Clinical trial NCT03309202
Conditions: Hepatic Impairment
Sponsor: Pfizer
Start date: 2017-12-19; Completion date: 2018-07-18
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hepatic impairment PK study

Detailed description:
This is a non randomized, open label, single dose, parallel cohort, multisite study to investigate the effect of varying degrees of hepatic impairment on the plasma pharmacokinetics (total and unbound) of PF-05221304 after a single oral dose administered in the fed state.

Arms: arm 1: Single, 25 mg dose of PF-05221304 arm 2: Single, 25 mg dose of PF-05221304 arm 3: Single, 25 mg dose of PF-05221304 arm 4: Single, 25 mg dose of PF-05221304
Interventions: intervention 1: PF-05221304
Intervention descriptions: intervention 1: 25 mg dose

Protocol documents:
Prot_001.pdf: 
PF-05221304  
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A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, PARALLEL 
COHORT STUDY TO COMPARE THE PHARMACOKINETICS OF PF-05221304 
IN ADULT SUBJECTS WITH VARYING DEGREES OF HEPATIC IMPAIRMENT
RELATIVE TO SUBJECTS WITHOUT HEPATIC IMPAIRMENT
Investigational Product Number:
PF-05221304 
Investigational Product Name:
Not applicable
United States (US) Investigational 
New Drug (IND) Number:
130418
European Clinical Trials Database 
(EudraCT) Number:
2017-003034-86
Protocol Number:
C1171006
Phase:
1
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Document History
Document
Version Date
Summary of Changes
Amendment 1
18 September 2017
This amendment is making the following substantial changes to 
align with the Pfizer Enterprise-level revision to appropriate 
measures to prevent pregnancy in the population of childbearing 
potential enrolled who are sexually active and align with the Clinical 
Trial Facilitation Group (CTFG) 2014 European Guidance  –

Section 4.4.4 revised to –  

Remove mandate to use highly effective contraception in 
female partners of male subjects of childbearing potential;

 
 
 
 
 

Define sexual abstinence in the context of this research 
study.  

Of note, this amendment keeps elements below (in 
Section 4.4.4) included in prior version of the protocol –

Use of male or female condom alone is viewed as an 
effective method of contraceptive but must continue to be 
used with a highly effective method of contraceptive;

In applicable female subjects, method of contraception must 
include a combination of a highly effective method with an 
additional method;

In applicable male subjects, use of barrier method to 
prevent seminal transfer of investigational product to their 
female partner(s) of childbearing potential must be used; 
In addition, the following changes are made –

Text in Section 1.3.1, Section 4.2.2 and Appendix 2, revised to 
more clearly articulate that subjects who are pharmacologically 
managed for encephalopathy are permitted – so long as they do 
not have signs of clinically active Grade 3 or 4 hepatic 
encephalopathy and as such can still provide informed consent;
encephalopathy grading applied at screening should be while on 
treatment (not pre-treatment) for encephalopathy to derive total 
score and Child-Pugh Classification;

In the Schedule and Activities and Section 4.3, while protocol 
permits unplanned assessments for subjects’ 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;
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Document
Version Date
Summary of Changes

In Section 4.2.2 and Section 4.3, in subjects with severe hepatic 
impairment, allowance permitted to enroll and progress with 
dosing on Day 1 with SBP 160 mmHg and DBP 105 mmHg, 
as long as subject is otherwise medically stable.

In Table 2 assessment of mean platelet volume has been deleted 
considering this study will utilize a sponsor-identified central 
laboratory hence not permitting assessment of this parameter 
which requires fresh blood sample. 
Original 
protocol
08 August 2017
Not applicable
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
APPENDICES ...........................................................................................................................8
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES: ..............................................................................................11
1. INTRODUCTION ...............................................................................................................12
1.1. Mechanism of Action/Indication.............................................................................12
1.2. Background .............................................................................................................12
1.3. Rationale for Study..................................................................................................15
1.3.1. Rationale for Study Population...................................................................15
1.3.2. Rationale for Design...................................................................................17
1.3.3. Rationale for PF-05221304 Dose Selected.................................................17
1.4. Summary of Benefit Risk Assessment....................................................................19
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................19
3. STUDY DESIGN.................................................................................................................20
3.1. Study Overview.......................................................................................................20
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................21
4.1. Inclusion Criteria.....................................................................................................21
4.1.1. Additional Inclusion Criteria for Subjects without Hepatic 
Impairment (Cohort 1, only) ............................................................................22
4.1.2. Additional Inclusion Criteria for Subjects with Impaired Hepatic 
Function (Cohorts 2, 3, and 4, only) ................................................................23
4.2. Exclusion Criteria....................................................................................................24
4.2.1. Additional Exclusion Criteria for Subjects without Hepatic 
Impairment (Cohort 1, only) ............................................................................25
4.2.2. Additional Exclusion Criteria for Subjects with Impaired Hepatic 
Function (Cohorts 2, 3, and 4, only) ................................................................26
4.3. Criteria for Dosing on Day 1...................................................................................27
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4.4. Lifestyle Requirements ...........................................................................................27
4.4.1. Meals and Dietary Restrictions...................................................................27
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................29
4.4.3. Activity .......................................................................................................29
4.4.4. Contraception..............................................................................................29
4.5. Sponsor’s Qualified Medical Personnel..................................................................31
5. STUDY TREATMENTS.....................................................................................................31
5.1. Allocation to Treatment ..........................................................................................31
5.2. Breaking the Blind ..................................................................................................32
5.3. Subject Compliance.................................................................................................32
5.4. Investigational Product Supplies.............................................................................32
5.4.1. Dosage Form and Packaging ......................................................................32
5.4.2. Preparation and Dispensing........................................................................32
5.5. Administration.........................................................................................................32
5.6. Investigational Product Storage ..............................................................................32
5.7. Investigational Product Accountability...................................................................33
5.7.1. Destruction of Investigational Product Supplies ........................................33
5.8. Concomitant Treatments .........................................................................................34
5.8.1. Subjects with Healthy Hepatic Function (Cohort 1, Only).........................34
5.8.2. Subjects with Impaired Hepatic Function (Cohorts 2, 3, and 4) ................34
5.9. Rescue Medication ..................................................................................................35
6. STUDY PROCEDURES .....................................................................................................35
6.1. Proposed Chronology of Procedures.......................................................................35
6.2. Screening.................................................................................................................36
6.3. Study Period ............................................................................................................36
6.4. Follow-up ................................................................................................................36
6.4.1. Follow-up Visit...........................................................................................36
6.5. Subject Withdrawal/Early Termination ..................................................................37
7. ASSESSMENTS..................................................................................................................38
7.1. Pharmacokinetics (PK)............................................................................................39
7.1.1. Plasma for Analysis of total PF-05221304 concentrations.........................39
7.1.2. Plasma for Determination of PF-05221304 Unbound Fraction..................40
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7.2. Safety.......................................................................................................................40
7.2.1. Laboratory Tests .........................................................................................40
7.2.1.1. Pregnancy Testing.....................................................................41
7.2.2. Physical Examinations................................................................................41
7.2.3. Blood Pressure and Pulse Rate ...................................................................42
7.2.4. Electrocardiogram.......................................................................................42
7.6. Blood Volume .........................................................................................................44
8. ADVERSE EVENT REPORTING......................................................................................45
8.1. Requirements...........................................................................................................45
8.1.1. Additional Details on Recording Adverse Events on the CRF...................46
8.1.2. Eliciting Adverse Event Information..........................................................46
8.1.3. Withdrawal From the Study Due to Adverse Events (see also 
Section 6.5) ......................................................................................................47
8.1.4. Time Period for Collecting AE/SAE Information......................................47
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................47
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................47
8.1.5. Causality Assessment .................................................................................47
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................48
8.2. Definitions...............................................................................................................48
8.2.1. Adverse Events...........................................................................................48
8.2.2. Abnormal Test Findings .............................................................................49
8.2.3. Serious Adverse Events ..............................................................................49
8.2.4. Hospitalization............................................................................................50
8.3. Severity Assessment................................................................................................51
8.4. Special Situations ....................................................................................................51
8.4.1. Protocol-Specific Serious Adverse Events.................................................51
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................51
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................53
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8.4.3.1. Exposure During Pregnancy......................................................53
8.4.3.2. Exposure During Breastfeeding ................................................55
8.4.3.3. Occupational Exposure .............................................................55
8.4.4. Medication Errors .......................................................................................55
8.4.4.1. Medication Errors......................................................................55
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................56
9.1. Sample Size Determination.....................................................................................56
9.2. Efficacy Analysis ....................................................................................................56
9.3. Pharmacokinetic Analysis.......................................................................................56
9.3.1. Analysis Populations ..................................................................................56
9.3.2. Derivation of Pharmacokinetic Parameters Prior to Analysis ....................57
9.3.3. Statistical Methods......................................................................................58
9.4. Pharmacodynamic Analysis ....................................................................................58
9.5. Analysis of Other Endpoints ...................................................................................59
9.6. Safety Analysis........................................................................................................59
9.6.1. Electrocardiogram Analysis........................................................................59
9.7. Interim Analysis ......................................................................................................60
9.8. Data Monitoring Committee ...................................................................................60
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................60
11. DATA HANDLING AND RECORD KEEPING .............................................................60
11.1. Case Report Forms/Electronic Data Record .........................................................60
11.2. Record Retention...................................................................................................61
12. ETHICS..............................................................................................................................62
12.1. Institutional Review Board/Ethics Committee......................................................62
12.2. Ethical Conduct of the Study ................................................................................62
12.3. Subject Information and Consent..........................................................................62
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................63
13. DEFINITION OF END OF TRIAL...................................................................................63
13.1. End of Trial in a Member State.............................................................................63
13.2. End of Trial in All Other Participating Countries.................................................63
14. SPONSOR DISCONTINUATION CRITERIA ................................................................63
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15. PUBLICATION OF STUDY RESULTS..........................................................................64
15.1. Communication of Results by Pfizer ....................................................................64
15.2. Publications by Investigators ................................................................................64
16. REFERENCES ..................................................................................................................66
LIST OF TABLES
Table 1.
Hepatic Function Categories Based on Child Pugh Score....................................20
Table 2.
Safety Laboratory Tests........................................................................................40
Table 3.
Blood Volume Collected in Study C1171006 ......................................................45
Table 4.
Precision for 2-fold Change in AUCinf as Function of Assumed Variability .......56
Table 5.
Plasma PK Parameters..........................................................................................57
LIST OF FIGURES
Figure 1.
C1171006 Study Design.......................................................................................21
APPENDICES
Appendix 1. Abbreviations......................................................................................................68
Appendix 2. Child-Pugh Classification (CPC) of Liver Dysfunction .....................................71
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PROTOCOL SUMMARY
Background and Rationale:
The current study is designed to evaluate the effect of varying degrees of hepatic impairment 
on the plasma pharmacokinetics of PF-05221304.
Objectives and Endpoints:
Primary Objective: 
Primary Endpoints: 
To compare the pharmacokinetics of PF-05221304 
(both total and unbound) following administration 
of a single oral dose in adult subjects with varying 
degrees of hepatic impairment relative to age- and 
body weight-matched subjects without hepatic 
impairment.
PF-05221304 PK parameters derived from plasma: 

