts will be made to ensure that the male to female distribution in Group 1 is 
comparable to that in the pooled renal impairment groups (Cohorts 3, 4, and 5).
5.1.3. Additional Inclusion Criteria for T2DM Participants with Normal Renal 
Function (Group 2)
1. A prior diagnosis of T2DM with an HbA1c ≥6% and ≤10.5%, at Screening visit S1, 
confirmed by a single repeat, if deemed necessary.
2. Normal renal function (mean eGFR ≥90 mL/min) based on an average of measures 
from Screening visits S1 and S2.
3. See Appendix 8 for details regarding prohibited prior/concomitant medications.
4. Demographically comparable to participants with impaired renal function:
a.
A body weight within ±15 kg of the mean body weight of the pooled renal 
impairment groups (Groups 3, 4, and 5), as provided by sponsor;


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b. An age within ±10 years of the mean age of the pooled renal impairment groups 
(Groups 3, 4, and 5), as provided by sponsor;
c.
Attempts will be made to ensure that the male to female distribution in Group 2 is 
comparable to that in the pooled renal impairment groups (Cohorts 3, 4, and 5).
5.1.4. Additional Inclusion Criteria for T2DM Participants with Impaired Renal 
Function (Groups 3-5)
1. A prior diagnosis of T2DM with an HbA1c ≥6% and ≤10.5%, at Screening visit S1, 
confirmed by a single repeat, if deemed necessary.
2. Meet the eGFR criteria listed for Groups 3, 4, or 5 (for participants not on dialysis) in 
Table 1 based on an average of measures from Screening visits S1 and S2.
3. Stable concomitant medications, as defined in Section 6.5, for the management of 
medical conditions relevant to an individual participant’s medical history. 
Participants receiving fluctuating concomitant medications/treatments may be 
considered, on a case-by-case basis with input from sponsor, if the underlying 
disease is stable.
4. For Group 5 participants on dialysis only, participants must have required 
hemodialysis for at least 6 weeks and need dialysis sessions 3 times per week.
5.2. Exclusion Criteria
5.2.1. Exclusion Criteria for All Participants
Participants in all 5 Groups are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or IP administration or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study.
2. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or 
pancreatic insufficiency). NOTE: subjects who have undergone cholecystectomy 
and/or appendectomy are eligible for this study so long as the surgery occurred more
than 6 months prior to Screening;
3. Any malignancy not considered cured (except basal cell carcinoma and squamous cell 
carcinoma of the skin); a participant is considered cured if there has been no evidence 
of cancer recurrence in the previous 5 years.


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4. Personal or family history of medullary thyroid carcinoma (MTC) or multiple 
endocrine neoplasia syndrome type 2 (MEN2), or participants with suspected MTC 
per the investigator’s judgement.
5. History of chronic or acute pancreatitis within 5 years.
6. Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes.
7. History of diabetic ketoacidosis.
8. History of myocardial infarction, unstable angina, arterial revascularization, stroke, 
New York Heart Association Functional Class II-IV heart failure, or transient 
ischemic attack within 3 months of Screening visit S1.
9. Urinary incontinence.
10. Participants with acute renal disease.
11. Renal allograft recipients.
12. Participants with other clinically significant disease, in the judgment of the 
investigator that may affect the safety of the participant or that may affect the PK of 
PF-06882961.  See Section 6.5 for further information.
Prior/Concomitant Therapy:
13. See Appendix 8 (Section 10.8) for details regarding prohibited prior/concomitant 
medications.
Prior/Concurrent Clinical Study Experience:
14. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of IP used in this 
study (whichever is longer). 
15. Known prior participation in a trial involving PF-06882961 or known hypersensitivity 
or intolerance to a GLP-1R agonist.
Diagnostic Assessments:
16. Screening standard 12-lead ECG that demonstrates a clinically relevant abnormality 
that requires further diagnostic evaluation or intervention (eg, new, clinically relevant 
arrhythmia, conduction disturbance, findings suggestive of ischemia).  A potential 
participant whose pre-dose ECG (on Day 1, 0 hour) demonstrates a clinically relevant 
abnormality that requires further diagnostic evaluation or intervention will be
considered a screen failure.


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17. A positive COVID-19 test in the screening period.
18. A positive urine drug test (or other type of drug test in anuric participants on dialysis 
only).  

Note: Participants who have been medically prescribed opiates/opioids, 
benzodiazepines or marijuana and report the use of these drugs to the investigator 
at Screening may be eligible to participate with sponsor approval. Use of 
marijuana during inpatient stay is prohibited. 
19. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study specific central laboratory and confirmed by a 
single repeat test, if deemed necessary: 

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
≥2 × upper limit of normal (ULN);

Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN.

Fasting C-peptide <0.8 ng/mL.

Fasting plasma glucose (FPG) >270 mg/dL (15 mmol/L) at screening (S1).
Other Exclusions:
20. History of regular alcohol consumption exceeding 7 drinks/week for female 
participants or 14 drinks/week for male participants (1 drink = 5 ounces [150 mL] of 
wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 
6 months before screening.
21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
22. History of sensitivity to heparin or heparin-induced thrombocytopenia only if heparin 
is planned to flush intravenous catheters.
23. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of the protocol.
24. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study. 


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5.2.2. Additional Exclusion Criteria for Healthy Participants with Normal Renal 
Function (Group 1)
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or 
allergic disease (including clinically relevant and significant drug allergies, but 
excluding untreated, asymptomatic, seasonal allergies at time of dosing).
2. Use of prescription or non-prescription drugs and dietary and herbal supplements 
within 14 days or 5 half-lives (whichever is longer) prior to the first dose of IP (Refer 
to Section 6.5 for additional details).  As an exception, ibuprofen or acetaminophen 
may be used at doses of ≤1 g/day.  Limited use of non-prescription medications that 
are not believed to affect participant safety or the overall results of the study may be 
permitted on a case-by-case basis following approval by the sponsor.
3. Screening seated systolic blood pressure (SBP) >140 mmHg or diastolic blood 
pressure (DBP) >90 mmHg, following at least 5 minutes of supine rest.  If SBP is 
>140 mmHg or DBP >90 mmHg, the BP should be repeated 2 more times and the 
average of the 3 BP values should be used to determine the participant’s eligibility.
4. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study specific central laboratory and confirmed by a 
single repeat test, if deemed necessary:

HbA1c ≥6.0% at Screening visit S1;

FPG ≥126 mg/dL at screening (S1);

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
≥1.5 × upper limit of normal (ULN).
5.2.3. Additional Exclusion Criteria for T2DM Participants with Normal Renal 
Function (Group 2)
1. At Screening, seated systolic blood pressure (SBP) ≥160 mm Hg and/or diastolic 
blood pressure (DBP) ≥105 mm Hg after ≥5minute of seated rest, with a single repeat 
permitted to assess eligibility, if needed, at each of these 2 visits.
5.2.4. Additional Exclusion Criteria for T2DM Participants with Impaired Renal 
Function (Groups 3-5) only
1. At Screening, persistent severe, uncontrolled hypertension; for example: seated
systolic blood pressure (SBP) ≥180 mm Hg and/or diastolic blood pressure (DBP) 
≥105 mm Hg after ≥5minute of seated rest, with a single repeat permitted to assess 
eligibility, if needed, at each of these 2 visits:


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
For subjects with SBP ≥160 mm Hg or DBP ≥100 mm Hg, the period between 
Screening and Day 1 must be used to refine the doses of the agents used for 
management of blood pressure with the aim to have stable BP on Day 1 (See 
Section 5.2.5).
2. For participants in Group 5 on Dialysis only: Hemodynamic instability during or at 
the conclusion of dialysis during the 2 weeks prior to dosing, as marked by 
symptomatic hypotension. 
5.2.5. Criteria for Dosing on Day 1
Participants will progress to dosing on Day 1 provided they have satisfied all the following 
criteria:

In women of childbearing potential, urine pregnancy test on Day -1 is negative;

Cohort 1 and Cohort 2 only: Approval from the sponsor must be obtained before 
proceeding with dosing participants in either Cohort 1 or Cohort 2;

Cohorts 2-5 only: Participants must have measurement on Day 1 of SBP 
<160 mm Hg and DBP <100 mm Hg;

A single repeat assessment is permitted, to confirm that the above criterion is met 
[and in such cases, the repeat assessment overrides initial results].
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions
While inpatient, the meals consumed are expected to follow the restrictions outlined below:

Participants must abstain from all food and drink (except water) for at least 8 hours 
prior to scheduled safety laboratory and the predose PK evaluations. 
Dose administered in the fed state on Day 1:

Water may be consumed as desired (ad libitum).

After collection of predose safety and PK samples on Day 1, participants should 
begin consumption of a standard breakfast approximately 30 minutes prior to oral 
PF-06882961 administration.  The breakfast will be consumed over approximately a 
20 minute period, with the IP administered within approximately 10 minutes of 
completion of the meal.  Participants will be encouraged to complete the entire 
breakfast.  


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
Lunch will be provided approximately 4 hours after oral dosing of PF-06882961. 
Dinner will be provided approximately 10 hours after oral dosing of PF-06882961.  

An evening snack may be permitted.

Noncaffeinated drinks (except grapefruit or grapefruit related citrus fruit juices, see 
below) may be consumed with meals and the evening snack.

Participants will refrain from consuming red wine, grapefruit, or grapefruit related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of IP until collection of the final PK blood sample.  

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein.  The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco

Caffeine containing products will be permitted during the study with the following 
restrictions: caffeine containing products may not be consumed within 2 hours prior 
to measuring vital signs and ECGs.

Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample of each study 
period.  Participants may undergo an alcohol breath test at the discretion of the 
investigator.  Alcohol breath test will be considered source data and will not be 
required to be reported.

