Clinical trial NCT04604496
Conditions: Hepatic Impairment Healthy Volunteers
Sponsor: Pfizer
Start date: 2020-12-30; Completion date: 2022-01-10
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The current study is proposed to evaluate whether there is any clinically meaningful effect of hepatic impairment on the plasma Pharmacokinetic (PK) of PF-06882961

Detailed description:

Arms: arm 1: This arm includes participants who will receive an oral dose of PF-06882961 20 milligrams (mg) on Day 1 arm 2: This arm includes participants who will receive an oral dose of PF-06882961 20 mg on Day 1 arm 3: This arm includes participants who will receive an oral dose of PF-06882961 20 mg on Day 1 arm 4: This arm includes participants who will receive an oral dose of PF-06882961 20 mg on Day 1
Interventions: intervention 1: PF-06882961 20MG
Intervention descriptions: intervention 1: PF-06882961 in 20 mg oral tablet will be administered on Day 1

Protocol documents:
Prot_000.pdf: 
PF-06882961 
Protocol C3421014
Final Protocol, 05 October 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, PARALLEL
COHORT STUDY TO COMPARE THE PHARMACOKINETICS OF PF-06882961
IN ADULT PARTICIPANTS WITH VARYING DEGREES OF HEPATIC
IMPAIRMENT RELATIVE TO PARTICIPANTS WITHOUT HEPATIC
IMPAIRMENT
Study Intervention Number:
PF-06882961
Study Intervention Name:
Not Applicable
US IND Number:
EudraCT Number:
Not Applicable
Protocol Number:
C3421014
Phase:
1
Short Title: Pharmacokinetic Study of PF-06882961 in Participants With and 
Without Varying Degrees of Hepatic 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 Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original Protocol
05 October 2020 
N/A


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................11
1.3. Schedule of Activities .............................................................................................12
2. INTRODUCTION ...............................................................................................................14
2.1. Study Rationale .......................................................................................................14
2.2. Background .............................................................................................................14
2.2.1. Nonclinical Overview.................................................................................15
2.2.1.1. Nonclinical Pharmacology........................................................15
2.2.1.3. Nonclinical Safety.....................................................................16
2.2.2. Clinical Overview.......................................................................................16
2.2.2.1. Clinical Safety...........................................................................17
2.2.2.2. Clinical Pharmacokinetics.........................................................17
2.3. Benefit/Risk Assessment.........................................................................................18
2.3.1. Risk Assessment.........................................................................................18
2.3.2. Benefit Assessment.....................................................................................20
2.3.3. Overall Benefit/Risk Conclusion................................................................20
3. OBJECTIVES AND ENDPOINTS.....................................................................................21
4. STUDY DESIGN.................................................................................................................21
4.1. Overall Design.........................................................................................................21
4.2. Scientific Rationale for Study Design.....................................................................22
4.3. Justification for Dose ..............................................................................................24
4.4. End of Study Definition ..........................................................................................24
5. STUDY POPULATION......................................................................................................24
5.1. Inclusion Criteria.....................................................................................................25
5.1.1. Participants in All Cohorts..........................................................................25
5.1.2. Additional Inclusion Criteria for Participants without Hepatic 
Impairment (Cohort 1 Only) ............................................................................25
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5.1.3. Additional Inclusion Criteria for Participants with Impaired Hepatic 
Function (Cohorts 2, 3, and 4 Only) ................................................................26
5.2. Exclusion Criteria....................................................................................................27
5.2.1. Participants in All Cohorts..........................................................................27
5.2.2. Additional Exclusion Criteria for Participants without Hepatic
Impairment (Cohort 1 Only) ............................................................................29
5.2.3. Additional Exclusion Criteria for Participants with Impaired Hepatic 
Function (Cohorts 2, 3, and 4 Only) ................................................................30
5.2.4. 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 .......................................................................................................33
5.3.4. Contraception..............................................................................................33
5.4. Screen Failures ........................................................................................................33
6. STUDY INTERVENTION..................................................................................................33
6.1. Study Intervention(s) Administered........................................................................34
6.1.1. Administration............................................................................................34
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 Study Intervention ................................................................35
6.4. Study Intervention Compliance...............................................................................36
6.5. Concomitant Therapy..............................................................................................36
6.5.1. Participants without Hepatic Impairment (Cohort 1, Only) .......................36
6.5.2. Participants with Impaired Hepatic Function (Cohorts 2, 3, and 4) ...........37
6.5.3. Rescue Medicine.........................................................................................37
6.6. Dose Modification...................................................................................................37
6.7. Intervention After the End of the Study..................................................................37
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................37
7.1. Discontinuation of Study Intervention ....................................................................37
7.2. Participant Discontinuation/Withdrawal From the Study.......................................37


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7.2.1. Withdrawal of Consent...............................................................................38
7.3. Lost to Follow up ....................................................................................................38
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................39
8.1. Efficacy Assessments..............................................................................................40
8.2. Safety Assessments .................................................................................................40
8.2.1. Physical Examinations................................................................................40
8.2.2. Vital Signs ..................................................................................................40
8.2.2.1. Temperature ..............................................................................41
8.2.3. Electrocardiograms.....................................................................................41
8.2.4. Clinical Safety Laboratory Assessments ....................................................42
8.2.5. COVID-19 Specific Assessments...............................................................43
8.2.6. Glucose Monitoring....................................................................................43
8.2.6.1. Definition and Severity of Hypoglycemic Adverse Event 
(HAE) ................................................................................................43
8.2.7. Pregnancy Testing ......................................................................................44
8.3. Adverse Events and Serious Adverse Events..........................................................45
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......45
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................46
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................46
8.3.2. Method of Detecting AEs and SAEs ..........................................................46
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 ..........................................................................................................47
8.3.5.1. Exposure During Pregnancy......................................................47
8.3.5.2. Exposure During Breastfeeding ................................................48
8.3.5.3. Occupational Exposure .............................................................49
8.3.6. Cardiovascular and Death Events...............................................................49
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................49
8.3.8. Adverse Events of Special Interest.............................................................49
8.3.8.1. Lack of Efficacy........................................................................49


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8.3.9. Medical Device Deficiencies......................................................................50
8.3.10. Medication Errors.....................................................................................50
8.4. Treatment of Overdose............................................................................................50
8.5. Pharmacokinetics ....................................................................................................51
8.5.1. Plasma for Analysis of PF-06882961.........................................................51
8.5.2. Plasma for Determination of PF-06882961 Unbound Fraction 
Protein Binding................................................................................................52
8.6. Pharmacodynamics..................................................................................................53
8.7. Genetics...................................................................................................................53
8.7.1. Specified Genetics ......................................................................................53
8.7.2. Banked Biospecimens for Genetics............................................................53
8.8. Biomarkers ..............................................................................................................53
8.9. Immunogenicity Assessments.................................................................................53
8.10. Health Economics .................................................................................................53
9. STATISTICAL CONSIDERATIONS ................................................................................53
9.1. Statistical Hypotheses .............................................................................................54
9.2. Sample Size Determination.....................................................................................54
9.3. Analysis Sets ...........................................................................................................54
9.4. Statistical Analyses .................................................................................................55
9.4.1. Pharmacokinetic Analyses..........................................................................55
9.4.1.1. Derivation of Pharmacokinetic Parameters...............................55
9.4.1.2. Statistical Methods for Pharmacokinetic Data..........................56
9.4.2. Safety Analyses ..........................................................................................57
9.4.2.1. Electrocardiogram Analyses......................................................58
9.4.3. Other Analyse(s).........................................................................................58
9.5. Interim Analyses .....................................................................................................58
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............58
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................59
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............59
10.1.1. Regulatory and Ethical Considerations ....................................................59


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10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................59
10.1.2. Financial Disclosure .................................................................................60
10.1.3. Informed Consent Process........................................................................60
10.1.4. Data Protection .........................................................................................61
10.1.5. Dissemination of Clinical Study Data ......................................................61
10.1.6. Data Quality Assurance ............................................................................63
10.1.7. Source Documents....................................................................................64
10.1.8. Study and Site Start and Closure ..............................................................64
10.1.9. Publication Policy.....................................................................................65
10.1.10. Sponsor’s Qualified Medical Personnel .................................................66
10.2. Appendix 2: Clinical Laboratory Tests .................................................................67
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................68
10.3.1. Definition of AE .......................................................................................68
10.3.2. Definition of SAE.....................................................................................69
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................70
10.3.4. Reporting of SAEs....................................................................................74
10.4. Appendix 4: Contraceptive Guidance ...................................................................75
10.4.1. Male Participant Reproductive Inclusion Criteria....................................75
10.4.2. Female Participant Reproductive Inclusion Criteria.................................75
10.4.3. Woman of Childbearing Potential ............................................................75
10.4.4. Contraception Methods.............................................................................76
10.5. Appendix 5: Genetics............................................................................................78
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........79
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................81
10.8. Appendix 8: Child-Pugh Classification (CPC) of Liver Dysfunction...................83
10.9. Appendix 9: Prohibited Prior/Concomitant Medications......................................84
10.10. Appendix 10.Abbreviations ................................................................................85
11. REFERENCES ..................................................................................................................89


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LIST OF TABLES
Table 1. Hepatic Function Categories Based on Child-Pugh Score ........................................21
Table 2.
Expected Widths of the 90% CIs (with 80% Coverage Probability) 
for Different Possible Estimated Effects ..................................................54
Table 3.
Plasma PK Parameters..............................................................................56
Table 4.
Protocol-Required Safety Laboratory Assessments .................................67
Table 5.
Scoring for Child Pugh Classification22 ...................................................83
Table 6.
Derivation of Child Pugh Classification Score.........................................83
Table 7.
Determination of Encephalopathy Grade .................................................83


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: Pharmacokinetic Study of PF-06882961 in Participants With and Without
Varying Degrees of Hepatic Iimpairment.
Rationale
The primary purpose of this non-randomized, open-label study is to characterize the effect of 
varying degrees of hepatic impairment on the plasma pharmacokinetics (PK) of 
PF-06882961 following administration of a single oral dose of PF-06882961.
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 varying degrees of hepatic 
impairment relative to age- and body 
weight-matched participants without hepatic 
impairment.

