Clinical trial NCT04193436
Conditions: Hepatic Impairment Healthy Participants
Keywords: Non-alcoholic Fatty Liver Disease Non-alcoholic steatohepatitis
Sponsor: Pfizer
Start date: 2020-01-21; Completion date: 2021-07-09
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is proposed to characterize the effect of varying degrees of hepatic impairment on the plasma PK of PF-06835919

Detailed description:

Arms: arm 1: This arm includes participants with severe hepatic impairment who will receive a 25mg oral dose of PF-06835919 arm 2: This arm includes participants with moderate hepatic impairment who will receive a 25mg oral dose of PF-06835919 arm 3: This arm includes participants with mild hepatic impairment who will receive a 25mg oral dose of PF-06835919 arm 4: This arm includes participants without hepatic impairment who will receive a 25mg oral dose of PF-06835919
Interventions: intervention 1: PF-06835919 25 mg
Intervention descriptions: intervention 1: PF-06835919 in 25 mg oral tablet will be administered on Day 1

Protocol documents:
Prot_000.pdf: 
PF-06835919
Protocol C1061013
Final Protocol Amendment 1, 18 February 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, 
PARALLEL-COHORT STUDY TO COMPARE THE PHARMACOKINETICS OF 
PF-06835919 IN ADULT PARTICIPANTS WITH VARYING DEGREES OF 
HEPATIC IMPAIRMENT RELATIVE TO PARTICIPANTS WITHOUT HEPATIC 
IMPAIRMENT
Investigational Product Number:
PF-06835919
Investigational Product Name:
Not Applicable
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2019-003480-21
Protocol Number:
C1061013
Phase:
1
Short Title: A Study to Investigate the Effects of Hepatic Impairment on the 
Pharmacokinetics of PF-06835919
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Protocol C1061013
Final Protocol Amendment 1, 18 February 2020
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
18 February 2020
A country-specific amendment relevant 
only to sites in the Czech Republic, to
revise language in Section 10.4.3. Woman 
of Childbearing Potential (WOCBP)
related to the definition of post-menopausal 
state. The change removes subject age as a 
qualifying criteria, and will now read: “A 
postmenopausal state is defined as no
menses for 12 months without an 
alternative medical cause”.
This change was requested by the local
country Regulatory Authority, and is not
applicable to sites outside of the Czech 
Republic. 
Original protocol
23 September 2019
Not applicable (N/A)


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Protocol C1061013
Final Protocol Amendment 1, 18 February 2020
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................10
1.3. Schedule of Activties (SoA)....................................................................................11
2. INTRODUCTION ...............................................................................................................13
2.1. Study Rationale .......................................................................................................13
2.2. Background .............................................................................................................13
2.2.1. Nonclinical Experience with PF-06835919................................................14
2.2.1.2. Nonclinical Safety and Tolerability ..........................................15
2.2.2. Clinical Overview.......................................................................................16
2.3. Benefit/Risk Assessment.........................................................................................18
3. OBJECTIVES AND ENDPOINTS.....................................................................................19
4. STUDY DESIGN.................................................................................................................19
4.1. Overall Design.........................................................................................................19
4.2. Scientific Rationale for Study Design.....................................................................20
4.3. Justification for Dose ..............................................................................................22
4.4. End of Study Definition ..........................................................................................22
5. STUDY POPULATION......................................................................................................23
5.1. Inclusion Criteria.....................................................................................................23
5.1.1. Participants in All Cohorts..........................................................................23
5.1.2. Additional Inclusion Criteria for Participants without Hepatic 
Impairment (Cohort 1 Only)............................................................................23
5.1.3. Additional Inclusion Criteria for Participants with Impaired Hepatic 
Function (Cohorts 2, 3, and 4 Only) ................................................................24
5.2. Exclusion Criteria....................................................................................................25
5.2.1. Participants in All Cohorts..........................................................................25
5.2.2. Additional Exclusion Criteria for Participants without Hepatic 
Impairment (Cohort 1 Only)............................................................................26
5.2.3. Additional Exclusion Criteria for Participants with Impaired Hepatic 
Function (Cohorts 2, 3, and 4 Only) ................................................................27
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5.3. Lifestyle Considerations..........................................................................................28
5.3.1. Meals and Dietary Restrictions...................................................................28
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................29
5.3.3. Activity .......................................................................................................29
5.3.4. Contraception..............................................................................................30
5.4. Screen Failures ........................................................................................................30
5.5. Criteria for Dosing on Day 1...................................................................................30
6. STUDY INTERVENTION..................................................................................................31
6.1. Study Intervention(s) Administered........................................................................31
6.1.1. Administration............................................................................................31
6.2. Preparation/Handling/Storage/Accountability ........................................................31
6.2.1. Preparation and Dispensing........................................................................32
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................33
6.3.1. Allocation to Investigational Product .........................................................33
6.4. Study Intervention Compliance...............................................................................33
6.5. Concomitant Therapy..............................................................................................33
6.5.1. Participants with Healthy Hepatic Function (Cohort 1, Only) ...................33
6.5.2. Participants with Impaired Hepatic Function (Cohorts 2, 3, and 4) ...........34
6.5.3. Rescue Medicine.........................................................................................34
6.6. Dose Modification...................................................................................................34
6.7. Intervention After the End of the Study..................................................................35
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................35
7.1. Discontinuation of Study Intervention ....................................................................35
7.2. Participant Discontinuation/Withdrawal From the Study.......................................35
7.3. Lost to Follow up ....................................................................................................36
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................36
8.1. Efficacy Assessments..............................................................................................38
8.2. Safety Assessments .................................................................................................38
8.2.1. Physical Examinations................................................................................38
8.2.2. Vital Signs ..................................................................................................38
8.2.3. Electrocardiograms.....................................................................................39


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8.2.4. Clinical Safety Laboratory Assessments ....................................................40
8.2.5. Pregnancy Testing ......................................................................................40
8.3. Adverse Events and Serious Adverse Events..........................................................40
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......41
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................41
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................41
8.3.2. Method of Detecting Aes and SAEs...........................................................42
8.3.3. Follow-up of Aes and SAEs .......................................................................42
8.3.4. Regulatory Reporting Requirements for SAEs...........................................42
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................42
8.3.5.1. Exposure During Pregnancy......................................................43
8.3.5.2. Exposure During Breastfeeding ................................................43
8.3.5.3. Occupational Exposure .............................................................43
8.3.6. Medication Errors .......................................................................................43
8.4. Treatment of Overdose............................................................................................44
8.5. Pharmacokinetics ....................................................................................................45
8.5.1. Analysis of PF-06835919 Concentrations..................................................45
8.6. Pharmacodynamics..................................................................................................46
8.9. Health Economics ...................................................................................................46
9. STATISTICAL CONSIDERATIONS ................................................................................47
9.1. Statistical Hypotheses .............................................................................................47
9.2. Sample Size Determination.....................................................................................47
9.3. Populations for Analysis .........................................................................................47
9.4. Statistical Analyses .................................................................................................48
9.4.1. Efficacy Analyses .......................................................................................48
9.4.2. Pharmacokinetic Analysis ..........................................................................48
9.4.3. Pharmacokinetic Analysis Populations.......................................................48
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9.4.4. Derivation of Pharmacokinetic Parameters Prior to Analysis ....................48
9.4.5. Statistical Methods for Pharmacokinetic Data ...........................................49
9.4.6. Safety Analyses ..........................................................................................50
9.4.6.1. Electrocardiogram Analyses......................................................51
9.5. Interim Analyses .....................................................................................................51
9.5.1. Data Monitoring Committee.......................................................................51
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................52
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............52
10.1.1. Regulatory and Ethical Considerations ....................................................52
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................52
10.1.2. Financial Disclosure .................................................................................53
10.1.3. Informed Consent Process........................................................................53
10.1.4. Data Protection .........................................................................................54
10.1.5. Dissemination of Clinical Study Data ......................................................54
10.1.6. Data Quality Assurance ............................................................................56
10.1.7. Source Documents....................................................................................57
10.1.8. Study and Site Closure..............................................................................57
10.1.9. Publication Policy.....................................................................................58
10.1.10. Sponsor’s Qualified Medical Personnel .................................................58
10.2. Appendix 2: Clinical Laboratory Tests .................................................................60
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................62
10.3.1. Definition of AE .......................................................................................62
10.3.2. Definition of SAE.....................................................................................63
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................64
10.3.4. Reporting of SAEs....................................................................................67
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................68
10.4.1. Male Participant Reproductive Inclusion Criteria....................................68
10.4.2. Female Participant Reproductive Inclusion Criteria.................................68
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10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................69
10.4.4. Contraception Methods.............................................................................70
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........74
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................76
10.8. Appendix 8: Child-Pugh Classification (CPC) of Liver Dysfunction...................78
10.9. Appendix 9: Abbreviations ...................................................................................79
11. REFERENCES ..................................................................................................................83
LIST OF TABLES
Table 1.
Hepatic Function Categories Based on Child Pugh Score........................20
Table 2.
90% Confidence Intervals (with 80% Tolerance Probability) for 
Various Possible Effects in AUCinf and Cmax with n=6 
Subjects/Cohort.........................................................................................47
Table 3.
Plasma PK Parameters..............................................................................49
Table 4.
Protocol Required Safety Laboratory Assessments..................................60
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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title:
A Study to Investigate the Effects of Hepatic Impairment on the Pharmacokinetics of 
PF-06835919.
Background and Rationale:
Ketohexokinase (KHK) is an enzyme catalyzing the conversion of fructose and adenosine 
triphosphate to fructose-1-phosphate and adenosine diphosphate, the first committed step in 
fructose metabolism.  PF-06835919 is a KHK inhibitor that is currently being developed for 
the treatment of NASH with fibrosis.  It is anticipated that inhibition of KHK will decrease 
hepatic de novo lipogenesis and steatosis, thereby ameliorating the pathogenesis of 
nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis 
(NASH). 
The purpose of this study is to evaluate the effect of varying degrees of hepatic function on 
the pharmacokinetics of PF-06835919.  NAFLD/NASH is associated with varying degrees of 
hepatic impairment.  Recognizing that the target population of PF-06835919 is patients with 
NAFLD/NASH and that the major clearance mechanism of PF-06835919 is predicted to be 
active uptake into the liver followed by metabolism in the liver, the current study is proposed 
to evaluate whether there is any clinically meaningful effect of hepatic impairment on the 
plasma pharmacokinetics (PK) of PF-06835919.