Tobacco and nicotine use may be allowed according to CRU practices.  
Tobacco/nicotine use will not be permitted during frequent sampling procedures and
will not be permitted within 2 hours prior to any vital sign or ECG assessments.  
Tobacco/nicotine use will also not be permitted 2 hours before and 2 hours following 
any dose of IP.
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
a female participant has selected an appropriate method of contraception (see Appendix 4
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use.  At time points indicated in the SoA, the investigator or designee will inform the 
participant of the need to use highly effective contraception consistently and correctly and 


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document the conversation and the participant’s affirmation in the participant’s chart 
(participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
A participant who qualified for this study but did not enroll within the protocol prescribed 
screening period may be re-screened with approval from the sponsor.  All screening 
procedures must be repeated, and the participant assigned a new 8-digit study specific subject 
identification (SSID) number.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.  
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product (IP) may be used 
synonymously with study intervention.
6.1. Study Intervention Administered
For this study, the IP is PF-06882961.
PF-06882961 will be supplied by Pfizer as 10 mg tablets in bulk along with individual dosing 
containers, as necessary, for unit dosing.
6.1.1. Administration
Participants will receive IP at approximately 0800 hours (plus or minus 2 hours).  Details on
meals and dietary requirements and activity restrictions on the day of dosing (Day 1) are 
given in Section 5.3.
Investigator site personnel will administer IP with ambient temperature water to a total 
volume of approximately 240 mL. Participants will swallow the IP whole, and will not 
manipulate or chew the IP prior to swallowing.  


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6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature -monitored shipments. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). All study 
interventions will be accounted for using an IP accountability form/record.  
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels. 
7. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer on discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention
must be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use 
of the study intervention after the temperature excursion. Use of the study 
intervention prior to Pfizer approval will be considered a protocol deviation. Specific 
details regarding the definition of an excursion and information the site should report 
for each excursion will be provided to the site in the IP manual.


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8. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site). 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, and all destruction must be adequately 
documented.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the IP ready for administration or dispensing to the participant by qualified staff.  Dispensing 
is defined as the provision of IP, concomitant treatments, and accompanying information by 
qualified staff member(s) to a healthcare provider, participant in accordance with this 
protocol.  Local health authority regulations or investigator site guidelines may use 
alternative terms for these activities.
Tablets will be prepared at the CRU in the individual dosing containers by 2 operators, 1 of 
whom is an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist).  
The tablets will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements. 
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
This is a non-randomized, open-label study. The investigator’s knowledge of the treatment 
should not influence the decision to enroll a particular participant or affect the order in which 
participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study. The first 4 digits of the SSID will reflect the sponsor assigned site number and the 
remaining 4 digits will reflect each participants’ unique number assigned in chronological 
order of when informed consent is obtained.
6.4. Study Intervention Compliance
IP will be administered under the supervision of investigator site personnel.  The oral cavity 
of each participant will be examined following dosing to ensure the IP was taken.
6.5. Concomitant Therapy
Healthy participants will abstain from all concomitant medications, except for the treatment 
of AEs, as described in Section 5.2.2 of this protocol. 
Participants with T2DM will be allowed to be on certain concomitant medications that have 
been prescribed. Any concomitant medications may be administered in the morning if they 
can be administered under fed conditions or may be administered at 2 hours after IP 
administration.  On all other study days, participants are to receive their background 


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medications at their usual times.  Attempts should be made not to alter the doses and 
regimens of any concomitant medications after enrollment and for the duration of 
participation in this study, except in circumstances where a change in dose is deemed 
medically necessary.  Any changes must be captured in the CRF.
In addition, T2DM participants using insulin are permitted to have sliding scale insulin or 
dose adjustment in insulin while confined to the CRU to attempt to maintain fasting and post 
prandial glucose readings at similar levels that are achieved at home and based on the 
calories consumed while confined in the CRU.  
Phosphate binders, antacids, and bile acid binding resins (eg, cholestyramine, colestipol) 
must not be administered within 8 hours before dosing to 4 hours after dosing. 
All concomitant treatments, both prescription and over-the-counter, taken during the study 
must be recorded with indication, daily dose, and start and stop dates of administration.  All 
participants will be questioned about concomitant treatments at each clinic visit.
Treatments taken within 28 days before the first dose of IP will be documented as a prior 
treatment.  Treatments taken after the first dose of IP will be documented as concomitant 
treatments.
See Appendix 8 for details regarding prohibited concomitant medications.  Sites are 
encouraged to contact the sponsor should there be questions as to whether a medication is 
permitted or prohibited.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
6.5.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with PF-06882961.  Standard medical 
supportive care must be provided to manage the AEs, including administration of 
carbohydrates to treat HAEs (see Section 8.2.6).
6.6. Dose Modification
Dose modification of PF-06882961 is not allowed.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Not applicable as this is a single dose study.


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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early termination visit applies only to participants who received IP and then are 
prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.  If a participant withdraws from the study, he/she may request 
destruction of any remaining samples taken and not tested, and the investigator must 
document any such requests in the site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 


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available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
Participants will be screened within 28 days prior to administration of the IP to confirm that 
they meet the study population criteria for the study.  The investigator (or an appropriate 
delegate at the investigator site) must obtain a signed and dated ICD before performing any 
study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.


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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 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
90 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Not Applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 


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Height and weight will also be measured and recorded as per the SoA.  For measuring 
weight, a scale with appropriate range and resolution is used and must be placed on a stable, 
flat surface.  Participants must remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains.  They must also remove the contents of their pockets and remain 
still during measurement of weight. 
8.2.2. Vital Signs
Vital signs (systolic BP, diastolic BP, temperature and pulse rate) will occur as specified in 
the SoA. Seated BP will be measured with the participant’s arm supported at the level of the 
heart and recorded to the nearest mmHg after approximately 5 minutes of rest.  The same 
arm (preferably the dominant arm) will be used throughout the study.  Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
8.2.2.1. Temperature
Body temperature will be measured at the timepoints listed in the SoA.  No eating, drinking, 
or smoking is allowed for 15 minutes prior to this measurement.  
8.2.3. Electrocardiograms
Standard 12-Lead ECGs should be collected at times specified in the SoA section of this
protocol using an ECG machine that automatically calculates the heart rate and measures PR, 
QT, and QTcF intervals and QRS complex. All scheduled ECGs should be performed after 
the participant has rested quietly for at least 10 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥30 msec from the baseline and is >450 msec; or b) 
an absolute QTcF value is ≥500 msec for any scheduled ECG. If either of these conditions 
occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to 
confirm the original measurement. If the QTcF values from these repeated ECGs remain 
above the threshold value, then a single ECG must be repeated at least hourly until QTcF
values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.


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If a postdose QTcF interval remains ≥30 msec from the baseline and is >450 msec; or b) an 
absolute QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTcF intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7 Section 10.7.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 to 35 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
Participants may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for participants to receive IP. 
8.2.5. Glucometer Monitoring of Glucose
Investigators will monitor fingerstick blood glucose (FSBG) using glucometer measurements 
in participants with T2DM at the times specified in the Schedule of Activities. FSBG
measurements should be taken before breakfast while the participant is confined to the CRU. 


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FSBG readings will be maintained at the sites in source documents, and only the glucose 
results from the laboratory will be reported in the study database.  
Specifically, if an FSBG result is ≤70 mg/dL, a second FSBG should be obtained to confirm 
the glucose value, in addition to a venous sample that will be sent to the clinical laboratory 
for confirmation.  If the value from this second FSBG is also ≤70 mg/dL, the second value 
will be recorded as a hypoglycemic AE.  FSBG will continue to be monitored until the 
glucose value returns to >70 mg/dL.  Samples may be taken more frequently if deemed 
necessary by the investigator.  FSBG readings from a glucometer are permitted at any time if 
the investigator or participant notes symptoms of hypoglycemia.
8.2.6. Management of Hypoglycemia
Any episode of hypoglycemia must be captured on the HAE CRF.  For the definition of a 
hypoglycemic episode and severity categorization see Section 8.2.6.1 below.
For medical management of hypoglycemia, the investigator may administer oral 
carbohydrate, glucagon, or IV glucose according to his or her medical judgment.  At a 
minimum however, treatment or administration of a scheduled meal should be given if 
glucose falls <60 mg/dL for at least 15 minutes, irrespective of whether the participant 
exhibits symptoms.  Investigators may choose to administer treatment sooner if participants 
have bothersome symptoms of hypoglycemia along with glucose values of ≤70 mg/dL.
8.2.6.1. Definition and Severity of Categorization of Hypoglycemic Adverse Event 
(HAE)
Based on review of the participant on site glucose monitoring, as well as results reported by 
the central laboratory, the investigator must assess the glucose values as well as any 
symptoms documented.
HAE is defined as 1 of the following:
1. Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a plasma glucose value of ≤70 mg/dL (3.9 mmoL/L) using glucometer (or 
sponsor-identified central laboratory).
2. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose value of ≤70 mg/dL (3.9 mmol/L) using 
glucometer (or sponsor-identified central laboratory) and the clinical picture includes 
prompt resolution with food intake, subcutaneous glucagon, or intravenous (IV) 
glucose.
3. Probable symptomatic hypoglycemia: An event during which symptoms of HAE 
are not accompanied by a plasma glucose determination but was presumably caused 
by a plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L), and the clinical 
picture includes prompt resolution with food intake, subcutaneous glucagon, or IV 
glucose.


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Each episode of HAE must be categorized with respect to severity.  To characterize the event 
as severe, all 3 criteria below must be met:
1. The participant exhibits altered mental and/or physical functioning that requires 
assistance from another person for recovery.
2. The participants exhibit at least 1 of the following neurological symptoms:

Memory loss;

Confusion;

Uncontrolled behavior;

Irrational behavior;

Unusual difficulty in awakening;

Suspected seizure;

Seizure;

Loss of consciousness.
3. Either:

If blood glucose was measured and was ≤54 mg/dL (2.7 mmol/L) using 
glucometer (or central laboratory); or

If blood glucose was not measured, the clinical manifestations were reversed by 
oral carbohydrates, subcutaneous glucagon, or intravenous glucose.
Events that do not meet all criteria above for severe HAE should be characterized as mild or 
moderate in severity.
Any episode of HAE must be captured on the HAE CRF.
8.2.7. Management of Hyperglycemia
Hyperglycemia is defined as the following:

Fasting plasma glucose ≥270 mg/dL (15.0 mmol/L) using glucometer (or central 
laboratory). 
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.