Plasma: Cmax, AUCinf, AUClast, fu as data permit.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of a 
single oral dose of PF-06882961 when 
administered to adult participants with varying 
degrees of hepatic impairment and in age- and 
body weight-matched participants without 
hepatic impairment.

Assessment of treatment emergent AEs, clinical 
laboratory abnormalities, vital signs, ECG 
parameters.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To compare additional PK parameters of 
PF-06882961 following administration of a 
single oral dose in adult participants with 
varying degrees of hepatic impairment and in 
age- and body weight-matched participants 
without hepatic impairment.

Plasma: Cmax,u, AUCinf,u, AUClast,u, CL/F, CLu/F, 
Vz/F, Vz,u/F, Tmax, t1/2 as data permit.
Overall Design
This is a non-randomized, open-label, single-dose, parallel-cohort, multicenter study to 
investigate the effect of varying degrees of hepatic function on the plasma PK of
PF-06882961 after a single, oral 20 mg dose administered in the fed state.  Safety and 
tolerability will be evaluated throughout the study.


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Number of Participants
Approximately 24 participants will be enrolled to study intervention such that approximately 
24 evaluable participants complete the study.
Note: "Enrolled" means a participant's agreement to participate in a clinical study following 
completion of the informed consent process. 
Intervention Groups and Duration
A total of approximately 24 participants with varying degrees of hepatic function will be 
administered a single, oral 20 mg dose of PF-06882961 in the fed state as shown in the table 
below. 
Hepatic Function Categories Based on Child Pugh-Score
Cohort
Description
Child-Pugh Score
Number of 
Participants
1
Without hepatic impairment
Not Applicable
6a
2
Mild hepatic impairment
Class A (5 to 6 points)
6
3
Moderate hepatic impairment
Class B (7 to 9 points)
6
4
Severe hepatic impairment
Class C (10 to 15 points)
6b
a.
Additional participants may be dosed to a maximum of 8 participants to ensure mean age 5 years and mean body 
weight 10 kg of this cohort is aligned with the pooled average assessed when ≥75% of participants are dosed 
across the other 3 cohorts.
b.
If recruitment across the sites selected proves to be prohibitive, study will dose only 4 participants in this cohort.   
Categorization of participants into Cohort 2-4, inclusive, will be done based on Child-Pugh 
scores determined, as described in Appendix 8, at the screening visit. Participants will be 
dosed in a staged manner such that those with moderate and severe hepatic impairment 
(Cohorts 3 and 4) will be evaluated first followed by participants with mild hepatic 
impairment (Cohort 2).  Participants without hepatic impairment (Cohort 1) will be recruited 
near the end of the study to match the average demographics (at a minimum, age and weight; 
and gender as much as practically possible) across the pooled Cohorts 2 through 4.
Approval from the sponsor must be obtained before proceeding with recruitment for 
participants on Cohort 1 or Cohort 2.
For individual participants, the total duration of participation from the screening visit to the
follow-up visit will range from approximately 5 weeks (minimum) to approximately 9 weeks 
(maximum).
Data Monitoring Committee or Other Independent Oversight Committee
A data monitoring committee or independent oversight committee will not be utilized.


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Statistical Methods
The effect of varying degrees of hepatic impairment on PK parameters will be assessed by
constructing 90% confidence intervals (CI) around the estimated difference between each of 
the Test (hepatic impaired) cohorts and the Reference (without hepatic impairment) cohort.
A 1-way analysis of variance (ANOVA) will be used to compare the natural log transformed
PF-06882961 AUCinf, Cmax, AUClast, and fraction unbound (fu), as data permit, for each of 
the hepatic impairment cohorts (Test) to the cohort without hepatic impairment (Reference). 
Estimates of the adjusted mean differences (Test - Reference), and corresponding 90% CIs, 
will be obtained from the model. These will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.
1.2. Schema


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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct 
evaluations or assessments required to protect the well-being of the participant.
Visit Identifier/Day
[for list of abbreviations refer to Section 10.10]
Screening
-28 to -2
Day 
-1
Day 1
Day 2
Day 3
ET
Follow-upa
Day 30±2
Hours Post Dose
--
0
1
2
3
4
5
6
7
8
10
12
14
24
36
48
--
--
Informed consent & demography 
x
Outpatient visit 
x
x
Inpatient stay at Clinical Research Unit 
x








x
Eligibility assessment 
x
x
Medical history
x
x
Physical exam (height & body weight at screening, only)b
x
x
x
x
Breath alcohol test & Urine drug test
x
x
Alcohol/tobacco & contraception use
x
x
x
x
xc
(Update) prior/concomitant treatments
x
x
x
x
Single, supine 12-lead ECG
x
x
x
x
Single, seated vital signs (BP,pulse rate, temperature)
x
x
x
x
x
x
Serious and non-serious adverse event monitoring
x
x








x
x
x
Standard mealsd
x
x
x
x
x
x
x
x
Investigational product administration
xe
Blood & Urine for clinical laboratory tests after 4-hour fast
x
x
x
x
Serology for FSH (females only), HbA1c, HIV, HBsAg, 
HCVAb/RNA
x
Serum pregnancy test (females only)
x
x
x
x
COVID-19 symptoms and risk assessment
x
x
COVID-19 testing
xf
x
Pfizer Prep D1.5 Banked Biospecimeng
x
Blood for pharmacokinetic sampling for PF-06882961
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood for unbound fraction protein binding PF-06882961
x
x
Urine pregnancy test (WOCBP, only)h
x
x
a.
Visit to be performed as telephone contact and must occur 28 to 32 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.
b.
Complete physical exam (PE) at screening; at all other time points limited PE , at investigator discretion (see Section 8.2.1).


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c.
In confirmation of appropriate contraception use only.
d.
Meals/snacks to be served at clock times matching approximately 0H, 4H, 7H, 10H, and 14H (optional) relative to dosing on Day 1 (while inpatient).
e.
Dosing to occur with standard morning meal provided approximately 30 minutes prior to 0H, and completed approximately 10 minutes prior to dosing.
f.
COVID-19 viral test to occur between DAY-5 and DAY-2 to permit availability of test result prior to admission on Day -1.
g.
If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a participant visit.
h.
Test result must be reviewed and deemed acceptable (ie, negative) to continue participation in the study.


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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 primary purpose of this non-randomized, open-label study is to characterize the effect of 
varying degrees of hepatic impairment on the plasma pharmacokinetics (PK) of 
PF-06882961 following administration of a single oral dose of PF-06882961.  
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 Overview
2.2.1.1. 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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.
2.2.1.3. Nonclinical Safety
General toxicology studies have been completed in cynomolgus monkeys up to 6 months in 
duration (with a 3-week lead-in and 1-month recovery) and in rats up to 6 months in duration 
(with a 1-month recovery).  
 
 
 
 
 
  
Embryo-fetal developmental studies were completed in rats and rabbits.  
 
 
 
 
 
 
 
PF-06882961 was negative in genetic toxicity testing and photosafety endpoints.  
 
 
  
Refer to the IB for more details on the nonclinical safety of PF-06882961.
2.2.2. Clinical Overview
Three clinical studies, C3421001, C3421002 and C3421003 have completed dosing with 
PF-06882961. 
 
  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 
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Section 2.2.2.1. Refer to the IB for more details on these studies and the known drug class 
effects of marketed injectable GLP-1R agonists.
2.2.2.1. Clinical Safety
Clinical data from the completed C3421001, C3421002 and C3421003 studies are provided 
in the IB for PF-06882961.
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 1 symptomatic hypoglycemic adverse
event (HAE) that was reported in 1 participant in the 120 mg BID group. This AE was 
non-fasting, mild in severity and of limited duration. 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.
While there were isolated values for laboratory tests, vital signs and electrocardiogram 
(ECG) intervals outside of the reference ranges, no clear adverse trends were apparent in 
these parameters.  As has been reported for marketed GLP-1R agonists,10,11 increases in heart 
rate have been observed, with mean increases ranging from 5 to 15 beats per minute (bpm)
across doses administered to date, and most heart rate values within the normal range.
2.2.2.2. Clinical Pharmacokinetics
The clinical pharmacokinetics (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.  


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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.  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
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-06882961 may be found in the IB, which is the SRSD for this 
study. 
2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention(s) PF-06882961
Thyroid C-cell tumors
The potential risks are based on 
product labeling for injectable 
GLP-1R agonists (ie, liraglutide, 
dulaglutide, and exenatide) due 
to dose-dependent and treatment 
duration-dependent thyroid 
C-cell tumors in nonclinical 
studies in rats and mice at 
clinically relevant exposures. 
Thyroid C-cell tumors have not 
been observed with PF-06882961 
in clinical or nonclinical studies. 
Participants with a personal or 
family history of medullary thyroid 
carcinoma or MEN2 are excluded 
from the clinical development 
program. 
CCI
CCI


