Clinical trial NCT04091061
Conditions: Hepatic Impairment Healthy Volunteers
Keywords: Non-alcoholic Fatty Liver Disease Non-alcoholic steatohepatitis
Sponsor: Pfizer
Start date: 2019-10-03; Completion date: 2020-04-07
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 PK of PF-06865571.

Detailed description:

Arms: arm 1: This arm includes participants with moderate hepatic impairment who will receive an oral dose of PF-06865571 100 mg on Day 1 arm 2: This arm includes participants with severe hepatic impairment who will receive an oral dose of PF-06865571 100 mg on Day 1 arm 3: This arm includes participants with mild hepatic impairment who will receive an oral dose of PF-06865571 100 mg on Day 1 arm 4: This arm includes healthy participants who will receive an oral dose of PF-06865571 100 mg on Day 1
Interventions: intervention 1: PF-06865571 100 mg
Intervention descriptions: intervention 1: PF-06865571 in 100 mg oral tablet will be administered on Day 1

Protocol documents:
Prot_000.pdf: 
PF-06865571 
Protocol C2541009
Final Protocol, 27 June 2019
PFIZER CONFIDENTIAL
Page 1of 77
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, 
PARALLEL-COHORT STUDY TO COMPARE THE PHARMACOKINETICS OF 
PF-06865571 IN ADULT PARTICIPANTS WITH VARYING DEGREES OF 
HEPATIC IMPAIRMENT RELATIVE TO PARTICIPANTS WITHOUT HEPATIC 
IMPAIRMENT
Investigational Product Number:
PF-06865571
Investigational Product Name:
Not Applicable
United States(US)Investigational New 
Drug (IND)Number:
European Clinical TrialsDatabase 
(EudraCT) Number:
Not Applicable
Protocol Number:
C2541009
Phase:
1
Short Title:A STUDY TO INVESTIGATE THE EFFECTS OF HEPATIC 
IMPAIRMENT ON THE PHARMACOKINETICS OF PF-06865571
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting orreviewing 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 of Changesand Rationale
Original protocol
27 June 2019
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES...................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis....................................................................................................................8
1.2. Schema......................................................................................................................8
1.3. Schedule of Activities (SoA).....................................................................................9
2. INTRODUCTION...............................................................................................................10
2.1. Study Rationale.......................................................................................................10
2.2. Background.............................................................................................................10
2.2.1. Nonclinical Pharmacokinetics and Metabolism of PF-06865571..............10
2.2.2. Nonclinical Safety and Tolerability............................................................11
2.2.3. Clinical Overview.......................................................................................12
2.3. Benefit/Risk Assessment.........................................................................................12
3. OBJECTIVES AND ENDPOINTS.....................................................................................13
4. STUDY DESIGN.................................................................................................................13
4.1. Overall Design.........................................................................................................13
4.2. Scientific Rationale for Study Design.....................................................................15
4.3. Justification for Dose..............................................................................................17
4.4. End of Study Definition..........................................................................................17
5. STUDY POPULATION......................................................................................................18
5.1. Inclusion Criteria.....................................................................................................18
5.1.1. Participants in All Cohorts..........................................................................18
5.1.2.AdditionalInclusion Criteria for Participants without Hepatic 
Impairment (Cohort 1 Only)............................................................................19
5.1.3.AdditionalInclusion Criteria for Participants with Impaired Hepatic 
Function (Cohorts2, 3, and 4 Only)................................................................19
5.2. Exclusion Criteria....................................................................................................20
5.2.1.AdditionalExclusion Criteria for Participants without Hepatic 
Impairment (Cohort 1 Only)............................................................................21
5.2.2.AdditionalExclusion Criteria for Participants with Impaired Hepatic 
Function (Cohorts2, 3, and 4 Only)................................................................22
5.3. Criteria for Dosing on Day 1...................................................................................24


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5.4. Lifestyle Considerations..........................................................................................24
5.4.1. Meals and Dietary Restrictions...................................................................24
5.4.2. Caffeine, Alcohol, and Tobacco.................................................................25
5.4.3. Activity.......................................................................................................26
5.4.4. Contraception..............................................................................................26
5.5. Screen Failures........................................................................................................26
6. STUDY INTERVENTION..................................................................................................26
6.1. Study Intervention(s) Administered........................................................................27
6.1.1. Administration............................................................................................27
6.2. Preparation/Handling/Storage/Accountability........................................................27
6.2.1. Preparation and Dispensing........................................................................28
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................28
6.3.1. Allocation to Investigational Product.........................................................28
6.4. Study Intervention Compliance...............................................................................29
6.5. Concomitant Therapy..............................................................................................29
6.5.1.Participants Without Hepatic Impairment (Cohort 1, Only)......................29
6.5.2. Participants with Impaired Hepatic Function (Cohorts 2, 3, and 4)...........29
6.5.3. Rescue Medicine.........................................................................................30
6.6. Dose Modification...................................................................................................30
6.7. Intervention After the End of the Study..................................................................30
7. DISCONTINUATION OF STUDY INTERVENTIONAND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................30
7.1. Discontinuation of Study Intervention....................................................................30
7.2. Participant Discontinuation/Withdrawal From the Study.......................................31
7.3. Lost to Follow up....................................................................................................32
8. STUDYASSESSMENTS AND PROCEDURES...............................................................32
8.1. Efficacy Assessments..............................................................................................33
8.2. Safety Assessments.................................................................................................33
8.2.1. Physical Examinations................................................................................34
8.2.2. Vital Signs..................................................................................................34
8.2.3. Electrocardiograms.....................................................................................35
8.2.4. Clinical Safety Laboratory Assessments....................................................35


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8.2.5. Pregnancy Testing......................................................................................36
8.3. Adverse Events and Serious Adverse Events..........................................................36
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......37
8.3.1.1. Reporting SAEs to PfizerSafety...............................................37
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................37
8.3.2. Method of Detecting AEs and SAEs..........................................................37
8.3.3. Follow-up of AEs and SAEs.......................................................................38
8.3.4. Regulatory Reporting Requirements for SAEs...........................................38
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure..........................................................................................................38
8.3.5.1. Exposure During Pregnancy......................................................38
8.3.5.2. Exposure During Breastfeeding................................................39
8.3.5.3. Occupational Exposure.............................................................39
8.3.6. Medication Errors.......................................................................................39
8.4. Treatment of Overdose............................................................................................40
8.5. Pharmacokinetics....................................................................................................40
8.5.1. Plasma for Analysis of PF-06865571.........................................................40
8.6. Pharmacodynamics..................................................................................................41
8.9. Health Economics...................................................................................................42
9. STATISTICAL CONSIDERATIONS................................................................................42
9.1. Statistical Hypotheses.............................................................................................42
9.2. Sample Size Determination.....................................................................................42
9.3. Populations for Analysis.........................................................................................43
9.4. Statistical Analyses.................................................................................................43
9.4.1. Efficacy Analyses.......................................................................................43
9.4.2. Pharmacokinetic Analyses..........................................................................43
9.4.2.1. Pharmacokinetic Analysis Populations.....................................43
9.4.2.2. Derivation of Pharmacokinetic Parameters Prior to 
Analysis.............................................................................................44


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9.4.2.3. Statistical Methods for Pharmacokinetic Data..........................44
9.4.3. Safety Analyses..........................................................................................45
9.4.3.1. Electrocardiogram Analyses......................................................45
9.5. Interim Analyses.....................................................................................................46
9.5.1. Data Monitoring Committee.......................................................................46
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................47
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............47
10.1.1.Regulatoryand Ethical Considerations....................................................47
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................47
10.1.2. Financial Disclosure.................................................................................48
10.1.3. Informed Consent Process........................................................................48
10.1.4. Data Protection.........................................................................................49
10.1.5. Dissemination of Clinical Study Data......................................................49
10.1.6. Data Quality Assurance............................................................................51
10.1.7. Source Documents....................................................................................52
10.1.8. Study and Site Closure..............................................................................52
10.1.9. Publication Policy.....................................................................................53
10.1.10. Sponsor’s Qualified Medical Personnel.................................................53
10.2.Appendix 2:Clinical Laboratory Tests.................................................................55
10.3. Appendix3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting......................................................................57
10.3.1. Definition of AE.......................................................................................57
10.3.2. Definition of SAE.....................................................................................58
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................59
10.3.4. Reporting of SAEs....................................................................................62
10.4.Appendix 4:Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................63
10.4.1. Male Participant Reproductive Inclusion Criteria....................................63
10.4.2. Female Participant Reproductive Inclusion Criteria.................................63
10.4.3. Woman of Childbearing Potential (WOCBP)..........................................64


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10.4.4. Contraception Methods.............................................................................65
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments........69
10.7. Appendix 7: ECG Findings of Potential Clinical Concern...................................71
10.8.Appendix 8: Child-Pugh Classification (CPC) of Liver Dysfunction...................73
10.9. Appendix 9: Abbreviations...................................................................................74
11. REFERENCES..................................................................................................................77
LIST OF TABLES
Table1.
Hepatic Function Categories Based on Child Pugh Score........................14
Table2.
90% Confidence Intervals (With 80% Tolerance Probability) for 
Various Possible Effects in AUCinfand C
maxWith n=6 
Participants/Cohort...................................................................................43
Table3.
Plasma PK Parameters..............................................................................44
LIST OF FIGURES
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Figure 1.
Study Design.............................................................................................15


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1.PROTOCOL SUMMARY 
1.1.Synopsis
Not applicable.
1.2.Schema


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1.3.Schedule of Activities(SoA)  
The table provides an overview of the protocol visits and procedures.  Refer toSTUDY ASSESSMENTS AND PROCEDURES
section of the protocol for detailedinformation 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 SoAtable, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifier/Day
[for list of abbreviations referto Section 10.9]
Screen
≤-28 to -2
Day 
-1
Day 1
Day 2
Day 
3a
Day 
4a
ET
Follow-Up
Day 30±2
HoursPost Dose
--
0 0.5 1 2 4 6 7 8 10 12 14 16 24 36 48
72
--
--
Informed consent & demography 
x
Outpatient visit 
x
xa
x
Inpatient stay at Clinical Research Unit 
x