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A participant with hyperglycemia should receive treatment at the discretion of the 
investigator (see Section 6.5).
8.2.8. Pregnancy Testing
Pregnancy tests will be both urine and serum tests, and must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA.  
Following a negative pregnancy test result at screening (S1 and S2), appropriate 
contraception must be commenced/continued and a second negative pregnancy test result 
will be required prior the participant’s receiving the IP.  Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected).  Pregnancy tests may also be repeated if requested by 
Institutional Review Boards (IRBs)/ethics committees (ECs) or if required by local 
regulations.  
8.2.9. COVID-19 Specific Assessments
Participants will be pre-screened for COVID-19 related symptoms and risks26,27 and tested 
for SARS-CoV-2 infection using a locally approved test at the timepoints specified in the 
SoA. Additional testing may be conducted as required by local regulations or by the 
Principal Investigator. Results must be negative for admission to the CRU. 
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the
study (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.


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Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AE or SAE after the participant has concluded 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3. The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to IP must be 
reported to Pfizer Safety.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.


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


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8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study intervention and until 28 calendar days after the last 
administration of IP.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not Applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not Applicable.
8.3.8. Adverse Events of Special Interest
Not Applicable.
8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.


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8.3.9. Medical Device Deficiencies
Not Applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the IP by the wrong 
participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the IP under study may occur in clinical trial settings, such as medication 
errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the IP;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of PF-06882961 greater than 120 mg within a 24-hour time period 
(±2 hours) will be considered an overdose.
There is no specific antidote for overdose with PF-06882961.  Treatment of overdose should 
consist of general supportive measures.


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In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study intervention 
(whichever is longer).
3. Obtain a blood sample for PK analysis within 2 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of PF-06882961
Blood samples of approximately 3 mL, to provide a minimum of plasma volume 1 mL, will 
be collected into appropriately labeled tubes containing dipotassium 
ethylenediaminetetraacetic acid (K2EDTA) for measurement of plasma concentrations of 
PF-06882961 as specified in the SoA.  Instructions for the collection and handling of 
biological samples will be provided in the laboratory manual or by the sponsor. The actual 
date and time (24-hour clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time (eg, within 6 minutes of a 60-minute sample) relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and data collection tool (eg, CRF).  Collection of samples more than 
10 hours after dose administration that are obtained ≤1 hour away from the nominal time 
relative to dosing will not be captured as a protocol deviation, as long as the exact time of the 
collection is noted on the source document and data collection tool (eg, CRF). 
Samples will be used to evaluate the PK of PF-06882961. Samples collected for analyses of 
PF-06882961 plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, or for other internal exploratory purposes.


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Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent.  Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of PF-06882961 will be 
analyzed using a validated analytical method in compliance with applicable standard 
operating procedures (SOPs).
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
8.5.2. Plasma for Determination of PF-06882961 Unbound Fraction
During the study, a blood sample (approximately 12 mL) to provide sufficient plasma for 
unbound fraction determination will be collected into an appropriately labeled tube 
containing K2EDTA as defined in the SoA.
8.5.3. Urine for Analysis of PF-06882961
One aliquot of approximately 2 mL urine sample is needed for the analysis of PF-06882961.  
Urine will be collected at times specified in the SoA (but no urine will be collected for anuric 
dialysis participants).  

Prior to dosing on Day 1, each participant must complete a forced void with an 
aliquot (approximately 10 mL) from this urine (urine blank) labeled and stored frozen 
for measurement of drug concentrations, per detailed instructions offered in a 
laboratory manual prior to the start of the study. 

Following dosing on Day 1, each void post dose will be collected and saved in a 
container and stored in refrigerated conditions (ie, 2-8°C) for the duration of the 
collection interval, as specified in the SoA. 

At the end of the collection interval, participants must complete a forced void 
with this complete void included as part of the interval collection;

The urine container will be mixed thoroughly and total volume plus weight of the 
urine collected during the interval recorded.
Details regarding the processing, storage and shipping of the samples will be provided in the 
lab manual.  Samples collected for urine analyses of PF-06882961 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 


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exploratory purposes.  The shipment address and assay lab contact information will be 
provided to the investigator site prior to initiation of the study.  The urine samples must be 
processed as indicated to maintain sample integrity.  Any deviations from the urine sample 
processing steps given in the protocol or lab manual, including any actions taken, must be 
documented and reported to the sponsor.  On a case by case basis, the sponsor may make a 
determination as to whether sample integrity has been compromised.  Any sample deemed 
outside of established stability, or of questionable integrity, will be considered a protocol 
deviation.  Samples for analysis of PF-06882961 PK will be analyzed using validated 
analytical methods in compliance with Pfizer SOPs.
8.6. Pharmacodynamics
PD parameters are not evaluated in this study.
8.7. Pharmacogenomics
Pharmacogenomics (specified analysis) are not evaluated in this study.
8.8. Biomarkers
Collection of a sample for biomarker research is also part of this study.
8.8.1. Exploratory Biomarker for Measurement of CP-I
A blood sample (approximately 4 mL) to provide sufficient plasma will be collected as 
defined in the SoA.  This sample may be used for other exploratory biomarker studies, unless 
prohibited by local regulations or an ethics committee (EC) decision.
CCI


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8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Statistical Hypotheses
No formal statistical hypothesis testing will be performed in this study.
9.2. Sample Size Determination
Approximately 8 participants will be enrolled into each of the 5 groups (healthy normal, 
T2DM normal, T2DM mild, T2DM moderate and T2DM severe). This is an estimation 
study and the sample size is based on the recommendation from the EMA in “Guideline on 
the evaluation of the PK of medicinal products in patients with decreased renal function”28
and is consistent with the draft FDA Guidance for Industry “Pharmacokinetics in Patients 
with Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing and 
Labelling”.21
A sample size of 8 participants per group will provide 90% confidence intervals (CIs) for the 
difference between groups of ±0.490 on the natural logarithm scale for AUCinf (or Cmax) with 
80% coverage probability. The expected widths of the 90% CIs with 80% coverage 
probability for the comparisons of each of the T2DM renal impaired groups (Groups 3, 4, 5)
to the T2DM normal group (Group 2) and the comparison of the T2DM normal group
(Group 2) to the healthy normal group (Group 1) are shown in Table 2 for a range of possible 
effects.
Table 2.
Expected Widths of the 90% CIs (with 80% Coverage Probability) for
Different Possible Estimated Effects
Estimated Effect
(Test/Reference)
AUCinf or Cmax
Probable 90% CI
Probable CI Width
75%
(46%, 122%)
76%
100%
(61%, 163%)
102%
150%
(92%, 245%)
153%
200%
(123%, 326%)
203%
400%
(245%, 653%)
408%


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These estimates are based on an assumed conservative standard deviation of 0.489 
(equivalent to a geometric coefficient of variation of 52%) for both logeAUCinf and logeCmax
based on data from the first in human study in healthy volunteers (C3421001) and 
preliminary data from the multiple ascending dose study in T2DM (C3421002).
Participants who discontinue from the study before completing all assessments may be 
replaced at the discretion of the investigator and sponsor.
9.3. Populations for Analysis
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICD.
Evaluable
All participants assigned to IP and who take at least 1 dose of IP. 
Safety
All participants assigned to IP and who take at least 1 dose of IP.  
PK Concentration Set
The PK concentration population is defined as all participants who received 
at least 1 dose of PF-06882961 and in whom at least 1 plasma concentration 
value is reported.
PK Parameter Set
The PK parameter analysis population is defined as all participants who 
received at least 1 dose of PF-06882961 and have at least 1 of the PK 
parameters of interest calculated.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.
9.4.1. Efficacy Analyses
An efficacy analysis is not applicable to this study. 
9.4.2. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants.  Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described.  Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 


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identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported.  
COVID-19 specific assessments data will be considered source data and will not be required 
to be reported.
9.4.2.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
9.4.3. Other Analyses 
Pharmacogenomic (PGx) data will be collected and retained for future analyses, but will not 
be analyzed, specifically, for this study. 
9.4.3.1. Pharmacokinetic Analyses
9.4.3.1.1. Analysis Populations
The analysis populations are defined as in Section 9.3.
9.4.3.1.2. Derivation of Pharmacokinetic Parameters Prior to Analysis
9.4.3.1.2.1. Plasma
The plasma PK parameters for PF-06882961 following single dose administration will be 
derived from the concentration time profiles as detailed in Table 3. Actual PK sampling 
times will be used in the derivation of PK parameters. In the case that actual PK sampling 
times are not available, nominal PK sampling time will be used in the derivation of PK 
parameters.