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PFIZER CONFIDENTIAL 
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Objectives and Endpoints:
Objectives
Endpoints
Primary: 
Primary: 
•
To compare the PK of PF-06835919 (both total and 
unbound) 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-06835919 PK parameters derived from plasma: 
Cmax, AUCinf, fu, Cmax,u, and AUCinf,u.
Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of a single oral 
dose of PF-06835919 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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall Design:
This is a non-randomized, open-label, single-dose, parallel-cohort, multicenter study to 
investigate the effect of varying degrees of hepatic function on the plasma pharmacokinetics 
of PF-06835919.  A total of approximately 24 participants with varying degrees of hepatic 
function will be enrolled into the study: approximately 6 mild hepatic impairment 
participants, approximately 6 moderate hepatic impairment participants, approximately 
4-6 severe hepatic impairment participants, and approximately 6-8 participants without 
hepatic impairment.  Participants will be selected based upon Child-Pugh score at Screening.  
Participants without hepatic impairment will be age- and weight-matched with the 
participants in the 3 hepatic impairment cohorts. All three categories of hepatic impairment 
will be assessed because this represents the likely population to be used in later phase studies 
for the proposed indication (treatment of NASH with fibrosis).  Safety, tolerability, and 
PF-06835919 pharmacokinetics will be evaluated throughout the study.
Study Treatments:
A single oral 25 mg dose of PF-06835919 will be administered to each participant in the fed 
state.  This dose has been shown to be well-tolerated with an acceptable safety profile in 
previous clinical studies.  Selection of this dose also takes into account safety considerations 
for participants with varying degrees of hepatic impairment in whom an increase in plasma 
PF-06835919 exposure may be observed.  Based on observed safety and tolerability at higher 
doses, exposure increases up to 30-fold are not likely to pose a safety concern if observed in 
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participants with varying degrees of hepatic impairment.  Additionally, the pharmacokinetics 
of PF-06835919 are approximately dose-proportional, thus the result at the 25 mg dose can 
be extrapolated to other dose levels.
Statistical Methods:
The effect of varying degrees of hepatic impairment on pharmacokinetic parameters will be 
assessed by constructing 90% confidence intervals around the estimated difference between 
each of the Test (hepatic impaired) cohorts and the Reference (without hepatic impairment) 
cohort.  A one-way analysis of variance will be used to compare the natural log-transformed 
PF-06835919 area under the plasma concentration-time curve from time zero to infinite time 
(AUCinf), maximum plasma concentration (Cmax), fraction unbound (fu), unbound AUCinf
(AUCinf,u), and unbound Cmax (Cmax,u), 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.
1.2. Schema


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Protocol C1061013
Final Protocol Amendment 1, 18 February 2020
PFIZER CONFIDENTIAL 
CT02-GSOP-RF02 6.0 Clinical Pharmacology Protocol Template (04 September 2018)
Page 11
1.3. Schedule of Activties (SoA)
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.  In the Schedule and Activities, while protocol permits unplanned assessments for participants’ well-being and safety, on 
Day -1, allowance added for sites to undertake local assessment of safety-related laboratory tests to ensure population remains stable 
prior to dosing on Day 1.  The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order 
to conduct evaluations or assessments required to protect the well-being of the participant.
Visit Identifier/Day
Screen
≤-28 to 
-2
Day 
-1
Day 1
Day 2
Day 
3a,b
Day 
4
Day 
5
Day 
6
ET
Follow-Up
Day 30±2
Hours Post Dose
--
0
0.5 1
2
4
6
7
8
10 12
14
24
36
48
72
96
120
--
--
Informed consent & demography 
x
Outpatient visit 
x
xc
xc
xc
x
Inpatient stay at Clinical Research Unit 
x
→→
→→→→→→→→
→
→
→
xa,b
Eligibility assessment 
x
x
Medical history
x
x
Physical exam (height & body weight at Screen, only)d
x
x
xe
xc
x
Breath alcohol test
x
x
Alcohol/tobacco & contraception use
x
x
xc,f
xc,f
xc,f
x
xg
(Update) prior/concomitant treatments
x
x
xc,f
xc,f
xc,f
x
x
Single, supine 12-lead ECG
x
x
x
xc
x
Single, seated vital sign assessment (BP and pulse rate)
x
x
x
xc
x
Serious and non-serious adverse event monitoring
x
x
→→
→→→→→→→→
→
→
→
→
→c
→c
xc
x
x
Standard meals/snacksh
x
x
x
x
x
x
x
x
xc
xc
xc
Investigational product administration
xi
Clinical laboratory tests - after ≥4-hour fast
x
x
x
xc
x
FSH (for confirmation of postmenopausal status for 
females only), HIV, HBsAg, HCVAb
x
Serum pregnancy test (Females only)
x
x
xe
xc
x
Pharmacokinetic blood sampling for PF-06835919
x
x
x
x
x
x
x
x
xk
xk
xk
xk
xc,k
xc,k
xc,k
x
PF-06835919 unbound fraction for protein binding
x
On-site - Urine drug test
x
x
Urinalysis (and microscopy, if needed)
x
x
x
xc
x
On-site - Urine pregnancy test (WOCBP, only)
x
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Abbreviations: AE=adverse event; BP=blood pressure; ECG=electrocardiogram; ET=early termination; FSH=follicle-stimulating hormone; HIV=human immunodeficiency virus; 
HBsAg=hepatitis B surface antigen; HCVAb=hepatitis C antibody; PE=physical examination; PK=pharmacokinetics; WOCBP=women of childbearing potential.
a.
Participants without hepatic impairment (Cohort 1) will be discharged on Day 3 after PK samples and other assessments have been completed. Participants in Cohort 1 will 
also complete the follow-up contact. All participants with hepatic impairment (Cohorts 2, 3, and 4) will complete all activities through Day 6 and the follow-up phone contact.
b. Participants in Cohorts 2-4 will be discharged after completion of procedures on Day 3 (with subsequent outpatient visits). At Investigator discretion, participantss may remain 
inpatient from Days -1 to 6.
c.
Cohorts 2, 3, and 4 only.
d. Full physical exam (PE) at Screen; at all other time points, limited PE for findings during previous PE or new/open AEs only, at Investigator discretion.
e.
Cohort 1 only.
f.
Procedure to be completed only if participant was discharged on Day 3 and returning for outpatient visits on each of these days.
g. Confirmation of appropriate contraception use and inquiry about pregnancy, only.
h. Meals/snacks to be served at clock times matching approximately 0H, 4H, 7H, 10H, and 14H (optional) relative to dosing on Day 1 (while inpatient).  
i.
Dosing to occur with standard morning meal provided approximately 30 minutes prior to 0H, and completed approximately 10 minutes prior to dosing.
.
k. PK samples collected at times >10 hours post-dose will be collected within ±1 hour of the planned sampling time.
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2. INTRODUCTION
PF-06835919 is a ketohexokinase (KHK) inhibitor that is currently being developed for the 
treatment of NASH with fibrosis.  KHK is an enzyme catalyzing the conversion of fructose 
and adenosine triphosphate (ATP) to fructose-1-phosphate (F1P) and adenosine diphosphate 
(ADP), the first committed step in fructose metabolism.  Loss of function mutation in KHK, 
known as Essential Fructosuria, is a rare autosomal genetic condition (Online Mendelian 
Inheritance in Man or OMIM #229800)1 which is asymptomatic and only recognized by the 
appearance of fructose in the urine after fructose consumption.2,3  PF-06835919 is a potent, 
reversible inhibitor of human KHK.  It is anticipated that inhibition of KHK will decrease 
hepatic de novo lipogenesis and steatosis, thereby ameliorating the pathogenesis of 
nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis 
(NASH).  In addition, it is anticipated that KHK inhibition will improve circulating lipid and 
lipoprotein profiles as well as insulin sensitivity.
The purpose of this study is to evaluate the effect of varying degrees of hepatic impairment 
on the pharmacokinetics of PF-06835919.
2.1. Study Rationale 
The primary purpose of this non-randomized, single dose, open-label study is to characterize 
the effect of varying degrees of hepatic impairment on the plasma pharmacokinetics (PK) of 
PF-06835919 following administration of a single, oral, 25 mg dose.  NAFLD/NASH is
associated with varying degrees of hepatic impairment.  Recognizing that the target 
population of PF-06835919 is patients with NAFLD/NASH and that the major clearance 
mechanism of PF-06835919 is predicted to be active uptake into the liver followed by 
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-06835919.
2.2. Background 
Fructose metabolism, unlike glucose metabolism, is not subject to regulatory feedback 
inhibition in normal human biology.  As a consequence of unrestrained metabolism, fructose 
rapidly generates a number of reactive and signaling metabolites that contribute to metabolic 
disease progression.  Along with the lack of feedback inhibition, hepatic fructose metabolism
has been shown to reduce liver ATP concentrations after a single intravenous (IV) bolus of 
fructose.4  Depletion of ATP leads to the activation of adenosine monophosphate (AMP)
deaminase5 and subsequent increases in uric acid levels that have been shown to directly 
regulate hepatic lipogenesis through generation of mitochondrial oxidative stress.6  
Additionally, preclinical studies have demonstrated that fructose rapidly enriches glycolytic 
metabolite pools, leading to activation of the Carbohydrate Response Element Binding 
Protein (ChREBP), a highly lipogenic transcription factor, that can promote both steatosis 
and insulin resistance with carbohydrate over-feeding.7  Post-prandial hypertriglyceridemia is 
observed in both rodents and humans following fructose feeding, as fructose both decreases 
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Excessive fructose consumption has been shown to cause features of metabolic syndrome 
and NAFLD.8  In humans, supplementation of a normal diet with 25% of the calories as 
fructose, but not as glucose, caused hyperlipidemia within 2 weeks.9  Additionally, these 
participants developed insulin resistance as evidenced by increased insulin excursion during 
an oral glucose tolerance test.9  Increased sugar intake, in the form of carbonated beverages, 
has been associated with NAFLD in patients who lack other features of metabolic syndrome, 
suggesting that fructose intake independent of metabolic disease can increase liver fat.10,11  In 
a separate study with participants consuming weight-neutral diets containing 25% of dietary 
calories as fructose, increased hepatic lipid and decreased hepatic insulin sensitivity were 
observed after 9 days of high-fructose consumption.12  Conversely, restricting dietary sugar 
intake from 28% to 10% for 9 days improved insulin sensitivity and reduced hepatic lipid in 
obese adolescents.13  In a separate study, fructose at 5%, 8.75%, or 12.5% of the daily caloric 
intake showed a dose-responsive slight elevation in plasma triglycerides and elevation in uric 
acid.14  In studies with matched calories provided as free glucose, fructose was unique in its 
ability to promote insulin resistance, visceral obesity and hyperlipidemia.9  Collectively, 
these data suggest that the fructose, not glucose, component of dietary sugar is unique in its 
ability to promote features of metabolic syndrome, including steatosis, insulin resistance, and 
obesity.
NASH is a clinical and histological subset of NAFLD that is associated with increased 
all-cause mortality, cirrhosis and end-stage liver disease, increased cardiovascular mortality, 
and increased incidence of both liver-related and non-liver-related cancers.15  Prevalence of 
NAFLD is estimated at 30-40% of the United States (US) population, while prevalence of 
NASH is estimated at 3-5% of US population.15  Risk factors for NASH include obesity, 
insulin resistance, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia, as 
manifested by low levels of high density lipoprotein cholesterol (HDL-C) and elevated 
triglycerides.
There are no therapies currently approved for the treatment of NASH, although a growing 
body of evidence demonstrates the urgent need for such therapies.15  NASH is diagnosed 
clinically by liver biopsy demonstrating steatosis, inflammation, and cytological ballooning 
of hepatocytes, often with varying degrees of fibrosis.  The clinical progression of NASH 
involves increasing degrees of fibrosis, with cirrhosis and/or hepatocellular carcinoma 
developing in a subset of patients.15  Patients with NASH may be asymptomatic or have 
non-specific symptoms such as fatigue, despite having significant disease shown by liver 
biopsy. More severe NASH is associated with elevated risk for progression to cirrhosis and 
liver-related mortality.
2.2.1. Nonclinical Experience with PF-06835919
 
 
 
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2.2.1.2. Nonclinical Safety and Tolerability
PF-06835919 was administered by oral gavage to Wistar Han rats and Beagle dogs in studies 
up to 6 and 16 weeks in duration, respectively, and in a single-dose study in cynomolgus 
monkeys.  
 