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention(s) PF-06882961
Pancreatitis
The potential risks are based on 
product labeling for injectable 
GLP-1R agonists (ie, liraglutide, 
exenatide and dulaglutide). 
Pancreatitis has not been 
observed in the PF-06882961 
clinical trial program.
The single dose and dose level 
administered in this study minimize 
any potential risk.
Hypoglycemia
Clinical trials with injectable
GLP-1R agonists have not 
demonstrated an increased risk 
for hypoglycemia. However, 
when administered in 
combination with anti-diabetic 
agents that are known to have an 
increased risk of hypoglycemia 
(such as insulin or 
sulfonylureas), an increased risk 
for hypoglycemia was observed. 
Only 1 adverse event of mild 
hypoglycaemia has been reported
in the clinical development 
program to date.
Blood glucose is monitored 
frequently during clinical studies,
and participants are monitored for 
signs or symptoms of 
hypoglycemia. The single dose and 
dose level administered in this study 
minimize any potential risk.
Impairment in renal function
In rats, minimal renal tubular 
vacuolation was observed, but
this finding was considered to be 
non-adverse.
In the clinical trial program only 
1 mild adverse event (PT Blood 
creatinine increased) has been 
observed in the clinical trial 
program.
Study exclusion criteria include 
participants with significant renal
impairment.
Gastrointestinal adverse reactions
The potential risks are based on 
product labeling for injectable 
GLP-1R agonists (ie, liraglutide, 
exenatide and dulaglutide).
In addition, gastrointestinal
adverse events, the majority of 
which were mild in severity, 
have been observed in the 
clinical program with 
PF-06882961. In nonclinical 
studies with PF-06882961, 
gastrointestinal adverse effects 
have been seen in rats and 
monkeys.
Participants are monitored during 
the clinical studies to prevent 
potential sequelae of any severe 
gastrointestinal reactions, 
eg, dehydration. Exclusion criteria 
include any factor that may affect 
drug absorption, such as bariatric
surgery, active inflammatory bowel 
disease or any intestinal resection. 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention(s) PF-06882961
Diabetic Retinopathy 
complications
The potential risk is based on the 
product labeling for the 
injectable GLP-1R agonist 
semaglutide. This risk has not 
been listed in the prescribing
information for other marketed 
GLP-1R agonists.
There are no nonclinical or 
clinical data involving
PF-06882961 to suggest an 
increased risk of diabetic 
retinopathy complications.
Potential participants with diabetes 
mellitus are excluded from this 
clinical study.  In addition, the
single dose and dose level 
administered in this study minimize 
any potential risk.
Other
Risk of COVID-19 exposure
during study
During the pandemic, study 
participants could be infected 
with the SARS-CoV-2 virus 
during study participation. This 
could lead to increased health 
risk for this participant and 
others in the study.
Participants undergo COVID-19 
specific assessments prior to 
admission to study site and 
according to SOA.
2.3.2. Benefit Assessment
A single dose of PF-06882961 administered in this study is not expected to provide any 
clinical benefit to healthy participants or participants with hepatic impairment.  This study is 
designed primarily to characterize the effect of varying degrees of hepatic 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 hepatic impairment.
2.3.3. Overall Benefit/Risk Conclusion
In line with the clinical profile of marketed GLP-1R agonists,11-13 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 
hepatic impairment.  
Considering all available clinical and nonclinical data, the benefit-risk profile of 
PF-06882961 supports continued clinical development. Based on the safety profile of 
PF-06882961 observed in clinical studies to date, the risk to the participants in this study is 
deemed to be minimal. More detailed information about the known and expected benefits 


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and risks and reasonably expected AEs of PF-06882961 may be found in the IB for 
PF-06882961, which is the single reference safety document (SRSD) for this study.
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 varying degrees of hepatic 
impairment relative to age- and body 
weight-matched participants without hepatic 
impairment.

Plasma: Cmax, AUCinf, AUClast, fu as data permit.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of a single 
oral dose of PF-06882961 when administered to 
adult participants with varying degrees of hepatic 
impairment and in age- and body weight-matched 
participants without hepatic impairment.

Assessment of treatment emergent AEs, clinical 
laboratory abnormalities, vital signs, ECG parameters.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To compare additional PK parameters of 
PF-06882961 following administration of a single 
oral dose in adult participants with varying degrees 
of hepatic impairment and in age- and body 
weight-matched participants without hepatic 
impairment.

Plasma: Cmax,u, AUCinf,u, AUClast,u, CL/F, CLu/F, 
Vz/F, Vz,u/F, Tmax, t1/2 as data permit.
4. STUDY DESIGN
4.1. Overall Design
This is a non-randomized, open-label, single-dose, parallel-cohort, multicenter study to 
investigate the effect of varying degrees of hepatic function on the plasma PK of
PF-06882961 after a single, oral 20 mg dose administered in the fed state.  A total of 
approximately 24 participants with varying degrees of hepatic function will be dosed in the 
study as shown in Table 1. 
Table 1. Hepatic Function Categories Based on Child-Pugh Score
Cohort
Description
Child-Pugh Score
Number of 
Participants
1
Without hepatic impairment
Not Applicable
6a
2
Mild hepatic impairment
Class A (5 to 6 points)
6
3
Moderate hepatic impairment
Class B (7 to 9 points)
6
4
Severe hepatic impairment
Class C (10 to 15 points)
6b
a.
Additional participants may be dosed to a maximum of 8 participants to ensure mean age ±5 years and 
mean body weight ±10 kg of this cohort is aligned with the pooled average assessed when ≥75% of 
participants are dosed across the other 3 cohorts.
b.
If recruitment across the sites selected proves to be prohibitive, study will dose only 4 participants in this
cohort.


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Categorization of participants into Cohort 2-4, inclusive, will be done based on Child-Pugh 
scores determined, as described in Appendix 8 at the screening visit.  Participants will be 
dosed in a staged manner such that those with moderate and severe hepatic impairment 
(Cohorts 3 and 4) will be evaluated first.  Recruitment for participants with mild hepatic 
impairment (Cohort 2) will initiate when approximately 50% of the total participants in 
Cohorts 3 and 4 have been dosed.  Participants without hepatic impairment (Cohort 1) will be 
recruited near the end of the study to match the average demographics (at a minimum, age 
and weight; and gender as much as practically possible) across the pooled Cohorts 2 
through 4.  
Approval from the Sponsor must be obtained before proceeding with recruitment for 
participants in Cohort 1 and Cohort 2.
Participants who prematurely discontinue before completing all assessments may be 
replaced, at the discretion of the principal investigator (PI) and sponsor study team.
The overall study design is summarized in Section 1.2.  For individual participants, the total 
duration of participation from the screening visit to the follow-up visit will range from 
approximately 5 weeks (minimum) to approximately 9 weeks (maximum).
4.2. Scientific Rationale for Study Design
This study involves participants with varying degrees of hepatic impairment and participants
without hepatic impairment, matched for age as well as body weight (and gender as much as 
practically possible). A single dose of PF-06882961 is proposed, as single dose plasma PK 
of PF-06882961 is generally predictive of exposure upon repeated dosing and limited 
accumulation has been observed given the relatively short half-life of the compound. 
Following administration of single doses of PF-06882961, the arithmetic mean terminal t½ of 
PF-06882961 ranged from 5-7 hours. Even with a possible modest increase in half-life, 
serial PK samples will be collected over 48 hours post-dose is expected to adequately 
characterize the elimination phase of the plasma concentration-time profile in the cohorts 
with varying degrees of hepatic function.
Based on a review of the effect of hepatic impairment on human pharmacokinetics for 
compounds cleared in a similar manner to PF-06882961 
 mild 
hepatic impairment generally results in less than 2-fold increases in plasma exposure.14  In 
the same group of compounds, moderate hepatic impairment results in less than 3-fold 
increases in plasma exposure; however, overall, very limited clinical data are available 
regarding the effect of severe hepatic impairment
 
.15-17
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, 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 
CCI
CCI


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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%]).
In general, participants with normal hepatic function (Cohort 1) will abstain from 
concomitant treatments, except for the treatment of adverse events.  However use of selected 
limited prescription and non-prescription medications is permitted (refer to Section 6.5 for 
details). COVID-19 specific assessments have been incorporated to minimize the risks of 
COVID-19 related complications to participants and the study site personnel.
Participants with impaired hepatic function (Cohorts 2, 3, and 4) are permitted to be on stable 
doses of background medications for the management of their concomitant medical 
condition(s) with some exclusions (Appendix 9).
The Child-Pugh classification (CPC; refer to Appendix 8) will be used to define the 3 cohorts 
of participants with varying degrees of hepatic impairment.  This study will include 
participants with mild (Child-Pugh Class A, Cohort 2), moderate (Child-Pugh Class B,
Cohort 3), and severe (Child-Pugh Class C, Cohort 4) hepatic impairment as well as 
demographic-matched control participants without hepatic impairment (Cohort 1).  All 
3 categories of hepatic impairment will be assessed.  All participants will be required to 
provide their own consent to participate in this study, hence participants with 
clinically-active Grade 3 or Grade 4 encephalopathy will be excluded.  However, participants
who have a previous history of Grade 3 or 4 encephalopathy but are currently receiving an 
intervention [for example: lactulose or lactitol, alone or in combination with rifaximin, and/or 
neomycin] to manage their encephalopathy-related signs and symptoms are eligible provided 
the on-treatment encephalopathy grading at the screening visit is Grade 2 or lower thereby 
permitting them to provide their own informed consent.  Acknowledging the medical state of 
the population enrolled, certain eligibility criteria for participants with hepatic impairment
are distinctly different, with no specific exclusion of participants with Hepatitis B and 
Hepatitis C in Cohorts 2, 3, or 4.  
As stated in Section 2.2.2.2, there appears to be no clear effect of mild renal impairment on 
PF-06882961 pharmacokinetics. However, to enable a clearer assessment of the effect of 
hepatic impairment on PF-06882961 disposition, participants will be excluded if there is 
concomitant clinical evidence of renal impairment, defined as estimated glomerular filtration 
rate (eGFR) <60 mL/min.  
Both women 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).


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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.18
Banked Biospecimens will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
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 hepatic 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.  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 hepatic
impairment on the PK of PF-06882961 over the range of clinical doses planned for future 
studies.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the follow-up visit via telephone contact shown in the schedule of 
activities during the period of Day 28 to Day 32 (Day 30 ±2).
The end of the study is defined as the date of the follow-up visit via telephone contact, shown 
in the schedule of activities, for the last participant in the trial globally.
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.