  
   
xa
xa
Eligibility assessment 
x 
x
Medical history
x 
x
Physical exam (height & body weight at Screen, only)b
x 
x
xc
xc
x
Breath alcohol test
x 
x
Alcohol/tobacco & contraception use
x 
x
xc,d
x 
xe
(Update) prior/concomitant treatments
x 
x
xc,d
x 
x
Single, supine12-lead ECG
x
x
xc
xc
x
Single, seatedvital sign assessment (BP and pulse rate)
x
x
xc
xc
x
Serious and non-serious adverse event monitoring
x 
x

  
   
xc
xc
x 
x
Standard mealsf
x x
x 
x 
x 
x 
x 
x 
xc
Investigational product administration
xg
Blood for clinical laboratory tests after ≥4-hour fast
x
x
xc
xc
x
Blood FSH (females only), HIV, HBsAg, HCVAb/RNA
x
Blood for pregnancy test (females only)
x
x
xc
xc
x
Blood for pharmacokinetic sampling for PF-06865571
x x x x x x 
x x x 
x x x 
x 
xc
x
Urine drug test
x
Urinalysis (and microscopy, if needed)
x
x
xc
xc
x
Urine pregnancy test (WOCBP, only)
x
a.Participants discharged post completion of procedures (Cohort 1, only); in Cohorts 2-4, discharge (with subsequent outpatient visit) permitted orstay can continue to Day4.
b.Full physical (PE) exam at Screen; at all other time points, limited PE for findings during previous PE or new/open AEs only, at Investigator discretion.
c.On Day 3, procedures limited to Cohort 1, only; on Day 4, procedures limited to Cohorts 2-4, only.
d.In Cohorts 2-4 only, procedures to be completed only ifparticipant is discharged on Day 3 and returns for outpatient visit on Day 4.
e.Confirmation of appropriate contraception use only.
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f.Meals/snacks to be served at clock times matching approximately 0H, 4H, 7H, 10H, and 14H (optional) relative to dosing on Day1 (while inpatient).
g.Dosing to occur with standard morning meal provided approximately 30minutes prior to 0H, and completed approximately 10minutes prior to dosing.


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2.INTRODUCTION
Diacylglycerol acyltransferases (DGATs) catalyze the terminal step in triglyceride (TG) 
synthesis; specifically, the esterification of a fatty acid (FA) with diacylglycerol (DAG) 
resulting in the formation of TG.
1 In mammals, 2 structurally unrelated DGAT enzymes 
(DGAT1 and DGAT2) have been characterized. DGAT1 is highly expressed in the intestine 
and plays a central role in fat absorption.
2 DGAT2 is highly expressed in liver and adipose.
3
PF-06865571 is an oral, small molecule DGAT2 inhibitor that is postulated to decrease 
hepatic TG synthesis and hepatic lipid burden in non-alcoholic fatty liver disease (NAFLD) 
and non-alcoholic steatohepatitis (NASH).  Based on observations in nonclinical studies 
conducted with PF-06865571, it is hypothesized that DGAT2 inhibition will impact both 
physiological drivers contributing to NASH via direct inhibition of liver triglyceride 
synthesis, as well as adaptive responses leading to reduction in hepatic de novo lipogenesis 
(DNL). Following 2weeks of dosing inparticipants with NAFLD, PF-06865571 has been
shown to reduce liver fat in a dose-responsive manner.
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-06865571 following administration of asingle, oral, 100mg doseof PF-06865571.  
NAFLD/NASH is associated with varying degrees of hepatic impairment.  Recognizing that 
the target population of PF-06865571 is patients with NAFLD/NASH and
 
 the current study is 
proposed to evaluate whether there is any clinically meaningful effect of hepatic impairment 
on the plasma PK of PF-06865571.
2.2.Background 
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2.2.3.Clinical Overview
As of the issuance of this protocol, 6 clinical studies have completed dosing with 
PF-06865571 (C2541001, C2541002, C2541003, C2541005, C2541006, and C3711002). 
Refer to the PF-06865571 investigator’s brochure for more details on Studies C2541001, 
C2541002, C2541003, and C3711002. 
 
 A total of 168participants have been 
randomized across the 6clinical studies andexposed to at least 1dose of the investigational 
product (PF-06865571, and/or matching placebo) across the clinical studies conducted with 
PF-06865571.
 
 
 
 
 
 
 
 
 
 
 
 
2.3.Benefit/Risk Assessment
PF-06865571is not expected to provide any clinical benefit to participantsinthis study.  
This study is designed primarily to generate pharmacokinetic datato inform furtherclinical 
development in the target population of patients withNASH. The data from this study will 
contribute to dosing recommendations of PF-06865571 for the treatment of NASH 
acknowledging that the target patient population includesthose with varying degrees of 
hepatic impairment.  
PF-06865571 has been administered as single doses in healthy subjects, as repeated doses in 
healthy adults and patients with NAFLD, and as modified-release formulation, as well as in 
combination with metformin.It has been observed to be well-tolerated with an acceptable 
safety profile atsingle oral doses as high as 1500mg and repeated, oral doses of upto 
1800mg/day (as 600mg every 8hours [Q8H]) for a duration of up to 14dayswith the 
maximum tolerated dose not identified. As of the issuance of this protocol, no specific 
human risks have been identified.The clinical impact of anypotential
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risks in this study will 
be minimized through the proposed close, inpatient monitoring during the dosing period
along with the selection of a dose (100mg) which is 15-fold lower than the highest single 
dose administered thus far.  
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Based on the safety profile of PF-06865571 observed in clinical studies to date, the risk to 
the participantsin this studyis deemed to be minimal. More detailed information about the 
known and expected benefits andrisks and reasonably expected adverse events of 
PF-06865571may be found in the investigator’s brochurefor PF-06865571, 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-06865571 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.

PF-06865571 PK parameters 
derived from plasma: Cmax, AUC
last, 
andAUCinf.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of a single oral dose of 
PF-06865571 when administered to adult participants with 
varying degrees of hepatic impairment relative to age-and 
body weight-matched participants without hepatic 
impairment.

Assessment of treatment-emergent 
adverse events, clinical laboratory 
tests, vital signs, and 12-lead ECGs.
 
 
 
 
 
 
 
 
 
 
  
 
 
 
4.STUDY DESIGN
4.1.Overall Design
This is aPhase1, non-randomized, open-label, single-dose, parallel-cohort, multicenter study 
to compare the pharmacokinetics of PF-06865571 in adult participants with varying degrees 
of hepatic impairment relative to participants without hepatic impairment after a single, oral 
100mg dose administered in the fed state.  A total of approximately 24participants with 
varying degrees of hepatic function will be dosedin the study as shown in Table1
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Table1. Hepatic Function Categories Based on Child Pugh Score
Cohort
Description
Child-Pugh Score
Number of Subjects
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 ±5years and 
mean body weight ±10kg of this cohort is aligned with the pooled average assessed when ≥75% of 
participants are dosed across the other 3cohorts.
b. If recruitment across the sites selected proves to be prohibitive, study will dose only 4participants in this 
cohort. 
Categorization of participantsinto 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 
dosedin a staged manner suchthat those with moderate and severe hepatic impairment 
(Cohorts3 and 4) will be evaluated first.  Dosing inparticipants with mild hepatic 
impairment (Cohort2) will initiatewhen approximately 50% of the total participants in 
Cohorts3 and 4 have been dosed.  Participants without hepatic impairment (Cohort1) will be 
recruited near the end of the studyto match the average demographics (at a minimum, age 
and weight; and gender as much as practically possible) across the pooled Cohorts2 through 
4.  Approval from the sponsor must be obtained before proceeding with recruitment for
participants in Cohort1 or Cohort2.
Participants who prematurely discontinue for non-safety related reasons may be replaced, at 
the discretion of the principal investigator (PI) and sponsorstudy team.
The overall study design is summarized inFigure 1.  For individual participants, the total 
duration of participation from the Screening visit to the follow-upvisit willrange from 
5weeks (minimum) to 9weeks (maximum).


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Figure 1. Study Design
4.2.Scientific Rationale forStudy Design
This study involves participants withvarying degrees of hepatic impairment and participants 
without hepatic impairment, matched for age as well as body weight (and gender as much as 
practically possible). Asingle dose of PF-06865571 is proposed since single dose plasma 
PK is generally predictive of exposure upon repeated dosing,especially given that the 
observed relatively short terminal half-life (t
½)of PF-06865571 resulted in minimal 
accumulation upon repeated dosing of both Q8Hand Q12H frequency.  
 
serial PK samples will be collected over 48hours in participants 
without hepatic impairment(Cohort1). 
 
 
serial PK samples will be 
collected over72hours postdose to adequately characterize the elimination phase of the 
plasma concentration-time profile in the cohorts with varying degrees of hepatic function
(Cohorts2-4). 
Malnutrition is prevalent in patients with chronic liver disease, and regular meals are an
important aspect fortheir health. 
 