 
 
 
 
 
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2.2.2. Clinical Overview
At the time of finalization of this protocol, three Sponsor-initiated clinical trials that 
administered PF-06835919 (C1061001, C1061002, and C1061003) have been completed. In 
addition, a PF-06835919 midazolam DDI study (C1061016) is complete in the clinic and 
preliminary results are provided separately, below.
The safety and tolerability of PF-06835919 was assessed in two Phase 1 studies conducted in 
healthy participants, C1061001 and C1061002.  A total of 78 adult participants (all males) 
were randomized in these 2 studies.  Overall, 68 participants (87%) were exposed to at least a 
single oral dose of PF-06835919 with 52 of these participants exposed to repeated doses of 
PF-06835919. 
In healthy volunteers, oral doses of PF-06835919 as high as 600 mg (single dose) and 
330 mg once daily for up to 14 days were found to be well tolerated with an acceptable safety 
profile.  In healthy volunteer trials to date, there have been no serious adverse events (SAEs) 
or deaths related to PF-06835919 administration. One paricipant receiving 130 mg
PF-06835919 was withdrawn from the study after 3 days of dosing due to an adverse event 
(AE) of macular exanthema (moderate severity) localized mainly on the arms and thighs, 
with mild pruritus.  There has been no clear, dose-related increase in the frequency of AEs 
with increasing doses of PF-06835919.  
There were dose-dependent increases in mean plasma fructose concentrations observed 
following administration of PF-06835919.  In the multiple ascending dose study (C1061002),
fructose was administered orally with each of 3 daily meals.  As a measure of target 
engagement, plasma fructose area under the effect curve from time zero to 24 hours 
post-dose (AUEC24) was assessed on Day 14 of dosing and compared to baseline (ie, before 
dosing of PF-06835919 or placebo).  While there was no change in fructose AUEC24 for the 
placebo group, fructose AUEC24 increased in a dose-dependent manner, with increases up to 
approximately 13-fold at the top dose of 330 mg.
Following administration of single oral doses of 10 to 600 mg, PF-06835919 was rapidly 
absorbed with a median time for Cmax (Tmax) ranging from 1 to 3 hours.  Following 
attainment of Cmax, plasma concentrations declined with a half-life ranging from 
approximately 11.4 to 15.1 hours.  Both the Cmax and AUC24 increased in an approximate
dose-proportional manner across the dose range studied.
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Following multiple oral doses of PF-06835919 ranging from 15 to 330 mg once daily (QD) 
over 14 days, absorption was rapid, with median Tmax occurring at approximately 0.5 to 
1 hour postdose.  Steady-state was achieved within 4 days of dosing.  Consistent with study 
C1061001, AUC24 and Cmax increased in an approximately dose proportional manner over the 
doses studied.  Accumulation of PF-06835919 was modest, with an AUC24 accumulation 
ratio (Day 14/Day 1) averaging from approximately 1.4- to 1.5-fold.  No clear dose-related 
trend in terminal t½ was observed, with arithmetic mean values ranging from 13.29 to 
16.76 hours.  Less than 1% of the oral dose was excreted unchanged in urine.  
One Phase 2 study, C1061003, has been completed. This study was a randomized, 
double-blind study examining six weeks of once-daily administration of placebo, 75 mg 
PF-06835919, or 300 mg PF-06835919 in adults with NAFLD. A total of 53 participants
were randomized into C1061003 of which 19 were randomized to placebo, 17 received 
75 mg of PF-06835919, and 17 received 300 mg of PF-06835919. Both doses were found to 
be generally safe and well tolerated over the course of the study.  The overall incidence of 
treatment-emergent adverse events (TEAEs) was very low and the proportion of participants 
with TEAEs was similar across all treatment groups. There were no reported serious adverse 
events (SAEs) including deaths or dose reductions due to AEs at either of the doses studied.  
Cumulatively, 131 participants have participated in Sponsor-initiated clinical trials 
administering PF-06835919 worldwide (not including the C1061016 study), of which 
102 have received ≥1 dose of PF-06835919, and 31 participants have been dosed for up to 
40 days.  In clinical trials to date, there have been no SAEs reported.  There has been no 
clear, dose-related increase in the frequency of AEs with increasing doses of PF-06835919.
C1061016 was a Phase 1, randomized, open-label, 2-way crossover DDI study, which 
evaluated the impact of PF-06835919 on midazolam PK in healthy participants.  Each 
participant was given both of the following treatments in a cross-over manner: (A) a single 
7.5 mg oral dose of midazolam and (B) QD dosing of 300 mg PF-06835919 for 9 days 
followed by a single oral 300 mg dose of PF-06835919 and a 7.5 mg oral dose of midazolam.  
A total of 10 healthy adult participants were enrolled in this study.  Preliminary results 
indicate that PF-06835919 was well tolerated in this study, and there were no new safety 
laboratory abnormalities, ECG, or vital sign changes of clinical concern when PF-06835919 
was given concomitantly with midazolam, as compared with each agent alone.
Median plasma midazolam concentrations were similar following multiple doses of 
PF-06835919 compared to those observed for midazolam administered alone.  Midazolam 
Tmax values were similar between treatment periods (median Tmax of 0.5 hours).  Plasma 
concentrations declined in a monophasic manner with a similar mean terminal half-life (t1/2) 
observed between the treatments: 5.267 hours for midazolam administered alone and 
4.986 hours when administered with multiple doses of PF-06835919.


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Statistical comparison of plasma concentrations of midazolam administered alone and with 
multiple doses of PF-06835919 demonstrated that the adjusted geometric mean for AUCinf
and Cmax were similar, following co-administration with multiple doses of PF-06835919 as 
compared to midazolam administration alone. The ratio of the adjusted geometric means of 
midazolam AUCinf, and Cmax (90% confidence interval [CI]) were 97.55% (79.91%, 
119.08%) and 98.92% (76.44%, 128.01%), respectively, following administration of 
midazolam with multiple doses of PF-06835919, relative to midazolam administered alone.  
Overall, these results indicate that there is no evidence of a meaningful effect of 300 mg 
PF-06835919 on CYP3A4.
2.3. Benefit/Risk Assessment
No clinical benefit is expected for the participants in the current study.  The data from this 
study will contribute to dosing recommendations for the target patient population, which 
include those with varying degrees of hepatic impairment.  The dose proposed for the current 
study is 24-fold lower than the highest single oral dose (600 mg) administered to healthy 
participants, which was found to be well-tolerated with an acceptable safety profile.  
In completed clinical studies, PF-06835919 was determined to be well-tolerated and to have 
an acceptable safety profile.  There are no important identified risks for PF-06835919.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Based on Study C1061003, PF-06835919 administered at the 300 mg dose level was shown 
to reduce liver fat over a 6-week period.  There have been no significant adverse clinical 
trends in laboratory values, vital signs, or changes in ECG parameters.  The sponsor 
considers that the available information about PF-06835919 from the non-clinical and 
clinical studies completed to date provides a favorable benefit-risk profile and supports the 
continued investigation of the compound as a potential treatment for NASH with liver 
fibrosis.  However, standard, intensive, inpatient monitoring of participants following 
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administration of the single oral dose for at least 48 hours is included to ensure participant 
safety.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-06835919 may be found in the Investigator’s brochure for 
PF-06835919, 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-06835919 (both total and 
unbound) 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-06835919 PK parameters derived from plasma: 
Cmax, AUCinf, fu, Cmax,u, and AUCinf,u.
Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of a single oral 
dose of PF-06835919 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 a non-randomized, open-label, single-dose, parallel-cohort, multicenter study to 
investigate the effect of varying degrees of hepatic function on the plasma PK (total and 
unbound) of PF-06835919 after a single oral 25 mg dose administered in the fed state.  A 
total of approximately 24 participants with varying degrees of hepatic function will be 
enrolled into the study to ensure that approximately 6 evaluable participants in each of the 
3 hepatic impairment cohorts, and 6 to 8 in the cohort without hepatic impairment complete 
the study.  Participants will be selected based on their Child-Pugh score as shown in Table 1. 
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Table 1.
Hepatic Function Categories Based on Child Pugh Score
Cohort
Description
Child-Pugh Score
Number of 
Participants
1
Without hepatic impairment
Not Applicable
6-8a
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)
4-6b
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 3 hepatic impairment cohorts.
b. If recruitment across the sites selected proves to be prohibitive, study will dose only 4 participants in this cohort. 
Child-Pugh scores will be determined as described in Appendix 8 at the screening visit.  
Participants will be enrolled in a staged manner such that participants with moderate and 
severe hepatic impairment (Cohorts 3 and 4) will be evaluated first.  Enrollment of 
participants with mild hepatic impairment (Cohort 2) will occur when approximately 50% of 
the total participants in Cohorts 3 and 4 have been enrolled.  Participants without hepatic 
impairment (Cohort 1) will then be enrolled near the end of the study.  These participants
will be recruited to match the average demographics (at a minimum, age and weight; and 
gender as much as practically possible) across the pooled Cohorts 2 through 4.  Approval 
from the Sponsor must be obtained before proceeding with dosing participants in 
Cohort 1 or Cohort 2.
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 Section 1.2 Schema.  For individual participants, 
the total duration of participation from the Screening visit to the final clinic visit (Day 6) will 
be a maximum of approximately 5 weeks.
4.2. Scientific Rationale for Study Design
This study is a Phase 1, non-randomized, open-label, single-dose, parallel-group study of 
PF-06835919 in participants with varying degrees of hepatic impairment and participants
without hepatic impairment, matched for age as well as body weight (and gender as much as 
practically possible). This study will use a single dose of PF-06835919 since single dose 
plasma PK is generally predictive of exposure upon repeated dosing.  
There is uncertainty of the effect of hepatic impairment on PF-06835919 PK. The 
elimination half-life of PF-06835919 may be prolonged in participants with hepatic 
impairment. Based on a conservative estimate of a 2-fold increase of the half-life of 
PF-06835919 PK, plasma samples will be collected serially up to 120 hours post-dose to 
adequately characterize the elimination phase of the plasma concentration-time profile in the 
cohorts with varying degrees of hepatic function.  Based on the half-life of 11.4 to 15.1 hours 
observed in C1061001, PK samples will only be collected for three days in participants 
without hepatic impairment (Cohort 1).