Cmax, AUCinf, fu, Cmax,u, and AUCinf,u.
Secondary Objectives: 
Secondary Endpoints: 
To compare additional pharmacokinetic parameters 
(both total and unbound) of PF-05221304 following 
administration of a single oral dose in adult subjects 
with varying degrees of hepatic impairment relative 
to age- and body weight-matched subjects without 
hepatic impairment.
PF-05221304 PK parameters derived from plasma: 

Tmax, AUClast, AUClast,u, CL/F, CLu/F, Vz/F, 
Vz,u/F and t½, as data permit.
To evaluate the safety and tolerability of a single 
oral dose of PF-05221304 when administered to 
adult subjects with varying degrees of hepatic 
impairment relative to age- and body 
weight-matched subjects without hepatic 
impairment
Assessment of treatment-emergent adverse events, 
clinical laboratory tests, vital signs, and 12-lead 
ECGs.
Study Design:  
This is a non-randomized, open-label, single-dose, parallel-cohort, multisite study with 
overall design summarized below.
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Study Treatment:  
The investigational product is PF-05221304, provided as tablets, each containing 25 mg 
active drug.  A single, oral, 25 mg dose of PF-05221304 will be administered with a standard 
morning meal.
Statistical Method:  
A sample size of approximately 24 subjects with varying degrees of hepatic function
(6 subjects per cohort) will provide enough precision to determine the 90% confidence 
interval to detect a 2-fold change in exposure (AUCinf) with 80% tolerance probability
between each of the Test (impaired) cohorts and the Reference (without hepatic impairment)
cohort.
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SCHEDULE OF ACTIVITIES:  
Table A provides an overview of the protocol visits and procedures.  Refer to Section 6 and Section 7 for detailed information on each procedure and assessment 
required for compliance with the protocol. The investigator may conduct unplanned visits, including safety-related laboratory tests on Day -1 with results 
reported by local laboratory prior to dosing on Day 1 in addition to those listed below, to conduct procedures to protect the well-being of the subject.
TABLE A.  All procedures occurring at same nominal time as meals will occur prior to meal except dosing at 0H on Day 1 which is to occur with meal
Visit Identifier/Day
[for list of abbreviations refer to Appendix 1]
Screen
-28
-1
1
2
3a
4
5
6
Follow-Up
7
302
Hours Post Dose
--
0
1
2
3
4
5
8
10 16
24
36
48
72
96
120
144
--
Informed consent & demography 
x
Outpatient visit 
x
xa
xa
xa
xa
Inpatient stay at Clinical Research Unit 
x



x
x
x
x
x
Eligibility assessment with CPC at Screen, only (Appendix 2)
x
x
(Update) Medical history
x
x
x
Physical exam (height & body weight at Screen, only)b
x
x
x
x
Breath alcohol test
x
x
(Update) alcohol/tobacco & contraception use
x
x
xc
xc
xc
xc
xd
(Update) prior/concomitant treatments
x
x
xc
xc
xc
xc
x
Single, supine 12-lead ECG
x
x
x
x
x
Single, seated vital sign assessment (BP and pulse rate)
x
x
x
x
x
Serious and non-serious adverse event monitoring
x
x







x
x
Standard mealse
x
x
x
x
x
x
x
x
x
x
Investigational product administration
xf
Blood Samples for –
Clinical laboratory tests - after 4-hr fast (see Section 7.2.1)
x
x
x
x
Serum FSH in females amenorrheic 12-months only
x
Pregnancy (females only)
x
x
x
PF-05221304 PK
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PF-05221304 unbound fraction for protein binding
x
Urine Samples for –
Urine drug test
x
Urinalysis (and microscopy, if needed)
x
x
x
x
On-site pregnancy test (WOCBP, only)
x
x
a.
Subjects can be discharged post completion of procedures (with subsequent outpatient visits) or remain inpatient from Day -1 to Day 7, inclusive, at Investigator discretion.
b. Full physical (PE) exam at Screen; at all other time points, limited PE for findings during previous PE or new/open AEs only, at Investigator discretion.
c.
Procedure to be completed only if subject was discharged on Day 3 and returning for outpatient visits on each of these days.
d. Confirmation of appropriate contraception use, only.
e.
Meals to be served, at clock times matching approximately 0H, 4H, 7H, and 10H relative to dosing on Day 1 (while inpatient) and at 0H (while outpatient).
f.
Dosing to occur with standard morning meal provided approximately 30 minutes prior to 0H, and completed approximately 10 minutes prior to dosing.
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1. INTRODUCTION
PF-05221304 is a potent, selective, orally bioavailable, and reversible dual acetyl-CoA 
carboxylase 1 and 2 (ACC1/2) inhibitor designed to have asymmetric distribution to the liver,
as 
such PF-05221304 is expected to inhibit de novo lipogenesis (DNL) and stimulate fatty acid 
oxidation in the liver to a greater extent than in peripheral tissues.  In humans, administration 
of PF-05221304 has been shown to suppress hepatic DNL in a Phase 1 study in healthy adult
subjects; in addition, the drug is expected to stimulate hepatic fatty acid oxidation, and 
consequently reduce fat accumulation in the liver.  This inhibition of hepatic DNL is 
postulated to result in a decrease and normalization of the excessive DNL observed in 
nonalcoholic fatty liver disease (NAFLD).  In addition, the inhibition of ACC via 
administration of PF-05221304 also has the potential for anti-inflammatory effects in 
nonalcoholic steatohepatitis (NASH). 
The current study is designed to evaluate the effect of varying degrees of hepatic impairment 
on the plasma pharmacokinetics of PF-05221304. 
1.1. Mechanism of Action/Indication
PF-05221304 is a potent, selective, orally bioavailable, and reversible dual ACC1/2 inhibitor, 
designed to have asymmetric distribution to the liver.  It is being developed for the treatment 
of NASH with fibrosis.
1.2. Background 
The World Health Organization lists NAFLD and NASH as the most important of conditions 
contributing to the global health burden due to liver diseases, with NASH acknowledged as a 
potentially fatal condition leading to cirrhosis, liver failure, and hepatocellular carcinoma 
(HCC).1  NASH is diagnosed clinically by liver biopsy demonstrating steatosis, 
inflammation, and cytological ballooning of liver hepatocytes, often with varying degrees of 
fibrosis.  NASH progresses with increasing degrees of fibrosis, with cirrhosis developing in a 
subset of patients2,3 with the most common complication of cirrhosis being HCC.3  Patients 
with NASH may be asymptomatic or have non-specific symptoms such as fatigue, despite 
having significant disease on liver biopsy and associated risk for progression to cirrhosis and 
liver-related mortality.
NASH is a clinical and histological subset of NAFLD (defined as presence of 5% hepatic 
steatosis) 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.2,3  In a recent meta-analysis, the global prevalence of NAFLD is 
estimated at 25%, with the prevalence of NASH in the subset with biopsy-proven NAFLD 
assessed at 59%.5  The majority of the population with NAFLD has simple steatosis which 
has, in general, a benign clinical course.  A proportion of patients with NAFLD progress to 
having hepatocellular ballooning and lobular inflammation – taking close to a decade to 
progress from 1 stage to the next and 30-40 years to develop cirrhosis; however, a smaller 
subset of patients progress very rapidly (within 10 years) to liver cirrhosis from NAFLD.6
The 5-year (67%) and 10-year (38%) survival rates in patients with NASH is significantly 
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different than in those with NAFLD.7  The pooled liver-specific and overall mortality 
incidence rate estimates among those with NAFLD were calculated at 0.8 and 15.4, 
respectively, per 1,000 person-years.  In contrast, amongst the population with NASH, the 
incidence rate estimates were 11.8 (liver-specific) and 25.6 (overall) mortality.5 With the 
progression of NAFLD disease continuum from steatosis, inflammation, fibrosis, cirrhosis 
and HCC, varying degrees of impairment of liver function is noted with recent data 
suggesting potential implications of changes in drug transport and metabolism in this patient 
population.8
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigators’ Brochure (IB) for PF-05221304.  
A summary of the components relevant to this study are presented below.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.3. Rationale for Study
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 of 
PF-05221304 following administration of a single, oral, 25 mg dose.  Recognizing that the 
target population of PF-05221304 are patients with liver disease (NASH with fibrosis) and 
that the major clearance mechanism of PF-05221304 is predicted to be active uptake into 
liver 
the current 
study is proposed to evaluate whether there is any clinically meaningful effect of hepatic
impairment on the plasma pharmacokinetics of PF-05221304. 
1.3.1. Rationale for Study Population
The reference set of subjects (Cohort 1, demographic-matched subjects without hepatic 
impairment) will be characterized as subjects with no chronic medical conditions, and no 
significant abnormalities in clinical laboratory tests and other procedures conducted at 
Screening. 
The Child-Pugh classification system (refer to Appendix 2) will be used to define the three 
cohorts of subjects with varying degrees of hepatic impairment (Cohorts 2 to 4, inclusive), in 
this study; with the reference being subjects without hepatic impairment.  All three categories 
of hepatic impairment will be assessed as this represents the likely population in later phase 
studies for the proposed indication (treatment of NASH with fibrosis).  In addition to alanine 
aminotransferase (ALT), total bilirubin and aspartate aminotransferase (AST) will be 
assessed in this study as per the recommendations of the National Cancer Institute Organ 
Dysfunction Working Group Criteria for assessment of hepatic impairment.9  Notably, the 
historical requirement of an encephalogram for encephalopathy grading will not be required.  
This study will include subjects with mild (Child-Pugh Class A, Cohort 2), moderate 
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(Child-Pugh Class B, Cohort 3), and severe (Child-Pugh Class C, Cohort 4) hepatic 
impairment as well as demographic-matched control subjects, without hepatic impairment.  
All subjects will be required to offer their own consent to participate in this study; as such 
subjects with clinically active Grade 3 or Grade 4 encephalopathy (refer to Appendix 2) will 
be excluded.  However, subjects 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 
subjects with hepatic impairment are purposefully, distinctly different, including assessment 
of Hepatitis B and Hepatitis C, with no specific exclusion of those who have these conditions 
planned for subjects classified in Cohorts 2, 3, or 4 (refer to Section 4.1.2 and Section 4.2.2).
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 patients with hepatic impairment 
(Cohorts 2 to 4, inclusive) 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-05221304 
disposition. 
Both females of childbearing potential, as well as those who are of non-childbearing 
potential, will be enrolled given the availability of EFD toxicity studies with PF-05221304.  
However,
 
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measures will be taken to limit the risk of pregnancy in the female population enrolled [refer 
to Schedule of Activities (Table A) as well as Section 4.4.4 and Section 7.2.1.1]. 
1.3.2. Rationale for Design
This study is a Phase 1, non-randomized, open-label, single-dose, parallel-group study of 
PF-05221304 in subjects with varying degrees of hepatic impairment and subjects without 
hepatic impairment, matched for age as well as body weight (and as much as practically 
possible gender).  Details on age- and body weight- matching criteria are specified in 
Section 3.1.  This study is proposed following a single dose of PF-05221304 considering that 
single dose plasma PK of PF-05221304 is generally predictive of exposure upon repeated 
dosing.
The current study will include subjects without hepatic impairment who have been 
demographically-matched to subjects with mild, moderate, and severe hepatic impairment as 
defined by Child-Pugh Classification (refer to Appendix 2).  All subjects enrolled in this 
study will receive one single oral 25 mg dose of PF-05221304 in the fed state.  To adequately 
characterize the elimination phase of the plasma PF-05221304 concentration-time profile in 
the cohorts with varying degrees of hepatic impairment, where the elimination half-life of 
PF-05221304 may be prolonged, the PK sampling will be collected serially up to 144 hours 
post-dose.  To assess the in vivo protein binding of PF-05221304 with varying degrees of
hepatic impairment, the fraction unbound (fu) of PF-05221304 will be determined at 
approximately the expected time of maximum concentration (Tmax) in each subject.  
 