 PF-06865571 administration is planned to occur with the morning standard 
meal in this study to ensure consistency with the intended dosing scheme in the target patient 
population.  
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In general, participants with normal hepatic function (Cohort1) will abstain from all 
concomitant treatments, except forthe treatment of adverse events. Participants with 
impaired hepatic function (Cohorts2, 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.  Specfically, strong CYP3A inhibitors, strong and moderate CYP3A 
inducers, and time-dependent inhibitors of CYP3A are excluded from this study in 
participants with impaired hepatic function
 
In 
addition, moderateCYP3A inhibitors will not be co-administered with PF-06865571 on 
Day1 of this study.  Similarly, BCRP substrates (eg, rosuvastatin) and sensitive CYP2C9 
substrates will not be administered onDay 1
 
P-gp 
inhibitors (eg, digoxin) are excluded from this study.
 
 
articipants taking metformin must not take a morning dose of 
metformin on Day 1 of this study. 
The Child-Pugh classification (CPC; refer to Appendix 8) will be used to define the 3cohorts 
of participantswith varying degrees of hepatic impairment.  This study will include 
participantswith mild (Child-Pugh ClassA, Cohort2), moderate (Child-Pugh ClassB, 
Cohort3), and severe (Child-Pugh ClassC, Cohort4) hepatic impairment as well as 
demographic-matched control participantswithout hepatic impairment(Cohort1).  All 
3categories of hepatic impairment will be assessed, as these represent the likely population 
in later phase studies for the proposed indication of treatment of NASH.  All participantswill 
be required to provide their own consent to participate in this study,hence participantswith 
clinically-active Grade3 or Grade4 encephalopathy will be excluded.  However, participants
who have a previoushistory of Grade3 or Grade 4 encephalopathy but are currently 
receiving an intervention [for example: lactulose or lactitol, alone or in combination with 
rifaximin, and/or neomycin] to control their encephalopathy-related signs and symptoms are 
eligible provided the on-treatment
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encephalopathy grading at the Screening visit is Grade2 
or lower thereby permitting them to provide their own informed consent.  Acknowledging the 
medical state of the population enrolled, certain eligibility criteria for participantswith 
hepatic impairment are distinctly different, including assessment of HepatitisB and 
HepatitisC, with no specific exclusion of those who have these conditions planned for 
participantsclassified in Cohorts2, 3, or 4.  
 participantswill be excluded if there is 
concomitant clinical evidence of renal impairment,defined as estimated glomerular filtration 
rate (eGFR) ≤60mL/min.  This is to enable a more clear assessment of the effect of hepatic 
impairment on PF-06865571disposition. 
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 all female participants of childbearing potential, 
at risk of pregnancy, are required to use highly effective methods of contraception during this 
study.  In addition, male participants must use barrier methods of contraception to minimize 
transfer of drug to their female partner(s).  Refer to Section 10.4for details regarding 
contraception guidance.
 
4.3.Justification for Dose
A single oral dose of 100mg PF-06865571 will be usedin this study. Dosing will occur in 
the fed state, consistent with previous clinical studies with PF-06865571.This dose has been 
selected based on prior experience in healthy participantsand also takes into considerations 
that participantswith varying degrees of hepatic impairment may have anincrease in plasma 
PF-06865571 exposure.  PF-06865571 was found to be well-tolerated with single doses up to 
1500mg (C2541001) and repeated doses up to 1800mg/day (600mg Q8H; C2541002)with 
the maximum tolerated dose not identifiedwhen administered to healthy adult participants.  
The PK of PF-06865571 is approximately dose-proportional, and the results at the proposed 
dose of 100mg in this studycan be extrapolated to other doses.  While the PF-06865571 
dose in this study represents half the maximum total daily dose/exposure of 300mgBID 
envisioned in the Phase2b, dose-ranging/dose-finding study, it is likely to be within the 
efficacious dose range (based on effect on liver fat observed following 14-days of dosing in 
those with NAFLDin Study C2541005).
For a single 100mg dose of PF-06865571, Simcyp
®simulations predict C
maxincreases of 
1.2-,1.3-, and 1.5-fold in participants with Child-Pugh classifications A, B, and C, 
respectively.  AUCinfincreases of 1.4-, 2.1-, and 2.9-fold, respectively, are also predicted. 
The terminal t½is predicted to increase by <2-fold.In addition, these predictions are in line 
with less than 3-fold exposure increases observed in participants with moderate or severe 
hepatic impairment in clinical studies with sensitive CYP3A substrates, including midazolam 
and triazolam.
4,5 Thus, a 3-fold increase likely represents the worst-case estimate for change 
in plasma exposure in this study in those with severe hepatic impairmentand are not likely to 
pose a safety concern if observed in this study.
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
CCI
.
CCI


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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 participantis suitable for this 
protocol.
Prospective approval of protocol deviationsto recruitment and enrollment criteria,also 
known as protocol waivers or exemptions, is not permitted.
5.1.Inclusion Criteria
5.1.1.Participants in All Cohorts
Participants are eligible to be includedin the study only if all of the following criteria apply:
Age and Sex:
1. Male and female participants between the ages of 18 (or the minimum 
country-specific age of consent if >18) and 70years, inclusive, at the Screening visit:
Refer to Appendix4for reproductive criteria for male (Section10.4.1) and female 
(Section10.4.2) 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 17.5to 35.4kg/m2, inclusive; and a total body weight 
>50kg (110lb),at the Screeningvisit; with a single repeat assessment of total body 
weight (and hence BMI), on a separate daypermitted 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.


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5.1.2.AdditionalInclusion Criteria for Participants without Hepatic Impairment 
(Cohort 1 Only)
1. At Screening, no clinically relevant abnormalities identified by a detailed medical 
history, full physical examination, including blood pressure and pulse rate 
measurement, 12-lead ECG and clinical laboratory tests, as assessed by the 
sponsor-identifiedcentral laboratory.
2. At Screening, participants must meet the demographic-matching criteria, including:
A body weight that is ±10kg of the average of the pooled hepatic impairment 
cohorts (Cohorts2, 3, and 4), as provided by the sponsor;
An age that is ±5years of the average of the pooled hepatic impairment cohorts 
(Cohorts2, 3, and 4), as provided by the sponsor;
Attempts will be madeto ensure that the male-to-female distribution in Cohort1 
is comparable to that in the pooled hepatic impairment cohorts (Cohorts2, 3, 
and4).
3. No known or suspected hepatic impairment; including at Screening. Partcipants meet 
allthe 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 directbilirubin level is ULN plusALT and AST 
are ULN plusalkaline phosphatase, hemoglobin, andreticulocyte count are all 
ULN; 
Albumin ULN;
Prothrombin timeULN.
5.1.3.AdditionalInclusion Criteria for Participants with Impaired Hepatic Function 
(Cohorts2, 3,and 4 Only)
1. Stable hepatic impairment that meets the criteria for ClassA, B, orC of the modified 
Child-Pugh classification (refer to Appendix 8) with no clinically significant change 
in disease status within the 28days 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%).


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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 
Section5.4of this protocol.  
5.2.Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection). 
NOTE: Participants whohave undergone cholecystectomy and/or appendectomy are 
eligible for this study as long as the surgery occurred more than 6months 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. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into 
this study.
Prior/Concomitant Therapy:
4. Use of prior/concomitant therapies as outlined in Section 6.5.
Prior/Concurrent Clinical Study Experience:
5. Previous administration with an investigational drug within 30days(or as determined 
by the local requirement) or 5half-lives preceding the first dose of investigational 
product used in this study (whichever is longer).
6. Participants with known prior participation (ie, randomized and received at least 
1dose of investigational product) in a study involving PF-06865571.


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Diagnostic Assessments:
7. A positive urine drug test, for illicit drugs on Day -1, as assessed by 
sponsor-identified central laboratory.  However, participants in Cohorts2-4, 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.
8. At Screening orDay -1, a positive breath alcohol test, as assessed usingkits provided 
by sponsor-identified central laboratory, with a single repeat on a separate day
permitted to assess eligibility, if needed.
Other Exclusions:
9. Male participants with partners who are currently pregnant.
10.Blood donation (excluding plasma donations) of approximately 1pint (500mL) or 
more within 60days prior to dosing and until the follow-up contact.
11.History of sensitivity to heparin or heparin-induced thrombocytopenia, only if heparin 
is used to flush intravenous catheters used during serial blood collections. 
12.Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
13.Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study. 
5.2.1.AdditionalExclusion Criteria for Participants without Hepatic Impairment 
(Cohort 1 Only)
Participantspresenting with any of the followingwill not be included in the study:
1. Evidence of chronic liver disease including history of hepatitis, hepatitisB, or 
hepatitisC or evidence of any of the following, as assessed by sponsor-identified 
central laboratory, with a single repeat, permitted to assess eligibility, if needed:
HepatitisB virus, defined by presence of hepatitisB surface antigen (HBsAg);
NOTE: while notpart of the tests assessedin this study, participants with a 
previously positive hepatitisB surface antibody result due to vaccination are 
deemed eligible;


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Hepatitis C infection, defined by presence of hepatitisC 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 [240mL] beer, 
1ounce [30mL] of 40% spirit or 3 ounces [90 mL] of wine).
3. Screening supine12-lead ECG demonstrating Fridericia method-corrected QT 
(QTcF) interval >450millisecond (msec)or a QRS interval >120msec.  If QTcF 
exceeds 450msec, or QRS exceeds 120msec, 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 seatedsystolic blood pressure (SBP) 140mm Hg or diastolic blood 
pressure (DBP) 90mm Hg, following 5minutes of seated rest.  If SBP is 
140mmHg or DBP 90mm Hg, the blood pressure (BP)assessment should be 
repeated 2 more times and the average of the 3BP values should be used to determine 
eligibility.
5. Use of chronicprescription medications within 7days or 5half-lives (whichever is 
longer) prior to Day1;
NOTE:Useof selected, limited prescription and non-prescription medications is 
permitted (refer to Section 6.5fordetails). 
6. Otheracute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into 
this study.
5.2.2.AdditionalExclusion Criteria for Participants with Impaired Hepatic Function 
(Cohorts2, 3, and 4 Only)
Participantspresenting with any of the following will notbe included in the study: 
1. Hepatic carcinoma orhepatorenal syndrome orlimited predicted life expectancy 
(defined as less than1year in Cohorts2 & 3 and less than 6monthsfor Cohort4 
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, ormagnetic resonanceimaging 
(MRI).