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In vivo protein binding of PF-06835919 will be assessed in participants with varying degrees 
of hepatic function, as PF-06835919 is 92% bound to plasma proteins.  The fraction unbound 
(fu) of PF-06835919 will be determined at approximately the expected time of maximum 
concentration (Tmax) in each participant.  
Malnutrition is prevalent in patients with chronic liver disease, and food intake is important 
for their health.  In addition, previous clinical studies with PF-06835919 have been 
conducted in the fed state.  Therefore, PF-06835919 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.  
 
 
The Child-Pugh classification (CPC) (refer to Appendix 8) will be used to define the 
3 cohorts of participants with varying degrees of hepatic impairment.  This study will include 
participants with mild (Child-Pugh Class A, Cohort 2), moderate (Child-Pugh Class B, 
Cohort 3), and severe (Child-Pugh Class C, Cohort 4) hepatic impairment as well as 
demographic-matched control participants without hepatic impairment.  All 3 categories of 
hepatic impairment will be assessed, as these represent the likely population in later phase 
studies for the proposed indication (treatment of NASH with fibrosis).  All participants will 
be required to provide their own consent to participate in this study.  Participants with 
clinically-active Grade 3 or Grade 4 encephalopathy will be excluded.  However, participants
who have a previous history of Grade 3 or 4 encephalopathy but are currently receiving an 
intervention [for example: lactulose or lactitol, alone or in combination with rifaximin, and/or 
neomycin] to control their encephalopathy-related signs and symptoms are eligible provided 
the on-treatment encephalopathy grading at the Screening visit is Grade 2 or lower thereby 
permitting them to provide informed consent.  Acknowledging the medical state of the 
population enrolled, certain eligibility criteria for participants with hepatic impairment are 
distinctly different, including assessment of Hepatitis B and Hepatitis C, with no specific 
exclusion of those who have these conditions planned for participants classified in Cohorts 2, 
3, or 4.  
Although only <1% of PF-06835919 is renally eliminated, participants will be excluded if 
there is concomitant clinical evidence of renal impairment – defined as estimated glomerular 
filtration rate (eGFR) ≤60 mL/min.  This is to enable a more clear assessment of the effect of 
hepatic impairment on PF-06835919 disposition. 
Embryo-fetal development studies have not been conducted, so all participants in this study,
and his or her partner(s) are required to use highly effective methods of contraception during 
this study.
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4.3. Justification for Dose
A single oral dose of 25 mg PF-06835919 will be used in this study.  This dose has been 
selected based on prior experience in healthy participants and also takes into account safety 
considerations for participants with varying degrees of hepatic impairment in whom an 
increase in plasma PF-06835919 exposure may occur.  PF-06835919 was found to be 
well-tolerated with an acceptable safety profile with single doses up to 600 mg (C1061001) 
and repeated doses up to 330 mg/day (C1061002).  A maximum tolerated dose was not 
identified.  In addition, the PK of PF-06835919 is approximately dose-proportional, and the 
results at the 25 mg dose can be extrapolated to other dose levels.  Pharmacodynamic 
changes in plasma and urinary fructose were also observed in C1061002 at a similar dose to 
the 25 mg dose that will be used 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 last scheduled procedure shown in the schedule of activities.
The end of the study is defined as the date of the last scheduled procedure shown in the 
schedule of activities for the last participant in the trial globally.
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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
5.1.1. Participants in All Cohorts
Participants are eligible to be included in 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 70 years, inclusive, at the Screening visit:

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
3. Body mass index (BMI) of 17.5 to 35.4 kg/m2; and a total body weight >50 kg 
(110 lb).
Informed Consent:
4. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.1.2. Additional Inclusion Criteria for Participants without Hepatic Impairment 
(Cohort 1 Only)
1. 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-identified central 
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2. Participants must meet the demographic-matching criteria, including:

A body weight that is 10 kg of the average of the pooled hepatic impairment 
cohorts (Cohorts 2, 3, and 4), as provided by the sponsor;

An age that is 5 years of the average of the pooled hepatic impairment cohorts 
(Cohorts 2, 3, and 4), as provided by the sponsor;

Attempts will be made to ensure that the male-to-female distribution in Cohort 1, 
is comparable, to that in the pooled hepatic impairment cohorts (Cohorts 2, 3, 
and 4).
3. No known or suspected hepatic impairment; including at Screening, meet all the 
following criteria, as assessed by the sponsor-identified central laboratory, with a 
single repeat permitted to assess eligibility, if needed:

Alanine aminotransferase (ALT) ≤upper limit of normal (ULN);

Aspartate aminotransferase (AST) ≤ULN;

Total bilirubin ≤ULN;
NOTE: Participants with a history of Gilbert syndrome (and hence elevated total 
bilirubin) are eligible provided direct bilirubin level is ≤ULN plus ALT and AST 
are ≤ULN plus alkaline phosphatase, hemoglobin, and reticulocyte count are all 
≤ULN; 

Albumin ≤ULN;

Prothrombin time (PT) International Normalized Ratio (INR) ≤ULN.
5.1.3. Additional Inclusion Criteria for Participants with Impaired Hepatic Function 
(Cohorts 2, 3, and 4 Only)
1. Stable hepatic impairment that meets the criteria for Class A, B, or C of the modified 
Child-Pugh classification (refer to Appendix 8) with no clinically significant change 
in disease status within the 28 days prior to the Screening visit, as documented by the 
participant’s recent medical history (for example: no worsening clinical signs of 
hepatic impairment, no worsening of total bilirubin or prothrombin time (PT) by more 
than 50%).
2. Stable concomitant medications for the management of individual participants 
medical history; on a case-by-case basis, with input from the Sponsor, participants 
receiving fluctuating concomitant medication/treatment may be considered if the 
underlying disease is under control.


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3. Participant is willing and able to abide by the lifestyle guidelines described in
Section 5.4 of this protocol.  A previous history of alcohol abuse is permissible 
provided that the breath alcohol test at Screening is negative.
5.2. Exclusion Criteria
5.2.1. Participants in All Cohorts
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 who have undergone cholecystectomy and/or appendectomy are 
eligible for this study as long as the surgery occurred more than 6 months prior to 
Screening.
2. At Screening, participants with a positive result for human immunodeficiency virus 
(HIV) antibodies, as assessed by sponsor-identified central laboratory, with a single 
repeat permitted to assess eligibility, if needed.
3. 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 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of investigational 
product used in this study (whichever is longer).
6. Participants with known prior participation (ie, randomized and received at least 
1 dose of investigational product) in a study involving PF-06835919.


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Diagnostic Assessments:
7. A positive urine drug test, for illicit drugs, and/or a positive breath alcohol test at 
Screening.  However, participants who have been medially prescribed opiates/opiods 
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.
Other Exclusions:
8. Male participants with partners who are currently pregnant.
9. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing and until the follow-up contact.
10. History of sensitivity to heparin or heparin-induced thrombocytopenia, only if heparin 
is used to flush intravenous catheters used during serial blood collections.
11. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
12. 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.
5.2.2. Additional Exclusion Criteria for Participants without Hepatic Impairment 
(Cohort 1 Only)
In addition, participants without hepatic impairment (Cohort 1) presenting with any of the
following will not be included in the study:
1. Evidence of chronic liver disease including history of hepatitis, hepatitis B, or 
hepatitis C or evidence of any of the following, as assessed by sponsor-identified 
central laboratory, with a single repeat, permitted to assess eligibility, if needed:

Hepatitis B virus, defined by presence of hepatitis B surface antigen (HBsAg);
NOTE: while not part of the tests assessed in this study, participants with a 
previously positive HBsAb result due to vaccination are deemed eligible;

Hepatitis C virus (HCV), defined by presence of hepatitis C antibody (HCVAb).


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2. History of regular alcohol consumption exceeding 14 drinks/week for female 
participants or 21 drinks/week for male participants (1 drink = 5 ounces [150 mL] of 
wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 
6 months of before Screening.
3. Screening supine 12-lead ECG demonstrating Fridericia method-corrected QT 
(QTcF) interval >450 msec or a QRS interval >120 msec.  If QTcF exceeds 
450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and 
the average of the three QTcF or QRS values should be used to determine the 
participant’s eligibility.
4. Screening seated systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood 
pressure (DBP) ≥90 mm Hg, following ≥5 minutes of seated rest.  If SBP is 
≥140 mm Hg or DBP ≥90 mm Hg, the blood pressure (BP) assessment should be 
repeated 2 more times and the average of the three BP values should be used to 
determine the participant’s eligibility.
5. Use of chronic prescription medications within 7 days or 5 half-lives (whichever is 
longer) prior to Day 1.
NOTE: Use of selected, limited prescription and non-prescription medications is 
permitted (refer to Section 6.5 details).
5.2.3. Additional Exclusion Criteria for Participants with Impaired Hepatic Function 
(Cohorts 2, 3, and 4 Only)
In addition, participants in the hepatic impairment cohorts (Cohorts 2, 3 and 4) presenting 
with any of the following will not be included in the study: 
1. Hepatic carcinoma or hepatorenal syndrome or limited predicted life expectancy 
(defined as less than 1 year in Cohorts 2 & 3 and less than 6-months for Cohort 4 
only).
2. A diagnosis of hepatic dysfunction secondary to any acute ongoing hepatocellular 
process that is documented by medical history, physical examination, liver biopsy, 
hepatic ultrasound, computerized tomography scan, or magnetic resonance imaging 
(MRI).
3. History of surgery that would be expected to alter absorption, distribution, 
metabolism, or excretion (ADME) properties of PF-06835919 (eg, status post 
porta-caval shunt surgery).
NOTE: Participants with a transjugular intrahepatic portosystemic shunt (TIPS) are 
permitted provided that they meet the Child-Pugh criteria.
4. History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less 
than 4 weeks prior to Screening.