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Table 3.
Plasma PK Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-time profile 
from time zero to the time of the last quantifiable 
concentration (Clast).
Linear/Log trapezoidal method.
AUCinf*
Area under the plasma concentration-time profile 
from time zero extrapolated to infinite time.
AUClast + (Clast*/kel), where Clast* is the 
predicted plasma concentration at the last 
quantifiable time point estimated from the 
log-linear regression analysis.
Cmax
Maximum observed concentration.
Observed directly from data.
Tmax
Time to maximum observed concentration. 
Observed directly from data as time of 
first occurrence.
t1/2*
Terminal half-life.
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear regression 
of the log-linear concentration-time 
curve. Only those data points judged to 
describe the terminal log-linear decline 
will be used in the regression.
CL/F*
Apparent clearance.
Dose/AUCinf.
Vz/F*
Apparent volume of distribution.
Dose/(AUCinf*kel).
fu
Fraction of unbound drug in plasma.
Cu/C (where Cu represents unbound 
concentration and C represents total 
concentration).
AUClast,u
Unbound area under the plasma concentration-
time profile from time zero to the time of the last 
quantifiable concentration.
fu*AUClast.
AUCinf,u
Unbound area under the plasma 
concentration-time profile from time zero 
extrapolated to infinite time.
fu*AUCinf.
Cmax,u
Maximum observed concentration of unbound 
drug.
fu*Cmax.
CLu/F
Apparent clearance of unbound drug.
Dose/(AUCinf,u).
Vz,u/F
Apparent volume of distribution of unbound 
drug.
Dose/(AUCinf,u*kel).
* as data permit. 
9.4.3.1.2.2. Urine
The following urine PK parameters will be calculated for PF-06882961 (Table 4):


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Table 4.
Urine PK Parameters
Parameter
Definition
Method of Determination
Ae24
Total amount of unchanged drug excreted in the 
urine over 24 hours.
Sum of amount excreted for each 
collection period.
Ae24%
Total amount of unchanged drug excreted in the 
urine over 24 hours, expressed as percent of dose.
100*(Ae24/Dose).
CLr
Renal clearance.
Ae24/AUC24.
9.4.3.1.3. Statistical Methods
Linear regression will be used to characterize the potential relationship between appropriate 
PK parameters (CL/F, CLu/F and CLr) for PF-06882961 and renal function (eGFR). eGFR 
values obtained on Day 1 and only participants from the T2DM groups (Groups 2 to 5) will 
be included in the regression analysis. Estimates of the slope and intercept, together with 
their precision (90% CIs), and the coefficient of determination will be obtained from the 
model. The effect of covariates such as weight, gender, and age may be explored, and details 
will be provided in the SAP.
A one-way analysis of variance (ANOVA) will be used to compare the natural log 
transformed AUCinf (if data permit), AUClast, Cmax, fu, AUCinf,u (if data permit), AUClast,u and 
Cmax,u of PF-06882961 for each of the T2DM renal impairment groups (Test, Groups 3, 4, 5) 
to the T2DM normal renal function group (Reference, Group 2). Also, the T2DM normal 
renal function group (Test, Group 2) will be compared to the healthy normal renal group 
(Reference, Group 1). The ANOVA model will include all groups (ie, both T2DM and 
healthy participants from the 5 groups). Estimates of the adjusted mean differences (Test-
Reference) and corresponding 90% CIs will be obtained from the model. The adjusted mean 
differences and 90% CIs for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and corresponding 90% CIs. If 
substantial differences in demographic characteristics between healthy (Group 1), T2DM 
normal (Group 2) and T2DM renal impairment function participants (Groups 3, 4, 5) are 
observed, covariates such as weight, gender, and age may be explored.
The PK parameters for PF-06882961 will also be summarized descriptively by renal function 
group and population (healthy vs. T2DM). Box and whisker plots for individual PK
parameters (AUCinf, AUClast, Cmax, fu, AUCinf,u, AUClast,u and Cmax,u) will be constructed by 
renal function group and population and overlaid with geometric means.
For summary statistics and median or mean plots by sampling time, the nominal PK 
sampling time will be used. For individual participant plots by time, the actual PK sampling 
time will be used.
Plots of PK parameters (CL/F, CLu/F and CLr) for PF-06882961 versus renal function (eGFR
as obtained on Day 1) will be constructed. A regression line and 90% confidence region for 
the PK parameters and eGFR will be included if appropriate. Vertical lines for the renal 
function group cut-off values will also be presented on the plots. Different symbols will be 
used to identify participants from different renal function groups.


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Consistent with the draft FDA Guidance for Industry,21,18 relevant tables and figures may be 
generated based on eGFR calculated using the Cockcroft-Gault or the Modification of Diet in 
Renal Disease (MDRD) formulas as described in the SAP.
9.5. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label study,
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development. 
9.5.1. Data Monitoring Committee 
This study will not use a Data Monitoring Committee (DMC).


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, Investigator’s Brochure (IB), and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the IP, 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 ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.


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Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time and 
for any reason during the storage period. A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide 
this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code. 
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred. All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code. The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods. Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data. Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.


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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.


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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan (SMP).
10.1.8. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.


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The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.


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


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


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Table 5.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea 
Creatinine
eGFR
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
Magnesium
Phosphate
AST 
ALT
Total bilirubin
GGT
Alkaline phosphatase
Uric acid
Albumin
Total protein
Amylase
Lipase
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya

Serum and Urine 
Pregnancy test (-hCG)d

COVID-19 test
At screening only:

HbA1c

Serum FSHb

C-peptide

Urine drug screeningc
Additional Testse
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase (repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
At screening (S1) and in females only.
c.
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol (THC),
opiates/opioids, benzodiazepines, and amphetamines (others are site and study specific). Participants 
may undergo random drug testing at the discretion of the investigator. For a participant on dialysis who 
is anuric only, an alternative method (eg, saliva) for drug testing may be used.
d.
Serum and urine pregnancy testing for all women of childbearing potential (WOCBP); urine pregnancy
testing to be done on-site using kits provided by sponsor-identified central laboratory. For a participant 
on dialysis who is anuric only, an alternative method (eg, blood) for urine pregnancy testing may be 
used.
e.
Additional testing only for the management of participants with elevated liver enzymes as outlined in 
Appendix 6.
Investigators must document their review of each laboratory safety report.


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Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.  Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings.  These data will not be included in the Clinical Study Report (CSR).  
Samples to be used for this purpose will be shipped to either a Pfizer-approved Biospecimen 
Banking System (BBS) facility or other designated laboratory and retained for up to 1 year 
following the completion of the study.


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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 (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 


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


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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of
events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the IP under 
study during pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 


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


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


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reporting requirements.

If the investigator does not know whether or not the IP caused the event, then the 
event will be handled as “related to investigational product” 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 professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 


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data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3);
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), as described below, during the intervention period and for at 
least 28 days after the last dose of study intervention, which corresponds to the time 
needed to eliminate any study intervention(s). 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 (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.


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


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Highly Effective Methods That Are User Dependent 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.

Oral;

Intravaginal;

Transdermal;

Injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.
3. Sexual abstinence.

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the IP; or the female 
becomes or is found to be pregnant after discontinuing and/or being exposed to the 
IP;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
IP prior to or around the time of conception and/or is exposed during his partner’s 
pregnancy.


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If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the IP, the investigator must report this information to Pfizer 
Safety on the CT SAE Report Form and an EDP supplemental form, regardless of whether an 
SAE has occurred.  In addition, the investigator must submit information regarding 
environmental exposure to a Pfizer product in a pregnant woman (eg, a participant reports 
that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) to 
Pfizer Safety using the EDP supplemental form.  This must be done irrespective of whether 
an AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the IP. 
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.


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CCI
CCI


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


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


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate:
ie, rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ duration.

Frequent premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(rate <40 bpm), accelerated idioventricular rhythm (40< x <100), and 


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


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10.8. Appendix 8: Prohibited Prior/Concomitant Medications
The following medications are prohibited until the follow-up visit (ie, 28-35 days after the 
last dose), unless stated otherwise.  If a participant receives a prohibited medication, the 
investigator should contact the sponsor clinician or sponsor medical monitor to determine if 
the participant should be included in the study.
Drug Classes and/or Drugs 
Timeframe of Restriction 
GLP-1R agonists.
90 days prior to Screening 
Visit S1
DPP-4 inhibitors, pramlintide, repaglinide.
Screening Visit (S1) to 
Follow Up visit
Systemic glucocorticoids such as prednisone, dexamethasone, triamcinolone, 
budesonide, betamethasone.  Note: As an exception, steroid-containing 
inhalers, nasal sprays and topical formulations are permitted.  
Screening Visit (S1) to 
Follow Up visit
Immunosuppressants such as cyclosporine and tacrolimus.
Screening Visit (S1) to 
Follow Up visit
Rosuvastatin.  Note: Other statins are permitted.
Day 1 (day of dosing)
Sulfasalazine (sensitive BCRP substrate)
Day 1 (day of dosing)
Use of chronic agents which are clinically significant OATP inhibitors 
(eg, cyclosporine, gemfibrozil, rifampin).
Screening Visit (S1) o 
Follow Up visit
Use of chronic agents which are potent inducers of CYP3A (eg, rifampin,
phenytoin, carbamazepine, phenobarbital).
Screening Visit (S1) to 
Follow Up visit
Use of potent CYP3A4 inhibitors (eg, ritonavir, indinavir, itraconazole, 
clarithromycin).
Screening Visit (S1) to 
Follow Up visit
Use of moderate CYP3A4 inducers (eg, efavirenz, lopinavir, elagolix).
Screening Visit (S1) to 
Follow Up visit
Use of moderate CYP3A4 inhibitors (eg, diltiazem, verapamil, erythromycin, 
fluconazole).
Screening Visit (S1) to 
Follow Up visit


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10.9. Appendix 9: Proposed Chronology of Procedures
For the procedures described below, where multiple procedures are scheduled at the same 
timepoint(s) relative to dosing, the following chronology of events should be adhered to:

12-lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing (except for post-dose collection) (see Section 8.2.3); 

Vital Signs (BP, PR, temperature): obtain after 12-lead ECG collection but prior to 
obtaining blood samples and prior to dosing (except for post-dose collection) (see 
Section 8.2.2); 

Fasting blood samples [for safety (see Section 8.2.7), PK (see Section 8.5), 
exploratory biomarkers (see Section 8.8) and banked biospecimens (see 
Section 8.7.1)]: after assessment of 12-lead ECG and vital signs but prior to dosing; 

For the random, post dose PK blood collection to occur approximately 2 to 6 hours 
post dose (see Section 8.5): if collection time coincides with time of a meal/snack, 
these blood samples should be collected just prior to the meal/snack;

Other pre-dose procedures: obtain sample/perform procedure as close as possible to 
the scheduled time, but may be obtained before or after blood sample collection(s); 

Dosing: must occur with the morning meal; and where applicable, after any pre-dose 
blood sample collection(s). 