 
 In this study, PF-05221304 
administration is planned to occur with the morning standard meal (refer to Section 4.4.1) to
ensure consistency with the intended dosing scheme in the target patient population. 
1.3.3. Rationale for PF-05221304 Dose Selected 
A single oral dose of 25 mg will be used in this study.  This dose has been selected based on 
prior experience in healthy subjects and also taking into account safety considerations for the 
subjects with varying degrees of hepatic impairment in whom an increase in plasma 
PF-05221304 exposure may be observed.  
 
 
  
While the proposed dose (25 mg) is half the highest dose selected for evaluation in the 
Phase 2a dose-ranging study (50 mg QD), repeated dosing at 25 mg QD,
 
 
likely to be an efficacious dose thus viewed as an appropriate for the current 
study. 
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The dose proposed in the current study (25 mg single dose) reflects adequate safety margin 
compared to nonclinical toxicity studies.  
 
 
 
 
 
 
 
 
 
 
Based on a review of effect of hepatic impairment on human pharmacokinetics for 
compounds cleared in a similar manner to PF-05221304
 mild 
hepatic impairment generally results in less than 2-fold increases in plasma exposure.   In 
the same group of compounds, moderate hepatic impairment results in less than 3-fold 
increases in plasma exposure; however, overall, very limited clinical data is available 
regarding the effect of severe hepatic impairment on the pharmacokinetics of 
 
substrates.10  
 
 
 
 
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1.4. Summary of Benefit Risk Assessment
Study C1171006 entails administration of a single oral dose of PF-05221304 in patients with 
varying degrees of hepatic impairment and demographic-matched subjects without hepatic 
impairment, to assess the plasma PK of the investigational product. 
 
 For 
the subjects participating in the current study, no clinical benefit is expected.  The data from 
this study are envisioned to provide basis for development of dosing recommendations for 
the target patient population, including those with varying degrees of hepatic impairment.  
 
 
  However, to ensure subject safety, standard, 
intensive, inpatient monitoring of subjects following administration of the single oral dose 
for at least 48 hours is included. 
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective: 
Primary Endpoints: 
To compare the pharmacokinetics of PF-05221304
(both total and unbound) following administration 
of a single oral dose in adult subjects with varying 
degrees of hepatic impairment relative to age- and 
body weight-matched subjects without hepatic 
impairment.
PF-05221304 PK parameters derived from plasma: 

Cmax, AUCinf, fu, Cmax,u, and AUCinf,u.
Secondary Objectives: 
Secondary Endpoints: 
To compare additional pharmacokinetic parameters 
(both total and unbound) of PF-05221304 following 
administration of a single oral dose in adult subjects 
with varying degrees of hepatic impairment relative 
to age- and body weight-matched subjects without 
hepatic impairment.
PF-05221304 PK parameters derived from plasma: 

Tmax, AUClast, AUClast,u, CL/F, CLu/F, Vz/F, 
Vz,u/F and t½, as data permit.
To evaluate the safety and tolerability of a single 
oral dose of PF-05221304 when administered to 
adult subjects with varying degrees of hepatic 
impairment relative to age- and body 
weight-matched subjects without hepatic 
impairment.
Assessment of treatment-emergent adverse events, 
clinical laboratory tests, vital signs, and 12-lead 
ECGs.
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3. STUDY DESIGN
3.1. Study Overview
This is a non-randomized, open-label, single-dose, parallel-cohort, multisite study to 
investigate the effect of varying degrees of hepatic impairment on the plasma 
pharmacokinetics (total and unbound) of PF-05221304 after a single oral 25 mg dose 
administered in the fed state.  A total of approximately 24 subjects with varying degrees of 
hepatic function will be enrolled into the study to ensure that up to 6 evaluable subjects in 
each of the 4 hepatic function cohorts complete the study.  Subjects will be selected based on 
their Child-Pugh score as shown in Table 1. 
Table 1.
Hepatic Function Categories Based on Child Pugh Score
Cohort
Description
Child-Pugh Score
Number of Subjects
1
Without hepatic impairment
Not Applicable 
6a
2
Mild hepatic impairment
Class A (5 to 6 points)
6
3
Moderate hepatic impairment
Class B (7 to 9 points)
6
4
Severe hepatic impairment
Class C (10 to 15 points)
6b
a. Additional subjects may be dosed to a maximum of 10 subjects to ensure mean age is 5 years and mean body weight 
10 kg of this cohort is in line with pooled average assessed when 75% of subjects are dosed across other 3 cohorts.
b. If recruitment across the sites selected proves to be prohibitive, study will dose only 4 subjects in this cohort.  
Child-Pugh scores will be determined as described in Appendix 2, at the screening visit.  
Recruitment for subjects meeting the criteria for Cohorts 3 and 4 will initiate first.  
Recruitment for subjects in Cohort 2 will start when approximately 50% of total subjects 
across Cohorts 3 and 4 (ie, 6 of 12) have been dosed.  Subjects in Cohort 1 will be recruited 
last to match the average demographics (at a minimum, age and weight; and as much as 
practically possible gender) across the pooled Cohorts 2 through 4. Approval from the 
Sponsor must be garnered before proceeding with dosing subjects in Cohort 1.
The overall study design is summarized below in Figure 1.  For individual subjects, the total 
duration of participation from the Screening Visit to the on-site Follow-up Visit (Day 7) will 
be a minimum of approximately 3 weeks and a maximum of approximately 5 weeks.
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Figure 1.
C1171006 Study Design
In this study, subjects who prematurely discontinue for non-safety related reasons may be 
replaced, at the discretion of the principal investigator (PI) and Sponsor study team.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects 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 subject is suitable for this protocol.
4.1. Inclusion Criteria
Subjects in all 4 Cohorts must meet all of the following inclusion criteria to be eligible for 
enrollment in the study:
1. Male or female subjects between the ages of 18 (or the minimum country-specific age 
of consent if >18) and 70 years, inclusive, at the Screening visit:

Male and female subjects of childbearing potential must agree to use highly 
effective method(s) of contraception [refer to Section 4.4.4].  A subject is of 
childbearing potential if, in the opinion of the investigator, he/she is biologically 
capable of having children and is sexually active.

Female subjects of childbearing potential must not be pregnant, breastfeeding, 
or planning to become pregnant for the duration of their participation in this 
study and within 28-days following the single dose of investigational product.
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
Female subjects of non-childbearing potential must meet at least 1 of the 
following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) 
level confirming the postmenopausal state, with a single repeat assessment, 
via the sponsor-identified central laboratory, permitted to assess 
postmenopausal state, if needed;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure;
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential;
2. Body mass index (BMI) of 17.5 and 35.4 kg/m2; and a total body weight >50 kg 
(110 lbs);
3. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study;
4. Subjects who are willing and able to comply with all scheduled visits, treatment 
plans, laboratory tests, and other study procedures.
4.1.1. Additional Inclusion Criteria for Subjects without Hepatic Impairment (Cohort 1, 
only)
1. Male and/or female subjects –
a.
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 laboratory;
b. Breath alcohol test at Screen must be negative;
2. Subjects must fit the demographic-matching criteria, including –
a.
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;
b. An age that is 5 years of the average of the pooled hepatic impairment cohorts 
(Cohorts 2, 3, and 4), as provided by the sponsor;
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c.
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:

ALT upper limit of normal (ULN);

AST ULN;

Total bilirubin ULN;

NOTE: Subjects 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;

Prothromin time ULN.
4.1.2. Additional Inclusion Criteria for Subjects with Impaired Hepatic Function 
(Cohorts 2, 3, and 4, only)
1. Satisfy the criteria for Class A, B, or C of the modified Child-Pugh classification 
(refer to Appendix 2);
2. A diagnosis of hepatic dysfunction due to hepatocellular disease (and not secondary to 
any acute ongoing hepatocellular process) documented by medical history, physical 
examination, liver biopsy, hepatic ultrasound, computerized tomography scan, 
or magnetic resonance imaging (MRI);
3. Stable hepatic impairment, defined as no clinically significant change in disease status 
within the 28 days prior to the Screening Visit, as documented by the subject’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%);
4. Stable concomitant medications (as defined in Section 5.8.2) for the management of 
individual subjects medical history; on a case-by-case basis, with input from the 
Sponsor, subjects receiving fluctuating concomitant medication/treatment may be 
considered if the underlying disease is under control;
5. Previous history of alcohol abuse is permissible provided that the subject is willing 
and able to abide by the lifestyle guidelines described in Section 4.4.2 of this protocol
and breath alcohol test, at Screen, is negative.
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4.2. Exclusion Criteria
Subjects in all 4 Cohorts with any of the following characteristics/conditions will not be 
included in the study:
1. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection) –

NOTE: subjects who have undergone cholecystectomy and/or appendectomy are 
eligible for this study so long as the surgery occurred more than 6 months prior to 
Screening;
2. A positive urine drug test, for illicit drugs, at Screening;

NOTE: repeat urine drug testing is not permitted in this study;
3. Participation in other studies involving investigational drug(s) within 30 days (or as 
determined by the local requirement) or 5 half-lives prior to study entry (Screening)
and/or during study participation;
4. Subjects with known prior participation (ie, randomized and received at least 1 dose 
of investigational product) in a study involving PF-05221304;
5. At Screening, subjects 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;
6. Male subjects with partners who are currently pregnant, pregnant female subjects,
breastfeeding female subjects, as well as fertile male subjects and female subjects of 
childbearing potential who are unwilling or unable to use highly effective methods of 
contraception as outlined in Section 4.4.4 for the duration of the study and for 
at least 28 days after the dose of investigational product;
7. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to the dose of investigational product and until the on-site 
Follow-up visit (Day 7);
8. History of sensitivity to heparin or heparin-induced thrombocytopenia, only if heparin 
is used to flush intravenous catheters used during serial blood collections);
9. Unwilling or unable to comply with the Lifestyle Requirements outlined in 
Section 4.4;
10. Subjects who are 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 subjects who are Pfizer employees, including their family members, 
directly involved in the conduct of the study. 
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4.2.1. Additional Exclusion Criteria for Subjects without Hepatic Impairment
(Cohort 1, only)
In addition, subjects 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, subjects with a 
previously positive HBsAb result due to vaccination, are deemed eligible;