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3. History of surgery that would be expected to alter absorption, distribution, 
metabolism, or excretion (ADME) properties of PF-06865571(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 4weeksprior to Screening.
5. Signs of clinically active Grade3 or Grade 4 hepatic encephalopathy (ie,>Grade2 
Portal Systemic Encephalopathy score; refer to Appendix 8).
6. Severe ascites and/or pleural effusion, except for those categorized in Cohort4 who 
may be enrolled provided participant is medically stable, per the investigators’ 
medical judgment.
7. Participants who have previously had a transplanted kidney, liver, or heart.
8. Screening supine12-lead ECG demonstrating a QTcF interval >480msec or a QRS 
interval >120msec.  If QTcF exceeds 480msec, or QRS exceeds 120msec, the ECG 
should be repeated 2more times and the average of the 3QTcF or QRS values should 
be used to determine eligibility.
9. At Screening, persistent severe, uncontrolled hypertension; for example: seated
systolic blood pressure (SBP) 180mmHg and/or diastolic blood pressure (DBP) 
105mmHg after 5-minute of seated rest, with a single repeat permitted to assess 
eligibility, if needed, at each of these 2visits:
For participants with SBP 160(and <179) mm Hg orDBP ≥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 blood pressure with the aim to have stableBP 
byDay1[refer to Section 5.3].
10.Participants with ALT orAST>5x ULNon clinical laboratory tests at Screening, as 
assessed by the sponsor-identified central laboratory, with a single repeat permitted to 
assess eligibility, if needed.
11.At Screening, participants with an estimated glomerular filtration rate (eGFR) of 
≤60mL/min/1.73m
2using the Modification of Diet in Renal Disease (MDRD) 
equation, and serum creatinine (SCr), as assessed by the sponsor identified central 
laboratory, with a single repeat permitted to assess eligibility, if needed.


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5.3.Criteria for Dosing onDay 1 
Participantswill progress to dosing on Day1 provided they have satisfied allthe following 
criteria:
Breath alcohol test, using kits provided by sponsor-identified central laboratory,on 
Day -1 is negative;
In females of childbearing potential, urine pregnancy test on Day1 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 bysites’ local laboratory on 
Day-1, if performedat investigator discretion, upon review on Day1 must reflect the 
participantto be in stable medical condition;
Cohort 1 only:Approval from the sponsor must be obtained before proceeding with 
dosing participants in Cohort 1;
Cohorts 2 and 3 only:Participants must have measurement on Day1 of 
SBP≤159mm Hg andDBP ≤99mm Hg–
A single repeat assessment is permitted, to confirmthat the abovecriterion is met 
[and in such cases, the repeat assessment overrides initial results]; 
Cohort 4 only:Participants must have measurement on Day1 of SBP≤159mm Hg 
andDBP ≤105mm 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]. 
5.4.Lifestyle Considerations
After confirmation of eligibility,the participants will be instructed to maintain the guidelines 
described below for the duration of participation in the study. 
5.4.1. Meals and Dietary Restrictions
Participants must abstain from all food and drink (except water) at least 4hours prior 
to all fasting clinical laboratory evaluationsand at least 10hours prior to the 
collection of the predose pharmacokinetic (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 overnightfast of at least 10 hours, participants should 
begin breakfast approximately 30 minutes prior to PF-06865571 administration. 
The breakfast will be consumed over approximately a 20-minute period with 
PF-06865571 administered within approximately 10 minutes of completion of the 
meal. Participants will be encouraged to complete the entire breakfast. There 
will beno 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 Day1 (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 
3200kcal; 
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 eachis envisioned to constitute less than 1000calories;
Participants will refrain from consuming red wine, grapefruit, or 
grapefruit-related citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 
7days prior to Day 1 anduntil collection of the final PK blood sample.  
5.4.2.Caffeine, Alcohol, and Tobacco
Participants will abstain from alcohol for ≥24hours prior to admission for inpatient 
stay(plus have a negative breath alcohol test on Day-1) and continue abstaining from 
alcohol until the follow-up contact; 
Consumption of caffeinated drinks and 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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5.4.3.Activity
Participants will notbe permitted to engage in physically strenuous exercise (for
example: heavy lifting, weight training, calisthenics, and aerobics) within 48hours 
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.
5.4.4.Contraception
At the Screening visit, the investigator or his or her designee, in consultation with the 
participant, will confirm that the participanthas selected an appropriate method of 
contraception for the individual participantand his or her partner(s) from the permitted list of 
contraception methods (see Appendix4 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 participantof the need to use 
highly effective contraception consistently and correctly and document the conversation and 
the participant’s affirmationin 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 participantto call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the participant
or partner.
5.5.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 setreported in the clinical database.
In this study,participants may be re-screened.  This is permitted when, due to logistical 
constraints, the maximum period between Screening Visit and Day1, of 28days,is 
exceeded.  In addition, for participants in Cohorts2-4, inclusive, only, re-screening may be 
appropriate following mild intercurrent illness after the condition has resolved.  In such 
cases, all screening procedures must berepeated 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 beforeprogressing to Day1.
6.STUDYINTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.


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6.1.Study Intervention(s) Administered
For this study, the investigational product isPF-06865571, supplied by Pfizeras tablets, each 
containing100mg of active drug.  
Tablets will be supplied to the clinical research unit (CRU)aspackagedbottles forunit 
dosingand labeled according to local regulatory requirements.
6.1.1.Administration
Following an overnight fast of at least 10hours, participants will receive breakfast as 
outlined in Section 5.4.1(Meals and Dietary Restrictions).  The participants will then receive 
investigational product at approximately 08:00hours (plus or minus 2hours).  Investigator 
site personnel will administer investigational product with ambient temperature water to a 
total volume of approximately 120mL.  Participants will swallow the investigational product 
whole, and will not manipulate or chew the investigational product 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 interventionsreceived and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). All study 
interventionswill be accounted for using aninvestigational product accountability 
form/record.
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the investigational product (IP) manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventionsshould be stored in their original containers and in accordance 
with the labels. 


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7. Any excurstions 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 interventionmust be quarantined and not used until Pfizer provides permission 
to use the study intervention.  It will not be considered a protocol deviation if Pfizer 
approves the use of the study interventionafter the temperature excursion.Use of the 
study interventionprior to Pfizer approval will be considered a protocol deviation. 
Specific details regarding the definition of an excursion and information the site 
should report for each excursion will be provided to the site in the IP manual.
8. The sponsor or designee will provide guidance on the destruction of unused study 
intervention(eg, at the site).  If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer, and all destruction must be adequately 
documented.
6.2.1.Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the participantby 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying informationby qualified staff member(s) to a 
healthcare provider, participantin accordance with this protocol.  Local health authority 
regulations or investigator site guidelines may use alternative terms for these activities.
Investigational product should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, pharmacy assistant/technician, or pharmacist) as allowed by local, state, and 
institutional guidance.
PF-06865571will be prepared by qualified site personnel according to the IP manual. 
The PF-06865571 tabletwill be provided to the participant in a unit dose container.
6.3.Measures to Minimize Bias: Randomization and Blinding
6.3.1.Allocation to Investigational Product
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 4digits of the SSID will 
reflect the sponsor-assigned site number and the remaining 4digits will reflect each 
participant’sunique number assigned in chronological order of when informed consent is 
obtained. Separately, prior to dosing on Day1, each participant will be assigned a 4-digit 
number consisting of site number (first digit), cohort (second digit) and chronological order 
of dosing, at a given site (third and fourth digit).


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6.4.Study Intervention Compliance
Investigational product will be administered under the supervision of investigator site 
personnel.  The oral cavity of each participant will be examined following dosing to ensure 
the investigational product was swallowed.
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.
Treatments taken within 28 daysbefore dosing on Day1will be documented as a prior 
treatment.  Treatments taken after the first dose of investigational product will be 
documented as concomitant treatments.
Females using hormonal contraceptives or taking hormone replacement therapy are eligible 
to participate in this study.
6.5.1.Participants Without Hepatic Impairment(Cohort 1, Only)
In general, participants will abstain from all concomitant treatments, except for the treatment 
of adverse events.  Of note, the following restrictions:
Acetaminophen/paracetamol may be used at doses of ≤1g/day;
Herbal supplements must be discontinued at least 28 days priorto Day 1 and until the 
follow-up contact;
Limited use of prescription and non prescription 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 medicalcondition(s).  Whenever possible, attempts must 
be made to notalter the doses and regimens of the concomitant medications after Day1 and 
until the follow-up contact.
Participants on the following medications, at the Screening visit, are excludedfrom 
the study:
Potent CYP3Ainhibitors(eg, boceprevir, clarithromycin, conivaptan, grapefruit 
juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole);
Time-dependent CYP3A inhibitors (eg, diltiazem, erythromycin, and verapamil);


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Potent and moderate CYP3Ainducers(eg, avasimibe, bosentan, carbamazepine, 
efavirenz, etravirine, modafinil, nafcillin, phenytoin, rifampin, St. John’s wort);
P-gp substrates (eg, digoxin);
(Medical grade) marijuana, regardless of medical indication.
Participants must not take the following medications on Day 1of this study:
Moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, 
ciprofloxacin, crizotinib, darunavir/ritonavir, fluconazole, fosamprenavir, 
imatinib);
Sensitive CYP2C9 substrates and substrates with a narrow therapeutic range 
(eg,fluvastatin, diclofenac, celecoxib, torsemide, warfarin, phenytoin).
Participants must not take a morning dose of the following medications on Day1of 
this study:
OCT2/MATE1 substrates (eg, metformin);
BCRP substrates (eg, rosuvastatin, atorvastatin, simvastatin, fluvastatin).
Herbalsupplements must be discontinued at least 28daysprior to Day1 and until the 
follow-up contact.
6.5.3.Rescue Medicine
There is no rescue therapy to reverse the adverse events (AEs)observed with PF-06865571; 
standard medical supportivecare must be provided to manage the AEs. 
6.6.Dose Modification
By design, this study only includes administration of a single, oral dose of PF-06865571.  As 
such, dose modifications will not be made during the study.
6.7.Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7.DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant who was dosed on Day1 to 
permanently discontinue from the study.  In such circumstances, procedures outlined under 
early termination visit in the Schedule of ActivitiesTable must be attempted.  