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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1. Participants in All Cohorts
Age and Sex:
1. Male and female participants between the ages of 18 (or the minimum 
country-specific age of consent if >18) and 70 years, inclusive, at the screening visit:

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
3. Body mass index (BMI) of 17.5 to 38.0 kg/m2, inclusive; and a total body weight 
>50 kg (110 lb), at the screening visit; with a single repeat assessment of total body 
weight (and hence BMI), on a separate day permitted to assess eligibility, if needed. 
Informed Consent:
4. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.1.2. Additional Inclusion Criteria for Participants without Hepatic Impairment 
(Cohort 1 Only)
1. At screening, no clinically relevant abnormalities identified by a detailed medical 
history, complete physical examination, including blood pressure (BP) and pulse rate
measurement, 12-lead ECG and clinical laboratory tests, as assessed by the 
sponsor-identified central laboratory;
2. At screening, participants must meet the demographic-matching criteria, including: 

A body weight that is 10 kg of the average of the pooled hepatic impairment 
cohorts (Cohorts 2, 3, and 4), as provided by the sponsor;

An age that is ±5 years of the average of the pooled hepatic impairment cohorts 
(Cohorts 2, 3, and 4), as provided by the sponsor;


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
Attempts will be made to ensure that the male-to-female distribution in Cohort 1, 
is comparable, to that in the pooled hepatic impairment cohorts (Cohorts 2, 3, 
and 4);
3. No known or suspected hepatic impairment; including at screening, meet all the
following criteria, as assessed by the sponsor-identified central laboratory, with a 
single repeat permitted to assess eligibility, if needed:

Alanine aminotransferase (ALT) ≤upper limit of normal (ULN);

Aspartate aminotransferase (AST) ≤ULN;

Total bilirubin ≤ULN;
NOTE: Participants with a history of Gilbert syndrome (and hence elevated total 
bilirubin) are eligible provided direct bilirubin level is ≤ULN plus ALT and AST 
are ≤ULN plus alkaline phosphatase, hemoglobin, and reticulocyte count are all 
≤ULN; 

Albumin ≤ULN;

Prothrombin time ≤ULN.
5.1.3. Additional Inclusion Criteria for Participants with Impaired Hepatic Function 
(Cohorts 2, 3, and 4 Only)
1. Stable hepatic impairment that meets the criteria for Class A, B, or C of the 
Child-Pugh classification (refer to Appendix 8) with no clinically significant change 
in disease status within the 28 days prior to the screening visit, as documented by the 
participant’s recent medical history (for example: no worsening clinical signs of 
hepatic impairment, no worsening of total bilirubin or prothrombin time (PT) by more 
than 50%);
2. Stable concomitant medications for the management of individual participants’
medical history; on a case-by-case basis, with input from the sponsor, participants 
receiving fluctuating concomitant medication/treatment may be considered if the 
underlying disease is under control;
3. Participant is willing and able to abide by the lifestyle guidelines described in 
Section 5.3 of this protocol.  


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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
5.2.1. Participants in All Cohorts
Medical Conditions:
1. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection);
NOTE: Participants who have undergone cholecystectomy and/or appendectomy are 
eligible for this study as long as the surgery occurred more than 6 months prior to 
Screening;
2. At screening, participants with a positive result for human immunodeficiency virus 
(HIV) antibodies, as assessed by sponsor-identified central laboratory, with a single 
repeat permitted to assess eligibility, if needed;
3. A diagnosis of type 2 diabetes mellitus (T2DM) that is documented by medical 
history;
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. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study;
Prior/Concomitant Therapy:
6. Use of prior/concomitant therapies as outlined in Section 6.5;
Prior/Concurrent Clinical Study Experience:
7. 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 investigational 
product used in this study (whichever is longer);
8. Participants with known prior participation (ie, randomized and received at least
1 dose of investigational product) in a study involving PF-06882961; 


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Diagnostic Assessments:
9. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Visit 1, as assessed by the study specific laboratory and confirmed by a single repeat 
test, if deemed necessary:

HbA1c ≥6.5%;

FPG ≥126 mg/Dl;

eGFR<60 mL/min/1.73m2;
10. A positive urine drug test, for illicit drugs at screening, as assessed by 
sponsor-identified central laboratory.  However, participants in Cohorts 2-4, only, 
who have been medically prescribed opiates/opioids or benzodiazepines and report 
the use of these drugs to the investigator at the Screening visit will be allowed to 
participate; 
NOTE: repeat urine drug testing is not permitted in this study;
11. At screening or Day -1, a positive breath alcohol test, as assessed using kits provided 
by sponsor-identified central laboratory, with a single repeat on a separate day
permitted to assess eligibility, if needed;
12. A positive COVID-19 test at screening;
Other Exclusions:
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing and until the follow-up contact;
14. History of sensitivity to heparin or heparin-induced thrombocytopenia, only if heparin 
is used to flush intravenous catheters used during serial blood collections;
15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol;
16. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.


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5.2.2. Additional Exclusion Criteria for Participants without Hepatic Impairment 
(Cohort 1 Only)
Participants presenting with any of the following will not be included in the study:
1. Evidence of chronic liver disease including history of hepatitis, hepatitis B, or 
hepatitis C or evidence of any of the following, as assessed by sponsor-identified 
central laboratory, with a single repeat, permitted to assess eligibility, if needed:

Hepatitis B virus, defined by presence of hepatitis B surface antigen (HBsAg);
NOTE: while not part of the tests assessed in this study, participants with a 
previously positive hepatitis B surface antibody result due to vaccination are 
deemed eligible;

Hepatitis C infection, defined by presence of hepatitis C antibody (HCVAb) and
HCV ribonucleic acid (RNA);
2. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening.  Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours.  As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
3. Screening supine 12-lead ECG demonstrating QTcF interval >450 msec or a QRS 
interval >120 msec.  If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG 
should be repeated 2 more times and the average of the 3 QTcF or QRS values should 
be used to determine the participant’s eligibility;
4. Screening seated systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood 
pressure (DBP) 90 mm Hg, following ≥5 minutes of seated rest.  If SBP is 
≥140 mm Hg or DBP ≥90 mm Hg, the BP assessment should be repeated 2 more 
times and the average of the 3 BP values should be used to determine eligibility;
5. Use of chronic prescription medications within 7 days or 5 half-lives (whichever is 
longer) prior to Day 1;
NOTE: Use of selected, limited prescription and non-prescription medications is 
permitted (refer to Section 6.5 for details); 


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5.2.3. Additional Exclusion Criteria for Participants with Impaired Hepatic Function 
(Cohorts 2, 3, and 4 Only)
Participants presenting with any of the following will not be included in the study: 
1. Hepatic carcinoma or hepatorenal syndrome or limited predicted life expectancy 
(defined as less than 1 year in Cohorts 2 & 3 and less than 6 months for Cohort 4 
only);
2. A diagnosis of hepatic dysfunction secondary to any acute ongoing hepatocellular 
process that is documented by medical history, physical examination, liver biopsy, 
hepatic ultrasound, computerized tomography scan, or magnetic resonance imaging 
(MRI);
3. History of surgery that would be expected to alter absorption, distribution, 
metabolism, or excretion (ADME) properties of PF-06882961 (eg, status post 
porta-caval shunt surgery); 
NOTE: Participants with a transjugular intrahepatic portosystemic shunt (TIPS) are 
permitted provided that they meet the Child-Pugh criteria;
4. History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less 
than 4 weeks prior to Screening; 
5. Signs of clinically active Grade 3 or 4 hepatic encephalopathy (ie, >Grade 2 Portal 
Systemic Encephalopathy score; refer to Appendix 8);
6. Severe ascites and/or pleural effusion, except for those categorized in Cohort 4 who 
may be enrolled provided participant is medically stable, per the investigators’ 
medical judgment;
7. Participants who have previously received a kidney, liver, or heart transplant;
8. Screening supine 12-lead ECG demonstrating a QTcF interval >470 msec or a QRS 
interval >120 msec.  If QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG 
should be repeated 2 more times and the average of the 3 QTcF or QRS values should
be used to determine eligibility;
9. At screening, persistent severe, uncontrolled hypertension; for example: seated SBP 
≥180 mm Hg and/or DBP ≥105 mm Hg after ≥5-minute of seated rest, with a single 
repeat permitted to assess eligibility, if needed, at each of these 2 visits:

For participants with SBP ≥160 (and <179) mm Hg or DBP ≥100 (and 
<104) mm Hg, the period between Screening and Day -1 must be used to refine 
the doses of the agents used for management of BP with the aim to have stable BP 
by Day 1 [refer to Section 5.2.4];


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10. Participants with ALT or AST >5x ULN on clinical laboratory tests at screening, as 
assessed by the sponsor-identified central laboratory, with a single repeat permitted to 
assess eligibility, if needed.
5.2.4. Criteria for Dosing on Day 1
Participants will progress to dosing on Day 1 provided they have satisfied all the following 
criteria:

Breath alcohol test, using kits provided by sponsor-identified central laboratory, on 
Day -1 is negative;

In women of childbearing potential, urine pregnancy test on Day -1 is negative as 
reported by on-site pregnancy test using supplies provided by the sponsor-identified 
central laboratory;

Safety-related laboratory tests collected and analyzed by sites’ local laboratory on 
Day -1, if performed at investigator discretion, upon review on Day 1 must reflect the 
participant to be in stable medical condition;

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 and 3 only: Participants must have measurement on Day 1 of 
SBP ≤159 mm Hg and DBP ≤99 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]; 

Cohort 4 only: Participants must have measurement on Day 1 of SBP ≤159 mm Hg 
and DBP ≤105 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
After confirmation of eligibility, participants will be instructed to maintain the guidelines 
described below for the duration of participation in the study. 
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to all fasting clinical laboratory evaluations and at least 10 hours prior to the 
collection of the predose PK sample;

Water may be consumed as desired (ad libitum);


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
While inpatient, all meals will be standardized as follows: 

On Day 1, following an overnight fast of at least 10 hours, participants should 
begin breakfast approximately 30 minutes prior to PF-06882961 administration.
The breakfast will be consumed over approximately a 20-minute period with 
PF-06882961 administered within approximately 10 minutes of completion of 
the meal. Participants will be encouraged to complete the entire breakfast.
There will be no water restrictions prior to dosing.