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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Term
Abs
absolute
AE
adverse event
Ae24
total amount of unchanged drug excreted in the urine over 24 hours
Ae24%
total amount of unchanged drug excreted in the urine over 24 hours, 
expressed as percent of dose
ALT
alanine aminotransferase
AM
Morning
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC24
area under the plasma concentration-time profile from time 0 to time 
24 hours
AUCinf
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time
AUCinf,u 
unbound area under the plasma concentration-time profile from time 
zero extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time zero to 
the time of the last quantifiable concentration (Clast).
AUClast,u
unbound area under the plasma concentration-time profile from time 
zero to the time of the last quantifiable concentration
AV
Atrioventricular
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BSA
body surface area
BUN
blood urea nitrogen
cAMP
cyclic adenosine monophosphate
CFB
change from baseline
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD
chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration equation
CLu/F
apparent clearance of unbound drug after oral administration
CLr
renal clearance


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Term
CL/F
apparent clearance
Cmax
maximum observed concentration
Cmax,u
maximum observed concentration of unbound drug
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CP-I
coproporphyrin I 
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
%CV
percent coefficient of variation
CYP
cytochrome P450
DBP
diastolic blood pressure
DPP
Dipeptidyl Peptidase
DDI
drug-drug interactions
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EFD
embryo fetal developmental
EMA
European Medicines Agency
eGFR
estimated glomerular filtration rate
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSBG
fingerstick blood glucose
FPG
fasting plasma glucose
FSH
follicle-stimulating hormone
fu
fraction of unbound drug in plasma
FU
follow up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
H or h or hr
hour
HAE
hypoglycemic adverse event


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PFIZER CONFIDENTIAL
Page 89
Term
HbA1c
glycated hemoglobin 
HIPAA
Health Insurance Portability and Accountability Act
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IP manual
investigational product manual
IR
immediate release
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVGTT
intravenous glucose tolerance test
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
Loge
natural logarithm
MATE
multidrug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MDR1
multidrug resistance mutation
MEN2
multiple endocrine neoplasia syndrome type 2
mg/kg
milligrams per kilogram
msec
millisecond
MTC
medullary thyroid carcinoma
N/A
not applicable
NOAEL
no-observed-adverse-effect level
OATP
organic anion transporting polypeptides
OCT2
organic cation transporter 2
PCD
primary completion date
PD
pharmacodynamic(s)
PE
physical examination
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PR
ECG parameter/interval
PT
prothrombin time
PVC
premature ventricular contraction/complex
QRS
ECG parameter/interval


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Protocol C3421012
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PFIZER CONFIDENTIAL
Page 90
Term
QT
time from the beginning of the QRS complex to the end of the 
T wave
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
Rac
accumulation ratio
RBC
red blood cell
RNA
ribonucleic acid
S1
screening visit 1
S2
screening visit 2
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBP
Systolic blood pressure
SCr
serum creatinine
SMP
study monitoring plan 
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SSID
Single Subject Identifier
ST
slow titration
SToD
study team on demand
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
terminal phase half-life
TBili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
Tmax
time to maximum observed concentration
T2DM
type 2 diabetes mellitus
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution 
Vz, u/F
Unbound Vz/F
WBC
white blood cell
WOCBP
woman of childbearing potential


PF-06882961
Protocol C3421012
Final Protocol, 13 October 2020
PFIZER CONFIDENTIAL
Page 91
11. REFERENCES
1.
Ørskov C, Holst JJ, Knuhtsen S,et al. Glucagon-like peptides GLP-1 and GLP-2, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology. 1986;119(4):1467-75.
2.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet. 1987;2(8571):1300-4.
3.
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol.
1997;273(5):E981-8.
4.
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest. 1998;101(3):515-20.
5.
Hu FB. Globalization of diabetes: the role of diet, lifestyle and genes. Diabetes Care.
2011;34:1249-57.
6.
IDF Diabetes Atlas; 9th Edition2019. Available from: http://www.idf.org/diabetesatlas. 
Accessed: 30 Jul 2020 04 Feb 2019.
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.
DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the 
treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-95.
9.
Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular 
and microvascular complications of type 2 diabetes (UKPDS 35): prospective 
observational study. BMJ. 2000;321:405-12.
10.
Drucker, DJ. The ascending GLP-1 road from clinical safety to reduction of 
cardiovascular complications. Diabetes. 2018; 67(9):1710-19. 
11.
Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon-like peptide-1 
receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16(1):6.
12.
Victoza [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2016.
13.
Ozempic [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2017.
14.
Trulicity [package Insert]. Indianapolis, IN: Eli Lilly and Co; 2017. 
15.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009; 50(9):604-12.


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Protocol C3421012
Final Protocol, 13 October 2020
PFIZER CONFIDENTIAL
Page 92
16.
Wang Y, Moss J, Thisted R. Predictors of body surface area. J Clin Anesth. 1992; 
4(1):4-10.
17.
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 
2004;42Suppl 1): S15-S135.
18.
Nolin, TD, Naud, J, Leblond, FA, et al. Emerging evidence of the impact of kidney 
disease on drug metabolism and transport. Clin Pharmacol Ther. 2008; 83(6): 898–903.
19.
Yeung, CK, Shen, DD, Thummel, KE, et al.. Effects of chronic kidney disease and 
uremia on hepatic drug metabolism and transport. Kidney Int. 2014; 85(3): 522–8.
20.
Tan, ML, Yoshida, K, Zhao, P, et al. Effect of chronic kidney disease on nonrenal 
elimination pathways: a systematic assessment of CYP1A2, CYP2C8, CYP2C9, 
CYP2C19, and OATP. Clin Pharmacol Ther. 2018; 103(5):854-67.
21.
US Food and Drug Administration. Guidance for industry: pharmacokinetics in patients 
with impaired renal function - study design, data analysis, and impact on dosing and 
labeling. Available from: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/pharmacokinetics-patients-impaired-renal-function-study-design-
data-analysis-and-impact-dosing-and. Published: March 2010. Accessed: 30 Jul 2020.
22.
ClinicalTrials.gov. Identifier NCT03036150: A study to evaluate the effect of 
dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic 
kidney disease (Dapa-CKD). Available 
from:https://clinicaltrials.gov/ct2/show/NCT03036150. Jan 2017. Accessed: 30 Jul
2020.
23.
ClinicalTrials.gov. Identifier NCT03594110: EMPA-KIDNEY (the study of heart and 
kidney protection with empagliflozin) Available from: 
https://clinicaltrials.gov/ct2/show/NCT03594110. July 2018. Accessed: 30 Jul 2020.
24.
Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 
diabetes and nephropathy. N Engl J Med. 2019; 380(24):2295-306.
25.
Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update. 
Clin Transl Med 2016;5(1):23-37.
26.
Centers for Disease Control and Prevention. Interim Clinical Guidance for Management 
of Patients with Confirmed Coronavirus Disease (COVID-19). 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-
patients.html. Updated: 10 September 2020. Accessed: 21 September 2020.


PF-06882961
Protocol C3421012
Final Protocol, 13 October 2020
PFIZER CONFIDENTIAL
Page 93
27.
Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2 
(COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html.
Updated: 18 September 2020. Accessed: 22 September 2020.
28.
European Medicines Agency. Guideline on the evaluation of the pharmacokinetics of 
medicinal products in patients with decreased renal function. Procedue No. 
EMA/CHMP/83874/2014. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-
pharmacokinetics-medicinal-products-patients-decreased-renal-function_en.pdf. 
Published: 01 July 2016. Accessed: 30 Jul 2020.

SAP_001.pdf: 
Protocol C3421012 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3421012
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL GROUP STUDY TO 
EVALUATE THE PHARMACOKINETICS OF PF-06882961 IN PARTICIPANTS 
WITH TYPE 2 DIABETES MELLITUS WITH VARYING DEGREES OF RENAL 
IMPAIRMENT RELATIVE TO PARTICIPANTS WITHOUT RENAL 
IMPAIRMENT
Statistical Analysis Plan 
(SAP)
Version:
1.0
Date:
10 DEC 2020
NOTE: Italicized text within this document has been taken verbatim from the Protocol.


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.2. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint(s) ..................................................................................................8
3.2. Secondary Endpoint(s) ..............................................................................................9
3.2.1. Additional Plasma PK parameters of PF-06882961.....................................9
3.2.2. Safety Endpoints.........................................................................................10
3.3. Other Endpoint(s)....................................................................................................11
3.3.1. Urine PK Parameters: CLr, Ae24, Ae24% ....................................................11
3.3.2. Coproporphyrin I (CP-I) concentration ......................................................11
3.4. Baseline Variables...................................................................................................11
3.5. Safety Endpoints .....................................................................................................11
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................11
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................12
5.1. Hypotheses and Decision Rules ..............................................................................12
5.2. General Methods .....................................................................................................13
5.2.1. Analyses for Continuous Endpoints ...........................................................13
5.2.2. Analyses for Categorical Endpoints ...........................................................13
5.2.3. One-way Analysis of Variance (ANOVA).................................................13
5.2.4. Linear Regression .......................................................................................13
5.3. Methods to Manage Missing Data. .........................................................................14
5.3.1. Plasma Pharmacokinetic Parameters ..........................................................14
6. ANALYSES AND SUMMARIES ......................................................................................15
6.1. Primary Endpoint(s) ................................................................................................15
6.1.1. Cmax, AUCinf, AUClast, fu for PF-06882961................................................15
6.1.1.1. Main Analysis ...........................................................................15
6.2. Secondary Endpoint(s) ............................................................................................16
6.2.1. Additional Plasma PK parameters of PF-06882961...................................16