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5. Signs of clinically active Grade 3 or 4 hepatic encephalopathy (ie, >Grade 2 Portal 
Systemic Encephalopathy score; refer to Appendix 8).
6. Severe ascites and/or pleural effusion, except for those categorized in Cohort 4 who 
may be enrolled provided participant is medically stable, per the investigators’ medical 
judgment.
7. Participants who have previously had a transplanted kidney, liver, or heart.
8. Screening supine 12-lead ECG demonstrating a QTcF interval >470 msec or a QRS 
interval >120 msec.  If QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG 
should be repeated 2 more times and the average of the 3 QTcF or QRS values should 
be used to determine the participant’s eligibility.
9. At Screening, persistent severe, uncontrolled hypertension; for example: seated 
systolic blood pressure (SBP) ≥180 mm Hg and/or diastolic blood pressure (DBP) 
≥105 mm Hg after ≥5-minute of seated rest, with a single repeat permitted to assess 
eligibility, if needed, at each of these 2 visits:

For participants with SBP ≥160 mm Hg or DBP ≥100 mm Hg, the period between 
Screening and Day -1 must be used to refine the doses of the agents used for 
management of blood pressure with the aim to have stable BP on Day 1.
10. Participants with ALT or AST >5x ULN on clinical laboratory tests at Screening, as 
assessed by the sponsor-identified central laboratory, with a single repeat permitted to 
assess eligibility, if needed.
11. At Screening, participants with an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73m2 using 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.
5.3. Lifestyle Considerations
After confirmation of eligibility and starting on Day -1, the participants will be instructed to 
maintain the guidelines described below for the duration of participation in the study. 
5.3.1. Meals and Dietary Restrictions
Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus fruits 
(eg, Seville oranges, pomelos) from 7 days prior to the first dose of investigational product 
until collection of the final PK blood sample in the last period.
While inpatient, the meals consumed are expected to follow the restrictions outlined below:

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to all fasting clinical laboratory evaluations;


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
Water may be consumed as desired (ad libitum);

Investigational product must be administered with the morning meal on Day 1;

While inpatient, all meals will be standardized as follows: 

Standard morning meal, lunch, afternoon snack, and evening meal (and an 
optional evening snack) will be provided at a similar clock time to the clock time 
when these meals are provided relative to dosing on Day 1 (ie, 0H, 4H, 7H, 10H, 
and 14H);

The total daily nutritional composition should be approximately 
55% carbohydrate, 30% fat and 15% protein.  The nutritional macronutrient 
composition consumed by each participant should be maintained, as much as 
practically possible;

The daily caloric intake per participant should not exceed approximately 
3200 kcal; 

The morning meal (matching 0H), afternoon snack, and optional evening snack is 
each envisioned to constitute 300 to 400 calories and a macronutrient composition 
of approximately 55% carbohydrates, 30% fat and 15% protein;

Lunch and evening meal each is envisioned to constitute less than 1000 calories;

On Day 1, the morning meal will be provided at approximately 30 minutes prior 
to dosing at 0H (or similar clock time on non dosing days) and is expected to be 
completed approximately 10 minutes prior to dosing.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from alcohol for ≥24 hours prior to the single dose of 
investigational product on Day 1 (plus have a negative breath alcohol test on Day -1) 
and continue abstaining from alcohol until the follow-up phone 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.
5.3.3. Activity

Participants will not be permitted to engage in physically strenuous exercise (for 
example: heavy lifting, weight training, calisthenics, and aerobics) within 48 hours 
before each blood sample collection for clinical laboratory tests while participating in 
the study; physical activity at an individual participant’s normal pace is permitted.


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5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use highly effective 
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception).  In addition, the investigator or 
designee will instruct the participant to call immediately if the selected contraception method 
is discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently dosed on Day 1. Screen failure data are collected and remain as source 
and are not reported to 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 Day 1, of 28 days, is 
exceeded.  In addition, for participants in Cohorts 2-4, inclusive, only, re-screening may be 
appropriate following mild intercurrent illness after the condition has resolved.  In such 
cases, all screening procedures must be repeated and the participant assigned a new 8-digit 
study-specific identification (SSID) number.  Participants must be deemed to meet all the 
eligibility criteria under the new 8-digit SSID before progressing to Day 1.
5.5. Criteria for Dosing on Day 1
Participants will progress to dosing on Day 1 provided they have satisfied all the following 
criteria:

Breath alcohol test on Day -1 is negative;

In females of childbearing potential, urine pregnancy test on Day 1 is negative prior 
to dosing as reported by on-site pregnancy test using supplies provided by the 
sponsor-identified central laboratory;

Safety-related laboratory tests collected and analyzed by sites’ local laboratory on 
Day -1, if performed at investigator discretion, upon review on Day 1 must reflect 
participant to be in stable medical condition;

Cohort 1 only: Approval from the Sponsor must be obtained before proceeding with 
dosing participants in Cohort 1;


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
Cohorts 2 and 3 only: Participants must have measurement on Day 1 of 
SBP ≤159 mm Hg and DBP ≤99 mm Hg with repeat permitted, if needed, to confirm 
stable BP; 

Cohort 4 only: Participants must have measurement on Day 1 of SBP ≤159 mm Hg 
and DBP ≤105 mm Hg with repeat permitted, if needed, to confirm stable blood 
pressure (BP).
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.
6.1. Study Intervention(s) Administered
For this study, the investigational product is PF-06835919.
PF-06835919 will be supplied by Pfizer as 25 mg tablets for oral administration.  Tablets will 
be supplied to the clinical research unit (CRU) in bulk along with individual dosing 
containers for unit dosing.
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive breakfast as 
outlined in Section 5.3.1 (Meals and Dietary Restrictions).  The participants will then receive 
investigational product (PF-06835919) at approximately 8:00 AM (2 hours).  A single, oral, 
25 mg dose of PF-06835919 will be administered.  Participants will swallow the tablet whole 
and will not manipulate or chew the tablet prior to swallowing.  Investigator site personnel 
will administer investigational product to participants with ambient temperature water of 
approximately 120 mL. 
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 


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must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). All study 
interventions will be accounted for using an investigational 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 interventions should be stored in their original containers and in accordance 
with the labels. 
7. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer upon discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention
must be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use 
of the study intervention after the temperature excursion. Use of the study 
intervention prior to Pfizer approval will be considered a protocol deviation. Specific 
details regarding the definition of an excursion and information the site should report 
for each excursion will be provided to the site in the IP manual.
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 participant by 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a 
healthcare provider or participant in accordance with this protocol.  Local health authority 
regulations or investigator site guidelines may use alternative terms for these activities.


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See the IP manual for instructions on how to prepare the investigational product for 
administration. Tablets will be prepared at the CRU in the individual dosing containers by 
2 operators, 1 of whom is an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance.  The 
tablets will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements. 
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
Following completion of informed consent at the Screening visit, each  participant will be
assigned a single 8-digit study-specific subject identification (SSID) number by the site staff.  
The first four digits of the SSID will reflect the sponsor-assigned site number and the 
remaining four-digits will reflect each subjects’ unique number assigned in chronological 
order of when informed consent is obtained.
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 taken.
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 days before the first dose of investigational product will be 
documented as a prior treatment.  Treatments taken after the first dose of investigational 
product will be documented as concomitant treatments.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are women of childbearing potential (see Appendix 4).
6.5.1. Participants with Healthy Hepatic Function (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 ≤1 g/day;

Herbal supplements must be discontinued at least 28 days prior to Day 1 and until the 
follow-up contact;


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
Limited use of prescription and 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 medical condition(s).  Whenever possible, attempts must 
be made to not alter the doses and regimens of the concomitant medications after Day 1 and 
until the follow-up contact.
Participants on the following medications, at the Screening visit, are excluded from the 
study:

Potent CYP inhibitors, including but not limited to:

CYP1A2 inhibitors: ciprofloxacin, enoxacin, fluvoxamine;

CYP2C8 inhibitors: gemfibrozil;

CYP2C19 inhibitors: fluconazole, fluvoxamine, ticlopidine;

CYP3A inhibitors: boceprevir, clarithromycin, conivaptan, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole;

CYP2D6 inhibitors: bupropion, fluoxetine, paroxetine, quinidine.

Potent CYP inducers, including but not limited to:

CYP3A: avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort.

Potent OATP inhibitors (eg, cyclosporine, gemfibrozil, rifampin, erythromycin, 
clarithromycin);

(Medical grade) marijuana, regardless of medical indication.
Herbal supplements must be discontinued at least 28 days prior to Day 1 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-06835919.
Standard medical supportive care must be provided to manage the AEs. 
6.6. Dose Modification
Dose modifications will not be made during the study.  


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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 to permanently discontinue 
investigational product. If investigational product is permanently discontinued, the 
participant will remain in the study to be evaluated at the Early Termination visit. See the 
SoA for data to be collected at the time of discontinuation of investigational product.
See the SoA for 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/Withdrawal From 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 SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are randomized and then are 
prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  The participant will be permanently discontinued both from the study 
intervention and from the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but data already 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 participant withdraws from the study because of an 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.


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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 participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate case report 
form (CRF) page.  In the event that vital status (whether the participant is alive or dead) is 
being measured, publicly available information should be used to determine vital status only 
as appropriately directed in accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
Participants will be screened within 28 days prior to administration of the investigational 
product to confirm that they meet the study population criteria for the study.  The investigator 
(or an appropriate delegate at the investigator site) must obtain a signed and dated ICD
before performing any study-specific procedures.  If the time between screening and dosing 
exceeds 28 days as a result of unexpected delays (eg, delayed drug shipment), then 
participants do not require rescreening if the laboratory results obtained prior to first dose 
administration meet eligibility criteria.


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A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. 
 
 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
If an intravenous (IV) catheter is utilized for blood sample collections, ECGs and vital sign 
assessments (pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
150 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
CCI


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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.
8.2.1. Physical Examinations
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation as defined in the Schedule of 
Activities. 

A full physical examination will include head, ears, eyes, nose, mouth, skin, heart 
and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and 
neurological systems. 

A limited physical examination will 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.  They must also remove the contents of their 
pockets and remain still during measurement of weight.
8.2.2. Vital Signs
Blood pressure and pulse rate will be measured as defined in the Schedule of Activities.  
Additional collection times, or changes to collection times of blood pressure and pulse rate 
will be permitted, as necessary, to ensure appropriate collection of safety data.

Single, seated blood 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 ≥5 minutes;

Same arm (preferably the dominant arm) will be used for blood pressure/pulse rate 
assessment throughout the study;

Blood pressure/pulse rate assessment should not be taken from the arm with an 
intravenous catheter, if placed;

Participants should be instructed not to speak during blood pressure/pulse rate 
measurements.


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The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
8.2.3. Electrocardiograms
12-Lead ECGs should be collected at times specified in the SoA section of this protocol
using an ECG machine that automatically calculates the heart rate and measures PR, QT, and 
QTcF intervals and QRS complex.  All scheduled ECGs should be performed after the 
participant has rested quietly for at least 10 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥30 msec from the baseline and is >450 msec; or 
b) an absolute QTcF value is ≥500 msec for any scheduled ECG. If either of these conditions 
occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to 
confirm the original measurement. If the QTcF values from these repeated ECGs remain 
above the threshold value, then a single ECG must be repeated at least hourly until QTcF
values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.
If a postdose QTcF interval remains ≥30 msec from the baseline and is >450 msec; or b) an 
absolute QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTcF intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.