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See the SoAfor data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.2.Participant Discontinuation/WithdrawalFrom the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.See the SoAfor assessmentsto be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuationvisit applies only to participants who are randomized and then are 
prematurely withdrawn from the study.  Participants shouldbe questioned regarding their 
reason for withdrawal.  The participant will be permanently discontinued both from the study 
intervention and from the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but dataalready generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.
If the participant withdraws from the study and also withdraws consent (see below) 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.
When a participantwithdraws from the study because of an serious adverse event (SAE), the 
SAE must be recorded on the case report form (CRF)and reported on the Clinical Trial (CT)
SAE Report.
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.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment 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 participantspecifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participantto 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 investigational product 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 participantis alive or dead) is being measured, 


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publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
7.3.Lost to Followup 
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, 3telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole ishandled as part of Appendix1.
8.STUDY ASSESSMENTS AND PROCEDURES
Participants will be screened within 28days prior to administration of the investigational 
product to confirm that they meet the study population criteria for thestudy.  The investigator 
(or an appropriate delegate at the investigator site) mustobtain a signed and dated ICD
before performing any study-specific procedures.  If the time between screening and dosing 
exceeds 28days as a result of unexpected delays (eg, delayed drug shipment), then 
participants do not require rescreening if the laboratory resultsobtained prior to first dose 
administrationmeet eligibility criteria.
A participantwho qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study.  
 
Study procedures and their timing are summarized in the SoA
C
CI
. Protocolwaivers or 
exemptions are not allowed.


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Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time theremay 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-requiredtest 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.
Ifan intravenous (IV) catheter is utilized for blood sample collections, ECGs and vital sign 
assessments (pulse rate andBP) 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.
The total blood sampling volume for individual participants in this study is approximately
175mL.  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 exceed300mL during any period of 60consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerationsand Concomitant Therapysections of the protocol.
8.1.Efficacy Assessments
Analysis of efficacy is not applicable to this study. 
8.2.Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.


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8.2.1.Physical Examinations
Physical examinations may be conducted by a physician, trained physician
's assistant, or 
nurse practitioner as acceptableaccording to local regulation as defined in theSchedule of 
Activities. 
A full physical examinationwill include head, ears, eyes, nose, mouth, skin, heart 
and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and 
neurological systems. 
A limited physical examinationwill be focused on general appearance, the 
respiratory, cardiovascular, and neurological systems, as well as towards participant 
reported symptoms, performed at Investigator discretion.
For measuring body 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.  Theymust 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 collectiontimes of blood pressure and pulse rate 
will be permitted,as necessary, to ensure appropriate collection of safety data.
Single, seatedblood pressure/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 ≥5minutes;
Same arm (preferably the dominant arm) will be used for blood pressure/pulse rate 
assessment throughout the study;
Blood pressure/pulse rate assessment should notbe taken from the arm with an 
intravenous catheter, if placed;
Participants should be instructed notto speak during blood pressure/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 
30seconds.  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.


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8.2.3.Electrocardiograms
Supine12-lead ECGs should be collected at times specified in the SoAsection of this 
protocolusing an ECG machine that automatically calculates the heart rate and measures PR, 
QT, and QTcF intervals and QRS complex.  All scheduled ECGs should be performed after 
the participant has rested quietly for at least 10minutes 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 ≥30msec from the baseline andis >450msec; or 
b)an absolute QTcF value is ≥500msec for any scheduled ECG.  If either of these conditions 
occurs, then 2additional ECGs will be collected approximately 2to 4minutes 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 2successive ECGs fall below the threshold value that triggered the repeat 
measurement.
If a postdose QTcF interval remains ≥30msec from the baseline andis >450msec; or b) an 
absolute QTcF value is ≥500msec for any scheduled ECG for greater than 4hours (or 
sooner, at the discretion of the investigator), or QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTcF intervals do not return to less than the criterion listed above after 8hours 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 valuesof potential clinical concern are listed inAppendix7.
8.2.4.Clinical Safety Laboratory Assessments
See Appendix 2for the list of clinical safety laboratory tests to be performed and the SoAfor 
the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associatedwith 
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 daysafter 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.


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If such values do not return to normal/baseline within aperiod of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.5.Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25mIU/mL.  Urine pregnancy tests will be performed in women of childbearing potential 
(WOCBP)at the times listed in the SoA, onsite.  In addition, blood sample will be analyzed 
by the sponsor-identified central laboratory, in all females consented in this study.  In 
WOCBP, following a negative pregnancy test result at screening, appropriate contraception 
must continue orbe commenced and a second negative pregnancy test result will be required 
at the baseline visit (ie, urine testing on Day 1) priortothe participant’sreceiving the 
investigational product.  Pregnancy tests will also be done whenever 1menstrual 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 
institutional review boards (IRBs)/ethics committees (ECs) or if required by local 
regulations.  On Day1, if a urine test cannot be confirmed as negative (eg, an ambiguous 
result), a serum pregnancy test is requiredwith results reported by the sponsor-identified 
central laboratory; and in this case, dosing with PF-06865571 must be delayed.  The 
participant must be excluded if the serum pregnancy result is positive.
8.3.Adverse Events and Serious Adverse Events
The definitions of an AE and anSAE can be found in Appendix 3.
AEswill be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant
's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study(see Section7). 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.


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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 participantbegins from the time the participantprovides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar daysafter the last administration of the investigational product.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF),not the AE section.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AEsor SAEsafter conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1.Reporting SAEs to Pfizer Safety
All SAEs occurring in a participantduring the active collection period are reported to Pfizer 
Safety on the CT SAE ReportForm immediately and under no circumstance should this 
exceed 24hours, asindicated in Appendix 3. The investigator will submit any updated SAE 
data to the sponsor within 24hours of it being available.
SAEs occurring in a participantafter the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
8.3.1.2.Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
8.3.2.Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEsand SAEsand 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 
AEoccurrences.


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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 informationwill 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 participantdeath, 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 anSAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study interventionunder clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing anSAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.
8.3.5.Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24hours of investigator 
awareness.
8.3.5.1.Exposure During Pregnancy
Details of all pregnancies in female participants or female partners of male participants will 
be collected after the start of study intervention and until the follow-up contact.
If a pregnancy is reported, the investigator should inform the sponsor within 24hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix4.


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Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2.Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3.Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participantenrolled 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.Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the investigational product 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 
24Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:
Medication errors involving participantexposure to the investigational product;
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the studyparticipant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.


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In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24hours on a CT SAE Report 
Form only when associated with an SAE.
8.4.Treatment of Overdose
For this study, any dose of PF-06865571greater than 1800mg within a 24-hour time period 
will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.  In the event of an 
overdose, the investigator/treating physician should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEsand laboratory abnormalities until 
PF-06865571can no longer be detected systemically (at least 5days).
3. Obtain a bloodsample for PK analysis at the time specified by the medical monitor if 
requested by the medical monitor (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with anSAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation withthe medical monitor based on the clinical evaluation of the participant.
8.5.Pharmacokinetics 
8.5.1.Plasma for Analysis of PF-06865571
Blood samples of approximately 4mL, to provide approximately 1.5mL plasma, will be 
collected into appropriately labeled tubes containingdipotassium ethylenediaminetetraacetic 
acid(K
2EDTA)for measurement of plasma concentrations of PF-06865571 as specified in 
the SoA.  Instructions for the collection and handling of biological samples will be provided 
in the laboratory manual or bythe sponsor.  The actual date and time (24-hour clock time) of 
each sample will be recorded.


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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 todosing.  Collection of 
PK samples up to and including 8hours after doseadministration that areobtained within 
10%of the nominal time (eg, within 6minutes of a 60-minute sample) relative todosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and data collection tool (eg,CRF/DCT).  
Samples collected atnominal times of ≥10hourspostdose must be collected within ±1hour 
of the planned sampling time(eg, 16H sample can be collected as early as 15H post dose and 
as late as 17H post dose) and such not consideredas protocol deviations, as long as the exact 
time of the collection is noted on the source document and data collection tool 
(eg,CRF/DCT). 
Samples will be used to evaluate the PK of PF-06865571.  PK samples 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, 
 
These data will not be included in the clinical study report (CSR).
Genetic analyses will not be performed on these plasma samples.  Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of PF-06865571 will be 
analyzed using a validated analytical method in compliance with applicable standard 
operating procedures (SOPs).  The PK samples must be processed and shipped as indicated 
in the instructions provided to the investigator site to maintain sample integrity.  Any 
deviations from the PK sample handling procedure (eg, sample collection and processing 
steps, interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor.  On a case-by-case basis, the sponsor may make a 
determination as to whether sample integrity has been compromised.  Any deviation from the 
specified sample handling procedure resulting in compromised sample integrity will be 
considered a protocol deviation.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.6.Pharmacodynamics
CCI
Pharmacodynamic (PD) parameters are not evaluated in this study.
CCI


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8.9.Health Economics
Health economics/medical resource utilization and health economicsparameters arenot 
evaluated in this study.
9.STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1.Statistical Hypotheses
There are no statistical hypotheses for this study.
9.2.Sample Size Determination
A sample size of approximately 24participants (approximately 6participants per cohort, 
with varying degrees of hepatic function in each of 4cohorts) has sufficient power to detect a 
2-fold difference from the Reference (without hepatic impairment) cohort.  These 
calculations are based on estimates of between-participant standard deviations of 0.19 for 
log
eAUCinfand 0.17for log
eCmax
CCI
.  These estimates were derived from single doses between
5mg and 1500mg administered inthefed state and one dose of 1000mg administered in the 
CCI


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fasted state in Study C2541001.  Table2presents the 90% confidence intervals (with 80% 
tolerance probability) for various possible effects.
Table2.
90% Confidence Intervals (With 80% Tolerance Probability) for Various 
Possible Effects in AUCinfand CmaxWith n=6 Participants/Cohort
Parameter
Estimated Fold Effect
(Test/Reference)
Expected 90% CI
AUCinf
0.5
0.40, 0.62 
1
0.81, 1.24 
2
1.62, 2.47 
4
3.24, 4.94 
Cmax
0.5
0.41, 0.60 
1
0.83, 1.21 
2
1.65, 2.42 
4
3.31, 4.83 
9.3.Populations for Analysis
Population
Description
Enrolled 
All participants who sign the ICD
Dosed withinvestigational product
All participants dosed withinvestigational product 
Safety
All participants who take at least 1 dose of investigational product.  
9.4.Statistical Analyses
The Statistical Analysis Plan (SAP)will be developed and finalized before database lock and 
will describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpointswith further details offered in the 
SAP, which will be maintained by the sponsor.  The SAP may modify what is outlined in the 
protocol where appropriate; however, any major modifications of the primary endpoint 
definitions or their analyses will also be reflected in a protocol amendment.
9.4.1.Efficacy Analyses
An efficacy analysis isnot applicable to this study. 
9.4.2.Pharmacokinetic Analyses
9.4.2.1.Pharmacokinetic Analysis Populations
The PK concentration population will be defined as all participants who received 
PF-06865571 and in whom at least 1plasma concentration value is reported.
The PK parameter analysis population is defined as all participants dosed who have at least 
1of the PK parameters of primary interest.