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
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6.2.2. Safety Endpoints.........................................................................................17
6.2.2.1. Adverse Events..........................................................................17
6.2.2.2. Laboratory Data.........................................................................17
6.2.2.3. Vital Signs.................................................................................17
6.2.2.4. ECG...........................................................................................18
6.3. Other Endpoint(s)....................................................................................................18
6.3.1. Urine PK Parameters: CLr, Ae24, Ae24% ....................................................18
6.3.2. CP-I concentration......................................................................................18
6.3.3. Banked Biospecimens.................................................................................19
6.4. Subset Analyses.......................................................................................................19
6.5. Baseline and Other Summaries and Analyses.........................................................19
6.5.1. Baseline Summaries....................................................................................19
6.5.2. Study Conduct and Participant Disposition................................................19
6.5.3. Concomitant Medications and Nondrug Treatments..................................19
6.5.4. Other Screening Data..................................................................................19
6.6. Safety Summaries and Analyses .............................................................................19
7. INTERIM ANALYSES.......................................................................................................20
7.1. Introduction .............................................................................................................20
7.2. Interim Analyses and Summaries............................................................................20
8. REFERENCES ....................................................................................................................20
9. APPENDICES .....................................................................................................................21
LIST OF TABLES
Table 1. Summary of Changes...................................................................................................5
Table 2. Study Groups ...............................................................................................................7
Table 3. Summary of Plasma PK Parameters of PF-06882961 to be calculated.......................8
Table 4. Summary of Additional Plasma PK parameters of PF-06882961 to be 
calculated ....................................................................................................9
Table 5. Summary of Plasma PK parameters of Unbound PF-06882961 to be calculated .......9
Table 6. Summary of Urine PK Parameters to be calculated ..................................................11
Table 7. Summary statistics to be produced for Plasma PK Parameters of PF-06882961......15
Table 8. Summary statistics to be produced for Additional Plasma PK Parameters of 
PF-06882961.............................................................................................16


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 4
Table 9. Summary statistics to be produced for Urine PK Parameters....................................18
LIST OF FIGURES
Figure 1. Study Schema.............................................................................................................8
APPENDICES
Appendix 1. Statistical Methodology Details..........................................................................21
Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....22
Appendix 3. List of Abbreviations...........................................................................................23


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 5
1. VERSION HISTORY
Table 1. Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1.0
10 Dec 2020
Original 
13 Oct 2020
N/A
N/A
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3421012. This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Primary: 
Primary: 

To compare the PK of PF-06882961 following 
administration of a single oral dose in adult 
participants with T2DM and varying degrees 
of renal impairment relative to T2DM 
participants without renal impairment.

Plasma: Cmax, AUCinf, AUClast, fu, as data permit
Secondary: 
Secondary: 

To compare additional PK parameters of 
PF-06882961 following administration of a 
single oral dose in adult participants with 
T2DM and varying degrees of renal 
impairment relative to T2DM participants 
without renal impairment.

Plasma: Cmax,u, AUCinf,u, AUClast,u, CL/F, CLu/F, 
Vz/F, Vz,u/F, Tmax, t1/2, as data permit

To evaluate the safety and tolerability of a 
single oral dose of PF-06882961 in T2DM 
participants with varying degrees of renal 
impairment and in participants with normal 
renal function.

Incidence and severity of treatment-emergent 
AEs, clinical laboratory abnormalities, vital 
signs (blood pressure and pulse rate), ECG 
parameters (heart rate, QT, QTcF, PR and QRS 
intervals).


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
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Tertiary/Exploratory: 
Tertiary/Exploratory: 

To compare urine PK parameters of 
PF-06882961 following administration of a 
single oral dose in adult participants with 
T2DM and varying degrees of renal 
impairment relative to T2DM participants 
without renal impairment.

Urine: CLr, Ae24, Ae24%

To compare the PK of PF-06882961 following 
administration of a single oral dose in adult 
participants with T2DM and normal renal 
function relative to healthy participants with 
normal renal function.

Plasma: Cmax, Tmax, AUCinf, AUClast, CL/F, Vz/F, 
t1/2, fu, as data permit

Urine: CLr, Ae24, Ae24%

To explore the relationship of markers of 
innate OATP activity in adult participants with 
T2DM and varying degrees of renal 
impairment relative to participants with 
normal renal function.

CP-I concentration

To enable exploratory research through 
collection of banked biospecimens, unless 
prohibited by local regulations or ethics 
committee decision.

Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study).
There are no estimands for this study.
2.2. Study Design
This Phase 1, open-label, single-dose, parallel group, multi-site study will assess the effect of
varying degrees of renal impairment on the PK, safety and tolerability of PF-06882961 after
a single oral dose of 20 mg administered in a fed state.
Approximately 40 participants will be enrolled in the study. Refer to Table 2 below for
details of study groups. Due to the potential difficulty in recruiting T2DM patients with
estimated glomerular filtration rate (eGFR) <30 mL/min, the number of participants to be
enrolled in this group is flexible (6 to 8 participants).
This study will permit enrollment of 2-4 participants on dialysis, as part of the severe renal
impairment group, to assist in recruitment of patients with more advanced renal impairment
and to permit assessment of the PK of PF-06882961 in participants with the highest degree
of renal impairment. Since PF-06882961 has a large unbound non-renal clearance and a
large unbound volume of distribution, dialysis is not expected to significantly impact the
clearance of PF-06882961 and therefore the dialysis clearance of PF-06882961 will not be
characterized in this study. Thus, Day 1, per the schedule of activities, will occur in dialysis
patients on a day in which dialysis is not administered.


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
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Page 7
Table 2. Study Groups
Group
Disease State
Renal Impairment
No.of 
Participants
eGFRa
(mL/min)
1
None (healthy)
None (Normal Renal 
Function)
8
≥90
2
T2DM
None (Normal Renal 
Function)
8
≥90
3
T2DM
Mild
8
60-89
4
T2DM
Moderate
8
30-59
5
T2DM
Severe
6-8b
<30
a. Estimate of eGFR based on the SCr-based CKD-Epi equation. The eGFR will be multiplied by each participant’s 
ratio of BSA/1.73 to obtain the BSA-unnormalized eGFR value. The average of the 2 unnormalized eGFR values 
from S1 and S2 will be used for study enrollment and group placement. Note: participants on dialysis will be placed 
in Group 5 regardless of unnormalized eGFR from S1 and S2.
b. This includes approximately 4 participants not on dialysis and 2-4 participants on dialysis.
Screening will occur within 28 days of the first dose of study intervention on Day 1. All
participants will provide informed consent and undergo Screening evaluations to determine
their eligibility. All participants who are not on dialysis must have stable renal function to
enter the study, defined as ≤25% difference between 2 measurements of BSA-unnormalized
eGFR obtained from the 2 screening visits, S1 and S2 as listed in the schedule of activities.
As indicated in Table 2, the estimate of eGFR will be based on the SCr-based CKD-Epi 
equation, defined in Section 3.2.1.
Participants with T2DM and varying degrees of renal impairment (Groups 3-5) will be
recruited and enrolled first. An average value for age and weight for these groups will be
determined and participants in Groups 1-2 will be recruited to match the average
demographics (at a minimum, age and weight, and as much as practically possible gender)
across the pooled Groups 3-5. Recruitment for participants in Groups 1-2 may start when
approximately 75% of total participants across Groups 3-5 (ie, approximately 17-18) have
been dosed. Approval from the sponsor must be garnered before proceeding with dosing
participants in Groups 1 and 2.
Refer to Figure 1 for study schema.
Participants who discontinue from the study before completing all assessments may be
replaced at the discretion of the investigator and sponsor.


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
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Page 8
Figure 1. Study Schema
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
Blood samples for PK analysis of PF-06882961 will be collected according to the Schedule 
of Activities given in the protocol.
PK parameters will be calculated (if possible) from the concentration-time data using 
standard non-compartmental methods.
3.1. Primary Endpoint(s)

PF-06882961 Plasma Pharmacokinetic parameters: Cmax, AUCinf, AUClast, fu, as data 
permit.
The plasma PK parameters in Table 3 will be determined using standard non-compartmental 
methods:
Table 3. Summary of Plasma PK Parameters of PF-06882961 to be calculated
Parameter
Analysis
Scale
PF-06882961 20mg
Cmax
ln
A, D
AUCinf*
ln
A, D
AUClast
ln
A, D
fu
ln
A, D


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
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Page 9
*=if data permits. Abbreviations: A = analyzed using a statistical model; D=displayed with 
descriptive statistics as outlined in  Table 7 in Section 6.1.1.1; ln=natural-log transformed; 
R=raw (untransformed).
3.2. Secondary Endpoint(s)
3.2.1. Additional Plasma PK parameters of PF-06882961

Cmax,u, AUCinf,u, AUClast,u, CL/F, CLu/F, Vz/F, Vz,u/F, Tmax, t1/2, as data permit
The plasma PK parameters for PF-06882961 in Table 4 will be determined using standard non-
compartmental methods:
Table 4. Summary of Additional Plasma PK parameters of PF-06882961 to be
calculated
Parameter
Analysis
Scale
PF-06882961 20mg
CL/F*
ln
A, D
Vz/F*
ln
D
Tmax
R
D
t1/2*
R
D
*=if data permits. Abbreviations: A = analyzed using a statistical model; D=displayed with 
descriptive statistics as outlined in Table 8 in Section 6.2.1; ln=natural-log transformed;
R=raw (untransformed).
The plasma PK parameters for unbound PF-06882961 will be calculated as described in 
Table 5:
Table 5. Summary of Plasma PK parameters of Unbound PF-06882961 to be calculated
Parameter
Method of Determination
Analysis
Scale
PF-06882961 20 mg
AUClast,u
fu × AUClast
ln
D
AUCinf,u*
fu × AUCinf
ln
D
Cmax,u
fu × Cmax
ln
D
CLu/F*
Dose/(AUCinf,u)
ln
A, D
Vz,u/F*
Dose/(AUCinf,u × kel)
ln
D
*=if data permits. Abbreviations: A = analyzed using a statistical model, D=displayed with 
descriptive statistics as outlined in Table 8 in Section 6.2.1; ln=natural-log transformed , 
R=raw (untransformed).
For the linear regression analysis assessing the relationship between CL/F, CLu/F and CLr
and eGFR, the primary equation for eGFR will be SCr-based:
CKD-Epi equation(1): eGFR (mL/min/1.73m2) = 141 × min (SCr /κ, 1)α × max(SCr /κ, 1)-1.209
× 0.993Age × 1.018 [if female] × 1.159 [if Black]
where: 