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8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of stidy intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
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 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the investigational product.  Pregnancy tests will also be 
done whenever 1 menstrual cycle is missed during the active treatment period (or when 
potential pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests may 
also be repeated if requested by institutional review boards (IRBs)/ethics committees (ECs) 
or if required by local regulations.  If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required.  In such cases, the participant must be 
excluded if the serum pregnancy result is positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
Aes will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).


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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study (see Section 7). 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting Aes and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar days after 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 AE or SAE after 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 participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3. The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to 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.


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8.3.2. Method of Detecting Aes and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of Aes and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(Ecs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
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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 (30±2 days 
after IP dosing).
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. 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 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE


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Medication errors include:

Medication errors involving participant exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified 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 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of PF-06835919 greater than 600 mg 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/SAEs and laboratory abnormalities until 
PF-06835919 can no longer be detected systemically (at least 5 days).
3. Obtain a blood sample 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 an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.


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8.5. Pharmacokinetics 
8.5.1. Analysis of PF-06835919 Concentrations
For analysis of total PF-06835919 concentrations blood samples (3 mL) to provide 
approximately 1.5 mL of plasma for pharmacokinetic analysis will be collected into 
appropriately labeled tubes containing dipotassium ethylenediaminetetraacetic acid 
(K2EDTA) as defined in the Schedule of Activities.
For analysis of unbound PF-06835919 concentrations, a blood sample (12 mL) to provide 
approximately 6 mL of plasma for unbound fraction determination of PF-06835919 will be 
collected into an appropriately labeled tube containing K2EDTA as defined in the Schedule 
of Activities.
PK sampling time points in this study may be adjusted to adequately assess the plasma PK 
profile based on emerging data from this study.  While the actual times may change, the total 
number of samples will remain the same.  All efforts will be made to obtain the PK samples 
at the exact nominal time relative to dosing.  However, collection of PK samples up to and 
including 10 hours after dose administration that are obtained within ±10% of the nominal 
time (eg, within ±6 minutes of a 60 minute sample) relative to dosing will not be captured as 
a protocol deviation, as long as the exact time of the sample collection is noted on the source 
document and data collection tool (eg, CRF).
PK samples collected at nominal times of >10 hours post dose must be collected within 
±1 hour 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 considered as 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 collected for measurement of plasma concentrations of PF-06835919 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.
Samples will be used to evaluate the PK of PF-06835919.  Samples collected for analyses of 
PF-06835919 plasma concentrations may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, 
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent document.  Participant confidentiality will be maintained.
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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.
Additional details regarding the collection, processing, storage and shipping of the blood 
samples will be provided, prior to study start, in a manual developed by the 
sponsor-identified central laboratory.
8.6. Pharmacodynamics
Pharmacodynamic (PD) parameters are not evaluated in this study.
.
 
 
 
 
 
 
 
 
 
 
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
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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 24 participants (approximately 6 participants per cohort, 
with varying degrees of hepatic function in each of 4 cohorts) has high power to detect a 
2-fold difference from the Reference (without hepatic impairment) cohort and is considered 
sufficient.  These calculations are based on estimates of between-subject standard deviations 
of 0.30 for loge AUCinf and 0.18 for loge Cmax.  These estimates were derived from single 
doses between 10 mg and 600 mg in Study C1061001.  Table 2 presents the 90% confidence 
intervals (with 80% tolerance probability) for various possible effects.
Table 2.
90% Confidence Intervals (with 80% Tolerance Probability) for Various 
Possible Effects in AUCinf and Cmax with n=6 Subjects/Cohort
Parameter
Estimated Fold Effect
(Test/Reference)
Expected 90% CI
AUCinf
0.5
(0.36, 0.70)
1
(0.72, 1.40)
2
(1.43, 2.79)
4
(2.86, 5.59)
Cmax
0.5
(0.41, 0.61)
1
(0.82, 1.22)
2
(1.64, 2.44)
4
(3.27, 4.89)
9.3. Populations for Analysis
Population
Description
Enrolled 
All participants who sign the ICD.
Randomly assigned to 
investigational product
All participants randomly assigned to investigational product 
regardless of whether or not investigational product was 
administered.
Safety
All participants randomly assigned to investigational product
and who take at least 1 dose of investigational product.  
Participants will be analyzed according to the product they 
actually received.


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9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.
9.4.1. Efficacy Analyses
An efficacy analysis is not applicable to this study. 
9.4.2. Pharmacokinetic Analysis
9.4.3. Pharmacokinetic Analysis Populations
The PK concentration population will be defined as all subjects who received 1 dose of 
PF-06835919 and in whom at least 1 plasma concentration value is reported.
The PK parameter analysis population is defined as all subjects dosed who have at least 1 of 
the PK parameters of primary interest.
9.4.4. Derivation of Pharmacokinetic Parameters Prior to Analysis
The plasma PK parameters for PF-06835919 following single dose administration will be 
derived from the concentration-time profiles as detailed in Table 3.  Actual PK sampling 
times will be used in the derivation of PK parameters.  The fraction of PF-06835919 unbound 
in plasma (fu) will be determined and reported for each subject by the analytical lab.


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Table 3.
Plasma PK Parameters
Parameter
Definition
Method of Determination
 
 
 
 
AUCinf*
Area under the plasma concentration-time 
curve 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.
AUCinf,u*
Unbound area under the plasma 
concentration-time curve from time zero 
extrapolated to infinite time.
fu* AUCinf*.
Cmax
Maximum plasma concentration.
Observed directly from data.
 
 
 
 
 
 
*As data permits.
9.4.5. Statistical Methods for Pharmacokinetic Data
Individual PF-06835919 concentrations will be listed and summarized descriptively by 
nominal PK sampling time and hepatic function cohort.  Individual subject and summary 
profiles of the concentration-time data will be plotted by hepatic function cohort for both 
total plasma PF-06835919 and unbound PF-06835919.  Unbound fractions (fu) will be listed 
and summarized descriptively by hepatic function cohort.  PF-06835919 AUCinf,
 
Cmax, unbound AUCinf (AUCinf,u),
and 
unbound Cmax (Cmax,u) individual subject parameters will be plotted by hepatic function 
cohort.  PK parameters of PF-06835919 will be summarized descriptively by hepatic 
function cohort.  
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The effect of varying degrees of hepatic impairment on PK parameters will be assessed by 
constructing 90% confidence intervals around the estimated difference between each of the 
Test (impaired) cohorts and the Reference (without hepatic impairment) cohort.  A one-way 
analysis of variance (ANOVA) will be used to compare the natural log transformed 
PF-6835919 AUCinf, Cmax, unbound AUCinf (AUCinf,u), and unbound Cmax (Cmax,u), 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.
 
 
 
 
 
 
 
9.4.6. 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.
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9.4.6.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS interval will be summarized by hepatic function cohort.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by hepatic function 
cohort: 
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
 
 
 
9.5. Interim Analyses
No formal interim analysis will be conducted for this study.  As this is an open-label study,
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK modeling, and/or supporting clinical 
development. 
9.5.1. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, investigator’s brochure (IB), and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the 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 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/EC or study 
center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.


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A copy of the ICD(s) must be provided to the participant.
 
 
 
 
 
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code. 
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred. All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code. The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
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www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (clinical study report (CSR) synopses in which any 
data that could be used to identify individual participants have been removed) on 
www.pfizer.com for Pfizer-sponsored interventional studies at the same time the US Basic 
Results document is posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods. Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data. 
Policy 0070 applies to new marketing authorization applications submitted via the 
centralized procedure since 01 January 2015 and applications for line extensions and for new 
indications submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
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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 paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
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When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the 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 time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.


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


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only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  For sites other than 
a Pfizer CRU, the contact number is not intended for use by the participant directly, and if a 
participant calls that number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the Schedule of 
Activities.  Additional laboratory results may be reported on these samples as a result of the 
method of analysis or the type of analyzer used by the clinical laboratory; or as derived from 
calculated values.  These additional tests would not require additional collection of blood.  
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety concerns.
The clinical safety laboratory tests outlined in Table 4 will be performed by the 
sponsor-identified central laboratory with the exception of urine pregnancy test which will be 
performed on-site.  Blood and urine samples for clinical laboratory tests will be collected 
following ≥4-hour fast.
Table 4.
Protocol Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Reticulocyte count (Abs)
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea
Creatinine (and eGFR via 
MDRD equation)
Plasma Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Phosphorus
Total CO2 (Bicarbonate)
AST
ALT
Alkaline phosphatase
GGT
Total bilirubin
Direct bilirubina,b
Indirect bilirubina,b
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyc
Other tests as part of clinical 
laboratory tests: 
aPTT, PT, INR
Serum FSHd,e
Serum and urine pregnancy 
test
Urine drug testf
Serology:d HBsAg, HCVAb, 
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
Abbreviations: Abs=absolute; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; CO2=carbon dioxide; eGFR=estimated glomerular 
filtration rate; FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; HBsAg=hepatitis B surface 
antigen; HCVAb=hepatitis C antibody; HIV=human immunodeficiency; INR=international normalized ratio; 
MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular 
volume; MDRD=Modification of Diet in Renal Disease; PT=prothrombin time; qual=qualitative; RBC=red blood cell; 
WBC=white blood cell.
a.
At Screening and Day 1, only.
b. After Day 1, direct and indirect bilirubin assessed when total bilirubin is > ULN, only.
c.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.


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d. At Screening only.
e.
For confirmation of post-menopausal status.
f.
Minimum requirements including cocaine, tetrahydrocannabinol (THC), opiates/opioids, benzodiazepines and 
amphetamines.
Investigators must document their review of each laboratory safety report.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.  
 
 
 
 
 
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.


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


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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of 
events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the 
investigational product under study during pregnancy or breastfeeding, and occupational 
exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
None
All (and exposure during 
pregnancy [EDP]
supplemental form for 
EDP)  


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
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE.  Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.


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
The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by the sponsor.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator must 
record this causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.


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


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds 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 is 
required in WOCBP partners of male participants (refer to the list of highly effective 
methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention,
which corresponds to the time needed to eliminate any study intervention(s).

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 not considered 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 60 years or older or no menses for 
12 months without an alternative medical cause. 

FOR CZECH REPUBLIC SITES ONLY: per Protocol Amendment 1, the 
following definition of postmenopausal state should be used in place of the 
above: A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause.

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.