Hepatitis C virus (HCV), defined by presence of hepatitis C antibody (HCVAb) 
and HCV RNA (when reflexed based on a positive result for HCVAb);
2. History of regular alcohol consumption exceeding 14 drinks/week for female subjects 
or 21 drinks/week for male subjects (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. Evidence or history of clinically significant hematological, renal, endocrine ,
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing);
4. Screening supine 12-lead ECG demonstrating QTcF interval >450 msec or a QRS 
interval >120 msec.  If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG 
should be repeated 2 more times and the average of the three QTcF or QRS values 
should be used to determine the subject’s eligibility;
5. Screening seated systolic blood pressure (SBP) 140 mm Hg or diastolic blood 
pressure (DBP) 90 mm Hg, following 5 minutes of seated rest.  If SBP is 
140 mm Hg or DBP 90 mm Hg, the BP assessment should be repeated 2 more 
times and the average of the three BP values should be used to determine the 
subject’s eligibility;
6. 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 5.8.1 for details; 
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7. 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 subject inappropriate for entry into this 
study.
4.2.2. Additional Exclusion Criteria for Subjects with Impaired Hepatic Function 
(Cohorts 2, 3, and 4, only)
In addition, subjects 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. History of surgery that would be expected to alter Absorption, Distribution, 
Metabolism and Excretion (ADME) properties of PF-05221304 – for example: status 
post porta-caval shunt surgery;

NOTE: Subjects with a transjugular intrahepatic portosystemic shunt (TIPS) are 
permitted provided that they meet the Child-Pugh criteria;
3. History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less 
than 4 weeks prior to Screening;
4. At Screening, subjects with an estimated glomerular filtration rate (eGFR) of 
60 mL/min 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. Signs of clinically active Grade 3 or 4 hepatic encephalopathy (ie, >Grade 2 Portal 
Systemic Encephalopathy score) – refer to Appendix 2;
6. Severe ascites and/or pleural effusion, except for those categorized in Cohort 4 who 
may be enrolled provided subject is medically stable, per Investigators’ medical 
judgment;
7. Subjects 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 subject’s eligibility;
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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 subjects with SBP 160 mm Hg or DBP 100 mm Hg, the period between 
Screening and Day -1 must be used to refine the doses of the agents used for 
management of blood pressure (refer to Section 5.8.2) with the aim to have 
stable BP on Day 1 [refer to Section 4.3];
10. Subjects 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.
4.3. Criteria for Dosing on Day 1
Subjects will progress to dosing on Day 1 provided they have satisfied all the following 
criteria –

Eligibility criteria outlined in Section 4.1 and Section 4.2;

Breath Alcohol test on Day -1 is negative;

In females of childbearing potential, urine pregnancy test on Day 1 prior to dosing as 
reported by on-site pregnancy test using supplies offered by sponsor-identified central 
laboratory, is negative for pregnancy – refer to Section 7.2.1.1;

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 
subject to be in stable medical condition;

Cohorts 2, and 3, only:  patients with elevated BP at Screening 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:  patients with elevated BP at Screening must have measurement on 
Day 1 of SBP 159 mm Hg and DBP 105 mm Hg with repeat permitted, if needed, 
to confirm stable BP.
4.4. Lifestyle Requirements
After confirmation of eligibility and starting on Day -1, the subjects will be instructed to 
maintain the guidelines described below for the duration of participation in the study. 
4.4.1. Meals and Dietary Restrictions
While inpatient, the meals consumed are expected to follow the restrictions outlined below 
with subjects encouraged to complete each meal. 
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
Subjects must abstain from all food and drink (except water) for 4-hours prior to all 
fasting clinical laboratory evaluations;

Water may be consumed as desired (ad libitum);

Investigational product must be administered with the morning meal;

While inpatient, meals including on non-dosing days – 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 offered 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 daily caloric intake per subject should not exceed approximately 3200 kcal;

The morning meal (matching 0H), afternoon snack, and optional evening 
snack is each envisioned to constitute 300-400 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;

The nutritional macronutrient composition consumed by each subject should be 
maintained, as much as practically possible;

If subjects cannot complete the meals, the portion consumed in 25% 
increments will be documented and potential impact on results assessed by the 
Sponsor study team on a case-by-case basis;

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;

During the outpatient visits on Days 4 through 7, inclusive, as applicable, a morning 
meal will be consumed at the site following completion of the other procedures at this 
nominal time point [with the meal either provided by the site or the subject provided 
a voucher (or similar) by the site to purchase the meal before arriving to the site for 
each visit].
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4.4.2. Alcohol, Caffeine, and Tobacco

Subjects will abstain from alcohol for 24 hours prior to the single dose of 
investigational product (IP) on Day 1 (plus have a negative breath alcohol test on 
Day -1) and continue abstaining from alcohol until the on-site Follow-up visit 
(Day 7);  

Subjects will undergo a breath alcohol test at time points indicated in the 
Schedule of Activities (Table A);

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.
4.4.3. Activity

Subjects 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 subject’s normal pace is permitted.
4.4.4. Contraception
 
 
Female subjects who, in the opinion of the investigator are sexually active and at risk for 
pregnancy must agree to use, with their partner(s), highly effective contraception throughout 
the study and continue use for at least 28 days after receiving the single dose of the 
investigational product.  The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected the appropriate method of contraception for 
the individual subject from the list of permitted contraception methods below and instruct the 
subject in their consistent and correct use.  At time points indicated in the Schedule of 
Activities (Table A), the investigator or designee will inform the female subject of the need 
to use the highly effective method of contraception consistently and correctly and document 
such conversation, and the subject’s affirmation, in the subject’s chart.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use).  
One of the below options must be used to satisfy the requirement for highly effective 
contraception in female subjects participating in this study:
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1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, inserted, injected, implanted; and including oral, as well as transdermal
methods unless prohibited by local regulations or ethics committee decision), with 
either:
a.
Male or female condom;
b. Male sterilization.
2. Correctly placed copper-containing intrauterine device (IUD) or intrauterine system 
combined with either:
a.
Male or female condom;
b. Male sterilization.
3. Male sterilization with absence of sperm in the post-vasectomy ejaculate in the 
female subjects’ partner combined with either:
a.
Male or female condom;
b. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive 
procedures.
4. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label) 
combined with one of the following:
a.
IUD or intrauterine system;
b. Male or female condom;
c.
Male sterilization.
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
female partner(s) to drug through ejaculate by using a condom consistently and correctly, 
beginning with the dose of investigational product (Day 1) and continuing for at least 
28 days after the dose of investigational product.
In female subjects, pregnancy testing will be performed at time points indicated in the 
Schedule of Activities (Table A).  The specific contraceptive method(s) in the females of 
childbearing potential will be documented, and at every visit their consistent and correct use 
will be ascertained and documented in the subject’s source document.  For additional details, 
refer to Section 7.2.1.1.
In addition, the investigator or designee will instruct all subjects of childbearing potential to 
call immediately if the selected contraception method is discontinued or if pregnancy is 
known or suspected in the female subject or male subjects’ female partner.
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NOTE:  Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with this study) 
may obviate the need for contraception ONLY if this is the preferred and usual lifestyle of 
the subject.
4.5. 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, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study 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 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. For sites other 
than a Pfizer clinical research unit (CRU), the contact number is not intended for use by the 
subject directly, and if a subject calls that number, he or she will be directed back to the 
investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product is PF-05221304, provided as tablets, each 
containing 25 mg active drug.
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject.
Following completion of informed consent at the Screening visit, each subject 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. 
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5.2. Breaking the Blind
Not applicable, this is an open-label study. 
5.3. Subject Compliance
The single dose of the investigational product will be administered under the supervision of 
investigator site personnel.  The oral cavity of each subject will be examined following 
dosing to ensure the investigational product was swallowed.
5.4. Investigational Product Supplies
5.4.1. Dosage Form and Packaging
The investigational product (PF-05221304) will be supplied by the Sponsor.  PF-05221304 
will be supplied to the sites as single strength tablets of 25 mg, in bulk.  PF-05221304 will be 
presented to the subjects in individual dosing containers for oral ingestion.
5.4.2. 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 subject/caregiver 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, subject, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities.
PF-05221304 for witnessed dosing in this study will be prepared by the site staff. 
Investigational product should be prepared and dispensed by the site into individual dosing 
containers by an appropriately qualified and experienced member of the study staff 
(eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, 
or pharmacist) as allowed by local, state, and institutional guidance.
5.5. Administration
Administration of investigational product (PF-05221304), will occur at 8:30 AM (1 hour) 
with the morning meal – refer to Section 4.4.1.  A single, oral, 25 mg dose of PF-05221304 
will be administered. Subjects will swallow the investigational product whole, and will not 
manipulate or chew the investigational product prior to swallowing.  Investigator site 
personnel will administer investigational product to subjects with ambient temperature water 
of approximately 120 mL. 
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
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Investigational products should be stored in their original containers and in accordance with 
the labels.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product-label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site. 
5.7. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
5.7.1. Destruction of Investigational Product Supplies 
At the end of the study, the sponsor or designee will provide guidance on the destruction of 
unused investigational product (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.
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5.8. Concomitant Treatments
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatment as defined in the Schedule of Activities (Table A).
Treatments taken within 28 days before the dose of investigational product (PF-05221304) 
will be documented as a prior treatment.  Treatments taken after dosing of investigational 
product will be documented as concomitant treatments.
Females using hormonal contraceptives or taking hormone replacement therapy are eligible 
to participate in this study.
5.8.1. Subjects with Healthy Hepatic Function (Cohort 1, Only)
In general, subjects 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 on-site Follow-up visit;

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.
5.8.2. Subjects with Impaired Hepatic Function (Cohorts 2, 3, and 4)
Subjects 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 on-site 
Follow-up visit (on Day 7).
Subjects on the following medications, at the Screening Visit, are excluded from the study –

 (eg, cyclosporine, gemfibrozil, rifampin, erythromycin, 
clarithromycin);

 (eg, ketoconazole, itraconazole);

(eg, rifampin);

 (eg, alfentanil, astemizole,
cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, and terfenadin);

(Medical-grade) marijuana, regardless of medical indication.
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Herbal supplements must be discontinued at least 28 days prior to Day 1 and until the 
on-site Follow-up visit (on Day 7).
5.9. Rescue Medication
There is no rescue therapy to reverse any adverse events (AEs) observed with administration 
of investigational product; standard medical supportive care must be provided to manage the 
AEs.
6. STUDY PROCEDURES
6.1. Proposed Chronology of Procedures
For the procedures described below, where multiple procedures are scheduled at the same 
timepoint(s) relative to dosing, the following chronology of events should be adhered to, 
where possible:

12-lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing (refer to Section 7.2.4).

Vital Signs (blood pressure and pulse rate: obtain after 12-lead ECG collection but 
prior to obtaining blood samples and prior to dosing (refer to Section 7.2.3).

If an intravenous catheter is placed for serial blood sample collections, ECGs and 
vital signs (blood pressure and pulse rate) assessments should be either collected 
prior to the insertion of the catheter or sufficient rest period after catheter insertion 
introduced to minimized impact of catheter placement on these assessments. 

Fasting blood samples for clinical laboratory tests: after assessment of 12-lead ECG 
and vital signs but prior to start of meal (and dosing, when applicable) - refer to
Section 7.2.1.

Serial blood samples for plasma PK (refer to Section 7.1): as close as practically 
possible to the nominal time.

Other pre-dose procedures: should be obtained/performed as close as possible to the 
scheduled time, but may be obtained before or after blood specimen collection.

If the post-dose blood collection nominal time coincides with the nominal time of a 
meal, these blood samples should be collected prior to start of the meal.