Standard morning meal, lunch, afternoon snack, and evening meal (and an 
optional evening snack) will be provided at a similar clock time to the clock time 
when these meals are provided relative to dosing on Day 1 while inpatient (ie, 0H,
4H, 7H, 10H, and 14H);

The total daily nutritional composition should be approximately 
55% carbohydrate, 30% fat and 15% protein.  The nutritional macronutrient 
composition consumed by each participant should be maintained, as much as 
practically possible;

The daily caloric intake per participant should not exceed approximately 
3200 kcal; 

The morning meal (matching 0H), afternoon snack, and optional evening snack is 
each envisioned to constitute 300 to 400 calories and a macronutrient composition 
of approximately 55% carbohydrates, 30% fat and 15% protein;

Lunch and evening meal each is envisioned to constitute less than 1000 calories;

Participants will refrain from consuming red wine, grapefruit, or 
grapefruit-related citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 
7 days prior to Day 1 and until collection of the final PK blood sample.  
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from alcohol for 24 hours prior to admission for inpatient 
stay (plus have a negative breath alcohol test on Day -1) and continue abstaining from 
alcohol until collection of the final PK blood sample;  

Consumption of caffeinated drinks and tobacco (or nicotine containing products) is 
permitted during participation in the study; however, there may be a need for brief 
interruption while at the site, depending on local site policy.


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5.3.3. Activity

Participants will not be permitted to engage in physically strenuous exercise (for 
example: heavy lifting, weight training, calisthenics, and aerobics) within 48 hours 
before each blood sample collection for clinical laboratory tests while participating in 
the study; physical activity at an individual participant’s normal pace is permitted.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use highly effective 
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception).  In addition, the investigator or 
designee will instruct the participant to call immediately if the selected contraception method 
is discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently dosed on Day 1.  Screen failure data are collected and remain as source 
with only a limited set reported in the clinical database.
In this study, participants may be re-screened only after contact with Pfizer Clinician.  This is 
permitted when, due to logistical constraints, the maximum period between screening visit 
and Day 1, of 28 days, is exceeded.  In addition, for participants in Cohorts 2-4, inclusive, 
only, re-screening may be appropriate following mild intercurrent illness after the condition 
has resolved.  In such cases, all screening procedures must be repeated and the participant 
assigned a new 8-digit study-specific identification (SSID) number.  Participants must be 
deemed to meet all the eligibility criteria under the new 8-digit SSID before progressing to 
Day 1.  Reconsent is required.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-06882961.


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6.1. Study Intervention(s) Administered
PF-06882961 will be supplied by Pfizer as 10 mg tablets in bulk along with individual dosing 
containers, as necessary, for unit dosing. For the 20 mg dose administered in this study, 
participants will take 2 tablets of PF-06882961 with the morning meal. 
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive breakfast as 
outlined in Section 5.3.1 (Meals and Dietary Restrictions).  The participants will then receive 
IP at approximately 08:00 hours (plus or minus 2 hours) on Day 1.  Investigator site 
personnel will administer IP with ambient temperature water to a total volume of 
approximately 120 mL.  Participants will swallow the IP whole, and will not manipulate or 
chew the IP prior to swallowing.  
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken.  The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible.  Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.


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6. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for
using a study intervention accountability form/record.  
7. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual.  All destruction must be adequately 
documented.  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff.  Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant in accordance with this protocol.  Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
Study intervention will be prepared by qualified unblinded site personnel according to the IP 
manual.  
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 Study Intervention
This is an open label, non-randomized study.  Following completion of informed consent at 
the screening visit, each participant will be assigned a single 8-digit SSID number by the site 
staff.  The first 4 digits of the SSID will reflect the sponsor-assigned site number and the 
remaining 4 digits will reflect each participant’s unique number assigned in chronological 
order of when informed consent is obtained. Separately, prior to dosing on Day 1, each 
participant will be assigned a 4-digit number consisting of site number (1st digit), cohort 
(2nd digit) and chronological order of dosing, at a given site (3rd and 4th digit).  


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6.4. Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5. Concomitant Therapy
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Participants with Hepatic Impairment will be allowed to be on certain concomitant 
medications that have been prescribed.  Any concomitant medications may be administered
in the morning of Day 1 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 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 case report form (CRF).
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. 
Treatments taken within 28 days before dosing on Day 1 will be documented as a prior 
treatment.  Treatments taken after the first dose of IP will be documented as concomitant 
treatments.
Females using hormonal contraceptives or taking hormone replacement therapy are eligible 
to participate in this study. See Appendix 4 for hormonal contraceptives that are permitted in
this study.
6.5.1. Participants without Hepatic Impairment (Cohort 1, Only)
In general, participants in Cohort 1 will abstain from all concomitant treatments, except for
the treatment of AEs.  Of note, the following restrictions:

Acetaminophen/paracetamol may be used at doses of ≤1 g/day;

Herbal supplements must be discontinued at least 28 days prior to Day 1 and until the 
follow-up contact;


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
Limited use of prescription and nonprescription medications that are not believed to 
affect the overall results of the study may be permitted on a case by case basis after
approval by the sponsor study team.
6.5.2. Participants with Impaired Hepatic Function (Cohorts 2, 3, and 4)
Participants are permitted to be on stable doses of background medications for the 
management of their concomitant medical condition(s).  Whenever possible, attempts must 
be made to not alter the doses and regimens of the concomitant medications after Day 1 and 
until the follow-up contact.
Participants on certain medications, at the screening visit, are excluded from the study
(see Appendix 9 for details regarding prohibited prior/concomitant medications).
6.5.3. 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. 
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
Since this is a single-dose study, this section is not applicable.
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. 


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


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
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
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.
ECGs and vital sign assessments (pulse rate and BP) should be collected prior to any blood 
draw. If an IV catheter is utilized for blood sample collections, ECGs and vital sign 
assessments (pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.


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The total blood sampling volume for individual participants in this study is approximately 
175 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 issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A limited physical examination will include, at a minimum, assessments of general 
appearance, the respiratory and cardiovascular systems, and participant-reported symptoms.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height 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
Blood pressure and pulse rate will be measured as defined in the Schedule of Activities.  
Additional collection times, or changes to collection times of blood pressure and pulse rate 
will be permitted, as necessary, to ensure appropriate collection of safety data.

Single, seated BP/pulse rate will be measured with the participant’s arm supported at 
the level of the heart, and recorded to the nearest mmHg, following a rest of 
≥5 minutes;


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
Same arm (preferably the dominant arm) will be used for BP/pulse rate assessment 
throughout the study;

BP/pulse rate assessment should not be taken from the arm with an IV catheter, if 
placed;

Participants should be instructed not to speak during BP/pulse rate 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
Supine standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc and QTcF intervals
and QRS complex. Alternative lead placement methodology using torso leads 
(eg, Mason-Likar) is not recommended given the potential risk of discrepancies with ECGs
acquired using standard limb lead placement. All scheduled ECGs should be performed after 
the participant has rested quietly for at least 10 minutes in a supine position. 
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 ≥60 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) a postdose QTcF interval remains ≥60 msec from the baseline and is >450 msec; or 
b) an absolute QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator); or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring.  A cardiologist should be 
consulted if QTc 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.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.  All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 5 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.


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8.2.5. COVID-19 Specific Assessments
During the screening period, participants will be assessed19 for COVID-19 related symptoms 
and risks per local regulations20 and institutional policies. Participants will also be tested for 
SARS CoV-2 infection at the timepoints specified in the SoA. Additional testing may be 
required by local regulations, institutional policies or by the Principal Investigator. The test
result must be negative in order for a participant to proceed with admission on Day -1 and 
dosing on Day 1. COVID-19 tests may be conducted at central or local labs.
8.2.6. Glucose Monitoring
While hypoglycemia is not expected in the study participants, FPG will be measured with 
laboratory assessments as noted in the SoA.  In addition, as a precaution, participants should 
be monitored for the signs and symptoms associated with hypoglycemia. 
Any episode of hypoglycemia must be captured on the AE CRF with specific details captured 
on the HAE Form CRF.  For the definition of a hypoglycemic episode and severity 
categorization see Section 8.2.6.1 below.
8.2.6.1. Definition and Severity of Hypoglycemic Adverse Event (HAE)
The investigator must assess the glucose values reported by the central laboratory, as well as 
any signs or symptoms reported by the study participant.
HAE is defined as one of the following:21
a.
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a glucose value of <70 mg/dL (3.9 mmol/L) using either glucometer 
(fingerstick blood glucose) at the study site or sponsor-identified central laboratory 
(plasma glucose).
b. 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 at the study site or sponsor identified central laboratory, and the clinical 
picture includes prompt resolution with food intake, subcutaneous glucagon, or IV 
glucose.
c.
Probable symptomatic hypoglycemia: An event during which symptoms of HAE are 
not accompanied by a glucose determination but was presumably caused by a glucose 
concentration of <70 mg/dL (3.9 mmol/L), and the clinical picture includes prompt 
resolution with food intake, subcutaneous glucagon, or IV glucose.
Each episode of HAE must be categorized with respect to severity.  In order to characterize 
the event as severe, all 3 criteria below must be met:
1. The participant was unable to treat him/herself.  Neurologic impairment, and not the 
age of the participant, is the explanation for why the participant could not treat 
him/herself and required the assistance of another person.


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2. The participant exhibited 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 IV glucose.
Events that do not meet all the criteria above for severe HAE are characterized as mild or 
moderate in severity.
8.2.7. Pregnancy Testing
Pregnancy tests may be urine and/or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention.  Pregnancy tests will also be done
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations.  If a urine test cannot 
be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In 
such cases, the participant must be excluded if the serum pregnancy result is positive.