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10.4.4. Contraception Methods
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That 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.
If a participant or 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 supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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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 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the 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 participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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


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


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


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monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 
pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as 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 laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.8. Appendix 8: Child-Pugh Classification (CPC) of Liver Dysfunction 
Table A10-1: Scoring for Child-Pugh Classification 
Cohort
CPC
Level of dysfunction
Total Score 
(tally based on assessment of 
parameters in Table A10-2)
1
Not Applicable
Without hepatic 
impairment
Not Applicable
2
A
Mild
5-6
3
B
Moderate
7-9
4
C
Severe
10
Table A10-2: Derivation of Child-Pugh Classification Score
Assessment Parameters
Assigned score for observed findings
1 point
2 points
3 points
Encephalopathy gradea
(refer to Table A10-3 below)
0
1 or 2
3 or 4a
Ascites
Absent
Asymptomatic
Requiring intervention
Serum total bilirubin, mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
Prothrombin time, sec prolonged
<4
4 to 6
>6
a.
Subjects with a prior history of Grade 3 or 4 encephalopathy who are currently receiving an intervention
[for example: lactulose or lactitol, alone or in combination with rifaximin, and/or neomycin] to manage 
encephalopathy-related signs and symptoms should be scored for encephalopathy grading based on their 
presentation while on intervention at the Screening visit and can be included in Study C1061013 so long as they do 
not have clinically active Grade 3 or 4 encephalopathy.
Table A10-3: 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 active Grade 3 or 4 encephalopathy are excluded.
CPC should be assessed at Screening, only to determine the classification of a given 
subject.


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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
ACC
acetyl-coenzyme A carboxylase
ADA
antidrug antibodies
ADME
absorption, distribution, metabolism, or excretion
ADP
adenosine diphosphate
AE
adverse event
ALT
alanine aminotransferase
AMP
adenosine monophosphate 
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration-time curve
AUC24
area under the plasma concentration-time curve from time zero to 24 
hours post-dose
AUCinf
area under the plasma concentration-time curve from time zero 
extrapolated to infinite time
AUCinf,u
unbound area under the plasma concentration-time curve from time 
zero extrapolated to infinite time
 
 
AUEC
area under the effect curve
AEUC24
area under the effect curve from time zero to 24 hours post-dose
AV
atrioventricular
BA
bioavailability
BCRP
breast cancer resistance protein (BCRP)
BE
bioequivalence
β-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
ChREBP
Carbohydrate Response Element Binding Protein
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CCI
CCI


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Abbreviation
Term
CK
creatine kinase
Clast
last quantifiable concentration
Cmax
maximum observed concentration
Cmax,u
unbound maximum plasma 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
DBP
diastolic blood pressure
DC
discontinuation
DCT
data collection tool
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DRE
disease-related event
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FIH
first-in-human
F1P
fructose-1-phosphate
FSH
follicle-stimulating hormone
fu
fraction unbound
CCI
CCI


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Abbreviation
Term
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
good laboratory practice
HBcAb
hepatitis B core antibody
HBsAg 
hepatitis B surface antigen
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
HDL-C
high density lipoprotein cholesterol
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 
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
KHK
ketohexokinase
LBBB
left bundle branch block
LFT
liver function test
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MRI
magnetic resonance imaging
msec
millisecond
N/A
not applicable
NAb
neutralizing antibodies
NOAEL
no-observed-adverse-effect level
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide


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Abbreviation
Term
OMIM
Online Mendelian Inheritance in Man
PBMC1
peripheral blood mononuclear cells
PCD
primary completion date
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
 
PI
principal investigator
PIB
powder in bottle
PK
pharmacokinetic(s)
PT
prothrombin time
PVC
premature ventricular complexes
QD
once daily
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 subject identification
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
T1/2
half life
T2DM
type 2 diabetes mellitus
TBili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
TIPS
transjugular intrahepatic portosystemic shunt
Tmax
time for Cmax
UGT
uridine diphosphate-glucuronosyltransferase
ULN
upper limit of normal
US
United States
UV
ultraviolet
VLDL
very low density lipoprotein
WBC
white blood cell
WOCBP
woman of childbearing potential
CCI
CCI


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11. REFERENCES
1.
Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, 
MD. MIM Number: {229800}: {June 2016}: World Wide Web URL: http://omim.org/.
2.
Sachs B, Sternfeld L, Kraus G. Essential fructosuria: Its pathophysiology. Am J Dis
Child 1942;63:252-69.
3.
Boesiger P, Buchli R, Meier D, et al. Changes of liver metabolite concentrations in 
adults with disorders of fructose metabolism after intravenous fructose by 31P magnetic 
resonance spectroscopy. Pediatr Res 1994;4:436-40.
4.
Abdelmalek MF, Lazo M, Horska A, et al. Fatty Liver Subgroup of Look, A. R. G., 
Higher dietary fructose is associated with impaired hepatic adenosine triphosphate 
homeostasis in obese individuals with type 2 diabetes. Hepatology 2012;56:952-60.
5.
Maenpaa PH, Raivio KO, Kekomaki MP. Liver adenine nucleotides: fructose-induced 
depletion and its effect on protein synthesis. Science 1968;161:1253-4.
6.
Lanaspa MA, Sanchez-Lozada LG, Choi YJ, et al. Uric acid induces hepatic steatosis by 
generation of mitochondrial oxidative stress: potential role in fructose-dependent and -
independent fatty liver. J Biol Chem 2012;287:40732-44.
7.
Erion DM, Popov V, Hsiao JJ, et al. The role of the carbohydrate response element-
binding protein in male fructose-fed rats. Endocrinology 2013;154:36-44.
8.
Softic S, Cohen DE, Kahn CR. Role of dietary fructose and hepatic de novo lipogenesis 
in fatty liver disease. Dig Dis Sci 2016;61:1282-93.
9.
Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not 
glucose-sweetened, beverages increases visceral adiposity and lipids and decreases 
insulin sensitivity in overweight/obese humans. J Clin Invest 2009;119:1322-34.
10.
Abid A, Taha O, Nseir W, et al. Soft drink consumption is associated with fatty liver 
disease independent of metabolic syndrome. J Hepatol 2009;51:918-24.
11.
Assy N, Nasser G, Kamayse I, et al. Soft drink consumption linked with fatty liver in 
the absence of traditional risk factors. Can J Gastroenterol 2008;22:811-6.
12.
Schwarz JM, Noworolski SM, Wen MJ, et al. Effect of a high-fructose 
weightmaintaining diet on lipogenesis and liver fat. J Clin Endocrinol Metab 
2015;100:2434-42.
13.
Lustig R, Mulligan K, Noworolski SM, et al. Isocaloric fructose restriction and 
metabolic improvement in children with obesity and metabolic syndrome. Obesity 
2016;24:453-60.


PF-06835919
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Final Protocol Amendment 1, 18 February 2020
PFIZER CONFIDENTIAL 
Page 84
14.
Stanhope KL, Medici V, Bremer AA, et al. A dose-response study of consuming 
highfructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for 
cardiovascular disease in young adults. Am J Clin Nutr 2015;101:1144-54.
15.
Sanyal AJ, Friedman SL, McCullough AJ, et al. American Association for the Study of 
Liver Diseases, United States Food and Drug Administration. Challenges and 
opportunities in drug and biomarker development for nonalcoholic steatohepatitis: 
findings and recommendations from an American Association for the Study of Liver 
Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology 2015; 
61:1392-05.
16.
Nelson CH, Weber E, Yue MS, et al.  The pharmacokinetics of GS-0976, an acetyl-CoA 
carboxylase inhibitor, in subjects with mild, moderate, and severe hepatic impairment.  
The Liver Meeting.  San Francisco, CA.  November 2018.

SAP_001.pdf: 
        Protocol C1061013 (PF-06835919) Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 1
Protocol C1061013
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, PARALLEL 
COHORT STUDY TO COMPARE THE PHARMACOKINETICS OF PF-06835919 IN 
ADULT PARTICIPANTS WITH VARYING DEGREES OF HEPATIC IMPAIRMENT 
RELATIVE TO PARTICIPANTS WITHOUT HEPATIC IMPAIRMENT
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
03-SEP-2021
NOTE: Italicized text within this document has been taken verbatim from the Protocol.


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PFIZER GENERAL BUSINESS 
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint(s) ..................................................................................................7
3.2. Secondary Endpoint(s) ..............................................................................................8
3.4. Baseline Variables.....................................................................................................9
3.5. Safety Endpoints .......................................................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................10
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.3. Methods to Manage Missing Data ..........................................................................11
5.3.1. Concentrations Below the Limit of Quantification ....................................11
5.3.2. Deviations, Missing Concentrations and Anomalous Values.....................11
5.3.3. Pharmacokinetic Parameters.......................................................................11
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoint(s) ................................................................................................12
6.2. Secondary Endpoint(s) ............................................................................................13
6.2.1. Treatment and Disposition of Subjects.......................................................14
6.2.2. Demographic and Clinical Examination Data............................................14
6.2.3. Discontinuation(s).......................................................................................14
6.2.4. Adverse Events ...........................................................................................14
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6.2.5. Laboratory Data..........................................................................................14
6.2.6. Vital Signs Data..........................................................................................14
6.2.7. ECG Data....................................................................................................15
6.2.8. Concomitant Treatments.............................................................................15
6.3. Subset Analyses.......................................................................................................15
6.4. Baseline and Other Summaries and Analyses.........................................................15
6.5. Safety Summaries and Analyses .............................................................................15
7. INTERIM ANALYSES.......................................................................................................16
7.1. Introduction .............................................................................................................16
7.2. Interim Analyses and Summaries............................................................................16
8. REFERENCES ....................................................................................................................16
9. APPENDICES .....................................................................................................................17
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
Table 2.
Hepatic Function Categories Based on Child Pugh Score..........................6
Table 3.
Noncompartmental PK Parameters.............................................................8
Table 5.
PK Parameters to be Summarized Descriptively by Group......................12
LIST OF FIGURES
Figure 1.
Study Design...............................................................................................7
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES..........................................................................17
Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical 
Concern.....................................................................................................19
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1
13 Nov 2019
Original 
23 Sep 2019
N/A
N/A
2
03 SEP 2021
Amendment 1
18 Feb 2021
PACL 1
30 Oct 2019
PACL 2
10 Mar 2020
PACL 3
20 Oct 2020
PACL 4
04 Nov 2020
PACL 5
14 Dec 2020
Amendment, 
PACLs and BDR

Version 1 transferred to new SAP template
(some sections have been moved and edited to 
accommodate new template; some additional 
text also added)

Section 4: Duplicate/redundant text removed

Section 6.2.5: Correction to baseline definition 
for lab data

Section 6.2.6: Additional text added for 
clarification of baseline definition for vitals

Appendix 1: Added ‘gender’ into CLASS 
statement

Appendix 2: Added text for summary of the 
number of participants with uncorrected QT 
values >500 msec; corrected units for ECG 
endpoints
2. INTRODUCTION
The primary purpose of this non-randomized, single dose, open-label study is to characterize 
the effect of varying degrees of hepatic impairment on the plasma pharmacokinetics (PK) of 
PF-06835919 following administration of a single, oral, 25 mg dose.  NAFLD/NASH is 
associated with varying degrees of hepatic impairment.  Recognizing that the target 
population of PF-06835919 is patients with NAFLD/NASH and that the major clearance 
mechanism of PF-06835919 is predicted to be active uptake into the liver followed by 
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-06835919.
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C1061013.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.


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2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Primary: 
Primary: 
•
To compare the PK of PF-06835919 (both total and 
unbound) 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-06835919 PK parameters derived from plasma:  
Cmax, AUCinf, fu, Cmax,u, and AUCinf,u.
Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of a single 
oral dose of PF-06835919 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.
 