Dosing (refer to Section 5.5): should occur as close as possible to the scheduled 
nominal time with a meal (refer to Section 4.4.1), and as close as practically 
possible following pre-dose blood sample collection. 
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6.2. Screening
Subjects will be screened within 28 days prior to administration of the investigational 
product to confirm that they meet the subject selection criteria for the study.  The investigator 
(or an appropriate delegate at the investigator site) will obtain informed consent from each 
subject in accordance with the procedures described in Section 12.3.  Refer to Schedule of 
Activities Table A for the study procedures to be completed at the Screening visit. 
In this study, subjects 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 subjects 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 subject assigned a new 8-digit SSID 
number.  Subjects must be deemed to meet all the eligibility criteria under the new 8-digit 
SSID before progressing to Day 1.
To prepare for study participation, subjects will be instructed on the information in the
Lifestyle Requirements (Section 4.4) and Concomitant Treatments (Section 5.8).
6.3. Study Period
Refer to Schedule of Activities Table A for the study procedures to be completed starting on 
Day -1 to Day 6, inclusive.
If a subject has any clinically significant, study-related abnormalities at the conclusion of the
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain at the site until 
such abnormalities are deemed not clinically significant, or it is safe for outpatient 
Follow-up.  If the subject is unable or unwilling to remain at the site and/or when outpatient 
Follow-up is deemed appropriate, the Pfizer medical monitor (or designated representative) 
should be so notified, and the investigator should make every effort to arrange Follow-up 
evaluations at appropriate intervals to document the course of the abnormalities.
6.4. Follow-up 
6.4.1. Follow-up Visit
In this study, there are two Follow-up visits, as follows: 

1st is an on-site visit which will occur on Day 7 following dosing of investigational 
product on Day 1;

2nd is a telephone contact to occur 30 2 days following dosing of investigational 
product on Day 1;

Refer to Schedule of Activities- Table A for the study procedures to be completed at 
each of the two Follow-up visits.
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6.5. Subject Withdrawal/Early Termination
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (refer to 
Section 8.1.3) or behavioral reasons, or the inability of the subject to comply with the 
protocol-required schedule of study visits or procedures at a given investigator site.  The 
early termination visit applies only to subjects who are dosed and then are prematurely 
withdrawn from the study.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, site staff may send a registered letter.  If no response is received from the subject, 
the subject will be considered lost to follow-up.  All attempts to contact the subject and 
information received during contact attempts must be documented in the subject’s medical 
record.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request that the 
subject return for a final visit, if applicable, and follow up with the subject regarding any 
unresolved AEs.
It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  At the early
withdrawal visit, every effort must be made to complete the following assessments:

Conduct an inquiry about any spontaneously reported AEs by asking the subject to 
respond to a non-leading question such as “how do you feel?”

Perform a limited physical examination, if there is a new or open AE or clinically 
significant abnormal physical finding from the last visit at PI discretion;

Obtain supine, single, standard, 12-lead ECG (refer to Section 7.2.4);

Obtain seated, single set of blood pressure and pulse rate measurements (refer to
Section 7.2.3);

Collect blood and urine specimens, following a 4-hour fast, for clinical laboratory 
tests (refer to Section 7.2.1);

Undertake on-site urine pregnancy testing (in females of childbearing potential 
only) – refer to Section 7.2.1.1;

Collect blood sample for pharmacokinetic analysis of PF-05221304 – refer to 
Section 7.1.1.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the subject’s safety was preserved.
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If the subject withdraws from the study and also withdraws consent 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.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor.
Withdrawal of Consent:
Subjects 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 subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.  
Subjects 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 post treatment 
study follow-up, and entered on the appropriate case report form (CRF) page.  In the event 
that vital status (whether the subject 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.
Lost to Follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter.  All attempts should be documented in the subject’s medical records.  If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
7. ASSESSMENTS
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 
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well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided via a manual developed by 
the sponsor-identified central laboratory to the investigator site prior to initiation of the study.
7.1. Pharmacokinetics (PK)
Pharmacokinetic sampling time points in this study may be adjusted to adequately assess the 
plasma PK profile based on emerging data from this study; and while the actual times may 
change, the total number of samples will remain the same.  All efforts will be made to obtain 
the pharmacokinetic samples at the exact nominal time relative to dosing.  However, samples 
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).

Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.

The PK samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity.  Any deviations from 
the PK sample handling procedure (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor.  On a case-by-case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulting in compromised 
sample integrity, will be considered a protocol deviation.

 
 

Refer to Section 6.1 for proposed chronology of procedures for nominal time points 
when PK collections coincide with other procedures.
Additional details regarding the collection, processing, storage and shipping of the blood 
samples will be offered, prior to study start, in a manual developed by the sponsor-identified
central laboratory.
7.1.1. Plasma for Analysis of total PF-05221304 concentrations
During the study, blood samples (3 mL) to provide sufficient plasma for pharmacokinetic 
analysis will be collected into appropriately labeled tubes containing K2EDTA as defined in 
the Schedule of Activities Table A.
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7.1.2. Plasma for Determination of PF-05221304 Unbound Fraction
During the study, a blood sample (12 mL) to provide sufficient plasma for unbound fraction 
determination will be collected into an appropriately labeled tube containing K2EDTA as
defined in the Schedule of Activities Table A.
7.2. Safety
7.2.1. Laboratory Tests
The clinical laboratory tests outlined in Table 2 will be performed, by the sponsor-identified 
central laboratory, as defined in the Schedule of Activities Table A.  Blood and urine 
samples for clinical laboratory tests will be collected following 4-hour fast.
Table 2.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Reticulocyte count (Abs)
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine (and eGRF via 
MDRD)
Plasma Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Phosphorus
Total CO2 (Bicarbonate)
AST
ALT
Alkaline phosphatase
GGT
Total bile acids
Total bilirubin
Direct bilirubina,b
Indirect bilirubina,b
Creatine Kinasea,c
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte 
esterase
Urobilinogen
Urine bilirubin
Microscopyd
Other tests as part of clinical 
laboratory tests: 

aPTT, PT, INR

Serum FSHe

Serum and urine
pregnancy test (refer to
Section 7.2.1.1)

Urine drug testf

Serologyg: HBsAg, 
HBcAb, HCVAb (and if 
positive, reflex HCV 
RNA), HIV
Additional Tests (Needed for Hy’s law) – also refer to Section 8.4.2.
AST 
ALT 
Total bilirubin
Albumin 
Alkaline phosphatase 
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug levels and/or protein adduct level
a.
At Screening and Day 1, only.
b. After Day 1, direct and indirect bilirubin assessed when total bilirubin is > ULN, only.
c.
After Day 1, creatine kinase assessed when ALT is > ULN, only.
d. Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
e.
At Screening; and in females, only.
f.
At Screening, only; with minimum requirements including cocaine, tetrahydrocannabinol (THC), opiates/opioids, 
benzodiazepines and amphetamines.
g. At Screening, only.
For list of abbreviations refer to Appendix 1.
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In all cases, samples will be collected prior to initiation of a meal.  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 sponsor-identified 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.  Additional details regarding sample collection, 
processing, and shipment will be provided in the manual developed by the sponsor-identified 
central laboratory and provided to the sites prior to the start of the study.
7.2.1.1. Pregnancy Testing
All pregnancy tests (serum and urine) used in this study must have a sensitivity of 
at least 25 mIU/mL, and must be performed using supplies offered by the sponsor-identified 
central laboratory. 
For female subjects of childbearing potential, following a negative serum pregnancy test 
result and after confirmed eligibility based on Screening tests(s), appropriate contraception 
must be used (either continued or commenced) and the subject will require a negative urine
pregnancy test on Day 1 before receiving IP on Day 1.  The female subject should have used 
highly effective method of contraception (refer to Section 4.4.4) for at least 28-days before 
Day 1. 
Pregnancy tests will be performed as defined in the Schedule of Activities (Table A) to
confirm that the subject has not become pregnant during the study.  Pregnancy tests will also 
be done whenever a potential pregnancy is otherwise suspected, and may be repeated if 
requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  In the case of a positive confirmed pregnancy, the subject will be 
withdrawn from administration of investigational product and from the study.
7.2.2. 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 Table A. 

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 subject 
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.  Subjects 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. 
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7.2.3. Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured as defined in the Schedule of Activities
Table A.  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 subject’s arm 
supported at the level of the heart, and recorded to the nearest mm Hg, following a 
rest of 5-minutes; the assessment at Visit 5 (Day 1) will serve as each subject’s 
baseline;

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;

Subjects should be instructed not to speak during blood pressure/pulse rate 
measurements.
The same properly sized and calibrated blood pressure cuff will be used to measure blood 
pressure each time.  The use of an automated device for measuring BP and pulse rate is 
acceptable, although, when done manually, pulse rate will be measured in the brachial/radial 
artery for 30 seconds. 
Refer to Section 6.1 for proposed chronology of procedures for nominal time points when 
vital sign assessments coincide with other procedures.
7.2.4. Electrocardiogram 
As defined in the Schedule of Activities Table A, 12-lead electrocardiograms (ECGs) should 
be collected. 
All scheduled ECGs should be performed after the subject has rested quietly for 10 minutes 
in a supine position. 
Refer to Section 6.1 for proposed chronology of procedures for nominal time points when 
12-lead ECG assessments coincide with other procedures.
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 are 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.
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7.5.1. Additional Research 
 
 
 
7.6. Blood Volume
The total blood sampling volume for individual subjects in this study will be approximately 
  Table 3 below reflects approximate sample volumes needed for each measured 
endpoint.
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Table 3.
Blood Volume Collected in Study C1171006
Sample Type
Sample 
Volume 
(mL)
Number of Sampling Times
Total 
Volume 
(mL)
Screen
Days 1-6, 
inclusive
Follow-
Up
Clinical Laboratory Tests
30
1
--
--
30
Clinical Laboratory Tests
25
--
2
1
75
PF-05221304 PK, total concentrations
3
--
15
1
48
Samples for plasma protein binding to assess unbound 
plasma PF-05221304 concentrations
12
--
1
--
12
TOTAL
Total volume does not include discarded blood from pre-draws used to remove fluid from flushed catheters, if applicable
The actual collection times of blood sampling may change, but the total blood volume 
collected will not increase.  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.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety 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) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
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Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE
(see Section 8.2.3 below).  In addition, the investigator may be requested by Pfizer Safety to 
obtain specific follow-up information in an expedited fashion.  This information is more 
detailed than that recorded on the CRF.  In general, this 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 subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer 
Safety.  Any pertinent additional information must be reported on the CT SAE Report Form; 
additional source documents (eg, medical records, CRF, laboratory data) are to be sent to
Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  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.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
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8.1.3. Withdrawal From the Study Due to Adverse Events (see also Section 6.5)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with 
Section 8.1 above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’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 subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject 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.
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.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
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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.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
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.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;
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
Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are 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.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);
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
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specific Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database.
8.4.2. 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 subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
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progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects 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 subject’s
individual baseline values and underlying conditions.  Subjects 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:

Subjects 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 subjects 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).
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 subject 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.
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In addition to repeating measurements of AST and ALT and TBili, 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, alkaline phosphatase and acetaminophen drug and/or protein adduct levels – refer to
Table 2.  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) 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.
8.4.3. Exposure to the Investigational Product 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 
awareness.
8.4.3.1. Exposure During Pregnancy
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).
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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 subject or subject’s partner becomes or is found to be pregnant during the subject’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 subject 
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 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the 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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
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subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. 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.
8.4.3.3. 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 subject 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.
8.4.4. Medication Errors
Other 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
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject 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 participating subject.
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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 non-serious, 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.
9. DATA ANALYSIS/STATISTICAL METHODS
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. Sample Size Determination
A sample size of approximately 24 subjects with varying degrees of hepatic function
(6 subjects per cohort) will provide 90% confidence interval to detect a 2-fold change in 
exposure (AUCinf) with 80% tolerance probability.  Table 4 presents the precision of the 
estimated effects with the associated width of 90% confidence intervals with increasing 
standard deviation.
Table 4.
Precision for 2-fold Change in AUCinf as Function of Assumed Variability
Level of 
Precision
Assumed SD*= 0.16
Assumed SD* = 0.23
Assumed SD* = 0.28
n=6/cohort
18% (1.65; 2.43)
24% (1.51; 2.64)
29% (1.42; 2.81)
*SD = Standard Deviation calculated on natural logarithmic scale
9.2. Efficacy Analysis
Efficacy analysis is not applicable to this study. 
9.3. Pharmacokinetic Analysis
9.3.1. Analysis Populations
The PK concentration population will be defined as all subjects who received 1 dose of 
PF-05221304 and in whom at least 1 plasma concentration value is reported.
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The PK parameter analysis population is defined as all subjects dosed who have at least 1 of 
the PK parameters of primary interest.
9.3.2. Derivation of Pharmacokinetic Parameters Prior to Analysis
The plasma PK parameters for PF-05221304 following single dose administration will be 
derived from the concentration-time profiles as detailed in Table 5.  Actual PK sampling 
times will be used in the derivation of PK parameters.  The fraction of PF-05221304 unbound 
in plasma (fu) will be determined and reported for each subject by the analytical lab.
Table 5.
Plasma PK Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-time 
profile from time zero to the time of the 
last quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUClast,u
Unbound area under the plasma 
concentration-time profile from time zero 
to the time of the last quantifiable 
concentration (Clast)
fu* AUClast
AUCinf*
Area under the plasma concentration-time 
profile from time zero extrapolated to 
infinite time
AUClast + (Clast*/kel), 
where Clast* is the predicted plasma 
concentration at the last quantifiable time point 
estimated from the log-linear regression 
analysis
AUCinf,u*
Unbound area under the plasma 
concentration-time profile from time zero 
extrapolated to infinite time
fu* AUCinf*
Cmax
Maximum plasma concentration
Observed directly from data
Cmax,u
Unbound maximum plasma concentration
fu* Cmax
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
t1/2*
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the 
log-linear concentration-time curve.  Only 
those data points judged to describe the 
terminal log-linear decline will be used in the 
regression.
CL/F*
Apparent clearance
Dose/AUCinf
CLu/F*
Unbound apparent clearance
fu* CL/F
Vz/F*
Apparent volume of distribution
Dose/(AUCinfkel)
Vzu/F*
Unbound apparent volume of distribution
fu* Vz/F
*As data permits
For list of abbreviations refer to Appendix 1
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9.3.3. Statistical Methods
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 using a 
one-way ANOVA model based on natural log transformed data. 
One-way analysis of variance (ANOVA) will be used to compare the natural log transformed 
PF-05221304 AUCinf, AUClast and Cmax, unbound AUCinf (AUCinf,u), unbound AUClast
(AUClast,u), and unbound Cmax (Cmax,u), as data permit, for each of the hepatic impairment 
classification 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.  The adjusted mean differences and 
90% confidence intervals for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for the 
ratios. 
 
 
The PF-05221304 PK parameters Cmax, AUClast, AUCinf, fu, Tmax, t½, CL/F, Vz/F, AUCinf,u, 
AUClast,u, Cmax,u, CLu/F, and Vzu/F will be summarized descriptively by hepatic function 
cohort.  Individual PF-05221304 concentrations will be listed and summarized descriptively 
by nominal PK sampling time and hepatic function cohort.  Individual subject and summary 
profiles (median and means) of the concentration-time data will be plotted by treatment for 
both total plasma PF-05221304 and unbound PF-05221304.  For summary statistics and 
summary 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.  PF-05221304 AUCinf, 
AUClast, Cmax, AUCinf,u, AUClast,u, and Cmax,u individual subject parameters will be plotted by 
hepatic function cohort.
Linear regression may be used to analyze the potential relationship between appropriate PK 
parameters (eg CL/F and VZ/F) and hepatic function (eg, serum albumin concentration, or 
prothrombin time).  Estimates of the slope and intercept, together with their precision 
(90% confidence interval [CI]), and the coefficient of determination will be obtained from 
the model.
Plots of PK parameters (CL/F and VZ/F) versus hepatic function (eg, serum albumin 
concentration, or prothrombin time) will be constructed.  A regression line and 
90% confidence region for the PK parameters and hepatic function will be included.
9.4. Pharmacodynamic Analysis
Not applicable for this study.
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9.6. Safety Analysis
During the study conduct, adverse events, ECGs, blood pressure, pulse rate, and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects.  Any clinical laboratory, ECG, BP, and pulse rate
abnormalities of potential clinical concern will be described.  Safety data will be presented in 
tabular and/or graphical format and summarized descriptively, where appropriate.  In the 
study report, for vital signs and ECGs, comparison will be made to the predose collections 
on Day 1. 
Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will not be required to be reported, 
unless otherwise noted. 
9.6.1. Electrocardiogram Analysis
During study conduct as well as reporting of study results, baseline will be defined as 
12-lead ECGs data collected on Day 1 prior to dosing of IP.  Changes from baseline for the 
ECG parameters QT interval, heart rate, QTcF interval, PR interval and QRS interval, will be 
summarized by time.
The number (%) of subjects with maximum post dose QTcF values and maximum increases 
from baseline in the following categories will be tabulated by regimen: 
Categorical Assessment of QTcF Interval
Borderline (msec)
Prolonged (msec)
Absolute Value
450 - <480
480
Absolute Change
30-<60
60
In addition, the number of subjects with corrected and uncorrected QT values 500 msec will 
be summarized.
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9.7. Interim Analysis
No formal interim analysis will be conducted for this study.  The sponsor may conduct 
reviews of the data during the course of the study for the purpose of safety assessment, 
facilitating PK modeling, and/or supporting clinical development. 
9.8. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, to ensure that the protocol and Good Clinical 
Practices (GCPs) are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs are accurate.  The investigator and institution will 
allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer 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 subject’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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. 
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
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A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
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12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
At the end of the study, the investigational product in this study will not be provided to the 
subjects who participated. 
12.4. 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. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last subject last visit (LSLV) 
reflected by completion of the 2nd Follow-up visit for the last subject randomized in the 
study. 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-05221304 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 14 calendar days.  As directed by Pfizer, all study materials must be 
collected and all CRFs completed to the greatest extent possible.
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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
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 all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are 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 subject 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 patients 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.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
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publication or other type of disclosure of the results of the study (collectively, “publication”)
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.
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16. REFERENCES
1.
LaBrecque D, Abbas Z, Anania F, et al. Nonalcoholic fatty liver disease and 
nonalcoholic steatohepatitis. In: WGO Global Guidelines NAFLD/NASH (long 
version). Milwaukee, WI: World Gastroenterology Organisation; 2012: 29 pages.
2.
Sanyal AJ, Friedman SL, McCullough AJ, et al. 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(4):1392-405.
3.
European Association for the Study of the Liver (EASL), European Association for the 
Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). 
EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic 
fatty liver disease. J Hepatol 2016; 64(6):1388-402.
4.
Khan FZ, Perumpail RB, Wong RJ, et al. Advances in hepatocellular carcinoma: 
Nonalcoholic steatohepatitis-related hepatocellular carcinoma. World J Hepatol 
2015; 7(18):2155-61.
5.
Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic 
fatty liver disease – meta-analytic assessment of prevalence, incidence, and outcomes.  
Hepatology 2016; 64(1):73-84.
6.
Noureddin M, Anstee Q, Loomba R.  Review article: emerging anti-fibrotic therapies in 
the treatment of non-alcoholic steatohepatitis.  Aliment Pharmacol Ther 
2016;43(11):1109-23.
7.
LaBrecque D, Abbas Z, Anania F, et al. Nonalcoholic fatty liver disease and 
nonalcoholic steatohepatitis. In: WGO Global Guidelines NAFLD/NASH (long 
version). Milwaukee, WI: World Gastroenterology Organisation; 2012: 29 pages.
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Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
ACC
acetyl-CoA carboxylase
ADR
adverse drug reaction
ADME
absorption, distribution, metabolism and excretion
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under curve (used when referring to PK)
AUC24
area under concentration-time curve from time 0 to 24 hours
AUCinf
area under the curve to infinity
AUCinf,u
area under unbound plasma concentration-time profile from time zero extrapolated to 
infinite time
AUClast
area under concentration-time curve from time 0 to time of last quantifiable concentration
AUClast,u
area under unbound plasma concentration-time profile from time zero to time of last 
quantifiable concentration (Clast)
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CI
confidence interval
CK
creatine kinase
CL/F
apparent oral clearance
CLu/F
unbound apparent clearance
Cmax
peak or maximum observed concentration
Cmax,u
maximum unbound plasma concentration
CO2
carbon dioxide (bicarbonate)
CP
coproporphyrin
CPC
child-pugh classification
CPT
carnitine-palmitoyl transferase
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
DBP
diastolic blood pressure
DCT
data collection tool
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DNL
de novo lipogenesis
EC
ethics committee
ECG
electrocardiogram
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Abbreviation
Term
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EFD
embryo-fetal development
eGFR
Estimated glomerular filtration rate
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FFA
free fatty acid
FSH
follicle-stimulating hormone
fu
fraction unbound
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HDL-C
high density lipoprotein cholesterol
HCVAb
hepatitis C antibody
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HCV
hepatitis C virus
hr
hour
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IUD
intrauterine device
K2EDTA
dipotassium ethylene diamine tetraacetic acid
LDL-C
low density lipoprotein-cholesterol
LFT
liver function test
LSLV
last subject last visit 
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDRD
modification of diet in renal disease
MedDRA
medical Dictionary for Regulatory Activities
min
minute
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
N/A
not applicable
PCD
primary completion date
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Abbreviation
Term
PD
pharmacodynamics
PE
physical exam
PG
pharmacogenomic
PI
principal investigator
PK
pharmacokinetics
PR
pulse rate
PT
prothrombin time
Q12H
once every 12 hours
QD
quaque die, once a day
QTcF
QT interval corrected for heart rate using Fridericia’s formulae
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SCr
serum creatinine
SRSD
single reference safety document
SSID
study subject identification
T1/2
terminal half-life
Tmax
time to reach maximum concentration
TBili
total bilirubin
TEAE
treatment-emergent adverse event
Th17
T helper 17
THC
tetrahydrocannabinol
TIPS
transjugular intrahepatic portosystemic shunt
Treg
regulatory T
ULN
upper limit of normal
US
United States
VLDL
very low density lipoprotein
Vz,u/F
unbound apparent volume of distribution
Vz/F
apparent volume of distribution
WBC
white blood cell
WOCBP
Women/females of childbearing potential
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Appendix 2. Child-Pugh Classification (CPC) of Liver Dysfunction 
Table 2-1: Scoring for Child-Pugh Classification
Cohort
CPC
Level of dysfunction
Total Score
(tally based on assessment of 
parameters in Table 2-2)
1
Not Applicable
Without hepatic 
impairment
Not Applicable
2
A
Mild
5-6
3
B
Moderate
7-9
4
C
Severe
10
Table 2-2: Derivation of Child-Pugh Classification Score
Assessment Parameters
Assigned score for observed findings
1 point
2 point
3 point
Encephalopathy grade a
(refer to Table 2-3 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 C1171006 so long as they 
do not have clinically active Grade 3 or 4 encephalopathy.
Table 2-3: 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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SAP_000.pdf: 
Protocol C1171006 (PF-05221304) 
Statistical Analysis Plan 
 
 
 
Page 1 of 21 
 
          
DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT STUDY  
30-Jun-2015 
 
 
TMF Doc ID: 98.03 
 
 
 
Protocol C1171006 
 
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, 
SINGLE-DOSE, PARALLEL COHORT STUDY TO 
COMPARE THE PHARMACOKINETICS OF PF-
05221304 IN ADULT SUBJECTS WITH VARYING 
DEGREES OF HEPATIC IMPAIRMENT RELATIVE 
TO SUBJECTS WITHOUT HEPATIC IMPAIRMENT 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
Version: 
1.0 
Author:  
 (Cambridge, USA) 
Date:  
17-Aug-2017 
 
PPD
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Revision History 
Version 
Date 
Author(s) 
Summary of Changes/Comments 
Version 1.0 
17-Aug-2017 
 
NA 
 
Distribution list of reviewers for this document prior to final sign-off. 
 