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 10

SCr is serum creatinine in mg/dL (based on the standardized assay)

κ is 0.7 for females and 0.9 for males

α is -0.329 for females and -0.411 for males

min indicates the minimum of SCr /κ or 1

max indicates the maximum of SCr /κ or 1

Age is in years
Additional outputs will also be produced using the following alternative equations to 
calculate eGFR:
Cockcroft-Gault (CG)(2): eGFR (ml/min/1.73 m2) =[(140-Age) × Weight × 0.85 if female]/(72
× SCr)
Modification of Diet in Renal Disease (MDRD)(3): eGFR (ml/min/1.73 m2) = 175 ×
(SCr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if black)
where:

Age is in years

Weight is in kg

SCr is in mg/dl (based on the standardized assay)
3.2.2. Safety Endpoints

Incidence and severity of treatment-emergent AEs, clinical laboratory abnormalities, 
vital signs (blood pressure and pulse rate), 12-lead electrocardiogram (ECG) 
parameters (heart rate, QT, QTcF, PR and QRS intervals).
An adverse event is considered treatment emergent (TEAE) relative to a given treatment if: 

the event starts during the effective duration of treatment (i.e. starting on or after the 
dose of PF-06882961 but before this dose plus lag time) 
The effective duration of treatment is determined by the lag time. Any event occurring within 
the lag time is attributed to the corresponding treatment. The lag time is defined by the Pfizer 
Standard of 365 days post last dose of IP.
A 3-tier approach for summarizing AEs will not be used due to the low number of 
participants planned to be recruited. 
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

adverse events,

laboratory data,

vital signs data,

ECG results.


Protocol C3421012 (PF-06882961) Statistical Analysis Plan
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For laboratory, vital signs and ECG data, baseline will be defined as the last pre-dose 
measurement on Day 1 or before.
3.3. Other Endpoint(s)
3.3.1. Urine PK Parameters: CLr, Ae24, Ae24%
Urine samples for PK analysis will be collected according to the Schedule of Activities given in 
the protocol. The urine PK parameters in Table 6 will be determined:
Table 6. Summary of Urine PK Parameters to be calculated
Parameter
Analysis 
Scale
PF-06882961 20mg
Ae24
ln
D
Ae24%
ln
D
CLr
ln
A, D
Abbreviations: A = analyzed using a statistical model; D=displayed with descriptive statistics 
as outlined in Section 6.3.1; R=raw (untransformed); ln=natural-log transformed
3.3.2. Coproporphyrin I (CP-I) concentration
Plasma CP-I concentrations will be collected prior to dosing on Day 1 only.
3.4. Baseline Variables
Not applicable.
3.5. Safety Endpoints
See Section 3.2.2.
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 releasing the database and classifications will 
be documented per standard operating procedures.


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Population
Description
Enrolled 
All participants who sign the ICD
Evaluable
All participants assigned to IP and who take at least 1 dose 
of IP. 
Safety
All participants assigned to IP and who take at least 1 dose 
of IP.  
PK Concentration Set
The PK concentration population is defined as all 
participants who received at least 1 dose of PF-06882961 
and in whom at least 1 plasma concentration value is 
reported.
PK Parameter Set
The PK parameter analysis population is defined as all
participants who received at least 1 dose of PF-06882961 
and have at least 1 of the plasma PK parameters of interest 
calculated.
Urine PK Concentration 
Set
The urine PK concentration population is defined as all 
participants who received at least 1 dose of PF-06882961 and 
in whom at least 1 urine concentration value is reported.
Urine PK Parameter Set
The urine PK parameter analysis population is defined as all
participants who received at least 1 dose of PF-06882961 and 
have at least 1 of the urine PK parameters of interest 
calculated.
CP-I Concentration Set
The CP-I concentration population is defined as all 
participants who received at least 1 dose of PF-06882961 and 
in whom at least 1 CP-I concentration value is reported.
5. GENERAL METHODOLOGY AND CONVENTIONS
The following group labels (or similar) will be used for tables and figures unless otherwise 
stated:
Group
Description of Group
Label
1
Healthy and normal renal function
Healthy Normal
2
T2DM Normal renal function
T2DM Normal
3
T2DM Mild renal impairment
T2DM Mild RI
4
T2DM Moderate renal impairment
T2DM Moderate RI
5
T2DM Severe renal impairment
T2DM Severe RI
5.1. Hypotheses and Decision Rules
There is no statistical hypothesis testing planned for this study and no statistical decision 
rules will be applied.


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5.2. General Methods
5.2.1. Analyses for Continuous Endpoints
Unless otherwise stated, continuous variables will be presented using summary statistics: 
number of observations, arithmetic mean, standard deviation, median, minimum and 
maximum values.
5.2.2. Analyses for Categorical Endpoints
Categorical variables will be presented using summary statistics: number of observations and 
percentages.
5.2.3. One-way Analysis of Variance (ANOVA)
The ANOVA model will include all groups (i.e. both T2DM and healthy participants from the 
5 groups) as a factor.
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will 
be obtained from the model. The adjusted mean differences and 90% CIs for the differences 
will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and corresponding 90% CIs. Example SAS code is given in Appendix 1.
Potential differences in demographic characteristics between healthy (Group 1), T2DM 
normal (Group 2) and T2DM renal impairment function participants (Groups 3, 4, 5) and 
their impact on study conclusions will be explored based on consideration of the covariates 
weight, gender and age. This will be implemented by utilizing a stepwise linear regression 
approach, with model selection using Akaike’s Information Criterion [AIC]). All the above 
covariates and factors will be considered (group as a factor will be restricted to always 
remain in the model) and if the final model selected includes at least one of these additional 
covariates/factors, this additional model will be reported in addition to the main ANOVA 
model above. Example SAS code is given in Appendix 1.
5.2.4. Linear Regression
Linear regression analysis will include eGFR as the explanatory variable, based on eGFR 
values obtained on Day 1 and will include only participants from the T2DM groups (Groups 
2 to 5). Estimates of the slope and intercept, together with their precision (90% CIs), and the 
coefficient of determination will be obtained from the model. Example SAS code is given in 
Appendix 1.
Additionally, as an exploratory analysis, the effect of weight, gender and age will be
explored as additional covariate/factors in the models, as appropriate. This will be 
implemented by utilizing a stepwise linear regression approach, with model selection using 
Akaike’s Information Criterion [AIC]). All the above covariates and factors will be
considered (eGFR will be restricted to always remain in the model) and if the final model 
selected includes at least one of these additional covariates/factors, this additional model will 
be reported in addition to the main linear regression above. Example SAS code is given in 
Appendix 1.


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5.3. Methods to Manage Missing Data.
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
In all PK data presentations (except listings) and CP-I, concentrations below the limit of 
quantification (BLQ) will be set to zero. In listings BLQ values will be reported as “<LLQ”, 
where LLQ will be replaced with the value for the lower limit of quantification.
In PK summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if one of the following cases is true:
1. A concentration has been collected as ND (i.e. not done) or NS (i.e. no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
Participants who experience events that may affect their PK profile (e.g. lack of compliance 
with dosing or vomiting) may be excluded from the PK analysis.  At the discretion of the 
pharmacokineticist, a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.3.1. Plasma Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of plasma PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (i.e. not calculated). (Note that NC values will not be generated beyond 
the day that a participant discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular group/analyte with ≥3 evaluable measurements. For 
statistical analyses (i.e. linear regression), PK parameters coded as NC will also be set to 
missing; and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
If an individual participant has a known biased estimate of a plasma PK parameter (due for 
example to an unexpected event such as vomiting before all the compound is adequately 
absorbed in the body – within ~2 times the median Tmax after the dose of PF-06882961), 
this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.


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6. ANALYSES AND SUMMARIES
Unless otherwise stated, all analyses, summaries and listings will be produced by group (as 
outlined in Section 5), which would include all 5 groups in the same analysis/output.
6.1. Primary Endpoint(s)
6.1.1. Cmax, AUCinf, AUClast, fu for PF-06882961
6.1.1.1. Main Analysis
Cmax, AUCinf (if data permit), AUClast and fu will be listed, summarized descriptively and 
analyzed by group for participants in the PK parameter set (as defined in Section 4). Missing 
values will be handled as detailed in Section 5.3.1.
Linear regression will be used to characterize the potential relationship between appropriate 
PK parameters (CL/F, CLu/F and CLr) for PF-06882961 and renal function (eGFR as 
obtained on Day 1 and defined by the SCr-based CKD-Epi equation in Section 3.2.1), as 
described in Section 5.2.4, where the PK parameter will be the dependent variable in the 
separate models. 
Plots of PK parameters (CL/F, CLu/F and CLr) for PF-06882961 versus renal function 
(eGFR as obtained on Day 1 and defined by the SCr-based CKD-Epi equation in Section 
3.2.1) will be constructed. A regression line and 90% confidence region for the PK 
parameters and eGFR will be included if appropriate. Vertical lines for the renal function 
group cut-off values will also be presented on the plots. Different symbols will be used to 
identify participants from different renal function groups.
For exploratory purposes, these analyses and figures will additionally be carried out 
separately for each of the alternative two methods for calculating eGFR, as defined in 
Section 3.2.1.
A one-way analysis of variance (ANOVA) described in Section 5.2.3, that includes all 5 
groups in the same model, will be used to compare the natural log transformed of Cmax, 
AUCinf, AUClast and fu of PF-06882961 separately, for each of the T2DM renal impairment 
groups (Test, Groups 3, 4, 5) to the T2DM normal renal function group (Reference, 
Group 2). Also, the T2DM normal renal function group (Test, Group 2) will be compared to 
the healthy normal renal group (Reference, Group 1). 
For summary statistics and median or mean plots by sampling time, the nominal PK 
sampling time will be used. For individual participant plots by time, the actual PK sampling 
time will be used. The plasma PK parameters of PF-06882961 for each group will be 
summarized as specified in Table 7 below.
Table 7. Summary statistics to be produced for Plasma PK Parameters of PF-06882961
Parameter
Summary Statistics