 
 
 
 
 
  
 
 
 
 
 
 
There are no estimands for this study.
2.2. Study Design
This is a non-randomized, open label, single dose, parallel cohort, multicenter study to 
investigate the effect of varying degrees of hepatic function on the plasma PK (total and 
unbound) of PF-06835919 after a single oral 25 mg dose administered in the fed state.  A 
total of approximately 24 participants with varying degrees of hepatic function will be 
enrolled into the study to ensure that approximately 6 evaluable participants in each of the 3 
hepatic impairment cohorts, and 6 to 8 in the cohort without hepatic impairment complete 
the study.  Participants will be selected based on their Child Pugh score as shown in Table 2.
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Table 2.
Hepatic Function Categories Based on Child Pugh Score
Cohort
Description
Child-Pugh Score
Number of Subjects
1
Without hepatic impairment
Not Applicable 
6-8a
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)
4-6b
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 3 hepatic impairment cohorts.
b. If recruitment across the sites selected proves to be prohibitive, study will dose only 4 participants in this cohort.   
Child-Pugh scores will be determined at the screening visit.  Participants will be enrolled in 
a staged manner such that participants with moderate and severe hepatic impairment 
(Cohorts 3 and 4) will be evaluated first.  Enrollment of participants with mild hepatic 
impairment (Cohort 2) will occur when approximately 50% of the total participants in 
Cohorts 3 and 4 have been enrolled.  Participants without hepatic impairment (Cohort 1) 
will then be enrolled near the end of the study.  These participants will be recruited to match 
the average demographics (at a minimum, age and weight; and gender as much as 
practically possible) across the pooled Cohorts 2 through 4.  Approval from the Sponsor 
must be obtained before proceeding with dosing participants in Cohort 1 or Cohort 2.
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 final clinic visit (Day 6) will be a
maximum of approximately 5 weeks.


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Figure 1.
Study Design
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Blood samples for PK analysis of PF-06835919 will be taken according to the Schedule of 
Activities given in the protocol.
The following PK parameters will be calculated for PF-06835919 (if possible) from the 
concentration-time data using standard noncompartmental methods:


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PFIZER GENERAL BUSINESS 
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Table 3.
Noncompartmental PK Parameters
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits 
PK 
Parameter
Analysis 
Scale
PF-06835919
Definition
AUCinf*
ln
A, D
Area under the plasma 
concentration-time profile from time 
zero extrapolated to infinite time
AUCinf,u*
ln
A, D
Unbound area under the plasma 
concentration-time curve from time 
zero extrapolated to infinite time
Cmax
ln
A, D
Maximum plasma concentration
Cmax,u
ln
A, D
Unbound maximum plasma 
concentration
fu
R
D
Fraction unbound
3.2. Secondary Endpoint(s)
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.
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
started during the effective duration of treatment. All events that start on or after the first 
dosing day and time/start time, if collected, but before the last dose plus the lag time will be 
flagged as TEAEs. The algorithm will not consider any events that started prior to the first 
dose date.


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3.4. Baseline Variables
No covariate will be included in the model for the primary analysis (i.e. ANOVA). 
As a sensitivity analysis age and body weight will be included in the model (i.e. ANCOVA). 
Additionally, gender may also be included as a covariate.
3.5. Safety Endpoints
See section 3.2.
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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
The PK concentration population will be defined as all participants who received 1 dose of 
PF-06835919 and in whom at least 1 plasma concentration value is reported.
The PK parameter analysis population is defined as all participants dosed who have at least 
1 of the PK parameters of primary interest.
The safety analysis set will be defined as all participants assigned to investigational product 
and who take at least 1 dose of investigational product.  
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are not treated.
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 
pharmacokineticist, a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.  
A full list of protocol deviations 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.  
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There is no statistical hypothesis testing planned for this study.
No statistical decision rules are applied.
5.2. General Methods
For all outputs produced, the following ordering will be used:
1. Without Hepatic Impairment
2. Mild Hepatic Impairment
3. Moderate Hepatic Impairment
4. 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) 
cohorts and the Reference (without hepatic impairment) cohort using a one-way ANOVA 
model based on natural log transformed data.


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The relationship between PK parameters and hepatic function (eg, serum albumin 
concentration or prothrombin time) will be determined by a linear regression model.
5.3. Methods to Manage Missing Data
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.
5.3.1. 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.)
5.3.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
5.3.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (ie not calculated). (Note that NC values will not be generated beyond 
the day that a participant discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular hepatic function group with ≥3 evaluable measurements.  
For statistical analyses (ie analysis of variance), PK parameters coded as NC will also be set 
to missing; and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
If an individual participant has a known biased estimate of a 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.


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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
The following PK parameters (including both primary and tertiary endpoints) will be 
summarized by hepatic function group:
Table 5.
PK Parameters to be Summarized Descriptively by Group
Parameter
Summary Statistics
 
AUCinf, AUCinf,u, 
Cmax, Cmax,u, 
 
 and 
fu
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
 
Box and whisker plots for individual subject parameters (AUCinf, AUCinf,u, 
 
 Cmax and Cmax,u) be presented by hepatic function group and overlaid with 
geometric means.
 
 
Presentations for PF-06835919 concentrations will include:
−
a listing of all concentrations sorted by hepatic function group (present in heading), 
subject id and nominal time post-dose.  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 post-dose, 
where the set of statistics will include n, mean, median, standard deviation, coefficient of 
variation (cv), minimum, maximum and the number of concentrations above the lower 
limit of quantification.
−
median concentrations time plots (on both linear and semi-log scales) against nominal 
time post-dose 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
post-dose).
−
mean concentrations time plots (on both linear and semi-log scales) against nominal time 
post-dose by hepatic function group (all hepatic function groups on the same plot per 
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scale, based on the summary of concentrations by hepatic function group and time post-
dose).
−
individual concentration time plots by hepatic function group (on both linear and semi-
log scales) against actual time post-dose (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 subject plots by time, the actual PK sampling time will be 
used.
A one-way analysis of variance (ANOVA) will be used to compare the natural log 
transformed PF-06835919 AUCinf, 
Cmax, unbound AUCinf (AUCinf,u),
 
  and unbound Cmax (Cmax,u), 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.
Additionally, as a sensitivity analysis, age, gender and body weight will be explored as an 
additional covariate/factor in the model, as appropriate.
Linear regression will be used to analyse the potential relationship between appropriate 
natural log transformed PK parameters [AUCinf, AUCinf,u,
] and hepatic function 
[serum albumin concentration, prothrombin time and total bilirubin].  Plots of PK 
parameters (eg, AUCinf, AUCinf,u, 
) versus hepatic function will be 
constructed, with a regression line and 90% confidence region included.  Estimates of the 
slope and intercept, together with a 90% confidence interval (CI), and the coefficient of 
determination (i.e. R-squared and adj-R-squared) will be obtained from the model.  
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.
6.2. Secondary Endpoint(s)
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-06835919.
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6.2.1. Treatment and Disposition of Subjects
Participant evaluation groups will show subject disposition.  Frequency counts will be 
supplied for participants discontinuation(s) by hepatic function group.
Data will be reported in accordance with the sponsor reporting standards.
6.2.2. 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’ in accordance
with the sponsor reporting standards.
6.2.3. Discontinuation(s)
Participant discontinuations will be detailed and summarized by hepatic function group.
Data will be reported in accordance with the sponsor reporting standards.
6.2.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
hepatic function group.
6.2.5. Laboratory Data
Laboratory data will be listed and summarized in accordance with the sponsor reporting 
standards.
The baseline measurement is the last pre-dose measurement on Day 1.  
6.2.6. Vital Signs Data
The baseline measurement (for blood pressure and pulse rate) is the last pre-dose 
measurement on Day 1.
Absolute values and changes from baseline in seated systolic and diastolic blood pressure,
and pulse rate will be summarized by hepatic function group and visit using sponsor 
reporting standards.
Maximum absolute values and changes from baseline for seated vital signs will be 
summarized descriptively by hepatic function group using categories as defined in 
Appendix 2.  Numbers and percentages of participants meeting the categorical criteria will 
be provided.  All planned and unplanned post-dose time-points will be counted in these 
categorical summaries.  All values meeting the criteria of potential clinical concern will be 
listed.
These data will be listed in accordance with the sponsor reporting standards.


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6.2.7. ECG Data
The baseline measurement is the last pre-dose measurement on Day 1.
Absolute and changes from baseline for the ECG parameters QT interval, heart rate, QTcF 
interval, PR interval, and QRS interval will be summarized by hepatic function group and 
visit using sponsor reporting standards. 
ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by hepatic function group using categories as defined in Appendix 2 (for QTc 
these correspond to the Pfizer Guidance in Section 9). Numbers and percentages of 
participants meeting the categorical criteria will be provided. All planned and unplanned 
post-dose time-points will be counted in these categorical summaries. All values meeting the 
criteria of potential clinical concern will be listed.
In addition, listings of participants with any single post-dose value 500 msec will also be 
produced for QTcF.
6.2.8. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
6.3. Subset Analyses
Not applicable.
6.4. Baseline and Other Summaries and Analyses
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.
A listing of Child-Pugh Classification by Severity of Hepatic Impairment will be produced.
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.
6.5. Safety Summaries and Analyses
See section 6.2.


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7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study. As this is an open-label
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating PK modeling, and/or supporting clinical 
development.
7.2. Interim Analyses and Summaries
Not applicable.  
8. REFERENCES
None.


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9. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
/* Letter assignments for cohort within the estimate statement in the code below are as 
follows;
A = Normal (Reference)
B = Mild (Test)
C = Moderate (Test)
D = Severe (Test);
*/; 
An example of the PROC GLM code is provided below:
proc glm data=tab.pk;
class cohort;
model l&var=cohort/ss3 clparm alpha=0.1;
lsmeans cohort;
estimate 'Mild vs Normal'
cohort -1 1 0 0;
estimate 'Moderate vs Normal'
cohort -1 0 1 0;
estimate 'Severe vs Normal'
cohort -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;
For ANCOVA: An example of the PROC GLM code is provided below:
proc glm data=tab.pk;
class cohort gender;
model l&var = cohort age gender weight / ss3 clparm alpha=0.1;
lsmeans cohort;
estimate 'Mild vs Normal'
cohort -1 1 0 0;
estimate 'Moderate vs Normal'
cohort -1 0 1 0;
estimate 'Severe vs Normal'
cohort -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; 


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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;


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Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
QTcF (msec)
450 and 480
>480 and 500
>500
QTcF (msec) increase from
baseline
30 and 60
>60
Categories for PR and QRS
PR (msec)
max. ≥300
PR (msec) increase from 
baseline
Baseline >200 and max. ≥25% 
increase
Baseline ≤200 and max. ≥50% 
increase
QRS (msec)
max. ≥140
QRS (msec) increase from 
baseline
≥50% increase
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
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.