Clinical Team* - List of reviewers 
Role Name 
Reviewer’s Name 
Clinical Lead 
 
Clinician 
 
Clinical Pharmacology Lead 
 
Pharmacometrician 
 
Clinical Statistics 
 
Regulatory Lead 
 
Clinical Programming 
 
Clinical Project Manager 
 
 
NOTE:  Italicized text within this document has been taken verbatim from the Protocol. 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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TABLE OF CONTENTS  
LIST OF TABLES ...........................................................................................................................4 
LIST OF FIGURES .........................................................................................................................4 
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................5 
2. INTRODUCTION .......................................................................................................................5 
2.1. Study Design ...................................................................................................................5 
2.2. Study Objectives .............................................................................................................7 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ........................................8 
4. HYPOTHESES AND DECISION RULES .................................................................................8 
4.1. Statistical Hypotheses .....................................................................................................8 
4.2. Statistical Decision Rules ................................................................................................8 
5. ANALYSIS SETS .......................................................................................................................8 
5.1. Pharmacokinetic (PK) Analysis Set ................................................................................8 
5.1.1. Concentration Analysis Set .................................................................................8 
5.1.2. Parameter Analysis Set .......................................................................................8 
5.2. Pharmacodynamic Analysis Set ......................................................................................8 
5.3. Safety Analysis Set ..........................................................................................................9 
5.4. Other Analysis Sets .........................................................................................................9 
5.5. Treatment Misallocations ................................................................................................9 
5.6. Protocol Deviations .........................................................................................................9 
5.6.1. Deviations Assessed Prior to Dosing ..................................................................9 
5.6.2. Deviations Assessed Post-Dosing .......................................................................9 
6. ENDPOINTS AND COVARIATES ...........................................................................................9 
6.1. Efficacy Endpoint(s) .......................................................................................................9 
6.2. Safety Endpoints .............................................................................................................9 
6.3. Other Endpoints .............................................................................................................10 
6.3.1. PK Endpoints ....................................................................................................10 
6.3.2. Other Endpoints ................................................................................................11 
6.4. Covariates ......................................................................................................................11 
7. HANDLING OF MISSING VALUES ......................................................................................11 
7.1. Concentrations Below the Limit of Quantification .......................................................11 
7.2. Deviations, Missing Concentrations and Anomalous Values .......................................11 
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7.3. Pharmacokinetic Parameters .........................................................................................11 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................12 
8.1. Statistical Methods ........................................................................................................12 
8.2. Statistical Analyses of PK Parameters ..........................................................................12 
8.3. Safety Analysis ..............................................................................................................14 
8.3.1. Treatment and Disposition of Subjects .............................................................14 
8.3.2. Demographic and Clinical Examination Data ..................................................14 
8.3.3. Discontinuation(s) .............................................................................................15 
8.3.4. Adverse Events .................................................................................................15 
8.3.5. Laboratory Data ................................................................................................15 
8.3.6. Vital Signs Data ................................................................................................15 
8.3.7. ECG Data ..........................................................................................................15 
8.3.8. Other Safety Data .............................................................................................15 
8.3.9. Concomitant Treatments ...................................................................................15 
8.3.10. Screening and Other Special Purpose Data ....................................................16 
8.4. Statistical Analyses of Other Endpoints ........................................................................16 
9. REFERENCES ..........................................................................................................................17 
10. APPENDICES .........................................................................................................................18 
 
LIST OF TABLES 
Table 1. 
Hepatic Function Categories Based on Child Pugh Score ..........................................6 
Table 2 
Child-Pugh Classification (CPC) of Liver Dysfunction ...............................................6 
Table 3. 
Noncompartmental PK Parameters .............................................................................10 
Table 4. 
PK Parameters to be Summarized Descriptively by Cohort .......................................13 
 
LIST OF FIGURES 
None. 
APPENDICES 
Appendix 1. SAS CODE FOR ANALYSES .................................................................................18 
 
 
 
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1. AMENDMENTS FROM PREVIOUS VERSION(S)  
None. 
This first version of the SAP reflects the C1171006 protocol (version: 08-Aug-2017) 
2. INTRODUCTION 
PF-05221304 is a potent, selective, orally bioavailable, and reversible dual acetyl-CoA 
carboxylase 1 and 2 (ACC1/2) inhibitor designed to have asymmetric distribution to the 
OLYHU
 
as such PF-05221304 is expected to inhibit de novo lipogenesis (DNL) and 
stimulate fatty acid oxidation in the liver to a greater extent than in peripheral tissues.  In 
humans, administration of PF-05221304 has been shown to suppress hepatic DNL in a 
Phase 1 study in healthy adult subjects; in addition, the drug is expected to stimulate hepatic 
fatty acid oxidation, and consequently reduce fat accumulation in the liver.  This inhibition of 
hepatic DNL is postulated to result in a decrease and normalization of the excessive DNL 
observed in nonalcoholic fatty liver disease (NAFLD).  In addition, the inhibition of ACC via 
administration of PF-05221304 also has the potential for anti-inflammatory effects in 
nonalcoholic steatohepatitis (NASH).   
 
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 of 
PF-05221304 following administration of a single, oral, 25 mg dose.  Recognizing that the 
target population of PF-05221304 are patients with liver disease (NASH with fibrosis) and 
that the major clearance mechanism of PF-05221304 is predicted to be active uptake into 
liver 
 
 the current 
study is proposed to evaluate whether there is any clinically meaningful effect of hepatic 
impairment on the plasma pharmacokinetics of PF-05221304.      
2.1. Study Design 
This is a non-randomized, open-label, single-dose, parallel-cohort, multisite study to 
investigate the effect of varying degrees of hepatic impairment on the plasma 
pharmacokinetics (total and unbound) of PF-05221304 after a single oral 25 mg dose 
administered in the fed state.  A total of approximately 24 subjects with varying degrees of 
hepatic function will be enrolled into the study to ensure that up to 6 evaluable subjects in 
each of the 4 hepatic function cohorts complete the study.  Subjects 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 Subjects 
1 
Without hepatic impairment 
Not Applicable  
6a 
2 
Mild hepatic impairment 
Class A (5 to 6 points) 
6 
3 
Moderate hepatic impairment 
Class B (7 to 9 points) 
6 
4 
Severe hepatic impairment 
Class C (10 to 15 points) 
6b 
a. Additional subjects may be dosed to a maximum of 10 subjects to ensure mean age is ± 5 years and mean body weight 
± 10 kg of this cohort is in line with pooled average assessed when ≥75% of subjects are dosed across other 3 cohorts 
b. If recruitment across the sites selected proves to be prohibitive, study will dose only 4 subjects in this cohort    
 
Child-Pugh scores will be determined as described in Table 2, at the screening visit.  
Recruitment for subjects meeting the criteria for Cohorts 3 and 4 will initiate first.  
Recruitment for subjects in Cohort 2 will start when approximately 50% of total subjects 
across Cohorts 3 and 4 (ie, 6 of 12) have been dosed.  Subjects in Cohort 1 will be recruited 
last to match the average demographics (at a minimum, age and weight; and as much as 
practically possible gender) across the pooled Cohorts 2 through 4.   
Table 2 
Child-Pugh Classification (CPC) of Liver Dysfunction  
Table 2-1: Scoring for Child-Pugh Classification  
Cohort 
CPC 
Level of dysfunction 
Total Score  
(tally based on assessment of 
parameters in Table 2-2) 
1 
Not Applicable 
Without hepatic 
impairment 
Not Applicable 
2 
A 
Mild 
5-6 
3 
B 
Moderate 
7-9 
4 
C 
Severe 
≥ 10 
Table 2-2: Derivation of Child-Pugh Classification Score 
Assessment Parameters 
Assigned score for observed findings 
1 point 
2 point 
3 point 
Encephalopathy grade 
(refer to Table 2-3 below) 
0 
1 or 2 
3 or 4a  
(or Requiring interventionb) 
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 clinically active Grade 3 or 4 encephalopathy are excluded 
b. 
In addition, subjects with a history of Grade 3 or 4 encephalopathy who are receiving an intervention [for 
example: lactulose or lactitol, alone or in combination with rifaximin, and/or neomycin] to prevent recurrent 
encephalopathy should be scored as Grade 3 or 4 encephalopathy (and hence excluded from Study C1171006) 
Table 2-3: Determination of Encephalopathy Grade 
Encephalopathy Grade 
Definition 
0 
Normal consciousness, personality, neurological exam 
1 
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting 
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2 
Lethargic, time-disoriented, inappropriate, asterixis, ataxia 
3 
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity 
4 
Unrousable coma, no personality/behavior, decerebrate 
 
The overall study design is summarized below in Figure 1.  For individual subjects, the total 
duration of participation from the Screening Visit to the on-site Follow-up Visit (Day 7) will 
be a minimum of approximately 3 weeks and a maximum of approximately 5 weeks. 
Figure 1. C1171006 Study Design 
 
In this study, subjects who prematurely discontinue for non-safety related reasons may be 
replaced, at the discretion of the principal investigator (PI) and Sponsor study team. 
2.2. Study Objectives 
Primary Objective:  
To compare the pharmacokinetics of PF-05221304 (both total and unbound) following administration of 
a single oral dose in adult subjects with varying degrees of hepatic impairment relative to age- and body 
weight- matched subjects without hepatic impairment 
Secondary Objectives:  
To compare additional pharmacokinetic parameters (both total and unbound) of PF-05221304 following 
administration of a single oral dose in adult subjects with varying degrees of hepatic impairment relative 
to age- and body weight- matched subjects without hepatic impairment 
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To evaluate the safety and tolerability of a single oral dose of PF-05221304 when administered to adult 
subjects with varying degrees of hepatic impairment relative to age- and body weight- matched subjects 
without hepatic impairment. 
 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
No formal interim analysis will be conducted for this study. The sponsor may conduct 
reviews of the data during the course of the study for the purpose of safety assessment, 
facilitating PK modeling, and/or supporting clinical development. Final analysis will follow 
the official database release.  As this will be an open-label study, there is no formal 
unblinding of the randomization code. 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
No hypotheses testing is planned. 
4.2. Statistical Decision Rules 
No decision rules are planned. 
5. ANALYSIS SETS 
5.1. Pharmacokinetic (PK) Analysis Set 
5.1.1. Concentration Analysis Set 
The PK concentration population will be defined as all subjects who received 1 dose of 
PF-05221304 and in whom at least 1 plasma concentration value is reported. 
5.1.2. Parameter Analysis Set 
The PK parameter analysis population is defined as all subjects dosed who have at least 1 of 
the PK parameters of primary interest. 
5.2. Pharmacodynamic Analysis Set 
None. 
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5.3. Safety Analysis Set 
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses and listings. 
 