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9.4.2.2.Derivation of Pharmacokinetic Parameters Prior to Analysis
The plasma PK parameters for PF-06865571 following single dose administration will be 
derived from the concentration-time profiles as detailed in Table3.  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 times will be used in the derivation of PK 
parameters.
Table3.
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 (C
last)
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.
 
 
 
 
 
 
*As data permit
9.4.2.3.Statistical Methods for Pharmacokinetic Data
Individual PF-06865571 concentrations will be listed and summarized descriptively by 
nominal PK sampling time and hepatic functioncohort.  Individual and summary profiles of 
the concentration-time data will be plotted by hepatic function cohort.  PF-06865571 AUCinf, 
AUClast, and Cmaxmean and individual parameters will be plotted by hepatic function cohort.  
PK parameters of PF-06865571 will be summarized descriptively by hepatic function cohort.  
The effect of varying degrees of hepatic impairment on PK parameters will be assessed by 
constructing 90% confidenceintervals around the estimated difference between each of the 
Test (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-06865571 AUCinf, AUC
last, and Cmax
CCI
, 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 


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ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for the 
ratios.
 
 
 
 
 
 
  
9.4.3.Safety Analyses
All safety analyses will be performed on the safety population.
Endpoint
Statistical Analysis Methods
Secondary
The safety data will be summarized in accordance with Pfizer Data 
Standards. All safety data will be summarized descriptively through 
appropriate data tabulations, descriptive statistics, categorical summaries, 
and graphical presentations. Safety endpoints for the study include:
Treatment-emergent AEs;
Clinical laboratory tests;
Vital signs;
12-lead ECGs.
9.4.3.1.Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, derived QTcF
interval, PR interval, and QRS complexwill be summarized by treatment and time.
The number (%) of participants with maximum postdose QTcFvalues and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTcFAssessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
CCI
In addition, the number of participants with uncorrected and corrected QT values >500msec
will be summarized.
CCI


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9.5.Interim Analyses
No formal interim analysis will be conducted for this study.  As this is an open-labelstudy,
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 further clinical 
development.
9.5.1.Data Monitoring Committee 
CCI
This study will not use a data monitoring committee(DMC).


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10.SUPPORTINGDOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1.Regulatoryand Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;
Applicable International Council for Harmonisation (ICH)Good Clinical Practice 
(GCP) guidelines;
Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, investigator’s brochure (IB), and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:
Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;
Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1.Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2.Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1year after completion of the study.
10.1.3.Informed Consent Process
The investigator or his/her representative will explain thenature of the study to the 
participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of21 CFR50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participantis 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 byClinical 
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 participantis 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.


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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. 
 
Participants who decline to participate in this optional research will not provide 
this separate signature.
10.1.4.Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participantdata.
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 roomto 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 eventof 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code. 
Any participant records or datasets 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 thestudy, 
linking each participant’s numerical code to his or her actual identity. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5.Dissemination of Clinical Study Data
CCI
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov(ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/orwww.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
In allcases, 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.
CCI


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www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1year of the primary completion date 
(PCD) for studies in adult populations or within 6months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participantwas examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1year of the PCD for studies in adult populations or within 6months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participantshave been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase1 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 Phase2 of this policy,includes the publishing of individual participantdata. 
Policy0070 applies to new marketing authorization applications submitted via the 
centralized procedure since 01January2015 and applications for line extensions and for new 
indications submitted viathe 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 contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.


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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6.Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paperform and are password protected or secured in a locked roomto 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities,and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring),are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study,including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15yearsafter 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 aslong as they are 
maintained.


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When participantdata are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocablydeleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare theinvestigator 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 documentsare filed at theinvestigatorsite.
Data reported on the CRF or entered in the electronic CRF (eCRF)that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the investigator site file.
10.1.8.Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any timeupon notification to the contract 
research organization (CRO)if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor
's procedures, or GCP guidelines;
Inadequate recruitment of participants by the investigator;
Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol,the contract will control as to termination rights.


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10.1.9.Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publicationof the overall study results or 1year after end of the study 
(orstudy termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts,and submitsall manuscripts or abstracts to the sponsor 
30days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10.Sponsor’s Qualified Medical Personnel
The contact information for the sponsor
's appropriately qualified medical personnel for the 
study is documented in thestudy contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product 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 


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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 clinical laboratory tests will be performed at times defined in the SoAsection 
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 assessany perceived safety concerns.
The clinical safety laboratory tests outlined in Table 10.2-1will be performed by the 
sponsor-identified central laboratory.  Blood and urine samples for clinical laboratory tests 
will be collected following ≥4-hour fast.


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Table 10.2-1. 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 (andeGFR via 
MDRD)
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Phosphorus
Total CO2(Bicarbonate)
AST
ALT
Alkaline phosphatase
GGT
Total bilirubin
Direct bilirubina,b
Indirect bilirubina,b
Creatine kinase
a,c
Uric acid
Albumin
Total protein
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
Serumfand urine
f
pregnancy test
Breath alcohol testg
Urine drug test
h
SerologyiHBsAg, 
HCVAb(and if positive, 
reflex HCV RNA), and 
HIV
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. AfterDay 1, direct and indirect bilirubin assessed when total bilirubin is > ULN, only.
c. AfterDay1, 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 allfemales (at Screening only).
f. Serum testing in allfemalesat 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, onlyusing kits provided by sponsor-identified central 
laboratory
h. Minimum requirements include cocaine, tetrahydrocannabinol (THC), opiates/opioids, benzodiazepines and 
amphetamines.
i. At Screening, only.
For list of abbreviations, refer to Section 10.9.
Investigators must document their review of each laboratory safety reportas soon as 
practically possible post receipt from sponsor-identified central laboratory.  Results from 
Screening visit must be reviewed to confirm eligibility beforeprogressing with dosing on 
Day1.


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


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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).
AnSAE is defined as any untoward medical occurrence that, at any dose:
c. Results in death
d. 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.
e. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
f. 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, 


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influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
g.Is a congenital anomaly/birth defect
h. 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.
10.3.3.Recording/Reporting and Follow-up of AEsand/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3types of 
events: (1)SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the 
investigational product under study during pregnancy or breastfeeding, and occupational 
exposure. 
It should be noted thatthe 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


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Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
None
All (and exposure during 
pregnancy [EDP]
supplemental form for 
EDP)  
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 notacceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the studyand 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 anSAE.  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.


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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.
Theinvestigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.
For each AE/SAE, the investigator mustdocument in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.
The investigator may change his/her opinion of causality in light of follow-up 
information and send anSAE 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 investigational product caused 
the event, then the eventwill be handled as “related to investigational product” for 
reporting purposes, as defined by the sponsor.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator must 
record this causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsorto elucidate the nature and/or causality of the AE or SAE as fully as 


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possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare professionals.
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortemfindings including histopathology.
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4.Reporting of SAEs
SAE Reporting to Pfizer Safetyvia an Electronic Data Collection Tool
The primary mechanism for reporting an SAE to Pfizer Safetywill 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 Safetyvia CT SAE Report Form
Facsimile transmission of the CT SAE Report Formis the preferred methodto 
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 Formsent by overnight mail or 
courier service.
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4.Appendix 4:Contraceptive Guidance and Collection of Pregnancy Information
10.4.1.Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28daysafter the last dose of study intervention,
whichcorresponds to the time needed to eliminate study intervention(s):
Refrain from donating sperm.
PLUS either:
Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.
OR
Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.
In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods belowin Section 10.4.4).
10.4.2.Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1of the following conditions applies:
Is not a WOCBP (see definitions belowinSection 10.4.3).
OR
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, as described belowduring the 
intervention period and for at least 28daysafter the last dose of study intervention,
which correspondsto the time needed to eliminate any study intervention(s).
A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during this period.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. 


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10.4.3.Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are notconsidered WOCBP:
1. Premenopausal female with 1 of the following:
Documented hysterectomy;
Documented bilateral salpingectomy;
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above,(eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.
A postmenopausal state is defined as age 60yearsor older or no menses for 
12months without an alternative medical cause. 
A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonereplacement therapy (HRT). 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.


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10.4.4.ContraceptionMethods
Highly Effective MethodsThat HaveLow User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner.
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is thesole sexual partner of the WOCBPand the absence of sperm has 
been confirmed.If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective MethodsThat Are User Dependent (WOCBP partners of male 
participants only)
1. Combined (estrogen-and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.
Oral;
Intravaginal;
Transdermal;
Injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation.
Oral;
Injectable.
3. Sexual abstinence.
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.