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Cmax, AUCinf (if data permit), 
AUClast and fu
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%.
Supporting data from the estimation of t1/2 will be listed by group: terminal phase rate 
constant (kel); goodness of fit statistic from the log-linear regression (r2); the percent of 
AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of time points 
used in the estimation of kel.  This data may be included in the clinical study report.
The following plot will be presented:

Box and whisker plots for individual PK parameters (AUCinf, AUClast, Cmax and fu) 
will be constructed by group and overlaid with geometric means.
6.2. Secondary Endpoint(s)
6.2.1. Additional Plasma PK parameters of PF-06882961
Cmax,u, AUCinf,u, AUClast,u, CL/F, CLu/F, Vz/F, Vz,u/F, Tmax, t1/2 will be listed, summarized 
descriptively and analyzed by group in the PK parameter set (as defined in Section 4).
Missing values will be handled as detailed in Section 5.3.
The additional plasma PK parameters of PF-06882961 for each group will be summarized as 
specified in Table 8 below.
Table 8. Summary statistics to be produced for Additional Plasma PK Parameters of 
PF-06882961
Parameter
Summary Statistics
Cmax,u, AUCinf,u, AUClast,u, 
CL/F, CLu/F, Vz/F, Vz,u/F
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%.
Tmax
N, median, minimum, maximum. 
t½
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum. 
The following plot will be presented:

Box and whisker plots for individual PK parameters (AUCinf,u, AUClast,u and Cmax,u) 
will be constructed by group and overlaid with geometric means.
The following summaries will additionally be presented for the plasma concentration data of 
PF-06882961 using the PK Concentration Set (as defined in Section 4):

a listing of all concentrations sorted by participant ID and nominal time post-dose for 
each group. The concentration listing will also include the actual times.  Deviations 
from the nominal time will be given in a separate listing.


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
a summary of concentrations for each nominal time post-dose (produced separately 
for each group), where the set of statistics will include n, mean, median, standard 
deviation, coefficient of variation (cv), minimum, maximum and the number of 
concentrations above the lower limit of quantification.

median concentration time plots (on both linear and semi-log scales) against nominal 
time post-dose by group in the same plot. 

individual concentration time plots by group (on both linear and semi-log scales) 
against actual time post-dose (there will be separate spaghetti plots for each group, 
with a line for each participant, per scale). 
The nominal PK sampling time will be used for summary statistics and relevant median 
plots, whereas for individual participant plots by time, the actual PK sampling time will be 
used.
6.2.2. Safety Endpoints
Any clinical laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern 
will be described.
No formal analyses are planned for safety data.
The safety endpoints detailed in Section 3.2.2 will be listed and summarized in accordance 
with sponsor reporting standards based on the safety population (as defined in Section 4), 
with more details provided below.
6.2.2.1. Adverse Events
Adverse events will be summarised by group and overall, in accordance with sponsor 
reporting standards using the safety population defined in Section 4.
If applicable, subject discontinuations due to adverse events will be detailed and 
summarized.  
6.2.2.2. Laboratory Data
Laboratory data will be listed and summarized by group and overall, in accordance with the 
sponsor reporting standards using the safety population defined in Section 4. Baseline is as 
defined in Section 3.2.2.
6.2.2.3. Vital Signs
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarised by group, according to sponsor reporting standards using 
the safety population defined in Section 4. Baseline is as defined in Section 3.2.2.
Maximum and minimum absolute values and maximum changes from baseline for supine 
vital signs will also be summarised descriptively by group using categories as defined in 
Appendix 2. 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 


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categorical summaries. All values meeting the criteria of potential clinical concern will be 
listed. 
6.2.2.4. ECG
Absolute values and changes from baseline in QT interval, heart rate, QTcF interval, PR 
interval and QRS interval will be summarised by group using sponsor reporting standards 
using the safety population defined in Section 4. Tables will be paged by parameter. Baseline 
is as defined in Section 3.2.2.
Maximum absolute values and changes from baseline for QTcF interval, PR interval and 
QRS interval will also be summarised descriptively by group using categories as defined in 
Appendix 2. Numbers and percentages of participants meeting the categorical criteria will be 
provided. All planned and unplanned post dose timepoints will be counted in these 
categorical summaries. All values meeting the criteria of potential clinical concern will be 
listed.  
6.3. Other Endpoint(s)
6.3.1. Urine PK Parameters: CLr, Ae24, Ae24%
Urine CLr, Ae24, Ae24% will be listed and summarized descriptively by group for participants 
in the Urine PK parameter set (as defined in Section 4). Missing values will be handled as 
detailed in Section 5.3.
The urine PK parameters of PF-06882961 for each group will be summarized as specified in 
Table 9 below.
Table 9. Summary statistics to be produced for Urine PK Parameters
Parameter
Summary Statistics
CLr, Ae24, Ae24%
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%.
The following summaries will additionally be presented:

a listing of all urine concentrations over each time interval sorted by group, subject 
ID and nominal collection duration postdose.

listing of all urine PK parameters sorted by group, subject ID and nominal collection 
duration postdose.
6.3.2. CP-I concentration
CP-I will be summarized descriptively by group and overall for participants in the CP-I 
concentration set (as defined in Section 4). Missing values will be handled as detailed in 
Section 5.3.


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Linear regression will be used to characterize the potential relationship between appropriate 
PK parameters (AUCinf [as data permit], AUCinf,u [as data permit], AUClast, AUClast,u, CL/F 
and CLu/F) for PF-06882961 versus innate OATP activity (as measured by CP-I on Day 1) as 
described in Section 5.2.4, where the PK parameter will be the dependent variable in the 
separate models and CP-I will be the explanatory variable. This will be applied to 
participants from the T2DM groups only.
Plots of PK parameters vs. CP-I will be constructed separately for each PK parameter. A 
regression line and 90% confidence region for the PK parameters will be included in the 
plots and different symbols will be used to identify participants from different renal function 
groups.
6.4. Subset Analyses
No subset analyses will be performed.
6.5. Baseline and Other Summaries and Analyses
Data will be reported in accordance with the sponsor reporting standards.
6.5.1. Baseline Summaries
Demographics data (age, biological sex, race, ethnicity, weight, body mass index and height) 
will be summarized by group and overall, as outlined in Sections 5.2.1 and 5.2.2 as 
applicable.
6.5.2. Study Conduct and Participant Disposition
Participant evaluation groups will show end of study participant disposition by group and 
will show which participants were analyzed for pharmacokinetics (plasma and urine, 
separately), PD and safety, which may not be produced in one table. Frequency counts and 
percentages will be supplied for participant discontinuation(s) by group.
6.5.3. Concomitant Medications and Nondrug Treatments
All prior and concomitant medication(s) as well as non-drug treatment(s) will be provided in 
listings.
6.5.4. Other Screening Data
These data will not be recorded in the study database, and therefore will not be listed.
6.6. Safety Summaries and Analyses
See Section 6.2.2.
CCI


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7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study. As this is an open-label 
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development.
7.2. Interim Analyses and Summaries
Not applicable.
8. REFERENCES
(1) Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009; 50(9):604-12.
(2) Cockcroft D.W. and Gault M.H. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976; 16(1):31-41.
(3) Levey AS, Coresh J, Greene T, et al. Expressing the Modification of Diet in Renal 
Disease Study equation for estimating glomerular filtration rate with standardized serum 
creatinine values. Clin Chem. 2007; 53(4):766-72.


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9. APPENDICES
Appendix 1. Statistical Methodology Details
An example of SAS code for ANOVA:
proc mixed data = tab.pk;
class group;
model l&var = group /residual;
lsmeans group/diff cl alpha=0.1;
ods output lsmeans = lsmeans&var;
   
ods output diffs=diffs&var;
run;
An example of SAS code for the PROC REG code for linear regression analyses:
proc reg data=tab.pk;
model l&var=clcr/clb alpha=0.1;
ods output ParameterEstimates = param&var;
ods output FitStatistics = fit&var;
ods output ANOVA = reg&var;
run;
An example of SAS code for stepwise regression with model selection using AIC:
proc glmselect data=tab.pk analysis plot=ALL;
     class gender;
     model pk_p = eGFR_cg age gender weight/ selection=stepwise (select = AIC stop = AIC) 
include=1 hierarchy=none showpvalues;
run;


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Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Absolute value of 
QTcF (msec)
450 and 480
>480 and 500
>500
Increase from baseline in 
QTcF (msec)
30 and 60
>60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from baseline
Baseline >200 
and max. ≥25% 
increase
Baseline ≤200 and 
max. ≥50% increase
QRS (ms)
max. ≥140
QRS (ms) increase 
from baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) change 
from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) change 
from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120
Measurements that fulfill these criteria are to be listed in the report.


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Appendix 3. List of Abbreviations
Abbreviation
Term
AE
adverse event
Ae
Amount excreted
ANOVA
analysis of variance
AUC
area under the curve
BLQ
below the limit of quantitation
BP
blood pressure
CG
Cockcroft-Gault 
CI
confidence interval
CL
Clearance
CL/F
Apparent total body clearance
Cmax
maximum observed concentration
CP-I
Coproporphyrin I
CSR
clinical study report
CV
Coefficient of variation
ECG
Electrocardiogram
ICD
informed consent document
IP
Investigational product
LLQ
Lower limit of quantification
Ln
Natural log
MAR
missing at random
MDRD
Modification of Diet in Renal Disease 
N/A
not applicable
NC
not calculated
ND
not done
NS
so sample
OATP
organic-anion-transporting polypeptide
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
SAP
statistical analysis plan
Tmax
Time to maximum observed concentration
T2DM
Type 2 Diabetis Mellitus
t1/2
Half life
Vz/F
Apparent volume of distribution