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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AE or SAE after the participant has concluded
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Form.


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8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.


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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until Day 28.


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
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.


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
A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the CT SAE Report Form.  When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
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 study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of PF-06882961 greater than 300 mg within a 24-hour time 
period ±2 hours will be considered an overdose as this was the highest dose administered in 
the C3421001 study.
Sponsor does not recommend specific treatment for an overdose.


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In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-06882961 (whichever 
is longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 2 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of PF-06882961
Blood samples of approximately 3 mL, to provide a minimum volume of 1 mL plasma, 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 times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF.  Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to 
samples to be collected more than 10 hours after dose administration at outpatient/follow-up 
visits with visit windows.
Samples will be used to evaluate the PK of PF-06882961. Samples collected for analyses of 
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.  Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of study intervention will be 
analyzed using a validated analytical method in compliance with applicable SOPs.  Potential 
metabolites may be analyzed with either validated or exploratory methods.
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.
8.5.2. Plasma for Determination of PF-06882961 Unbound Fraction Protein Binding 
During the study, a blood sample (approximately 12 mL, to provide approximately 5 mL of 
plasma) to provide sufficient plasma for unbound fraction determination, will be collected 
into an appropriately labeled tubes containing K2EDTA for measurement of plasma 
concentrations of PF-06882961 as specified in the SoA. Instructions for the collection and 
handling of biological samples will be provided in the laboratory manual or by the sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF.  Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to 
samples to be collected more than 10 hours after dose administration at outpatient/follow-up 
visits with visit windows.
Samples collected for analyses of PF-06882961 binding may also be used to evaluate safety 
or efficacy aspects related to concerns arising during or after the study, for metabolite 
identification and/or evaluation of the bioanalytical method, or for other internal exploratory 
purposes.
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent.  Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of study intervention/other will 
be analyzed using a validated analytical method in compliance with applicable SOPs.  
Potential metabolites may be analyzed with either validated or exploratory methods.


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The Protein Binding samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity.  Any deviations from the 
Protein Binding 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.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
A 2 mL blood sample optimized for DNA isolation (Prep D1.5) will be collected as local 
regulations and IRBs/ECs allow.
Banked Biospecimens may be used for research related to the study intervention(s).  Genes 
and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the banked 
samples. 
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in supporting documentation.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a 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.


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9.1. Statistical Hypotheses
No formal statistical hypothesis testing will be performed in this study.
9.2. Sample Size Determination
A sample size of approximately 24 participants (approximately 6 participants per cohort, 
with varying degrees of hepatic function in each of the 4 cohorts) has been selected to 
provide sufficient precision to detect a 2-fold difference in AUCinf between each Test cohort 
(with hepatic impairment) and the Reference cohort (without hepatic impairment). Table 2
presents the 90% CIs (with 80% coverage probability) for various possible effects on AUCinf.
The same table would be applicable for possible effects on Cmax.
Table 2.
Expected Widths of the 90% CIs (with 80% Coverage Probability) for 
Different Possible Estimated Effects
Estimated Effect
(Test/Reference)
AUCinf
Probable 90% CI
Probable CI Width
75%
43% to 129%
86%
100%
58% to 172%
114%
150%
87% to 259%
172%
200%
116% to 345%
229%
400%
232% to 690%
458%
These estimates are based on an assumed conservative between-participant standard 
deviation of 0.489 (equivalent to a geometric coefficient of variation of 52%) for logeAUCinf
(also applicable to logeCmax) based on data from 2 previous studies conducted in healthy 
volunteers with PF-06882961 administered as a single dose in the fed state (C3421001 & 
C3421003).
Participants who discontinue from the study before completing all assessments may be 
replaced at the discretion of the investigator and sponsor.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled 
"Enrolled" means a participant's agreement to participate in a 
clinical study following completion of the informed consent 
process. 
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.


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Participant Analysis 
Set
Description
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 any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary, secondary and 
selected tertiary/exploratory endpoints.
9.4.1. Pharmacokinetic Analyses
9.4.1.1. Derivation of Pharmacokinetic Parameters
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. The fraction of PF-06882961 unbound in plasma (fu) will be determined and 
reported for each participant by the analytical lab.


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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 plasma concentration.
Observed directly from data.
Tmax
Time for Cmax.
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 AUC0-last
fu*AUClast.
AUCinf,u
Unbound AUC0-inf
fu*AUCinf.
Cmax,u
Unbound Cmax
fu*Cmax.
CLu/F
Unbound CL/F
Dose/(AUCinf,u).
Vz,u/F
Unbound Vz/F
Dose/(AUCinf,u*kel).
* as data permit
9.4.1.2. Statistical Methods for Pharmacokinetic Data
The effect of varying degrees of hepatic impairment on PK parameters will be assessed by 
constructing 90% CIs around the estimated difference between each of the Test (hepatic 
impaired) cohorts and the Reference (without hepatic impairment) cohort. A 1-way analysis 
of variance (ANOVA) will be used to compare the natural log transformed PF-06882961 
AUCinf, Cmax, AUClast, and fraction unbound (fu), as data permit, for each of the hepatic 
impairment cohorts (Test) to the cohort without hepatic impairment (Reference). Estimates 
of the adjusted mean differences (Test - Reference), and corresponding 90% confidence 
intervals, will be obtained from the model. These will be exponentiated to provide estimates 
of the ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for 
the ratios.


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Additional exploratory analysis using linear regression will be used to analyze the potential 
relationship between appropriate PK parameters [eg, AUCinf, AUClast, Cmax and fu] and 
hepatic function (eg, serum albumin concentration, prothrombin time or total bilirubin).
Plots of PK parameters (eg, AUCinf, AUClast, Cmax and fu) versus hepatic function will be 
constructed, with a regression line and 90% confidence region included. Estimates of the 
slope and intercept, together with a 90% CI, and the coefficient of determination (ie, R-
squared and adj-R-squared) will be obtained from the model.
Additionally, as an exploratory analysis, age and body weight may be explored as an 
additional covariate/factor in the models, as appropriate.
Individual PF-06882961 concentrations will be listed and summarized descriptively by 
nominal PK sampling time and hepatic function cohort. Individual participant and summary 
profiles of the concentration-time data will be plotted by hepatic function cohort for both 
total plasma PF-06882961 and unbound PF-06882961.
PF-06882961 AUCinf, AUClast, Cmax, unbound AUCinf (AUCinf,u), unbound AUClast
(AUClast,u), and unbound Cmax (Cmax,u) individual participant parameters will be plotted by 
hepatic function cohort. PK parameters of PF-06882961 will be summarized descriptively 
by hepatic function cohort. Unbound fraction (fu) will be listed and summarized 
descriptively by hepatic function cohort.
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 
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.


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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 hepatic function cohort.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by hepatic function 
cohort: 
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 Analyse(s)
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during or 
after the trial and retained for future analyses; the results of such analyses are not planned to 
be included in the CSR.
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 modeling, and/or supporting clinical
development. 
9.6. Data Monitoring Committee or Other Independent Oversight 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 CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.


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


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


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www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.


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


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


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


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


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10.2. Appendix 2: Clinical Laboratory Tests
The following 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 issues.
Table 4.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Reticulocyte count (Abs)
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
eGFR eGFR)
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Phosphorus
Total CO2 (Bicarbonate)
AST
ALT
Alkaline phosphatase
GGT
Total bilirubin
Direct bilirubina,b
Indirect bilirubina,b
Creatine kinasea,c
Uric acid
Albumin
Total protein
Amylase
Lipase
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyd
Other tests as part of clinical 
laboratory tests: 

aPTT, PT, PT control, INR

Serum FSHe

Serumf and urineg pregnancy 
test

Breath alcohol testg

Urine drug testh

Serologyi: HBsAg, HCVAb
(and if positive, reflex HCV 
RNA), and HIV

HbA1c

COVID-19 testj
Additional Tests (Needed for Hy’s law)
AST 
ALT 
Total bilirubin
Albumin 
Alkaline phosphatase 
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug levels and/or protein adduct level
a.
At screening and Day 1, only.
b.
After Day 1, direct and indirect bilirubin assessed when total bilirubin is > ULN, only.
c.
After Day 1, creatine kinase assessed when ALT is > ULN, only.
d.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
e.
To be assessed in all females (at screening only).
f.
Serum testing in all females at all times when safety-related laboratory assessments are performed; urine testing to
be done on-site using kits provided by sponsor-identified central laboratory, in WOCBP, only.
g.
Testing to be performed on-site, at screening and Day -1, only using kits provided by sponsor-identified central
laboratory.
h.
For urine drug test, minimum requirements include cocaine, tetrahydrocannabinol (THC), opiates/opioids, 
benzodiazepines and amphetamines.
i.
At screening, only.
j.
May be conducted at central or local laboratory.
For list of abbreviations, refer to Section 10.10.
Investigators must document their review of each laboratory safety report.


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


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


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


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


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


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


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


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


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
Documented bilateral oophorectomy.
For individuals with permanent infertility due to 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.
3. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition, a

High FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential 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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6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.

Oral;

Intravaginal;

Transdermal;

Injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.
8. 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.
In addition, 1 of the following effective barrier methods must also be used when 
option 6 or 7 are chosen above:

Male or female condom with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).


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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to PF-06882961 or study interventions of this class to 
understand treatments for the disease under study or the disease themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Samples for banking will be stored indefinitely or for another period as per local 
requirements.  

Participants may withdraw their consent for the storage and/or use of their Banked 
Biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.  

Banked Biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.