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Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:
A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).
A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
Ifa participantor participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplementalform, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participantreports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusivefor a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 
Spontaneous abortion includes miscarriage and missed abortion;
Neonatal deaths that occur within 1month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1month should be reported as 
SAEs when the investigator assesses theinfant death as related or possibly related to 
exposure to the investigational product. 
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 participantwith the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participantwas given the Pregnant Partner Release of Information Form to provide to his 
partner.


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CCI
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.6.Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3times the 
upper limit of normal (×ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 ×ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 ×ULN (ie, AST/ALT and TBili values will be elevated within the same laboratory
sample).  In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) casesand 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 TBilibaseline 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 ORTBili 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 >2times 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 orif 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 participantshould return to the investigator site and be evaluated as soon as possible, 
preferably within 48hours 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 TBilifor suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), total bile acids, and alkaline phosphatase.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitisA, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT)abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7.Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events(AEs)
Marked sinus bradycardia (rate <40 beats per minute [bpm])lasting minutes.
New PR interval prolongation >280 msec.
New prolongation of QTcF to >480 msec(absolute) or by≥60msecfrom baseline.
New-onset atrial flutter or fibrillation, with controlled ventricular response rate: 
ie,rate<120 bpm.
New-onset type I second-degree (Wenckebach) atrioventricular (AV)block of 
>30seconds’duration.
Frequent premature ventricularcomplexes (PVCs),triplets,orshort intervals 
(<30seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events(SAEs)
QTcF prolongation >500 msec.
New ST-Tchanges suggestive of myocardialischemia.
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 fibrillationand bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
Atrial flutter or fibrillation,with rapid ventricular response rate: rapid = rate 
>120bpm.
Sustained supraventricular tachycardia (rate >120 bpm)(“sustained”= short 
durationwith relevant symptoms or lasting >1 minute).
Ventricular rhythms >30 seconds’duration, including idioventricular rhythm 
(rate<40bpm), accelerated idioventricular rhythm (40< x<100),and 


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monomorphic/polymorphic ventricular tachycardia >100 bpm (such astorsades de 
pointes).
TypeIIsecond-degree(MobitzII)AVblock.
Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events
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 laboratoryto the investigator and Pfizer study team,and not to be 
considered as allinclusive of what to be reported as AEs/SAEs.


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10.8.Appendix 8: Child-Pugh Classification (CPC) of Liver Dysfunction 
Table 10.8-1: Scoring for Child-Pugh Classification 
Cohort
CPC
Level of dysfunction
Total Score 
(tally based on assessment of 
parameters in Table 10.8-2)
1
Not Applicable
Without hepatic 
impairment
Not Applicable
2
A
Mild
5-6
3
B
Moderate
7-9
4
C
Severe
10
Table 10.8-2: Derivation of Child-Pugh Classification Score
Assessment Parameters
Assigned score for observed findings
1 point
2 points
3 points
Encephalopathy gradea
(refer to Table 10.8-3below)
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 prolongedb
<4
4 to 6
>6
a. Subjects with a prior history of Grade3 or Grade 4 encephalopathy who are currentlyreceiving anintervention[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 this study aslong as they do not
have clinically active Grade3 or Grade 4 encephalopathy.
b. As assessed relative to PT control (orupper limit of normal), as reported by sponsor-identified central laboratory
Table 10.8-3: 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 activeGrade3 or 4 encephalopathy are excluded.
CPC should be assessed at Screening onlyto determine the classification of a given 
participant.


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10.9.Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
ADME
absorption, distribution, metabolism, or excretion
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the curve
AUC24
area under the plasma concentration-time profile from 0 to 24 hours
AV
atrioventricular
BA
bioavailability
BCRP
breast cancer resistance protein
BE
bioequivalence
-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
CPC
Child-Pugh classification
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
clinical trial management system
CV
cardiovascular
CYP
cytochrome P450
DAG
diacylglycerol
DBP
diastolic blood pressure
DC
discontinuation
DCT
data collection tool
DDI
drug-drug interactions
DGATs
Diacylglycerol acyltransferases
DILI
drug-induced liver injury
DMC
data monitoring committee
DNL
de novo lipogenesis
CCI
CCI


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Abbreviation
Term
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
Electronic case report form
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ET
earlytermination
EU
European Union
EudraCT
European Clinical Trials Database
FA
fatty acid
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBsAg 
hepatitis B surface antigen
HCVAb
Hepatitis C antibody
HCV RNA
Hepatitis C ribonucleic acid
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IR
immediate release
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IWR
interactive Web-based response
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LBBB
left bundle branch block
LFT
liver function test
MATE
multidrug and toxic compound extrusion transporter
mBcrp
mouse breast cancerresistance protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
multi-drug resistance protein
MDRD
Modification of Diet in Renal Disease
MR
modified release
MRI
magnetic resonance imaging
msec
millisecond
N/A
not applicable


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Abbreviation
Term
NAb
neutralizing antibodies
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NOAEL
no-observed-adverse-effect level
OCT
organic cation transporter
PBMC1
peripheral blood mononuclear cells
PCD
primary completion date
PD
pharmacodynamic(s)
PE
physical exam 
P-gp
P-glycoprotein
 
PI
principal investigator
PIB
powder in bottle
PK
pharmacokinetic(s)
PT
prothrombin time
PVC
premature ventricular contraction/complex
Q8H
every 8 hours
Q12H
every 12 hours
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SCr
serum creatinine
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SSID
study-specific identification
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
t
½
half-life
TBili
total bilirubin
TG
triglyceride
THC
tetrahydrocannabinol
TIPS
transjugular intrahepatic portosystemic shunt
UGT
uridine diphosphate-glucuronosytransferase
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman of childbearing potential
CCI
CCI


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11.REFERENCES
1.
Yen CL, Stone SJ, Koliwad S, Harris C, Farese RV, Jr. Thematic review series: 
glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. Journal of Lipid 
Research. Nov 2008;49(11):2283-2301.
2.
Buhman KK, Smith SJ, Stone SJ, et al. DGAT1 is not essential for intestinal 
triacylglycerol absorption or chylomicron synthesis. The Journal of Biological 
Chemistry.Jul 12 2002;277(28):25474-25479.
3.
Cases S, Stone SJ, Zhou P, et al. Cloning of DGAT2, a second mammalian 
diacylglycerol acyltransferase, and related family members. The Journal of Biological 
Chemistry. Oct 19 2001;276(42):38870-38876.
4.
Rodighiero V. Effects of liver disease on pharmacokinetics an update. Clin 
Pharmacokinet1999 Nov; 37 (5): 399-431.
5. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic 
dysfunction. Eur J Clin Pharmacol(2008) 64:1147–1161.

SAP_001.pdf: 
Protocol C2541009 (PF-06865571) Statistical Analysis Plan
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PFIZER CONFIDENTIAL
Protocol C2541009
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, 
PARALLEL-COHORT STUDY TO COMPARE THE PHARMACOKINETICS OF 
PF-06865571 IN ADULT PARTICIPANTS WITH VARYING DEGREES OF 
HEPATIC IMPAIRMENT RELATIVE TO PARTICIPANTS WITHOUT HEPATIC 
IMPAIRMENT
Statistical Analysis Plan 
(SAP)
Version:
1.0
Author: 
 MA
Date:
13-AUG-2019
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Table 1.
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Version 1.0
13August2019
Original Version.
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
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TABLE OF CONTENTS 
LIST OF TABLES...........................................................................................................................4
LIST OF FIGURES .........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................5
2. INTRODUCTION .......................................................................................................................5
2.1. Study Design ...................................................................................................................5
2.2. Study Objectives .............................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING........................................7
4. HYPOTHESES AND DECISION RULES.................................................................................7
4.1. Statistical Hypotheses .....................................................................................................7
4.2. Statistical Decision Rules................................................................................................7
5. ANALYSIS SETS .......................................................................................................................7
5.1. Pharmacokinetic (PK) Analysis Set ................................................................................7
5.1.1. Concentration Analysis Set.................................................................................7
5.1.2. Parameter Analysis Set.......................................................................................8
5.2. Pharmacodynamic Analysis Set......................................................................................8
5.3. Safety Analysis Set..........................................................................................................8
5.4. Other Analysis Sets .........................................................................................................8
5.5. Treatment Misallocations................................................................................................8
5.6. Protocol Deviations.........................................................................................................8
5.6.1. Deviations Assessed Prior to Dosing..................................................................8
5.6.2. Deviations Assessed Post-Dosing.......................................................................8
6. ENDPOINTS AND COVARIATES ...........................................................................................9
6.1. Efficacy Endpoint(s) .......................................................................................................9
6.2. Safety Endpoints .............................................................................................................9
6.3. Other Endpoints...............................................................................................................9
6.3.1. PK Endpoints......................................................................................................9
6.3.2. PD Endpoints....................................................................................................10
6.4. Covariates......................................................................................................................10
7. HANDLING OF MISSING VALUES ......................................................................................10
7.1. Concentrations Below the Limit of Quantification.......................................................10
7.2. Deviations, Missing Concentrations and Anomalous Values .......................................10
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7.3. Pharmacokinetic Parameters .........................................................................................10
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................11
8.1. Statistical Methods ........................................................................................................11
8.2. Statistical Analyses .......................................................................................................11
8.3. Safety Analysis..............................................................................................................13
8.3.1. Treatment and Disposition of Participants .......................................................13
8.3.2. Demographic and Clinical Examination Data..................................................13
8.3.3. Discontinuation(s).............................................................................................13
8.3.4. Adverse Events .................................................................................................13
8.3.5. Laboratory Data................................................................................................14
8.3.6. Vital Signs Data................................................................................................14
8.3.7. ECG Data..........................................................................................................14
8.3.8. Other Safety Data .............................................................................................14
8.3.9. Concomitant Treatments...................................................................................14
8.3.10. Screening and Other Special Purpose Data ....................................................15
9. REFERENCES ..........................................................................................................................15
10. APPENDICES .........................................................................................................................16
Appendix 1: SAS CODE FOR ANALYSES .......................................................................16
Appendix 2: Categorical Classes for Vital Signs of Potential Clinical Concern .................16
LIST OF TABLES
Table 1.
Revision History...........................................................................................................2
Table 2. Hepatic Function Categories Based on Child Pugh Score.................................................5
Table 3. PK Parameters to be Summarized Descriptively by Group.............................................12
LIST OF FIGURES
None.
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
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-06865571 following administration of a single, oral, 100 mg dose of PF-06865571.  
NAFLD/NASH is associated with varying degrees of hepatic impairment.  Recognizing that 
the target population of PF-06865571 is patients with NAFLD/NASH and that the major 
clearance mechanism of PF-06865571 is metabolism in the liver, the current study is 
proposed to evaluate whether there is any clinically meaningful effect of hepatic impairment 
on the plasma PK of PF-06865571.
2.1. Study Design
This is a Phase 1, non-randomized, open-label, single-dose, parallel-cohort, multicenter 
study to compare the pharmacokinetics of PF-06865571 in adult participants with varying
degrees of hepatic impairment relative to participants without hepatic impairment after a 
single, oral 100 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 Subjects
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 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.  Dosing in 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.  
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Participants who prematurely discontinue for non-safety related reasons may be replaced, at 
the discretion of the principal investigator (PI) and sponsor study team.
The overall study design is summarized in Figure 1.  For individual participants, the total 
duration of participation from the Screening visit to the follow-up visit will range from 
5 weeks (minimum) to 9 weeks (maximum).
Figure 1.
Study Design
2.2. Study Objectives
Objectives
Endpoints
Primary: 
Primary: 
•
To compare the PK of PF-06865571 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.
•
PF-06865571 PK parameters 
derived from plasma: Cmax, AUClast, 
and AUCinf.
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Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of a single oral dose 
of PF-06865571 when administered to adult participants 
with varying degrees of hepatic impairment relative to age-
and body weight-matched participants without hepatic 
impairment.
•
Assessment of treatment-emergent 
adverse events, clinical laboratory 
tests, vital signs, and 12-lead ECGs.
 