 
5.5. Treatment Misallocations  
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are ultimately not dosed. 
5.6. Protocol Deviations 
Subjects who experience events that may affect their PK profile (eg vomiting immediately 
after the dose) may be excluded from the PK analysis.  At the discretion of the 
pharmacokineticist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason. 
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure. 
5.6.1. Deviations Assessed Prior to Dosing 
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 4.1 and 4.2 of the protocol. 
5.6.2. Deviations Assessed Post-Dosing 
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population. 
6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoint(s) 
None. 
6.2. Safety Endpoints 
Any events occurring following PF-05221304 dosing or increasing in severity will be 
counted as treatment emergent. 
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Events that occur in a non-treatment period (for example Follow-up) will be counted as 
treatment emergent and attributed to the dose taken. 
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. 
6.3. Other Endpoints 
6.3.1. PK Endpoints 
Blood samples for PK analysis of PF-05221304 will be taken according to the Schedule of 
Activities given in the protocol. 
The following PK parameters will be calculated for PF-05221304 (if possible) from the 
concentration-time data using standard non-compartmental methods: 
Table 3. 
Noncompartmental PK Parameters 
PK Parameter 
Analysis Scale 
PF-05221304 
Definition 
AUClast 
ln 
A, D 
Area under the plasma concentration-time 
profile from time zero to the time of the 
last quantifiable concentration (Clast) 
AUClast,u 
ln 
A, D 
Unbound area under the plasma 
concentration-time profile from time zero 
to the time of the last quantifiable 
concentration (Clast) 
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 profile from time zero 
extrapolated to infinite time 
Cmax 
ln 
A, D 
Maximum plasma concentration 
Cmax,u 
ln 
A, D 
Unbound maximum plasma concentration 
Tmax 
R 
D 
Time for Cmax 
t1/2
* 
R 
D 
Terminal half-life 
CL/F* 
ln 
A, D 
Apparent clearance 
CLu/F* 
ln 
A, D 
Unbound apparent clearance 
VZ/F* 
ln 
A, D 
Apparent volume of distribution 
Vzu/F* 
ln 
A, D 
Unbound apparent volume of distribution 
Fu+ 
R 
D 
Fraction unbound 
Key: 
A=analyzed using statistical model, D=displayed with descriptive statistics, 
 
ln=natural-log transformed, R=raw (untransformed), *=if data permits; u=unbound fraction 
 
+ = Reported in eNCA as protein free fraction. 
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6.3.2. Other Endpoints 
None. 
6.4. Covariates 
No covariate for primary analysis (ie ANOVA) will be included in the model. 
For secondary analysis (ie ANCOVA), age, and body weight will be included in the model. 
Additionally, gender may also be included as a covariate if approximately 50% of each 
cohort is female. 
7. HANDLING OF MISSING VALUES 
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied. 
7.1. Concentrations Below the Limit of Quantification 
In all data presentations (except listings), PK concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.) 
In all data presentations (except listings), CP-I and CP-III concentrations below the limit of 
quantification (BLQ) will be set to LLQ/2.  (In listings BLQ values will be reported as 
“<LLQ”, where LLQ will be replaced with the value for the lower limit of quantification.) 
 
7.2. Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true: 
1. A concentration has been collected as ND (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. 
7.3. Pharmacokinetic Parameters 
Actual PK sampling times will be used in the derivation of PK parameters. 
If a PK parameter cannot be derived from a subject’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 subject discontinues.) 
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In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular hepatic function cohort ZLWKHYDOXDEOHPHDVXUHPHQWV.  
For statistical analyses (ie analysis of variance), PK parameters coded as NC will also be set 
to missing; and statistical  analyses will not be performed for a particular parameter if more 
than 50% of the data are NC. 
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods 
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 (normal hepatic function cohort) using a one-way ANOVA model 
based on natural log transformed data. 
The relationship between PK parameters and hepatic function will be determined by a linear 
regression model. 
 
 
8.2. Statistical Analyses of PK Parameters 
One-way analysis of variance (ANOVA) will be used to compare the natural log transformed 
PF-05221304 AUCinf, AUClast and Cmax, unbound AUCinf (AUCinf,u), unbound AUClast 
(AUClast,u), and unbound Cmax (Cmax,u), as data permit, for each of the hepatic impairment 
classification cohorts (Test) to the cohort without hepatic impairment (Reference).  Estimates 
of the adjusted mean and corresponding 90% confidence intervals will be obtained from the 
model for each cohort.  Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% confidence intervals will be obtained from the model as well.  The 
adjusted mean estimates and adjusted mean differences and 90% confidence intervals for the 
estimates and differences will be exponentiated to provide estimates of adjusted geometric 
means and estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the estimates and for the ratios respectively (see Appendix 1 for 
SAS code). 
Additionally, as an exploratory analysis, age, body weight, and gender (see Section 6.4) will 
be explored as a covariate/factor in the ANOVA/ANCOVA model, as appropriate (see 
Appendix 1 for SAS code). 
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Linear regression may be used to analyze the potential relationship between the following 
PK parameters -AUCinf, and CL/F separately - and the following hepatic function - serum 
albumin,,prothrombin time, and total bilirubin separately -.  Estimates of the slope and 
intercept, together with their precision (90% confidence interval [CI]), and the coefficient of 
determination (ie R-squared and adj-R-squared) will be obtained from the model. 
Plots of PK parameters -AUCinf, and CL/F separately - versus hepatic function - serum 
albumin, ,prothrombin time, total bilirubin separately -  will be constructed.  A regression 
line and 90% confidence region for the PK parameters and hepatic function will be included. 
(See appendix 1 for example of SAS code to produce the figure). 
 
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.  
Alternative model structure may also be considered. Justification for any alternative to the 
planned analysis will be given in the report of the study. 
 
The following PK parameters will be summarized by hepatic function Cohort: 
Table 4. 
PK Parameters to be Summarized Descriptively by Cohort 
Parameter 
Summary Statistics 
Cmax, AUClast,  
AUCinf,  CL/F, 
Vz/F, AUCinf,u, 
AUClast,u, Cmax,u, 
CLu/F, and Vzu/F 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%. 
Tmax 
N, median, minimum, maximum. 
t1/2, fu 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum. 
Box and whisker plots for PF-05221304 AUCinf, AUClast, Cmax, AUCinf,u, AUClast,u, and Cmax,u 
individual subject parameters will be plotted by hepatic function cohort and overlaid with 
geometric means. 
Supporting data from the estimation of t½ and AUCinf will be listed by cohort:  terminal 
phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); the 
percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of time 
points used in the estimation of kel.  This data may be included in the clinical study report. 
Presentations for PF-05221304 concentrations will include: 
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− a listing of all concentrations sorted by hepatic function cohort (present in heading), 
subject id and nominal time postdose.  The concentration listing will also include the 
actual times.  Deviations from the nominal time will be given in a separate listing. 
− a summary of concentrations by hepatic function cohort and nominal time postdose, 
where the set of statistics will include n, mean, median, standard deviation, coefficient of 
variation (cv), minimum, maximum and the number of concentrations above the lower 
limit of quantification. 
− median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by hepatic function cohort (all hepatic function cohorts on the same plot 
per scale, based on the summary of concentrations by hepatic function cohort and time 
postdose). 
− mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by hepatic function cohort (all hepatic function cohorts on the same plot per 
scale, based on the summary of concentrations by hepatic function cohort and time 
postdose). 
− individual concentration time plots by hepatic function cohort (on both linear and semi-
log scales) against actual time postdose (there will be separate spaghetti plots for each 
hepatic function cohort 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. 
8.3. Safety Analysis 
A set of summary tables split by hepatic function cohort will be produced to evaluate any 
potential risk associated with the safety and toleration of administering PF-05221304. 
8.3.1. Treatment and Disposition of Subjects 
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, pharmacodynamics (CP-I and CP-III), as well 
as for safety (adverse events and laboratory data).  Frequency counts will be supplied for 
subject discontinuation(s) by hepatic function cohort. 
Data will be reported in accordance with the sponsor reporting standards. 
8.3.2. Demographic and Clinical Examination Data 
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards. 
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8.3.3. Discontinuation(s) 
Subject discontinuations, temporary discontinuations due to adverse events will be detailed 
and summarized by hepatic function cohort. 
Data will be reported in accordance with the sponsor reporting standards. 
8.3.4. Adverse Events 
Adverse events will be reported in accordance with the sponsor reporting standards by 
hepatic function cohort. 
8.3.5. Laboratory Data 
Laboratory data will be listed in accordance with the sponsor reporting standards. 
 
8.3.6. Vital Signs Data 
The baseline measurement is the last predose measurement. 
For each planned timepoint, baseline values and change from baseline values within each 
hepatic function cohort will be summarized with descriptive statistics (using sponsor default 
standards). 
These data will be listed in accordance with the sponsor reporting standards. 
 
8.3.7. ECG Data 
The baseline measurement is the predose measurement. 
For each planned timepoint, baseline values and change from baseline values within each 
hepatic function cohort will be summarized with descriptive statistics (using sponsor default 
standards). 
These data will be listed in accordance with the sponsor reporting standards. 
8.3.8. Other Safety Data 
None. 
8.3.9. Concomitant Treatments 
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings. 
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8.3.10. Screening and Other Special Purpose Data 
Prior medication(s) and non-drug treatment(s), serum FSH concentrations (in females), and 
serum ȕ-hCG (in females), obtained at Screening, will be databased. 
 
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9. REFERENCES 
None. 
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10. APPENDICES 
Appendix 1. SAS CODE FOR ANALYSES 
/* Letter assignments for cohort within the estimate statement in  
     the code below are as follows; 
A = Severe (Test) 
B = Moderate (Test) 
C = Mild (Test) 
D = Normal (Reference); 
  */; 
 
For ANOVA: 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 'Severe vs Normal'  
cohort 1 0 0 -1; 
 
estimate 'Moderate vs Normal' 
cohort 0 1 0 -1; 
 
estimate 'Mild vs Normal' 
 
cohort 0 0 1 -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; 
 
model l&var = cohort age weight / ss3 clparm alpha=0.1; 
 
lsmeans cohort; 
 
estimate 'Severe vs Normal'  
cohort 1 0 0 -1; 
 
estimate 'Moderate vs Normal' 
cohort 0 1 0 -1; 
 
estimate 'Mild vs Normal' 
 
cohort 0 0 1 -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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Statistical Analysis Plan 
 
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TMF Doc ID: 98.03 
 
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