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


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


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


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


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10.8. Appendix 8: Child-Pugh Classification (CPC) of Liver Dysfunction 
Table 5.
Scoring for Child Pugh Classification22
Cohort
CPC
Level of dysfunction
Total Score
(tally based on assessment of 
parameters in Table 6)
1
Not Applicable
Without hepatic 
impairment
Not Applicable
2
A
Mild
5-6
3
B
Moderate
7-9
4
C
Severe
≥10
Table 6.
Derivation of Child Pugh Classification Score
Assessment Parameters
Assigned score for observed findings
1 point
2 points
3 points
Encephalopathy gradea
(refer to Table 7 below)
0
1 or 2
3 or 4a
Ascites
Absent
Asymptomatic
Requiring intervention
Serum total bilirubin, mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
Prothrombin time, sec prolonged
<4
4 to 6
>6
a.
Participants with a prior history of Grade 3 or 4 encephalopathy who are currently receiving 
an intervention [for example: lactulose or lactitol, alone or in combination with rifaximin, and/or 
neomycin] to manage encephalopathy-related signs and symptoms should be scored for encephalopathy 
grading based on their presentation while on intervention at the screening visit and can be included in 
Study C3421014 so long as they do not have clinically active Grade 3 or 4 encephalopathy.
Table 7.
Determination of Encephalopathy Grade
Encephalopathy Grade
Definition
0
Normal consciousness, personality, neurological exam
1
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting
2
Lethargic, time-disoriented, inappropriate, asterixis, ataxia
3a
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity
4a
Unrousable coma, no personality/behavior, decerebrate
a.
Subjects with clinically active Grade 3 or 4 encephalopathy are excluded.
CPC should be assessed at screening, only to determine the classification of a given 
participant.


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10.9. Appendix 9: Prohibited Prior/Concomitant Medications
The following medications are prohibited until the follow-up visit (ie, 28-32 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).
Day -1 to 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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10.10. Appendix 10.Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Term
Abs
Absolute
ADME
absorption, distribution, metabolism, or excretion
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC24
area under the plasma concentration-time profile from time zero to 
the time 24 hours
AUC24, free
unbound Area under the plasma concentration-time profile from 
time zero to the 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
AUC0-inf
The total AUC or AUC0-is the area under the curve 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
AUClast,u
unbound area under the plasma concentration-time profile from time 
zero to the time of the last quantifiable concentration
AUC0-last
Area under the plasma concentration-time profile from time zero to 
the last measured concentration (AUC0-last)
AUC24, total
Total Area under the plasma concentration-time profile from time 
zero to the time 24 hours
AV
atrioventricular
BCRP
breast cancer resistance protein 
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
C
Celsius
cAMP
cyclic adenosine monophosphate
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL/F
apparent clearance of drug from plasma


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Term
CLu/F
unbound apparent clearance from plasma
Clast
last quantifiable concentration
Cmax
maximum observed concentration
Cmax, free
unbound maximum plasma contentration
Cmax, total
total maximum plasma concentration
Cmax,u
unbound maximum plasma concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease
CPC
Child-Pugh classification
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
CTMS
clinical trial management system
Cu
cubic
CV
coefficient of variation
CYP
cytochrome P450
DBP
diastolic blood pressure
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DPP
dipeptidyl peptidase 4
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EFD
Embryo fetal developmental
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ET
Early Termination 
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FPG
fasting plasma glucose
FSH
follicle-stimulating hormone
Fu
fraction unbound
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP-1
Glucagon-like peptide-1
GLP-1R
Glucagon-like peptide-1 receptor
HAE
Hypoglycemic adverse event


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Term
HbA1c
Glycated hemoglobin A1c
HBsAg 
hepatitis B surface antigen
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
Heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
IND
Investigational New Drug Application
INR
international normalized ratio
IP 
investigational product 
IPAL
investigational product administration log
IR
Immediate release
IRB
Institutional Review Board
IV
intravenous
IVGTT
intravenous glucose tolerance test
K2EDTA
dipotassium ethylenediaminetetraacetic acid
Kel
terminal phase rate constant calculated by a linear regression of the 
log-linear concentration-time curve
LFT
liver function test
MATE
multidrug and toxin extrusion
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MEN2
multiple endocrine neoplasia syndrome type 2
MRI
magnetic resonance imaging
Msec
millisecond(s)
MTC
medullary thyroid carcinoma
N/A
not applicable
NOAEL
no observed adverse effect level
OAT
organic anion transporter
OCT2
organic cation transporter 2
OATP
organic anion-transporting polypeptide
PD
pharmacodynamic(s)
PE
Physical exam
PI
principal investigator
PK
pharmacokinetic(s)
PR
pulse rate
PT
prothrombin time


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Term
PVC
premature ventricular contraction
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
Qual
qualitative
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBP
systolic blood pressure
SMP
study monitoring plan
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SSID
study-specific subject identification
SToD
study team on demand
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
terminal phase half-life
T2DM
type 2 diabetes mellitus
TBili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
TIPS
transjugular intrahepatic portosystemic shunt
Tmax
time to reach Cmax
UGT
uridine 5’-diphosphate-glucuronosyltransferase
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution
Vz,u/F
unbound apparent volume of distribution
WBC
white blood cell
WOCBP
woman of childbearing potential


PF-06882961 
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PFIZER CONFIDENTIAL
Page 89
11. REFERENCES
1.
Ørskov C, Holst JJ, Knuhtsen S, et al. Glucagon-like peptides GLP-1 and GLP-2, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology 1986;119(4):1467-75.
2.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet 1987;2(8571):1300-4.
3.
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 
1997;273(5):E981-8.
4.
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest 1998;101(3):515-20.
5.
Hu FB. Globalization of diabetes: the role of diet, lifestyle and genes. Diabetes Care 
2011;34:1249-57.
6.
IDF Diabetes Atlas; 8th Edition: Avaiable from: http://www.idf.org/diabetesatlas.
Accessed: 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;314:1021.
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, Haw N, et al. Association of glycaemia with macrovascular and 
microvascular complications of type 2 diabetes (UKPDS 35): prospective observational 
study. BMJ 2000;321:405-12.
10.
Drucker DL. The ascending GLP-1 road from clinical safety to reduction of 
cardiovascular complications. Diabetes 2018;67:1710-9. 
11.
VICTOZA [Package insert], Drugs@FDA. 2016 Apr., Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022341s025lbl.pdf.
Accessed: 04 Feb 2019.
12.
Ozempic [Package insert], Drugs@FDA. 2017 Dec., Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf. Accessed:
19 Jul 2019.
13.
Trulicity [Package Insert], Drugs@FDA, 2017 Jan., Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125469s007s008lbl.pdf.
Accessed: 19 Jul 2019.


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Protocol C3421014
Final Protocol, 05 October 2020
PFIZER CONFIDENTIAL
Page 90
14.
American Diabetes Association. Standards of medical care in diabetes -2019. Diabetes 
Care. 2019;Jan;42(Suppl 1):S1-S193.
15.
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;83:898–903.
16.
Yeung CK, Shen DD, Thummel KE, et al. Effects of chronic kidney disease and uremia 
on hepatic drug metabolism and transport. Kidney Int. 2014;85:522–8.
17.
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;May:103(5):854-67.
18.
Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon-like peptide-1
receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16:6.
19.
Centers for Disease Control and Prevention. Interim Clinical Guidance for Management 
of Patients with Confirmed Coronavirus Disease (COVID-19). Available from: 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-
patients.html. Accessed: 21 Sep 2020.
20.
Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2 
(COVID-19). Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-
overview.html. Accessed: 22 Sep 2020.
21.
American Diabetes Association. Standards of medical care in diabetes -2019. Diabetes 
Care 2019;42(Suppl 1):S1-S193.
22.
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646.

SAP_001.pdf: 
Protocol C3421014 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3421014
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, PARALLEL
COHORT STUDY TO COMPARE THE PHARMACOKINETICS OF PF-06882961
IN ADULT PARTICIPANTS WITH VARYING DEGREES OF HEPATIC
IMPAIRMENT RELATIVE TO PARTICIPANTS WITHOUT HEPATIC
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 C3421014 (PF-06882961) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint(s) ..................................................................................................7
3.2. Secondary Endpoint(s) ..............................................................................................8
3.3. Other Endpoint(s)......................................................................................................8
3.4. Baseline Variables.....................................................................................................9
3.5. Safety Endpoints .......................................................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.2.1. Analyses for Continuous Endpoints ...........................................................10
5.2.2. Analyses for Categorical Endpoints ...........................................................10
5.2.3. One-way Analysis of Variance (ANOVA).................................................10
5.2.4. Linear Regression .......................................................................................11
5.3. Methods to Manage Missing Data ..........................................................................11
5.3.1. Plasma Pharmacokinetic Parameters ..........................................................12
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoint(s) ................................................................................................12
6.1.1. Cmax, AUCinf, AUClast, fu for PF-06882961................................................12
6.1.1.1. Main Analysis ...........................................................................12
6.1.1.2. Exploratory/Supplementary Analysis .......................................13
6.2. Secondary Endpoint(s) ............................................................................................13
6.2.1. Adverse Events...........................................................................................13
6.2.2. Laboratory Data..........................................................................................13
6.2.3. Vital Signs ..................................................................................................14
6.2.4. ECG ............................................................................................................14


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6.3. Other Endpoint(s)....................................................................................................14
6.3.1. Additional Plasma Pharmacokinetic Parameters of PF-06882961.............14
6.3.2. Banked Biospecimens.................................................................................15
6.4. Subset Analyses.......................................................................................................15
6.5. Baseline and Other Summaries and Analyses.........................................................15
6.5.1. Baseline Summaries....................................................................................15
6.5.2. Study Conduct and Participant Disposition................................................15
6.5.3. Concomitant Medications and Nondrug Treatments..................................16
6.5.4. Other Screening Data..................................................................................16
6.6. Safety Summaries and Analyses .............................................................................16
7. INTERIM ANALYSES.......................................................................................................16
7.1. Introduction .............................................................................................................16
7.2. Interim Analyses and Summaries............................................................................16
8. REFERENCES ....................................................................................................................16
9. APPENDICES .....................................................................................................................17
LIST OF TABLES
Table 1. Summary of Changes...................................................................................................5
Table 2. Hepatic Function Categories Based on Child-Pugh Score .........................................6
Table 3. Summary of Plasma PK Parameters of PF-06882961 to be calculated.......................7
Table 4. Summary of Additional Plasma PK parameters of PF-06882961 to be 
calculated ....................................................................................................8
Table 5. Summary of Plasma PK parameters of Unbound PF-06882961 to be calculated .......9
Table 6. Summary statistics to be produced for Plasma PK Parameters of PF-06882961......12
Table 7. Summary statistics to be produced for Additional Plasma PK Parameters of 
PF-06882961.............................................................................................14
LIST OF FIGURES
Figure 1. Study Schema.............................................................................................................7
APPENDICES
Appendix 1. Statistical Methodology Details..........................................................................17