 
 
 
 
 
 
 
 
 
  
 
 
 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
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 further clinical 
development. 
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There is no statistical hypothesis testing planned for this study.
4.2. Statistical Decision Rules
No statistical decision rules are applied.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration population will be defined as all participants who received 
PF-06865571 and in whom at least 1 plasma concentration value is reported.
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5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all participants dosed who have at least 
1 of the PK parameters outlined in Section 6.3.1.
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All participants who receive at least 1 dose of investigational product will be included in the 
safety analyses and listings.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are not treated.
5.6. Protocol Deviations
Participants who experience events that may affect their PK profile (e.g. lack of compliance 
with dosing) may be excluded from the PK analysis.  At the discretion of the 
pharmacokinetist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Dosing
At Screening, the investigator will assess participants against the inclusion and exclusion 
criteria as set out in Sections 5.1 and 5.2 of the protocol.
5.6.2. Deviations Assessed Post-Dosing
A full list of protocol deviations for the study report will be compiled prior to database 
closure; only important protocol deviations will be reported in the Clinical Study Report 
(CSR).  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
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6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
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.
All events that start on or after the first dosing day and time and during the active collection 
period as specified in the protocol will be counted as treatment emergent adverse event 
(TEAE). Events that occur in a non-treatment period (for example, Follow-up) will be 
counted as treatment emergent and attributed to the treatment taken. For the safety endpoints 
Day 1 planned predose measurements will serve as baseline.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood samples for PK analysis of PF-06865571 will be taken according to the Schedule of 
Activities given in the protocol. The following PK parameters will be calculated for PF-
06865571 (if possible) from the concentration-time data using standard noncompartmental 
methods:
PK 
Parameter
Analysis 
Scale
PF-06865571
Definition
AUCinf
*
ln
A, D
Area under the plasma concentration-time 
profile from time zero to the time of the last 
quantifiable concentration (Clast)
AUClast
ln
A, D
Area under the plasma concentration-time 
profile from time zero extrapolated to 
infinite time
Cmax
ln
A, D
Maximum plasma concentration
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Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits
6.3.2. PD Endpoints
None.
6.4. Covariates
No covariate for primary analysis (i.e. ANOVA) will be included in the model. 
 
 
7. HANDLING OF MISSING VALUES
The handling of missing values for PK data is described in this section. For the analysis of 
safety endpoints, the sponsor data standard rules for imputation will be applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (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 pharmacokinetist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (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 hepatic function group with ≥3 evaluable measurements.  
For statistical analyses (i.e. analysis of variance), PK parameters coded as NC will also be set 
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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 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.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
For all outputs produced, the following ordering will be used:
Without Hepatic Impairment
Mild Hepatic Impairment
Moderate Hepatic Impairment
Severe Hepatic Impairment.
The effect of the hepatic impairment on PK parameters will be assessed by constructing 90% 
confidence intervals around the estimated difference between each of the Test (impaired 
groups) and the Reference (normal hepatic function group) using a one-way ANOVA model 
based on natural log transformed data.
The relationship between PK parameters and hepatic function parameters (eg, serum albumin 
concentration, or prothrombin time) will be determined by a linear regression model.
8.2. Statistical Analyses
A 1-way analysis of variance (ANOVA) will be used to compare the natural log transformed 
PF-06865571 AUCinf, AUClast, and Cmax, 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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Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report.  If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
The following PK parameters will be summarized by hepatic function group:
Table 3. PK Parameters to be Summarized Descriptively by Group
Parameter
Summary Statistics
AUClast, AUCinf, 
Cmax, 
 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
 
Box and whisker plots for individual participant parameters (AUCinf, AUClast and Cmax) may
be presented by hepatic function group and overlaid with geometric means.
Supporting data from the estimation of 
 AUCinf 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.
Presentations for PF-06865571 concentrations will include:
−
a listing of all concentrations sorted by hepatic function group (from without hepatic 
impairment 1st, followed by mild/C2, moderate/C3 and finally severe/C4, present in 
heading), participant ID and nominal time postdose.  The concentration listing will also 
include the actual times.  Deviations from the nominal time will be given in a separate 
listing.
−
a summary of concentrations by hepatic function group and nominal time postdose, 
where the set of statistics will include n, mean, median, standard deviation, coefficient of 
variation (cv), minimum, maximum and the number of concentrations above the lower 
limit of quantification.
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−
median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by hepatic function group (all hepatic function groups on the same plot per 
scale, based on the summary of concentrations by hepatic function group and time 
postdose).
−
mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by hepatic function group (all hepatic function groups on the same plot per 
scale, based on the summary of concentrations by hepatic function group and time 
postdose).
−
individual concentration time plots by hepatic function group (on both linear and semi-
log scales) against actual time postdose (there will be separate spaghetti plots for each 
hepatic function group per scale).
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual participant plots by time, the actual PK sampling time will 
be used.
8.3. Safety Analysis
A set of summary tables split by hepatic function group will be produced to evaluate any 
potential risk associated with the safety and toleration of administering PF-06865571.
8.3.1. Treatment and Disposition of Participants
Participant evaluation groups will show end of study participant disposition. Frequency 
counts will be presented for participants discontinuation(s) by hepatic function group.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A summary of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by hepatic function group and ‘Total Participants’ in 
accordance with the sponsor reporting standards.
8.3.3. Discontinuation(s)
Participant discontinuations due to adverse events will be detailed and summarized by 
hepatic function group.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
hepatic function group.
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8.3.5. Laboratory Data
Laboratory data will be listed and summarized by hepatic function group in accordance with 
the sponsor reporting standards.  Baseline will be the planned predose measurement obtained 
on Day 1.
8.3.6. Vital Signs Data
Baseline value will be the planned predose measurement obtained on Day 1.
Maximum absolute values and changes from baseline for seated vital signs will be 
summarized descriptively by hepatic function group using categories as defined in 0.  
Numbers and percentages of participants meeting the categorical criteria will be provided. 
All planned and unplanned postdose time-points will be counted in these categorical 
summaries.  All values meeting the criteria of potential clinical concern will be listed.
These data will be listed in accordance with the sponsor reporting standards.
8.3.7. ECG Data
Baseline value will be the planned predose measurement obtained on Day 1.
Changes from baseline for the ECG parameters QT interval, heart rate, derived QTcF 
interval, PR interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected and corrected QT values >500 msec 
will be summarized and listed.
8.3.8. Other Safety Data
None.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
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8.3.10. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, serum B-hCG for 
all females will be obtained at Screening. These data will only be listed.
Urine drug screen, urine B-hCG for women of child bearing potential and physical 
examination findings will be collected at baseline or prior to baseline visit. These data will 
not be brought in-house, and therefore will not be listed.
9. REFERENCES
None.
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10. APPENDICES
Appendix 1: SAS CODE FOR ANALYSES
An example of the PROC GLM code is provided below:
proc glm data=tab.pk;
class group;
model l&var=group/ss3 clparm alpha=0.1;
lsmeans group;
estimate 'Mild vs Normal'
group -1 1 0 0;
estimate 'Moderate vs Normal'
group -1 0 1 0;
estimate 'Severe vs Normal'
group -1 0 0 1;
ods output Estimates = est&var;
ods output FitStatistics = fit&var;
ods output ModelANOVA = tst&var;
ods output OverallANOVA = overall&var;
run;
An example of the PROC REG code is provided below:
proc reg data=tab.pk;
model l&var=&HepaticFunction/clb alpha=0.1;
ods output ParameterEstimates = param&var;
ods output FitStatistics = fit&var;
ods output ANOVA = reg&var;
run;
Appendix 2: Categorical Classes for Vital Signs of Potential Clinical Concern
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
Seated pulse rate (bpm)
min. <40
max. >120
Measurements that fulfill these criteria are to be listed in report.
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