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Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....18
Appendix 3. List of Abbreviations...........................................................................................19


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1. VERSION HISTORY
Table 1. Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1.0
10 Dec 2020
Original 
5th 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 C3421014.  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 varying degrees of hepatic 
impairment relative to age- and body 
weight-matched participants without hepatic 
impairment.
Plasma: Cmax, AUCinf, AUClast, fu as data permit.
Secondary
Secondary
To evaluate the safety and tolerability of a single 
oral dose of PF-06882961 when administered to 
adult participants with varying degrees of hepatic 
impairment and in age- and body weight-matched 
participants without hepatic impairment.
Assessment of treatment emergent AEs, clinical 
laboratory abnormalities, vital signs, ECG 
parameters.
Tertiary/Exploratory
Tertiary/Exploratory
To compare additional PK parameters of
PF-06882961 following administration of a single 
oral dose in adult participants with varying degrees 
of hepatic impairment and in age- and body 
weight-matched participants without hepatic 
impairment.
Plasma: Cmax,u, AUCinf,u, AUClast,u, CL/F, CLu/F,
Vz/F, Vz,u/F, Tmax, t1/2 as data permit.
There are no estimands for this study.
2.2. Study Design
This is a non-randomized, open-label, single-dose, parallel-cohort, multicenter study to 
investigate the effect of varying degrees of hepatic function on the plasma PK of 


Protocol C3421014 (PF-06882961) Statistical Analysis Plan
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PF-06882961 after a single, oral 20 mg dose administered in the fed state.  A total of 
approximately 24 participants with varying degrees of hepatic function will be dosed in the 
study as shown in Table 2. 
Table 2. Hepatic Function Categories Based on Child-Pugh Score
Cohort
Description
Child-Pugh Score
Number of 
Participants
1
Without hepatic impairment
Not Applicable
6a
2
Mild hepatic impairment
Class A (5 to 6 points)
6
3
Moderate hepatic impairment
Class B (7 to 9 points)
6
4
Severe hepatic impairment
Class C (10 to 15 points)
6b
a.
Additional participants may be dosed to a maximum of 8 participants to ensure mean age ±5 years and 
mean body weight ±10 kg of this cohort is aligned with the pooled average assessed when ≥75% of 
participants are dosed across the other 3 cohorts.
b.
If recruitment across the sites selected proves to be prohibitive, study will dose only 4 participants in 
this cohort.
Categorization of participants into Cohort 2-4, inclusive, will be done based on Child-Pugh 
scores determined, as described in Appendix 8 (of the protocol) at the screening visit.  
Participants will be dosed in a staged manner such that those with moderate and severe 
hepatic impairment (Cohorts 3 and 4) will be evaluated first.  Recruitment for participants 
with mild hepatic impairment (Cohort 2) will initiate when approximately 50% of the total 
participants in Cohorts 3 and 4 have been dosed.  Participants without hepatic impairment 
(Cohort 1) will be recruited near the end of the study to match the average demographics (at 
a minimum, age and weight; and gender as much as practically possible) across the pooled 
Cohorts 2 through 4.  
Participants who prematurely discontinue before completing all assessments may be 
replaced, at the discretion of the principal investigator (PI) and sponsor study team.
The overall study design is summarized in Figure 1.


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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


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*=if data permits. Abbreviations: A = analyzed using a statistical model; D=displayed with 
descriptive statistics as outlined in Table 6 in Section 6.1.1.1; ln=natural-log transformed; 
R=raw (untransformed).
3.2. Secondary Endpoint(s)

Assessment of treatment emergent AEs, clinical laboratory abnormalities, vital signs, 
ECG parameters.
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.
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)

Additional PF-06882961 Plasma Pharmacokinetic parameters: CL/F, Vz/F, Tmax, t1/2
as data permit.

Unbound PF-06882961 Plasma Pharmacokinetic parameters: Cmax,u, AUCinf,u, 
AUClast,u, CLu/F, Vz,u/F 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


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CL/F*
ln
D
Vz/F*
ln
D
Tmax
R
D
t1/2*
R
D
*=if data permits. Abbreviations: D=displayed with descriptive statistics as outlined in Table 
7 in Section 6.3; 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
D
Vz,u/F*
Dose/(AUCinf,u × kel)
ln
D
*=if data permits. Abbreviations: D=displayed with descriptive statistics as outlined in Table 
7 in Section 6.3; ln=natural-log transformed , R=raw (untransformed).
3.4. Baseline Variables
Not Applicable.
3.5. Safety Endpoints
See Section 3.2.
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. 
Participant Analysis 
Set
Description
Enrolled 
"Enrolled" means a participant's agreement to participate in a 
clinical study following completion of the informed consent 
process.  
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.


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Participant Analysis 
Set
Description
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.
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
Normal hepatic function
Without Hepatic Impairment
2
Mild hepatic impairment
Mild Hepatic Impairment
3
Moderate hepatic impairment
Moderate Hepatic Impairment
4
Severe hepatic impairment
Severe Hepatic Impairment
5.1. Hypotheses and Decision Rules
There is no statistical hypothesis testing planned for this study and no statistical decision 
rules will be applied.
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 one-way analysis of variance (ANOVA) model will include group as a factor.  
Estimates of the adjusted mean differences (Test - Reference), and corresponding 90% CIs, 
will be obtained from the model.  These will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Example 
SAS code is given in Appendix 1.
Additionally, as an exploratory analysis, age and body weight may be explored as an 
additional covariate in the models, as appropriate. This will be implemented by utilizing a 
stepwise linear regression approach, with model selection using Akaike’s Information 


Protocol C3421014 (PF-06882961) Statistical Analysis Plan
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Criterion [AIC]). All the above covariates 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, 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 hepatic function as a continuous explanatory variable 
(using continuous serum albumin, prothrombin time or total bilirubin, each modelled 
separately). Estimates of the slope and intercept, together with a 90% CI, and the coefficient 
of determination (i.e. R-squared and adj-R-squared) will be obtained from the model.
Example SAS code is given in Appendix 1.
Additionally, as an exploratory analysis, age and body weight may be explored as an 
additional covariate 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 will be considered (hepatic function will be 
restricted to always remain in the model) and if the final model selected includes at least one 
of these additional covariates, this additional model will be reported in addition to the main 
linear regression above. Example SAS code is given in Appendix 1.
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), 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.


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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 treatment group/analyte with ≥3 evaluable measurements. 
For statistical analyses (i.e. mixed effect model), 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), this will be footnoted in summary tables and will not be included in 
the calculation of summary statistics or statistical analyses.
6. ANALYSES AND SUMMARIES
Unless otherwise stated, all analyses, summaries and listings will be produced by group (as 
outlined in Section 5) which would include all 4 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.
A one-way analysis of variance (ANOVA) described in Section 5.2.3, that includes all 4 
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 hepatic impairment 
groups (Test, Groups 2, 3, 4) to the healthy normal hepatic function 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 6 below.
Table 6. 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.
6.1.1.2. Exploratory/Supplementary Analysis
Exploratory analysis using linear regression will be used to analyze the potential 
relationship between appropriate PK parameters [eg, AUCinf, AUClast, Cmax and fu] and 
hepatic function (eg, serum albumin concentration, prothrombin time or total bilirubin), as 
described in Section 5.2.3.
Plots of PK parameters (eg, AUCinf, AUClast, Cmax and fu) versus hepatic function (e.g. serum 
albumin, prothrombin time or total bilirubin, plotted separately) will be constructed, with a 
regression line and 90% confidence region included from the main linear regression model.
6.2. Secondary Endpoint(s)
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 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.
6.2.1. 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. 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.


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6.2.3. Vital Signs
Absolute values and changes from baseline in seated 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.
Maximum and minimum absolute values and maximum changes from baseline for seated
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 
categorical summaries. All values meeting the criteria of potential clinical concern will be 
listed. 
6.2.4. 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.
Maximum absolute values and changes from baseline for QTcF, PR and QRS 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 categorical summaries. All values 
meeting the criteria of potential clinical concern will be listed.  
6.3. Other Endpoint(s)
6.3.1. Additional Plasma Pharmacokinetic 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 and summarized 
descriptively 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 7 below.
Table 7. 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:


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
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.

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.
6.3.2. Banked Biospecimens
Banked biospecimens will be collected and retained for future analyses, but will not be 
analyzed specifically for this study and will not be included in the CSR.
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 and safety, which may not 
be produced in one table. Frequency counts and percentages will be supplied for participant 
discontinuation(s) by group.


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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.
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 modeling, and/or supporting clinical 
development. 
7.2. Interim Analyses and Summaries
Not applicable.
8. REFERENCES
None.


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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;
     model pk_p = albumin age 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
CI
confidence interval
CL
Clearance
CL/F
Apparent total body clearance
Cmax
maximum observed concentration
CSR
clinical study report
CV
Coefficient of variation
ECG
Electrocardiogram
IP
Investigational Product
LLQ
Lower limit of quantitation
Ln
Natural log
N/A
not applicable
NC
not calculated
ND
not done
NS
no sample
PK
pharmacokinetic(s)
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
SAP
statistical analysis plan
Tmax
Time to maximum observed concentration
t1/2
Half life
Vz/F
Apparent volume of distribution